Scientists are working to eliminate a type of heart disease in dogs using gene therapy.

They're zoning in on a heart condition called mitral valve disease thats common in 6% of dogs.

Scientists are using Cavalier King Charles spaniels for the research.

They tend to develop it at a younger age.

Scientists at Tufts University have already tested gene therapy in mice.

A virus is injected into them to deliver DNA to cells which causes them to create a protein.

What it essentially does is stops the heart valve from getting thicker, stopping the valve from leaking.

Researchers are now moving on to testing this in dogs.

But they think the treatment could go beyond just canines.

Many of the dog diseases are naturally occurring and really great models for human disease, says Dr. Vicky Yang, a veterinary cardiologist and research assistant professor at Cummings School of Veterinary Medicine at Tufts University. And I can see this, if it becomes successful in dogs, potentially going into thinking about treatment for humans for mitral valve disease.

The biotech company behind the treatment agrees. It says it could also expand beyond heart problems.

I think a larger question, though, is if we are able to prove this thesis of treating aging, making the animal generally healthier, could also treat heart failure, what other diseases could we treat in dogs? says Daniel Oliver, the CEO of Rejuvenate Bio. And could we progress this treatment onto past dogs and other animals and possibly humans?

The gene therapy would only be used for dogs just starting to experience heart problems.

Researchers still need to make sure the gene therapy is safe for all breeds before they make it available to the public.

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Scientists are using gene therapy to treat a heart disease in dogs. Could humans be next? - 10News

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A new protein that can enhance the accuracy of CRISPR gene therapy was recently developed by researchers from City University of Hong Kong (CityU) and Karolinska Institutet. This work, published in the Proceedings of the National Academy of Sciences, could potentially have a strong impact on how gene therapies are administered in the future.

CRISPR-Cas9, often referred to as just CRISPR, is a powerful gene-editing technology that has the potential to treat a myriad of genetic diseases such as beta-thalassemia and sickle cell anemia. As opposed to traditional gene therapies, which involve the introduction of healthy copies of a gene to a patient, CRISPR repairs the genetic mutation underlying a disease to restore function.

CRISPR-Cas9 was discovered in the bacterial immune system, where it is used to defend against and deactivate invading viral DNA. Cas9 is an endonuclease, or an enzyme that can selectively cut DNA. The Cas9 enzyme is complexed with a guide RNA molecule to form what is known as CRISPR-Cas9. Cas9 is often referred to as the molecular scissors, being that they cut and remove defective portions of DNA. Being that it is not perfectly precise, the enzyme will sometimes make unintended cuts in the DNA that can cause serious consequences. For this reason, enhancing the precision of the CRISPR-Cas9 system is of paramount importance.

Two versions of Cas9 are currently being used in CRISPR therapies: SpCas9 (derived from the bacteriaStreptococcus pyogenes) and SaCas9 (derived fromStaphylococcus aureus). Researchers have engineered variants of the SpCas9 enzyme to improve its precision, but these variants are too large to fit into the adeno-associated viral (AAV) vector that is often used to administer CRISPR to living organisms. SaCas9, however, is a much smaller protein that can easily fit into AAV vectors to deliver gene therapy in vivo. Being that no SaCas9 variants with enhanced precision are currently available, these CityU researchers aimed to identify a viable variant.

This recent research led to the successful engineering of SaCas9-HF, a Cas9 variant with high accuracy in genome-wide targeting in human cells and preserved efficiency. This work was led by Dr. Zheng Zongli, Assistant Professor of Department of Biomedical Sciences at CityU and the Ming Wai Lau Centre for Reparative Medicine of Karolinska Institutet in Hong Kong, and Dr. Shi Jiahai, Assistant Professor of Department of Biomedical Sciences at CityU.

Their work was based on a rigorous evaluation of 24 targeted human genetic locations which compared the wild-type SaCas9 to the SaCas9-HF. The new Cas9 variant was found to reduce the off-target activity by about 90% for targets with very similar sequences that are prone to errors by the wild-type enzyme. For targets that pose less of a challenge to the wild-type enzyme, SaCas9-HF made almost no detectable errors.

Our development of this new SaCas9 provides an alternative to the wild-type Cas9 toolbox, where highly precise genome editing is needed, explained Zheng. It will be particularly useful for future gene therapy using AAV vectors to deliver genome editing drug in vivo and would be compatible with the latest prime editing CRISPR platform, which can search-and-replace the targeted genes.

Dr. Shi and Dr. Zheng are the corresponding authors of this publication. The first authors are PhD student Tan Yuanyan from CityUs Department of Biomedical Sciences and Senior Research Assistant Dr. Athena H. Y. Chu from Ming Wai Lau Centre for Reparative Medicine (MWLC) at Karolinska Institutet in Hong Kong. Other members of the research team were CityUs Dr. Xiong Wenjun, Assistant Professor of Department of Biomedical Sciences, research assistant Bao Siyu (now at MWLC), PhD students Hoang Anh Duc and Firaol Tamiru Kebede, and Professor Ji Mingfang from the Zhongshan Peoples Hospital.

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This year, researchers from the University of Pennsylvania launched the first-ever clinical trial to genetically edit the immune cells of cancer patients using the technology.

Penn Perelman Center for Advanced Medicine | Courtesy photo

Researchers from the Abramson Cancer Center at the University of Pennsylvania are the first in the United States to attempt to genetically edit a cancer patients immune cells in the lab using CRISPR-Cas9 technology. Penn launched the first-ever U.S. clinical trial for this research earlier this year with support from the Parker Institute for Cancer Immunotherapy(PICI) andTmunity Therapeutics. On Wednesday, researchers confirmed they have successfully infused three participants in the trial thus far two with multiple myeloma and one with sarcoma and have observed the edited cells expand and bind to their tumor target with no serious side effects.

This trial is primarily concerned with three questions: Can we edit T cells in this specific way? Are the resulting T cells functional? And, are these cells safe to infuse into a patient? This early data suggests that the answer to all three questions may be yes, said Edward Stadtmauer, the studys principal investigator and the section chief of hematologic malignancies at Penn.

Its still too early, however, to answer the more pressing question the trial has posed: Can these genetically modified cells destroy cancer cells? But researchers believe the feasibility and safety theyve demonstrated so far provides optimism that the approach may be applicable across multiple areas of gene therapy research.

These early findings are the first step as we determine if this new breakthrough technology can help rewrite how we treat patients with cancer and perhaps other deadly diseases, said Sean Parker, the billionaire entrepreneur and founder and chairman of PICI. CRISPR editing could be the next generation of T-cell therapy, and we are proud to be a part of the first human trial in the United States.

It has taken Penn more than two years to get the appropriate institutional and federal regulatory approvals, and to recruit optimal participants for the trial. Patients had to be screened ahead of time to make sure their tumors were a match for the approach. Participants who met the requirements received other therapy as needed while they waited for their cells to be manufactured. Once that process was complete, all three received the gene-edited cells in a single infusion after a short course of chemotherapy.

Analysis of blood samples revealed that the CRISPR-edited T cells expanded and survived in all three participants. While none of the patients cancer cells have yet responded to the therapy, researchers say there were no treatment-related serious adverse events.

CRISPR has been more popularly known for its ethically questionable potential to alter human DNA, but the studys senior author and immunotherapy pioneer Carl June says his team is squarely focused on moving the field of gene therapy forward.

Our use of CRISPR editing is geared toward improving the effectiveness of gene therapies, not editing a patients DNA, June said. We leaned heavily on our experience as pioneers of the earliest trials for modified T-cell therapies and gene therapies, as well as the strength of Penns research infrastructure, to make this study a reality.

Previous human trials using CRISPR technology have predominantly been conducted in China until several trials launched in the U.S. this year. The technology is currently being tested by researchers in Massachusetts to potentially treat genetic blood disorders like sickle cell disease and certain forms of inherited blindness. Penns team aims to test the approach on a total of 18 patients by the end of the trial.

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Here Are the Early Results From the First US CRISPR Trial for Cancer - Philadelphia magazine

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"We are excited to have reached this important milestone in the clinical evaluation of INXN-4001 for treatment of end-stage heart failure," stated Amit Patel, MD, MS, Co-Founder and Medical Director of TripleGene. "Heart failure rarely results from a single genetic defect, and while single gene therapy approaches have been studied, these treatments may not fully address the causes of the disease. Our unique multigenic approach is designed to stimulate biological activity targeting multiple points in the disease progression pathway."

Triple-Gene's investigational therapy uses non-viral delivery of a constitutively expressed multigenic plasmid designed to express human S100A1, SDF-1, and VEGF165 gene products, which affect progenitor cell recruitment, angiogenesis, and calcium handling, respectively, and target the underlying molecular mechanisms of pathological myocardial remodeling. The plasmid therapy is delivered via RCSI which allows for cardiac-specific delivery to the ventricle.

"Heart failure is the leading cause of death worldwide and represents a significant and growing global health problem. Aside from heart transplant and LVAD, current treatment options for those patients with end-stage disease are limited," commented Timothy Henry, MD, FACC, MSCAI, Medical Director of the Carl and Edyth Lindner Center for Research and Education at The Christ Hospital and a member of the Triple-Gene Medical Advisory Board. "The INXN4001 investigational therapy represents a biologically-based method focused on repairing the multiple malfunctions of cardiomyocytes, and I look forward to seeing the results of this initial safety study and further exploring the promise of this innovative treatment approach."

Triple-Gene will present preliminary data from the Phase 1 study at theAmerican Heart Association Scientific Sessionsat the Pennsylvania Convention Center in Philadelphia. A poster titled "Safety of First in Human Triple-Gene Therapy Candidate for Heart Failure Patients" will be presented on Sunday, November 17thfrom 3:00 pm - 3:30 pm ETin Zone 4 of the Science and Technology Hall.

About the Phase 1 Trial of INXN-4001INXN-4001 is being evaluated in a Phase I open label study in adult patients with implanted Left Ventricular Assist Device (LVAD). The study is designed to investigate the safety and feasibility of supplemental cardiac expression of S100A1, SDF-1 and VEGF-165 from a single, multigenic plasmid delivered via Retrograde Coronary Sinus Infusion (RCSI) in stable patients implanted with a LVAD for mechanical support of end-stage heart failure. Twelve stable patients with an implanted LVAD were allocated into 2 cohorts (6 subjects each) to evaluate the safety and feasibility of infusing 80mg of INXN4001 in either a 40mL (Cohort 1) or 80mL (Cohort 2) volume. The primary endpoint of safety and feasibility is assessed at the 6-month endpoint. Daily activity data are also collected throughout the study using a wearable biosensor. Dosing on both Cohorts 1 and 2 has been completed, and patients continue follow-up per protocol.

About Triple-GeneTriple-Gene LLC is a clinical stage gene therapy company focused on advancing targeted, controllable, and multigenic gene therapies for the treatment of complex cardiovascular diseases. The Company's lead product is a non-viral investigational gene therapy candidate that drives expression of three candidate effector genes involved in heart failure. Triple-Gene is a majority owned subsidiary ofIntrexon Corporation(NASDAQ: XON) co-founded by Amit Patel, MD, MS, and Thomas D. Reed, PhD, Founder and Chief Science Officer of Intrexon. Learn more about Triple-Gene atwww.3GTx.com.

About Intrexon CorporationIntrexon Corporation (NASDAQ: XON) is Powering the Bioindustrial Revolution with Better DNAto create biologically-based products that improve the quality of life and the health of the planet through two operating units Intrexon Health and Intrexon Bioengineering. Intrexon Health is focused on addressing unmet medical needs through a diverse spectrum of therapeutic modalities, including gene and cell therapies, microbial bioproduction, and regenerative medicine. Intrexon Bioengineering seeks to address global challenges across food, agriculture, environmental, energy, and industrial fields by advancing biologically engineered solutions to improve sustainability and efficiency. Our integrated technology suite provides industrial-scale design and development of complex biological systems delivering unprecedented control, quality, function, and performance of living cells. We call our synthetic biology approach Better DNA, and we invite you to discover more atwww.dna.comor follow us on Twitter at@Intrexon, onFacebook, andLinkedIn.

TrademarksIntrexon, Powering the Bioindustrial Revolution with Better DNA,and Better DNA are trademarks of Intrexon and/or its affiliates. Other names may be trademarks of their respective owners.

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Triple-Gene Announces Completion of Enrollment and Dosing in Phase 1 Trial of INXN4001, First Multigenic Investigational Therapeutic Candidate for...

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by Sam Manzella 11/8/2019

A group of medical researchers in Maryland believe the answer for curing HIV/AIDS may be gene therapy.

American Gene Technologies (AGT), a Rockville-based medical research company, has submitted a Investigational New Drug (IND) application with the FDA to begin gene therapy trials that researchers believe could eliminate HIV in people already living with the virus.

The drugan HIV treatment program called AGT103-Tis a single-dose, lentiviral vector-based gene therapy that AGT says could remove infected cells from the body and decrease or eliminate the need for lifelong antiretroviral treatment in HIV-positive patients.

If approved, the company hopes to begin a Phase 1 clinical trial that will examine the safety of AGT103-T in humans.

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In a press statement, AGT chief science officer C. David Pauza, PhD, said the companys objective is to treat HIV disease with an innovative cell and gene therapy that reconstitutes immunity to HIV and will control virus growth in the absence of antiretroviral drugs.

AGTs approach differs from other medical researchers attempts to cure HIV. As NewNowNext reported earlier this year, researchers in Europe made headlines when two separate HIV-positive patients no longer had the virus after obtaining bone marrow transplants from donors with an HIV-resistant mutation to treat unrelated cancers.

Those patients marked the second and third time doctors were able to effectively cure patients living with HIV via bone marrow transplant in the history of modern medicine. However, HIV/AIDS activists and medical professionals were quick to raise concerns about the feasibility of curing HIV with bone marrow transplants on a more widespread basis.

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Kenneth Freedberg, MD, a professor of medicine at Harvard Medical School and Massachusetts General Hospital, told NewNowNext in March that the method is not a remotely plausible strategy for HIV treatment for the vast majority of patients.

A bone marrow transplant is an extraordinarily toxic and life-threatening intervention, which you do if someone has an illness thats clearly going to be fatal, Freedberg explained. There must be no other treatment options available. It puts people at massive risk for infections and toxicity complications.

As the fight against HIV/AIDS wages on, communities at risk of contracting the virus continue to take preventative measures against new infectionsincluding daily use of Pre-exposure prophylaxis (PrEP), a potentially life-saving HIV prevention drug that is massively popular among gay, bisexual, and queer men.

In the United States, PrEP is pretty much exclusively available as Truvada, its brand-name version manufactured by Gilead Sciences with a very high retail markup. That may change soon, though: Earlier this week, the government filed a lawsuit against Gilead alleging patent infringement on PrEP, which was patented by public health researchers at the Department of Health and Human Services years ago.

Brooklyn-based writer and editor. Probably drinking iced coffee or getting tattooed.

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Gene Tech Company Claims to Have Found a Cure for HIV/AIDS - NewNowNext

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Now is a great time to have biotech stocks in your portfolio. While biotech investing can be scary, because the small-cap companies are often unprofitable research-and-development labs, this is also where a lot of the cutting-edge science is happening.

Let's see how Mirati Therapeutics (NASDAQ:MRTX), Iovance Biotherapeutics (NASDAQ:IOVA), and Personalis (NASDAQ:PSNL) are all using gene therapy in the fight against cancer.

Image source: Getty Images.

Mirati Therapeutics is in a race with Amgen (NASDAQ:AMGN) to find a drug that successfully inhibits KRAS mutations. KRAS is a gene in our bodies that has been identified as a cause of multiple cancers. Right now one of Mirati's drugs is targeting a specific sub-mutation identified as KRAS G12C. This genetic malfunction is seen in 14% of non-small cell lung cancers, 5% of colon cancers, and 2% of pancreatic cancers. The company's drug is an attempt to shut down this mutated gene so it will stop producing cancer cells.

Investors who want to play it safe might want to invest in Amgen, not Mirati; Amgen is also pursuing drugs to inhibit the KRAS mutations. However, Amgen is a highly profitable, $130 billion megacap biotech with multiple drugs in clinical trials. If its KRAS program fails, Amgen's stock will take a minor hit and the company will continue onwards and upwards. On the other hand, if Amgen and Mirati are both right about the importance of KRAS genes, then Mirati shareholders are likely to see far bigger returns on their investments. With the smaller biotech, the risk is higher but the rewards are greater.

Mirati is a $4 billion small cap with extensive knowledge of KRAS. Failure here would be brutal to the stock. On the other hand, any success would boost the stock into the stratosphere. So far, investors in Mirati have been winning big. Amgen has returned 56% to investors over the last five years, slightly underperforming the S&P 500, but tiny Mirati has returned 523%.

Iovance Biotherapeutics is introducing a novel way to fight against cancer. The company relies upon medicine that is specialized for each patient. When a cancer starts attacking your body, your system starts producing lymphocytes that are designed to infiltrate and attack the tumor. Cancer cells adopt and mutate to avoid destruction.

What Iovance does is remove some of these cancer-fighting agents, referred to as tumor-infiltrating lymphocytes (TILs), from your body. The company's technology amplifies and multiplies these cells in the lab, creating billions of them. Then your own cancer-fighting agents are injected back into your body.

Iovance is running a phase 3 trial trial for Lifileucel, its treatment for skin cancer. But what's causing the most excitement is LN-145, which is being tested on multiple cancers. The company is running a phase 3 trial for cervical cancer, and a phase 2 trial for head and neck cancers. Also, MD Anderson Cancer Network is running a phase 2 test on LN-145 for ovarian cancer and sarcoma.

The stock took off after it was reported that LN-145 had a 44% overall response rate against cervical cancer, and Lifileucel had a 38% overall response rate against melanoma. Iovance is a $2.72 billion small cap. It has $400 million in cash, $12 million in debt, and no revenue. So far in 2019 it's returned 132% to investors.

Personalis is developing the NeXT platform, a hugely ambitious undertaking that is mapping approximately 20,000 genes in the human body. Spun out of Stanford University, the company has a contract with the U.S. Department of Veterans Affairs. The federal agency is providing it the DNA information of over 775,000 veterans, so with this data, Personalis is mapping over 15 billion human genes. With all these volunteers, it's developing a massive library of genetic data. Biotechs that subscribe to its service can access this information as they design cancer-fighting drugs in the lab.

The company's immediate market is all the biotech companies doing cancer research. Using its library, subscribers can find cancer targets and design specific drugs to suppress the mutating genes that spread cancer in human beings. Right now Personalis has over 45 biopharma subscribers to its service. The company estimates this is a $5 billion market opportunity.

Next year Personalis hopes to compete in the $14 billion market of cancer diagnostics. It will offer its own liquid biopsy designed to detect cancer, and compete with Guardant Health (NASDAQ:GH), as well as NantHealth, Grail (a start-up funded in part by Jeff Bezos and Bill Gates), Thrive (a start-up spun out of Johns Hopkins), and others. We don't yet know how much Personalis will charge for its biopsy, or how successful it will be.

But what we do know is that right now the company is a lot cheaper than its market-leading peer:

Data source: Bloomberg and Yahoo Finance. P/S = price to sales; IPO = initial public offering.

The market appears to be taking a wait-and-see attitude toward Personalis; certainly there's no excitement right now about its shares. That might change when its liquid biopsy is introduced next year.

In the meantime, Personalis is developing a very impressive library of knowledge of the human genome. Maybe one day the company will be competing with 23andme to provide personalized medicine to individuals (a market estimated to be worth $40 billion). It's definitely a stock to keep an eye on, as the future looks bright.

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BRISBANE, Calif.--(BUSINESS WIRE)--Sangamo Therapeutics, Inc. (NASDAQ: SGMO), a genomic medicine company, today announced that hemophilia A gene therapy clinical data and hemoglobinopathies ex vivo gene-edited cell therapy data will be featured in poster presentations at the 61st Annual Meeting of the American Society of Hematology (ASH). The ASH abstracts, which were submitted on August 3, 2019, were released online this morning. The conference will take place in Orlando, FL, from December 7-10, 2019.

Gene Therapy

The SB-525 poster will show updated Alta study data including durability of Factor VIII (FVIII) levels, bleeding rate, factor usage, and safety, for all five patients in the high dose cohort of 3e13 vg/kg, with approximately 4 months to 11 months of follow-up after treatment with SB-525.

As of the abstract submission date, four patients in the 3e13 vg/kg cohort achieved FVIII levels within the normal range with no bleeding events reported up to 24 weeks post-administration. These patients did not require FVIII replacement therapy following the initial prophylactic period of up to approximately 3 weeks post-SB-525 administration. The fifth patient in the 3e13 vg/kg cohort had only recently undergone treatment with SB-525 at the time of the abstract submission. As previously reported, one patient had treatment-related serious adverse events (SAEs) of hypotension and fever, which occurred approximately 6 hours after completion of the vector infusion and resolved with treatment within 24 hours, with no loss of FVIII expression. SB-525 is being developed as part of a global collaboration between Sangamo and Pfizer.

The rapid kinetics of Factor VIII expression, durability of response, and the relatively low intra-cohort variability in the context of a complete cessation of bleeding events and elimination of exogenous Factor VIII usage continues to suggest SB-525 is a differentiated hemophilia A gene therapy, said Bettina Cockroft, M.D., M.B.A., Chief Medical Officer of Sangamo, commenting on the published abstract. We are pleased with the progress of the program toward a registrational Phase 3 study led by Pfizer, who announced it has enrolled its first patient in the 6-month Phase 3 lead-in study. We have recently completed the manufacturing technology transfer to Pfizer and initiated the transfer of the IND.

Ex Vivo Gene-Edited Cell Therapy

The ST-400 beta thalassemia poster will show preliminary results from the first three patients enrolled in the Phase 1/2 THALES study. In this study, hematopoietic stem progenitor cells (HSPCs) are apheresed from the patient, edited to knock out the erythroid specific enhancer of the BCL11A gene, and cryopreserved prior to infusion back into the patient following myeloablative conditioning with busulfan. The first three patients all have severe beta thalassemia genotypes: 0/0, homozygous for the severe + IVS-I-5 (G>C) mutation, and 0/+ genotype including the severe IVS-II-654 (C>T) mutation, respectively.

As of the abstract submission date, Patient 1 and Patient 2 had experienced prompt hematopoietic reconstitution. Patient 1 had increasing fetal hemoglobin (HbF) fraction that contributed to a stable total hemoglobin. After being free from packed red blood cell (PRBC) transfusions for 6 weeks, the patient subsequently required intermittent transfusions. Patient 2 had rising HbF levels observed through 90 days post-infusion. For both patients, as of the most recent follow-up reported in the abstract, on-target insertions and deletions (indels) were present in circulating white blood cells. Patient 3 had just completed ST-400 manufacturing at the time of abstract submission. As previously disclosed, Patient 1 experienced an SAE of hypersensitivity during ST-400 infusion considered by the investigator to be related to the product cryoprotectant, DSMO, and which resolved by the end of the infusion. No other SAEs related to ST-400 have been reported and all other AEs have been consistent with myeloablation. No clonal hematopoiesis has been observed. Longer follow-up will be required to assess the clinical significance of these early results. ST-400 is being developed as part of a global collaboration between Sangamo and Sanofi, along with support through a grant from the California Institute for Regenerative Medicine (CIRM).

The first three patients enrolled in the THALES study all have severe beta thalassemia genotypes that result in almost no endogenous beta globin production. The increases in fetal hemoglobin and presence of on-target indels in circulating blood cells suggests successful editing using zinc finger nucleases. The results are preliminary and will require additional patients and longer-term follow-up to assess their clinical significance, said Adrian Woolfson, BM., B.Ch., Ph.D., Head of Research and Development. It is important to note that myeloablative hematopoietic stem cell transplantation reboots the hematopoietic system, and that sufficient time is required for the stem cells to fully repopulate the marrow and for new blood cells to form. In other myeloablative conditioning studies in a similar patient population, full manifestation of the effects of gene modification in the red blood cell compartment has taken as long as 12 months or more to become evident.

Sanofis in vitro sickle cell disease poster details a similar approach to ST-400, using mobilized HSPCs from normal donors and SCD patients and utilizing the same zinc finger nuclease for gene editing, delivered as transient non-viral RNA, and designed to disrupt the erythroid specific enhancer of the BCL11A gene, which represses the expression of the gamma globin genes, thereby switching off HbF synthesis. Results from ex vivo studies demonstrated enriched biallelic editing, increased HbF, and reduced sickling in erythroid cells derived from non-treated sickle cell disease patients. Sanofi has initiated a Phase 1/2 trial evaluating BIVV003, an ex vivo gene-edited cell therapy using ZFN gene editing technology to modify autologous hematopoietic stem cells using fetal hemoglobin to produce functional red blood cells with higher BhF content that are resistant to sickling in patients with severe sickle cell disease. Recruitment is ongoing.

About the Alta study

The Phase 1/2 Alta study is an open-label, dose-ranging clinical trial designed to assess the safety and tolerability of SB-525 gene therapy in patients with severe hemophilia A. SB-525 was administered to 11 patients in 4 cohorts of 2 patients each across 4 ascending doses (9e11 vg/kg, 2e12 vg/kg, 1e13vg/kg and 3e13vg/kg) with expansion of the highest dose cohort by 3 additional patients. The U.S. Food and Drug Administration (FDA) has granted Orphan Drug, Fast Track, and regenerative medicine advanced therapy (RMAT) designations to SB-525, which also received Orphan Medicinal Product designation from the European Medicines Agency.

About the THALES study

The Phase 1/2 THALES study is a single-arm, multi-site study to assess the safety, tolerability, and efficacy of ST-400 autologous hematopoietic stem cell transplant in 6 patients with transfusion-dependent beta thalassemia (TDT). ST-400 is manufactured by ex vivo gene editing of a patient's own (autologous) hematopoietic stem cells using non-viral delivery of zinc finger nuclease technology. The THALES study inclusion criteria include all patients with TDT (0/0 or non- 0/0) who have received at least 8 packed red blood cell transfusions per year for the two years before enrollment in the study. The FDA has granted Orphan Drug status to ST-400.

About Sangamo Therapeutics

Sangamo Therapeutics, Inc. is focused on translating ground-breaking science into genomic medicines with the potential to transform patients' lives using gene therapy, ex vivo gene-edited cell therapy, in vivo genome editing, and gene regulation. For more information about Sangamo, visit http://www.sangamo.com.

Forward-Looking Statements

This press release contains forward-looking statements regarding Sangamo's current expectations. These forward-looking statements include, without limitation, statements regarding the Company's ability to develop and commercialize product candidates to address genetic diseases with the Company's proprietary technologies, as well as the timing of commencement of clinical programs and the anticipated benefits therefrom. These statements are not guarantees of future performance and are subject to certain risks, uncertainties and assumptions that are difficult to predict. Factors that could cause actual results to differ include, but are not limited to, the outcomes of clinical trials, the uncertain regulatory approval process, uncertainties related to the execution of clinical trials, Sangamo's reliance on partners and other third-parties to meet their clinical and manufacturing obligations, and the ability to maintain strategic partnerships. Further, there can be no assurance that the necessary regulatory approvals will be obtained or that Sangamo and its partners will be able to develop commercially viable product candidates. Actual results may differ from those projected in forward-looking statements due to risks and uncertainties that exist in Sangamo's operations and business environments. These risks and uncertainties are described more fully in Sangamo's Annual Report on Form 10-K for the year ended December 31, 2018 as filed with the Securities and Exchange Commission and Sangamo's most recent Quarterly Report on Form 10-Q. Forward-looking statements contained in this announcement are made as of this date, and Sangamo undertakes no duty to update such information except as required under applicable law.

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Sangamo Announces Gene Therapy and Ex Vivo Gene-Edited Cell Therapy Data Presentations at the American Society of Hematology Annual Meeting - Business...

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Gene therapy has traditionally been applied to well-understood diseases where a single genetic mutation was to blame. A new generation of technology is expanding the potential of gene therapy to treat conditions that were previously unreachable.

Since the first gene therapy clinical trials in the 1990s, the technology has made its way into the market for conditions ranging from blindness to cancer.

Gene therapy has the potential to fix any genetic mutation causing disease by inserting a new copy of the faulty gene. However, its reach has historically been limited.

Weve been constrained with the things we can do with gene therapy, said Dmitry Kuzmin, Managing Partner at 4BIO Capital, a London-based VC that specifically invests in advanced therapies. If you look across the successes in gene therapy in the last five years, most of these were in diseases that are pretty straightforward from the engineering perspective.

Technical limitations have meant that gene therapy has been restricted to rare diseases caused by a single genetic mutation, as well as to certain areas of the body, such as the eye and the liver.

According to Kuzmin, there have been so far three generations of gene therapy technology. Generation one would be classic single-gene replacement, such as Luxturna, a gene therapy to fix a specific genetic mutation causing blindness. Generation two would consist of using gene therapy to introduce new functions. An example is Kymriah, where immune cells are equipped with a molecule that helps them hunt down cancer cells.

The third generation is the one that could hold the key to unlocking the full potential of gene therapy. It englobes several technologies that can be used to introduce a new drug target into the patient, making it possible to turn the therapy on and off as well as to tune its intensity.

As the first two generations get optimized and the third generation enters the clinic, we are now expanding our reach into areas that have been previously rather inaccessible, Kuzmin told me. One of them is the brain.

Treating the brain has long been a huge challenge for medicine. Take epilepsy, for example.

Epilepsy affects 1% of the whole population and about 30% of people with seizures of epilepsy continue to have seizures despite medication, said Dimitry Kullmann, Professor at University College London. Theres a paradox. We have a good understanding of the mechanisms behind epilepsy, but were unable to suppress seizures in a significant proportion of people with epilepsy.

The reason is that the molecules that we use for drugs dont target the epileptic zone of the brain; they bathe the entire body with medication, Kullmann told me. These drugs dont differentiate between neurons and synapses that derive the seizures, and those parts of the brain that are responsible for memory, sensory functions, motor functions and balance.

Gene therapy could provide a solution for this problem. Kullmanns group has been researching this approach for years and is now getting ready to start the first clinical trial in humans within a year.

A gene therapy can be directly injected in the area of the brain causing seizures. Furthermore, using DNA sequences called promoters, it is possible to restrict the effect of gene therapy to specific neurons within that area. In the case of epilepsy, gene therapy can be used to decrease the activity of only excitatory neurons, which cause epileptic seizures when they are overactive.

Another approach that Kullmans group is testing is chemogenetics. The idea here is to use gene therapy to put a specific receptor into the neurons, explained Kullmann. This receptor is designed to respond to a drug that, when given to the patient, decreases the activity of the neuron to suppress seizures.

The advantage is that you can switch on and off the therapeutic effect on demand by just giving, or not giving the drug, Kullmann said. This approach can thus make gene therapy more precise, being able to tune it to the specific needs of each patient. In addition, it reduces the big challenge of getting the dose right in a one-off treatment.

Ultimately, this technology could allow scientists to target a wide range of conditions that come under the umbrella of epilepsy, rather than just a specific form of the condition caused by a genetic mutation.

The approach could be extended to other conditions involving the brain, such as Parkinsons, ALS and pain. However, this kind of research is still at an early stage and it will take a while until its potential is proven in humans.

Blindness has been a major target of gene therapy because of the fact that the eye is an ideal target for this technology. The activity of the immune system is suppressed in the eye, minimizing the chances of rejection. In addition, unlike other cells in the body, those involved in vision are not renewed over time, being able to retain the injected DNA for years.

However, there are hundreds of genetic mutations that can cause blindness. With the classical gene therapy approach, a different therapy would have to be developed from scratch for each mutation. While some companies are doing just this for the most common mutations causing blindness, many other less frequent mutations are being left behind.

Others are turning to new generations of gene therapy technology. We figured out that it would be very, very difficult to use the classical gene therapy approach in each individual mutation, said Bernard Gilly, CEO of GenSight, a Parisian biotech developing gene therapies for blindness.

While the companys leading programs follow this classical approach, the company has also started clinical trials using a technology called optogenetics. Following a similar principle to gene therapy, optogenetics consists of introducing a protein that reacts to light into a cell.

GenSight is using optogenetics to develop a single therapy for the treatment of retinitis pigmentosa. This genetic condition can be caused by mutations in any of over 200 genes and results in progressive vision loss in children due to the degeneration of photoreceptor cells that perceive light and send signals to the brain.

With optogenetics, it would be possible to transfer the lost photoreceptor function to the cells in the retina that are responsible for relaying visual information to the brain. Using specialized goggles, the images captured by a camera are transformed into light patterns that stimulate these cells in the precise way needed for the brain to form images.

The company is currently testing this approach in clinical trials. We believe that this approach will allow us to restore vision in those patients who became blind because of retinitis pigmentosa, Gilly told me.

Optogenetics would not work a miracle, but it might be able to give people back the ability to navigate an unknown environment with a certain level of autonomy. Recognizing faces is a more challenging goal; although reading is not yet on the horizon, according to Gilly.

Still, the potential of optogenetics to address multiple genetic mutations with a single treatment might be revolutionary. As long as the neurons responsible for sending light signals to the brain are intact, this approach could be extended to other forms of blindness. In addition, conditions affecting the brain such as epilepsy, Parkinsons or ALS could be treated with this approach by introducing an implant to shine light on the target neurons.

However, approaches applying optogenetics to the brain are still further down the line. While optogenetics technology has been around for over 20 years, its application in humans is still very limited and in the early stages of research.

Chemogenetics and optogenetics are just two out of a wave of new technologies addressing the historical limitations of gene therapy. Other approaches are in development, such as using thermogenetics, which consists of introducing proteins that are activated by the heat created by infrared light.

With a growing range of tools available, it is becoming easier than ever for scientists to develop gene therapies that can address the specific challenges of different conditions affecting areas of the body. Traditionally, locations such as the heart, the lungs or the pancreas have been particularly difficult to target with gene therapy. That might soon stop being the case.

As we go forward, were interested in taking gene therapy out of this little box and trying to use all the knowledge we have to benefit patients in larger indications, said Kuzmin.

As gene therapy expands into more mainstream conditions, it could take precision medicine to a whole new level and help address the big variability that is often seen across patients with the same diagnosis.

Continued here:
How Gene Therapy Is Evolving to Tackle Complex... - Labiotech.eu

Recommendation and review posted by Bethany Smith

CAMBRIDGE Nov 11, 2019 (Thomson StreetEvents) -- Edited Transcript of Voyager Therapeutics Inc earnings conference call or presentation Wednesday, November 6, 2019 at 1:00:00pm GMT

* G. Andre Turenne

Voyager Therapeutics, Inc. - CEO, President & Director

* Matthew P. Ottmer

Voyager Therapeutics, Inc. - COO

Voyager Therapeutics, Inc. - Chief Medical Officer and Head of Research & Development

H.C. Wainwright & Co, LLC, Research Division - Analyst

Wells Fargo Securities, LLC, Research Division - MD and Senior Biotechnology Analyst

* Philip M. Nadeau

Good morning, and welcome to the Voyager Therapeutics Third Quarter 2019 Financial Results and Corporate Highlights Conference Call. (Operator Instructions) Please be advised that this call is being recorded. At this time, I'd like to turn the call over to Vasilis Kariolis, Voyager's Assistant Controller. Please proceed.

Thank you. Good morning, and thank you for joining us. With me on the call today are Andre Turenne, our President and Chief Executive Officer; Omar Khwaja, Chief Medical Officer and Head of R&D; and Matt Ottmer, Chief Operating Officer.

Earlier today, we issued a press release, which outlines the financial results and corporate highlights for the third quarter of 2019. The release is available at voyagertherapeutics.com.

Before we begin, just a reminder that the forward-looking statements included in this call represent the company's view as of today, November 6, 2019. Voyager disclaims any obligation to update these statements to reflect future events or circumstances, except as required by law. Please refer to today's press release as well as Voyager's filings with the SEC for information concerning risk factors that could cause actual results to differ materially from those expressed or implied by such statements.

With that, I'll pass the call over to Andre.

G. Andre Turenne, Voyager Therapeutics, Inc. - CEO, President & Director [3]

Thank you, Vasilis, and good morning, everyone. Welcome to our Q3 earnings and corporate highlights call. Our CFO, Allison Dorval, is unable to participate in the call this morning due to a death in her immediate family, which sadly occurred on Sunday. Our heartfelt thoughts are with Allison and her family. I thank Vasilis, our Assistant Controller, for stepping in and covering our financial highlights.

I'll begin today by walking you through some of our recent corporate developments. Omar will then provide a pipeline update, and Vasilis will wrap up with the financial results. Once we've concluded our remarks, we'll have some time to take your questions.

We've had another productive quarter in Q3 at Voyager, building on a transformative first half of the year during which we entered into 2 important collaborations and a restructured one. It's an exciting time at Voyager as we gain momentum and expand on our foundation. Voyager sits squarely at the intersection of gene therapy and neuroscience. This dual focus on AAV gene therapy and neurological diseases provides us with several advantages. For one, as we've continued to hire key talent, we've been able to add colleagues with specialized expertise precisely in our chosen area. Their experience is already proving to add significant value to our efforts.

Another benefit of our focus as we keep advancing our pipeline is that we're finding invaluable learnings translating from program to program. We're seeing this, for example, as we've begun planning for the rapid transition from IND to first patient treated in our Huntington's disease program. Given the similar nature of the neurosurgical procedure involved for the onetime HD treatment and the onetime PD treatment, we expect to more rapidly enable sites to enroll study participants than what have otherwise been possible without our prior experience.

The benefits of our focused experience also apply to our earlier-stage programs. Our work on a vectorized antibody against pathological species of alpha-synuclein with our partner, AbbVie, is progressing faster than expected in light of the early learnings from our anti-tau vectorized antibody efforts. These learnings in turn are now being applied to our own additional efforts in vectorized antibodies. Moving forward, we'll continue to rigorously apply our learnings and those from others working in the space as we further advance our pipeline and platform.

Regarding our lead program, VY-AADC for Parkinson's disease, which is partnered with Neurocrine, we expect to present final 3-year data from all 3 cohorts of the 1101 Phase I trial at a medical conference in 2020.

2020 is also expected to be an important year for our Huntington's program as we anticipate filing an IND application and beginning screening and enrollment into the clinical trial. As we announced in a press release this morning, we presented some positive data on VY-HTT01 at ESGCT last month. Omar will share more details on this shortly.

Finally, we're pleased to announce today that Allen Nunnally has been promoted to the position of Chief Business Officer, from his previous role as VP of Corporate and Business Development. Allen has been a key collaborator in my first year at Voyager, and I look forward to his continued success in his new role.

I'll now turn the call over to Omar to provide more detail on our pipeline programs.

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Omar Khwaja, Voyager Therapeutics, Inc. - Chief Medical Officer and Head of Research & Development [4]

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Thank you, Andre. First, I'll go through recent updates on our Parkinson's disease program. As Andre mentioned, the collaboration with Neurocrine, which we entered earlier this year, is off to a good start. We've agreed to the proposed statistical analysis plan for RESTORE-1 and are requesting feedback from the FDA before year-end. Steady progress continues to be made towards enrollment of the RESTORE-1 trial. We'll provide a more detailed update on RESTORE-1 after we receive feedback from the agency.

As a reminder, our approach to Parkinson's disease with the VY-AADC program is highly differentiated. It consists of the targeted delivery of a small volume of gene therapy to the region of the brain where it is needed for motor function. The result is a regulatable system, controllable by the standard-of-care oral medication. This ability to regulate the transient activity is highly desirable and a rather unique feature for AAV gene therapy. By creating a reservoir of AADC, the enzyme needed to convert levodopa to dopamine in the putamen, we're bypassing dying presynaptic neurons and introducing AADC into healthy postsynaptic neurons, where it can then be used to produce dopamine. AADC delivered into the putamen will do nothing on its own. But AADC in combination with levodopa will produce dopamine. Our approach gives the patient the exogenous control as to the amount of dose they needed to manage their motor function and the ability to avoid the negative impacts of too much dopamine in brain regions where it is not needed.

The Phase Ib trial was initiated in 2014. So we're now starting to see longer-term results that may speak to both the durability of effect and in the context of a progressive degenerative disease, contrast against the predicted course of disease progression. We expect to present 36 months data from all 3 cohorts in PD 1101 as well as 2-year data from PD 1102 at scientific meetings in 2020. The patients completing the 3-year protocol on PD 1101 and PD 1102 are now enrolling in our longer-term extension study. This will eventually provide us with over 5 years of data in addition to the placebo-controlled data at the time of the BLA filing and payer discussions.

Our Huntington's disease program is also progressing well. We've held advisory meetings with both neurologists and neurosurgeons and have received positive feedback on our delivery approach as well as our proposed clinical trial design and biomarker assessment. Our delivery approach leverages our learnings from the Parkinson's program, with local delivery of VY-HTT01 into the putamen. For Huntington's disease, we're also delivering directly into the thalamus. We chose this delivery approach based on our understanding of the disease pathology and the importance of delivering vector to the striatum as well as to the cortex. Pathological changes of Huntington's disease are evident earliest in the striatum, with changes in the cortex becoming noticeable as the disease progresses.

In fact, certain areas of the brain of a patient with Huntington's disease are deteriorating well before symptoms appear. The thalamus, in contrast, is a largely preserved structure in the early stages of Huntington's disease. Delivery of our gene therapy to the thalamus as well as to the putamen should allow us to deliver enough vector to impact the striatum as well as leverage the rich connections between the thalamus and the cortex to reach the outer brain.

Last month, at the European Society of Gene and Cell Therapy Meeting in Barcelona, we presented an update on our VY-HTT01 program during an oral platform presentation. We've previously presented data on dose-dependent vector biodistribution as well as HTT mRNA knockdown in the brains of nonhuman primates. In our recent presentation, we provided new evidence that VY-HTT01 also efficiently lowers huntingtin protein, and that huntingtin protein reduction is commensurate with the mRNA lowering and vector genome distribution in the NHP brain regions analyzed. These findings provide further evidence that our gene therapy, delivered to the thalamus and putamen, results in significant reductions in HTT, mRNA and in huntingtin protein to levels that are predicted to be clinically efficacious.

We now expect filing an IND for VY-HTT01 for Huntington's disease during the first half of 2020. As the kinetics of Huntington knockdown appear to be different in nonhuman primates than in rodents, we plan on submitting an IND application with final 1-year data from our preclinical studies instead of the previously planned interim 6 months data. Our goal is to minimize the amount of time between IND acceptance and first patient dose. We will be leveraging our related clinical experience in Parkinson's disease to achieve this.

Activities towards site selection engagement have already begun and will continue to take place in the fourth quarter and the beginning of 2020. We continue to expect screening and dosing of the first patient planned clinical study during 2020.

Our other pipeline programs, including the Friedreich's ataxia program with Neurocrine, and our 2 vectorized antibody programs with AbbVie, continue to progress. We are working on studies to support lead candidate selection for Friedreich's ataxia and continue to deliver on or ahead of schedule against our work plans on the AbbVie collaborations. Additionally, we've agreed on the 2 discovery sets with Neurocrine and are working on our own discovery efforts against new targets.

With our focus and expertise in neurological disease, we're pursuing several opportunities that are compelling targets for AAV gene therapy. We expect to provide more information on new programs during 2020.

I'll now pass the call on to Vasilis with the financial update.

--------------------------------------------------------------------------------

Vasilis Kariolis, [5]

--------------------------------------------------------------------------------

Thank you, Omar. Voyager reported net loss of $15 million or $0.41 per share for the third quarter ended September 30, 2019 compared to net loss of $20.3 million or $0.63 per share for the third quarter of 2018. Collaboration revenues of $20.4 million for the third quarter ended September 30, 2019, compared to collaboration revenues of $2.1 million for the third quarter of 2018. These 2019 revenues reflect the recognition of noncash amounts for research services that were performed for various programs under the Abbvie and Neurocrine collaboration agreements, in addition to amounts expected to be reimbursed by Neurocrine as per that collaboration agreement. Amounts can vary based on quarterly assessments of our efforts under each of these collaborations.

The increase in collaboration revenue during the third quarter of 2019 compared to the same period in 2018 primarily relates to the recognition of amounts from the Neurocrine and AbbVie alpha-synuclein collaborations, both of which were entered into in Q1 2019. Additionally, revenue related to the Abbvie tau collaboration increased year-over-year as our efforts continue to increase. These increases were offset by a reduction in collaboration revenue from our collaboration with Sanofi Genzyme, which was restructured in June 2019.

R&D expenses of $29.8 million for the third quarter ended September 30, 2019, compared to $16.6 million for the third quarter of 2018. These expenses include costs incurred under the Neurocrine collaboration, which are expected to be reimbursed. The increase in R&D expenses in the third quarter of 2019 related primarily to external research and development costs and increased employee-related and facility costs to support the advancement of our pipeline programs, including our RESTORE-1 Phase II clinical trial for VY-AADC.

General and administrative expenses of $8.5 million for the third quarter ended September 30, 2019, compared to $6.6 million for the third quarter of 2018. The increase in G&A expenses in the third quarter of 2019 is primarily due to an increase in employee-related and facility costs to support the advancement of our pipeline programs and growing operations.

As of September 30, 2019, we had $307.4 million in cash, cash equivalents and marketable debt securities compared to $155.8 million at December 31, 2018. Operating expenses are anticipated to be $150 million to $155 million, exceeding our previously forecasted range of $140 million to $150 million, largely as a result of higher-than-planned noncash expenses. Nevertheless, we continue to project year-end cash, cash equivalents and marketable debt securities to be in the previously forecasted range of $280 million to $290 million. Based on our current operating plans, we expect these amounts to be sufficient to meet our operating needs and capital expenditure requirements into mid-2022.

With that, we would like to now open the call up for questions. Operator?

================================================================================

Questions and Answers

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Operator [1]

--------------------------------------------------------------------------------

(Operator Instructions) And our first question comes from Phil Nadeau with Cowen and Company.

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Philip M. Nadeau, Cowen and Company, LLC, Research Division - MD & Senior Research Analyst [2]

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My question's on the Huntington's program. You mentioned in your prepared remarks that, I think, 1-year data is necessary for the IND, given the difference in kinetics in the knockdown between rodents and nonhuman primates. Can you talk a little bit more about the difference? What exactly are you seeing? And why is 1-year data more informative than 6 months in?

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G. Andre Turenne, Voyager Therapeutics, Inc. - CEO, President & Director [3]

--------------------------------------------------------------------------------

Yes. Thanks, Phil, for the question. I'll ask Omar to address it.

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Omar Khwaja, Voyager Therapeutics, Inc. - Chief Medical Officer and Head of Research & Development [4]

--------------------------------------------------------------------------------

Yes. So in -- back in 2017, Voyager had a pre-IND meeting with the FDA. And in the discussions around the definitive toxicology and biodistribution study that was planned, the feedback from the FDA was that the selected time points for assessment of toxicology should match the kinetics of transient expression and the specific request was that the time points would co-onset with the onset peak and plateaued expression of the transgene. At 26 weeks, the -- in terms of the bioanalytics we have, we don't yet -- aren't yet confident that we can say that the transgene expression has plateaued, and that their knockdown impact is also at its plateau as well. So that's why -- that's the reason that we've decided to not submit with interim 26-week data, but to continue the study to 53 weeks and submit with a full data set.

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Philip M. Nadeau, Cowen and Company, LLC, Research Division - MD & Senior Research Analyst [5]

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That's helpful. And I guess, when you say hasn't plateaued, is the level of knockdown continuing to increase? Or is it decreasing towards a plateau? And what are the implications for the human data? When -- at what time point do you think human proof-of-concept data, therefore would be available? Is it going to take 52 weeks to follow-up for that as well?

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Omar Khwaja, Voyager Therapeutics, Inc. - Chief Medical Officer and Head of Research & Development [6]

--------------------------------------------------------------------------------

Yes. That's a great question. I mean, I think it's not so much that the knockdown in protein levels haven't plateaued, but we really need another data time point to ensure that, that is a true plateau rather than, that's just 2 time points that we're saying that we've got knocked down and it's stable. I think we need to have a third one to be certain for that.

I think we'll probably have to directly extrapolate that to the human situation until we actually conduct the human study. It's going to be difficult to know how that extrapolates, but it certainly implies, based on what we've observed so far, that on the profile that we see so far, it means that it's likely that it's going to be at least 3 months in the human that we would see the maximum expression of the transgene.

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G. Andre Turenne, Voyager Therapeutics, Inc. - CEO, President & Director [7]

--------------------------------------------------------------------------------

To -- just to add to the clarification, Phil, what we're seeing is a continued reduction in the -- or increase in the knockdown over time. So that's the direction. So if that could be a positive clinically, that you have the peak lowering that is higher than what we've observed at the 5 weeks in the earlier studies, what -- as Omar said, what we're looking to have is just the comfort that we have an understanding of how low it goes and at what point that is achieved.

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Operator [8]

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And our next question comes from Charles Duncan with Cantor Fitzgerald.

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Charles Cliff Duncan, Cantor Fitzgerald & Co., Research Division - Senior Analyst [9]

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Condolences to Allison. Had a question on the PD program and then a follow-up on the HD program. Regarding the PD program, I'm wondering, you said that you have agreed to the staff plan with Neurocrine for RESTORE. And I'm just kind of wondering if you can provide additional color now that you're thinking about what to do there. In terms of the patient population, sizing and timing for RESTORE-1, can you provide any additional color on that?

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G. Andre Turenne, Voyager Therapeutics, Inc. - CEO, President & Director [10]

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Yes. Thanks, Chaz, for the question. So at this stage, we're not ready yet to give the further guidance as to the exact size of the study. We anticipate, as we've said previously, that it will be in the range that we've guided, 75 to 100 patients. And the work that we've done is just to determine with our new partner what the precise target is going to be within that range and then to get that same alignment with the agency. So when we have that in alignment with the agency, we're going to be able to provide that update, along with an update on -- given the number of patients and where we're at in the enrollment, some new targets for when we expect to be able to complete the enrollment to the full enrollment of the study.

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Charles Cliff Duncan, Cantor Fitzgerald & Co., Research Division - Senior Analyst [11]

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Okay. It sounds consistent with your previous thinking. And then, if I can ask a follow-up on that. There are other AADC gene therapy programs for neuro indications, and Omar did a great job in terms of talking about your differentiation with regard to where the drug is really administered. But I guess, if you look across AADC programs, how do you see you being differentiated from others in terms of, say, vector use or basic construct?

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G. Andre Turenne, Voyager Therapeutics, Inc. - CEO, President & Director [12]

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Yes. No, thanks for that question, and Omar can add to it. But I think in his prepared remarks, he touched on a key differentiation, which is this activity to modulate the response with the control of the exogenous levodopa. So that, I think, is in contrast with the alternative approach that's in development, which provides a more direct production of dopamine.

Our approach is, one, again, as highlighted, that allows for the dialing of the amount of dopamine to be produced, like in our delivery in the putamen is in common. And that's a good target, to have a stable reservoir of that enzyme, as it's a structure that is not too impacted in Parkinson's disease. And we've been able to observe in our experience to date, in our preclinical experience that a very durable expression of the enzyme production in the -- after administration in the putamen. I don't know if Omar, you want to highlight any additional points?

--------------------------------------------------------------------------------

View original post here:
Edited Transcript of VYGR earnings conference call or presentation 6-Nov-19 1:00pm GMT - Yahoo Finance

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The womans genetic profile showed she would develop Alzheimers by the time she turned 50.

She, like thousands of her relatives, going back generations, was born with a gene mutation that causes people to begin having memory and thinking problems in their 40s and deteriorate rapidly towards death around age 60.

But remarkably, she experienced no cognitive decline at all until her 70s, nearly three decades later than expected.

How did that happen?

New research provides an answer, one that experts say could change the scientific understanding of Alzheimers disease and inspire new ideas about how to prevent and treat it.

In a study published in the journal Nature Medicine, researchers say the woman, whose name they withheld to protect her privacy, has another mutation that has protected her from dementia, even though her brain has developed a major neurological feature of Alzheimers disease. This ultra-rare mutation appears to help stave off the disease by minimising the binding of a particular sugar compound to an important gene. That finding suggests that treatments could be developed to give other people that same protective mechanism.

A drug or gene therapy would not be available any time soon because scientists first need to replicate the protective mechanism found in this one patient by testing it in laboratory animals and human brain cells. Still, this case comes at a time when the Alzheimers field is craving new approaches after billions of dollars have been spent on developing and testing treatments and some 200 drug trials have failed. It has been more than 15 years since the last treatment for dementia was approved, and the few drugs available do not work very well for very long.

The woman is entering her late 70s now and lives in Medelln, the epicentre for the worlds largest family to experience Alzheimers. It is an extended Colombian family of about 6,000 people whose members have been plagued with dementia for centuries, a condition they called La Bobera the foolishness and attributed to superstitious causes.

Decades ago Colombian neurologist Dr Francisco Lopera began painstakingly collecting the familys birth and death records in Medelln and remote Andes mountain villages. He documented the sprawling family tree and took dangerous risks in guerrilla and drug-trafficking territory to cajole relatives of people who died with dementia into giving him their brains for analysis.

Through this work, Dr Lopera, whose brain bank at the University of Antioquia now contains 300 brains, helped discover that their Alzheimers was caused by a mutation on a gene called Presenilin 1. Although this type of hereditary early-onset dementia accounts for only a small proportion of the roughly 30 million people worldwide with Alzheimers, it is important because, unlike most forms of the disease, the Colombian version has been traced to a specific cause and a consistent pattern. So Dr Lopera and a team of American scientists have spent years studying the family, searching for answers both to help the Colombians and to address the mounting epidemic of the more typical old-age Alzheimers disease.

When they found that the woman had the Presenilin 1 mutation, but had not yet even developed a pre-Alzheimers condition called mild cognitive impairment, the scientists were mystified. We have a single person who is resilient to Alzheimers disease when she should be at high risk, said Dr Eric Reiman, executive director of the Banner Alzheimers Institute in Phoenix and a leader of the research team.

The woman was flown to Boston, where some of the researchers are based, for brain scans and other tests. Those results were puzzling, said Yakeel Quiroz, a Colombian neuropsychologist who directs the familial dementia neuroimaging lab at Massachusetts General Hospital.

The womans brain was laden with the foremost hallmark of Alzheimers: plaques of amyloid protein. She had the highest levels of amyloid that we have seen so far, said Quiroz, adding that the excessive amyloid probably accumulated because the woman had lived much longer than other family members with the Alzheimers-causing mutation.

But the woman had few other neurological signs of the disease not much of a protein called tau, which forms tangles in Alzheimers brains, and little neurodegeneration or brain atrophy. Her brain was functioning really well, said Quiroz, who, like Dr Reiman, is a senior author of the study. Compared to people who are 45 or 50, shes actually better.

She said the woman, who raised four children, had only one year of formal education and could barely read or write, so it was unlikely her cognitive protection came from educational stimulation. She has a secret in her biology, Dr Lopera said. This case is a big window to discover new approaches.

Quiroz consulted Dr Joseph Arboleda-Velasquez, who, like her, is an assistant professor at Harvard Medical School (he is also Quirozs husband). Dr Arboleda-Velasquez, a cell biologist at Massachusetts eye and ear, conducted extensive genetic testing and sequencing, determining that the woman had an extremely rare mutation on a gene called APOE.

APOE is important in general-population Alzheimers. It has three variants. One, APOE4, greatly increases risk and is present in 40 per cent of people with Alzheimers. The Colombian woman has two copies of APOE3, the variant that most people are born with but both copies have a mutation called Christchurch (for the New Zealand city where it was discovered). The Christchurch mutation is extremely rare, but several years ago, Reimans daughter Rebecca, a technologist, helped determine that a handful of Colombian family members have that mutation on one of their APOE genes. They developed Alzheimers as early as their family members typically did. The fact that she had two copies, not just one, really kind of sealed the deal, Dr Arboleda-Velasquez said.

Dr Guojun Bu, chairman of the neuroscience department at the Mayo Clinic in Jacksonville, Florida, who studies APOE, said that while the findings involved a single case and more research was needed, the implications could be profound.

When you have delayed onset of Alzheimers by three decades, you say wow. New York Times

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The woman who should have got Alzheimers by 50, but didnt - The Irish Times

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BOTHELL Nov 8, 2019 (Thomson StreetEvents) -- Edited Transcript of Sarepta Therapeutics Inc earnings conference call or presentation Thursday, November 7, 2019 at 9:30:00pm GMT

* Alexander G. Cumbo

Sarepta Therapeutics, Inc. - Executive VP & Chief Commercial Officer

* Douglas S. Ingram

Sarepta Therapeutics, Inc. - President, CEO & Director

Sarepta Therapeutics, Inc. - Executive VP of R&D and Chief Medical Officer

* Ian M. Estepan

Sarepta Therapeutics, Inc. - Senior VP of Corporate Affairs & Chief of Staff

Sarepta Therapeutics, Inc. - SVP of Gene Therapy

Sarepta Therapeutics, Inc. - Executive VP, CFO & Chief Business Officer

Robert W. Baird & Co. Incorporated, Research Division - Senior Research Analyst

* Christopher N. Marai

Nomura Securities Co. Ltd., Research Division - MD & Senior Analyst of Biotechnology

* Debjit D. Chattopadhyay

H.C. Wainwright & Co, LLC, Research Division - MD of Equity Research & Senior Healthcare Analyst

BTIG, LLC, Research Division - MD and Specialty Pharmaceutical & Biotechnology Research Analyst

Janney Montgomery Scott LLC, Research Division - Equity Research Analyst & Director of Biotechnology Research

Good day, ladies and gentlemen, and welcome to the Sarepta Therapeutics Third Quarter 2019 Earnings Call. (Operator Instructions) As a reminder, today's call is being recorded.

And now I'd like to introduce your host for today's program, Ian Estepan, Senior Vice President, Chief of Staff and Corporate Affairs.

Ian M. Estepan, Sarepta Therapeutics, Inc. - Senior VP of Corporate Affairs & Chief of Staff [2]

Thank you, Michelle, and thank you all for joining today's call. Earlier today, we released our financial results for the third quarter of 2019. The press release is available on our website at http://www.sarepta.com, and our 10-Q was filed with the SEC earlier this afternoon. Joining us on the call today are Doug Ingram, Sandy Mahatme; Bo Cumbo, Dr. Gilmore O'Neill; and Dr. Rodino-Klapac. After our formal remarks, we'll open up the call for questions.

I'd like to note that during this call, we'll be making a number of forward-looking statements. Please take a moment to review our slide on the webcast which contains our forward-looking statements. These forward-looking statements involve risks and uncertainties, many of which are beyond Sarepta's control. Actual results could materially differ from these forward-looking statements, and any such risks can materially and adversely affect the business, the results of operations and the trading prices of Sarepta's common stock.

For a detailed description of applicable risks and uncertainties, we encourage you to review the company's most recent quarterly report on Form 10-Q filed with the Securities and Exchange Commission as well as the company's other SEC filings. The company does not undertake any obligation to publicly update its forward-looking statements, including any financial projections provided today, based on subsequent events or circumstances.

And with that, let me turn the call over to our CEO, Doug Ingram, who will provide an overview on our recent progress. Doug?

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Douglas S. Ingram, Sarepta Therapeutics, Inc. - President, CEO & Director [3]

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Thank you, Ian. Good afternoon and evening, and thank you all for joining us for Sarepta Therapeutics Third Quarter 2019 Conference Call.

Our ambitious strategy involving one of the deepest multi-platform genetic medicine pipelines in biotech has required focused execution over the course of 2019. To remind you, we have more than 25 active programs across our RNA and gene therapy platforms, and we're either actively in or in late-stage planning for some 9 human clinical trials to advance our plans. I am pleased to say that over the course of 2019 and in the third quarter specifically, we have made very significant strides in advancing our programs and our strategic vision, and I'm excited to discuss those advancements. However, while doing so, I must also acknowledge what we all know that we had a setback in the third quarter. And rather than burying it among or after a discussion of our successes, I will begin by commenting on a CRL disappointment that occurred in August.

Having worked diligently on our submission for VYONDYS 53, the generic name of that is golodirsen, for well over a year and based on all of our interactions with the Division of Neurology Products, we were very confident that we would obtain an approval on our PDUFA date, which was August 19. Instead, as you know, we were surprised to have received a complete response letter, also known as a CRL, signed by the Office of Drug Evaluation I. Our disappointment extends beyond Sarepta to the 8% of exon 53 amenable DMD patients in the United States who degenerate every day while they await access to this therapy.

When I joined Sarepta, I made some commitments externally and to the Division of Neurology, that we intended to build a positive relationship with the Division of Neurology, one founded on transparency and on solid evidence-based science. And consistent with that commitment, we will work with the agency to address the reasons for the CRL and determine a pathway for a potential approval if one is possible.

I've heard from those who would prefer that I speak more often and more publicly on this issue and/or that I would attempt to engage the patient community or others to assist, for instance, in applying external pressure to bring this therapy along faster. I have no intention of doing either of those things. If we can win the day with this therapy and with this issue, we will have done so on the science and on the regulations and in collaborative evidence-based discussions with our reviewers at the FDA.

Now I've also heard some speculation about the implications of the CRL. So let me take a moment to address these as well. First, the VYONDYS CRL does have implications for our submission for our next PMO, casimersen. As they are closely related, we will await clarity on the VYONDYS matter before we submit for casimersen in the United States. But let me [just dissuade] anyone who might have concerns for our other programs. The CRL does not have any read-through to our micro-dystrophin gene therapy program. The CRL involves 2 safety signals in connection with an application for an accelerated approval. Our micro-dystrophin program is overseen by a different part of the FDA, CBER, and we are not seeking accelerated approval there. There is simply no overlap in either substance or personnel.

Secondly, to those who may believe that the CRL suggests some sort of bias on behalf of the Division of Neurology towards Sarepta, I would unequivocally and emphatically disagree. Let me reiterate that I remain convinced that we were treated very fairly and professionally by the Division of Neurology. Also, I'm very proud of the Sarepta team and how they comported themselves during this review. From my perspective, we have gone a long way in the last 2.5 years in forging a positive evidence-based working relationship with the division. We will work diligently to address the VYONDYS CRL. But with that, I do not intend to provide a prediction on outcome or on timing or to provide interviews during the process. However, I will provide an update to the patient, physician and investment communities once we have definitive clarity on the outcome of those discussions.

Now moving to our positive achievements in the quarter. We have made some enormous amount of progress in this third quarter. EXONDYS continues to perform well with third quarter sales above consensus at $99 million. That is a 26% increase over the same quarter last year. Commenting for a moment on a confirmatory trial for EXONDYS, to remind you, this trial comprises 3 arms: one with EXONDYS at 100 mg per kg and another at 200 mg per kg versus our current dose at 30 mg per kg. The trial design, which was an FDA requirement, will answer whether higher doses of EXONDYS provide even more benefit than the currently approved dose. Now since the comparator arms involve higher doses than the currently approved dose, we were required to begin our confirmatory trial with a healthy human volunteer study. We have completed this trial, and based on the results, we have initiated the main confirmatory trial. We will begin dosing this quarter.

Staying on our RNA franchise. We have moved to our multi-ascending dose trial for our next-generation RNA platform, the PPMO, and we are dosing trial participants now. We will have safety and dosing insight in 2020. If our PPMO shows encouraging results, in addition to SRP-5051, that's the construct that we're currently in a multi-ascending dose regarding, we have 5 additional constructs that have already been built, which in total have the potential to treat as much as 43% of the DMD community. We are also conducting research now on new therapeutic targets that could be served by our PPMO platform.

Moving next to our gene therapy platform. As you know, we are spending enormous resource and energy to build out our vision of an enduring gene therapy engine. Between our research and clinical-stage programs, we have more than 14 therapeutic candidates advancing through research and development. We have made great progress thus far this year and quarter, led by our most advanced program, SRP-9001, for DMD, which, at least to my knowledge, is the highest-potential late-stage gene therapy program currently in biotech. As you should be aware, our double-blind, placebo-controlled SRP-9001 micro-dystrophin trial, the trial that we call Study 2, was fully dosed by midyear, but we took advantage of the availability of additional study material and previously announced that we had increased the study n from 24 patients to 40 patients, significantly increasing the study power and confidence in this study. In addition to our initial site with Dr. Jerry Mendell at Nationwide Children's Hospital, we have added a second site at UCLA with Dr. Perry Shieh. And I'm very proud to be associated with that clinician and investigator. Both sites are actively dosing patients, and we remain on target to complete our dosing by year-end.

Micro-dystrophin manufacturing is progressing well. From a capacity perspective, Brammer has now completed the buildout of our single-use micro-dystrophin manufacturing facility in Lexington, Massachusetts. We also have dedicated suites with Paragon in Maryland with actually substantially greater capacity than our dedicated Lexington facility, which means we have robustly secured capacity well in advance of launch.

Our analytical development work proceeds well, and we continue to make progress on process development and yield optimization. Given our recent capacity, analytical development and process development progress, we remain on track to commence our next trial, Study 301, with commercial development supply by mid-2020. Now Study 2 is being conducted with clinical material from Nationwide Children's Hospital. Study 301 will be a multicenter, multi-country, placebo-controlled trial using commercial process material from our hybrid manufacturing model with Brammer and Paragon. The main study will include DMD patients ages 4 to 7, but we are also planning a separate study for older and non-ambulatory patients as well.

Commenting on a few of our other gene therapy programs. Following exceptional expression and biomarker results in our first 3-patient cohort dosed with our construct for limb-girdle 2E, in October, we announced positive 9-month functional results in that same cohort. Consistent with robust expression of the native beta-sarcoglycan protein, that is the cause of the disease, all patients improved on every functional endpoint by the 9-month time point. Consistent with the protocol, we will treat an additional 3-patient cohort with a higher dose, and then in early 2020, we will decide on the dose for what we hope to be the pivotal trial. These results will help inform dosing not only of our 2E program but also on the other limb-girdle programs in our pipeline. We will also meet with the FDA in the near term to discuss the development pathway for our limb-girdle programs. And informed by this and further work on manufacturing, we will provide an update on the clinical pathway and the timing for our limb-girdle portfolio in 2020.

Next, led by our partner Lysogene, the AAVance gene therapy study for MPS IIIA, also known as Sanfilippo Syndrome Type A, is proceeding well with 13 patients having been dosed to date. MPS IIIA is a rare autosomal recessive lysosomal storage disease that primarily affects the brain and the spinal cord, causing severe cognitive decline, motor disease, behavioral decline and unfortunately death at a young age. AAVance is a single-arm trial evaluating the safety and efficacy of an rh10-mediated gene therapy to deliver the missing SGSH gene with the goal of robustly expressing the missing enzyme in the brain that is the cause of MPS IIIA.

Moving to Charcot-Marie-Tooth, or CMT. Dr. Zarife Sahenk of Nationwide Children's Hospital intends to commence dosing of the proof-of-concept study for CMT 1A subject only to obtaining final release of trial material for that study. CMT is the largest inherited neuromuscular disease in the world. And CMT 1A, a devastating peripheral nerve disease, is also the most prevalent form of CMT. Dr. Sahenk's gene therapy is an AAV 1-mediated construct to deliver the neurotrophic factor-3, NT-3. In animal models, NT-3 has been shown to promote nerve regeneration, improved motor function, histopathology and electrophysiology of peripheral nerves. And in early proof-of-principle studies, NT-3 has shown markers of clinical benefits in patients with CMT 1A when administered subcutaneously.

In summary, we have made great progress in the third quarter and over the course of 2019 toward our ambitions, advancing our RNA and gene therapy platforms, advancing our many development programs, building out our gene therapy manufacturing capacity and building out our tower. As with any ambitious strategy, our progress this quarter was met with an obstacle in the form of VYONDYS CRL. The breadth of our ambition inevitably comes with challenges and obstacles to address and to overcome. But to those who might at times feel discouraged or disheartened by the need to overcome the occasional barrier, we should keep top of mind what we are doing with all of this. If we are successful in our mission, we will not merely be among the most significant gene therapy and genetic medicine biotechnology companies in existence, but we will have, more importantly, extended, improved and saved the lives of countless patients who would otherwise have been left hopeless.

And with that, I will turn the call over to Sandy to provide an update on the financials. Sandy?

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Sandesh Mahatme, Sarepta Therapeutics, Inc. - Executive VP, CFO & Chief Business Officer [4]

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Thanks, Doug. Good afternoon, everyone. Let me start by saying that we had another strong quarter both in terms of financial performance and in progress towards the pipeline and manufacturing capabilities. With a current top line run rate of approximately $400 million and a cash balance over $1 billion, we are in a strong position to continue to accelerate our strategic imperatives and invest in the growth of Sarepta. Net product revenue for the third quarter of 2019 was $99 million compared to $78.5 million for the same period of 2018. The increase primarily reflects higher demand for EXONDYS 51.

On a GAAP basis, the company reported a net loss of $126.3 million and $76.4 million or approximately $1.70 and $1.15 per share for the third quarter of 2019 and 2018, respectively. We reported a non-GAAP net loss of $84.4 million or $1.14 per share compared to non-GAAP net loss of $37.1 million or $0.56 per share in the third quarter of 2018.

In the third quarter of 2019, we recorded approximately $13 million in cost of sales compared to $8.7 million in the same period of 2018. The increase was primarily driven by inventory costs related to higher demand for EXONDYS 51 during the third quarter of 2019 as well as accrued royalty payments to BioMarin and the University of Western Australia.

On a GAAP basis, we recorded $133.9 million and $86.6 million of R&D expenses for the third quarters of 2019 and 2018, respectively, which is a year-over-year increase of $47.3 million. R&D expenses were $110.5 million for the third quarter of 2019 compared to $64.2 million for the same period of 2018, an increase of $46.3 million. The year-over-year growth in non-GAAP R&D expense was driven primarily due to continuing ramp-up of our micro-dystrophin program, our ESSENCE program and initiation of certain post-marketing studies for EXONDYS 51.

Turning to SG&A. On a GAAP basis, we recorded $75.4 million and $53 million of expenses for the third quarters of 2019 and '18, respectively, a year-over-year increase of $22.4 million. On a non-GAAP basis, the SG&A expenses were $59.6 million for the third quarter of 2019 compared to $42.5 million for the same period of 2018, an increase of $17.1 million. The year-over-year increase was primarily driven by significant organizational growth and continued expansion to support a commercial launch -- to support our commercial launch plans globally and almost 30 therapies in various stages of development across several therapeutic modalities.

On a GAAP basis, we recorded $2.5 million in other expenses for the third quarter of 2019 compared to $7 million for the same period of 2018. The favorable change is primarily driven by the payoff of certain debt instruments during the third quarter of 2018 as well as a higher return on investments over the third quarter of 2019.

We had approximately $1.1 billion in cash, cash equivalents and investments as of September 30, 2019.

With that, I'd like to turn the call over to Bo for a commercial update. Bo?

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Alexander G. Cumbo, Sarepta Therapeutics, Inc. - Executive VP & Chief Commercial Officer [5]

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Thank you, Sandy. Good afternoon, everyone. To begin, we are pleased with the continued strong performance of EXONDYS 51 in the third quarter. Total revenues reached $99 million. We were also pleased to be in a position to increase our 2019 revenue guidance range from $365 million to $375 million to a range of $370 million to $380 million for EXONDYS 51. Sales have increased quarter-over-quarter for over 3 years now, and we continue to see consistent demand for EXONDYS 51 as we speak today.

Compliance and adherence have remained high and stable since launch and to date continue to remain steady. It should be noted that in the past 2 years, we've experienced ordering volatility at the end of the year and suspect that we could see a change in ordering patterns with both Christmas and New Year's falling in the middle of the week. Internally, we are assuming the pattern from previous years could be more extreme this year due to both holidays falling midweek. With that said, we feel comfortable with the guidance provided.

The success we achieved this year reflects the impact EXONDYS 51 continues to have on patient lives. We remain the leading voice with KOLs and payers across the world in support of Duchenne patients and are recognized as the leader in RNA and gene therapies within the Duchenne field. Our strategy to advance the very best science, build awareness and appreciation for Duchenne and pave new pathways so Duchenne patients gain access to therapy have resulted in the successful trajectory of EXONDYS 51 since its approval just over 3 years ago and will play a role for future therapies.

As for golodirsen, if approved, we will be ready to launch, leveraging our knowledge and experience to facilitate rapid access to individuals amenable to exon 53. Our work is focused on delivering, and grounding us in all we do is the patient. That journey begins with identifying patients in our core therapeutic areas: Duchenne, the limb-girdle muscular dystrophy and MPS IIIA. Patient identification will be central to the commercial organization for the balance of 2019 and leading into 2020 and beyond. The genetic testing program, Decode Duchenne, which we started with PPMD many years ago, consistently identifies patients. We are also in the process of building genetic testing programs for our other disease states we are working on as well. We believe patient identification will always be one of our primary commercial goals, and we will continue to place resources on these programs.

Another important goal will be gene therapy site readiness. We are already working on global site readiness for our DMD micro-dystrophin program and working with many of the Zolgensma and Spinraza sites treating SMA. Based on the very strong results Novartis demonstrated with their recent launch of Zolgensma and understanding the label and the differences in patient population sizes between the 2 disease states, we believe having a strong network of sites ready and trained to handle gene therapies will be critical. We will continue to focus on this as we move through worldwide development and, if successful, commercialization.

We also believe it is critical to focus on access and reimbursement as early as possible. We're already speaking to and educating large to midsized insurance plans as well as CMS and Medicaid providers on the differences between chronic therapies and onetime gene therapies and the importance of quickly gaining access to these therapies for diseases like Duchenne. We have built constructive relationships with payers over time and look forward to continuing to work with them to support broad access.

In the limb-girdle muscular dystrophy, we are focused on disease education and identifying patients. The limb-girdle muscular dystrophies are a family of diseases, over 30 subtypes in all. Therefore, patient identification is of critical importance. Our plan is to leverage our knowledge and experience to ensure that we're able to serve these communities as we have in Duchenne. We've already attended limb-girdle muscular dystrophy conferences, held educational symposiums at major neuromuscular conferences, held advisory boards to understand how physicians identify and treat patients and already have a digital presence within the community. All of this will help us prepare for the potential to support multiple launches in the years to come.

Sarepta's prospects to transform the lives of patients with rare diseases is unparalleled in the industry. We have the largest neuromuscular RNA and gene therapy pipeline in the industry, and we understand the responsibility that comes with such an important mission.

With that, I will turn the call back to Doug for closing remarks.

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Douglas S. Ingram, Sarepta Therapeutics, Inc. - President, CEO & Director [6]

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Thank you, Bo. So looking forward, we have a number of significant milestones to achieve over the rest of 2019 and through 2020. First, we intend to complete dosing of our SRP-9001 Study 2, that's our micro-dystrophin study, by year-end with functional readout 48 weeks thereafter. We soon intend to launch process development for SRP-9001, not manufacturing for purposes of conducting our next clinical trial, gain insight from the agency on CMC and on our trial itself and then to commence Study 301 by mid-2020. We intend to dose an additional high-dose cohort for limb-girdle 2E and then make a dose selection. We intend to gain regulatory and manufacturing insight and to present an update on the development pathway and time line for our entire limb-girdle program in 2020. Dr. Sahenk intends to commence a proof-of-concept study for CMT gene therapy, NT-3. And we intend to obtain safety and dosing insight for our PPMO program in the first half of 2020. So we obviously have a lot to do but a lot of milestones as well over the coming months and quarters.

Thank you all for joining us tonight, and I'll open up the line for questions now.

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Questions and Answers

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Operator [1]

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(Operator Instructions) Our first question comes from Alethia Young of Cantor Fitzgerald.

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Alethia Rene Young, Cantor Fitzgerald & Co., Research Division - Head of Healthcare Research [2]

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Congrats on all the progress over the quarter. This may be a simple one, but I was just curious to get your perspective around Zolgensma partial hold. And like should we -- is there any -- are there any reads to potentially make thinking about other gene therapy programs?

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Douglas S. Ingram, Sarepta Therapeutics, Inc. - President, CEO & Director [3]

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Thank you for that question, Alethia. Okay. So well, first, let me say this. Let's make sure we're all on the same page. For those of you maybe unaware, I expect everyone is aware, Novartis recently announced that their clinical trial for their AAV9-mediated SMA gene therapy for intrathecal administration was placed on a partial clinical hold due to neurotoxicity that was seen in animal models. So first, understand this, we do not have a unique insight into the Zolgensma clinical hold itself or the Zolgensma program. Certainly, one should look at Novartis to gain accurate insight on that program and those issues.

So with that said, I should tell you, we see no read-through to our program, and there's a host of reasons for that. First, understand that we are dosing peripherally with IV administration. We're not dosing intrathecally as was the issue, as announced by Novartis, regarding that partial clinical hold. And second of all, understand that we're not using AAV9. Dr. Louise Rodino-Klapac who is with us tonight and Dr. Jerry Mendell chose rh74 for a number of specific attributes. One of the significant ones was that rh74, unlike AAV9 as an example, does not promiscuously cross the blood-brain barrier. And unlike SMA where that would be of value, there is absolutely no value to these micro-dystrophin constructs in the CNS at all. They have promoters that wouldn't turn on in the CNS, so there would be no value there. So this seems to have been a very wise choice.

And also note this, that we have an enormous amount of preclinical and animal model evidence with respect to rh74. And even at doses that are multiples higher than we're using in our clinical trial, we have never seen evidence of neurotoxicity as relates to AAVrh74.

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Operator [4]

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Our next question comes from Whitney Ijem of Guggenheim.

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Whitney Glad Ijem, Guggenheim Securities, LLC, Research Division - Senior Analyst of Biotechnology [5]

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Congrats on all the progress. I'll ask a question on the original 4 micro-dystrophin patients. Curious if we'll get an update on them in 2020 either in an update from you or possibly a publication from Dr. Mendell.

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Douglas S. Ingram, Sarepta Therapeutics, Inc. - President, CEO & Director [6]

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Yes. Thanks for that question. Thank you for your comments. So yes, Dr. Mendell has always had a keen interest in publishing the 1-year data on the 4 patients, and he is working on the manuscript even as we speak. So I feel very confident that we'll have a publication in 2020 on the first 4 patients.

Original post:
Edited Transcript of SRPT earnings conference call or presentation 7-Nov-19 9:30pm GMT - Yahoo Finance

Recommendation and review posted by Bethany Smith

Registrational Trial for Wiskott-Aldrich Syndrome Met Key Primary and Secondary Endpoints at Three Years; Data from Integrated Analysis Reinforce Treatment Benefits of Gene Therapy and Durability of Effect in Additional Patients

Similar Profiles Reported Between Cryopreserved and Fresh Formulations of OTL-101, Further Supporting Upcoming Regulatory Filing and Broad Patient Availability

BOSTON and LONDON, Nov. 06, 2019 (GLOBE NEWSWIRE) -- Orchard Therapeutics (ORTX), a leading commercial-stage biopharmaceutical company dedicated to transforming the lives of patients with serious and life-threatening rare diseases through innovative gene therapies, today announced the upcoming presentation of registrational data from multiple programs at the 61st American Society of Hematology (ASH) Annual Meeting in Orlando, FL.

Investigators will describe ongoing clinical progress for two lead development programs in the companys primary immune deficiencies portfolio: OTL-103, an investigational gene therapy in development for the treatment of Wiskott-Aldrich syndrome (WAS) at theSan Raffaele-Telethon Institute for Gene Therapy(SR-Tiget) inMilan, Italy; and OTL-101, an investigational gene therapy in development for the treatment of adenosine deaminase severe combined immunodeficiency (ADA-SCID).

In addition, investigators will deliver an oral presentation featuring updated data from the ongoing proof-of-concept study of OTL-203, an investigational gene therapy in development for the treatment of mucopolysaccharidosis type I (MPS-I) atSR-Tiget.

This growing body of positive data, from dozens of patients across multiple diseases, provides a solid foundation as we advance each program toward its next phase of development, including upcoming regulatory submissions for ADA-SCID and WAS, saidMark Rothera, president and chief executive officer ofOrchard Therapeutics. We now have two supportive data sets one from our OTL-101 program in ADA-SCID and one from our OTL-200 program in metachromatic leukodystrophy that demonstrate cryopreserved formulations are engrafting as expected, similar to the fresh formulation. This supports our strategy for making these therapies, if approved, broadly available to patients in need throughout the world.

We are extremely pleased with our continued clinical progress, including the duration of benefits seen in our WAS trial, which is the longest published follow-up of hematopoietic stem cell gene therapy durability to date using lentiviral vector transduction, said Bobby Gaspar, M.D., Ph.D., chief scientific officer of OrchardTherapeutics. The totality of these data underscores the broad applicability of our gene therapy platform approach and the opportunity we have to deliver potentially curative treatments for a variety of devastating and rare genetic disorders.

Full presentation details are below:

Poster Presentation Details

Lentiviral Hematopoietic Stem and Progenitor Cell Gene Therapy for Wiskott-Aldrich Syndrome (WAS): Up to 8 Years of Follow up in 17 Subjects Treated Since 2010Publication Number: 3346Session: 801. Gene Therapy and Transfer: Poster IIDate and time:Sunday, December 8, 6:00-8:00pm ET

This presentation includes results from an integrated analysis of 17 patients treated with OTL-103 for the treatment of WAS, including the complete data set for the eight patients from the registrational study and nine who received OTL-103 as part of an expanded access program (EAP). Participants have been followed for a median of three years.

In the eight-patient registrational trial, investigators reported that the study achieved its key primary and secondary endpoints at three years, including the elimination of severe bleeding episodes and a significant reduction in the frequency of moderate bleeding episodes. Successful engraftment was observed within three months, leading to an increase in WAS protein expression and a vector copy number that has been maintained for up to eight years. Nine months post-administration, all patients stopped receiving platelet transfusions, and no severe bleeding events were reported. A significant reduction in the rate of severe infections was also observed and all patients were able to stop immunoglobin replacement therapy (IgRT), suggesting a complete reconstitution of immune function with durability of effect of up to eight years of follow-up post-gene therapy.

Story continues

Similar clinical results were seen in the integrated analysis of 17 patients and overall survival was 94% (16/17). One death occurred among the EAP cohort that was considered by the investigator to be unrelated to OTL-103.

Across the original and integrated data sets, there were no adverse events considered to be related to OTL-103, including no evidence of oncogenesis, replication competent lentivirus or abnormal clonal proliferation. Clinical benefit was also attained in patients older than five years of age, a group considered at higher risk when treated with allogeneic hematopoietic stem cell transplantation (HSCT).

Lentiviral Gene Therapy with Autologous Hematopoietic Stem and Progenitor Cells (HSPCs) for the Treatment of Severe Combined Immune Deficiency Due to Adenosine Deaminase Deficiency (ADA-SCID): Results in an Expanded CohortPublication Number: 3345Session: 801. Gene Therapy and Transfer: Poster IIDate and time: Sunday, December 8, 6:00-8:00pm ET

This presentation details the safety and efficacy of OTL-101 in 30 individuals with ADA-SCID, treated with either fresh (n=20) or cryopreserved (n=10) formulations. Patients were followed for a median of 24 months (range 12-24 months overall and 12-18 months for patients treated with the cryopreserved formulation), and results were compared with a historical cohort of 26 ADA-SCID patients treated with allogeneic hematopoietic stem cell transplantation (HSCT), including HSCT both with, and without, a matched related donor.

Results showed engraftment of genetically modified hematopoietic stem cells in 29 of 30 OTL-101 patients by six to eight months, which persisted through follow-up in both studies. Analysis of both the vector copy number in granulocytes (a measure of engraftment) and T-cell reconstitution (a relevant measure of immune recovery) showed consistent performance across the fresh and cryopreserved-treated patients.

In the OTL-101 treated patients, overall survival was 30/30 (100%) and event-free survival was 29/30 (97%). One of the 30 patients restarted treatment with enzyme replacement therapy (ERT) and subsequently withdrew from the study and received a rescue HSCT. In the historical control population, 42% of HSCT patients required re-initiation of ERT, rescue HSCT or other intervention, or died. As expected, there was no incidence of graft versus host disease in the OTL-101 group, compared with eight patients who received HSCT.

Eighteen of 20 patients (90%) in the fresh formulation study stopped immunoglobin replacement therapy (IgRT) after two years, compared to 52% of HSCT patients. Of the seven patients treated with the cryopreserved formulation with 18 months of follow-up, five had discontinued IgRT (71%), which is comparable to the 18-month data for patients treated with the fresh formulation.

Oral Presentation Details

Extensive Metabolic Correction of Hurler Disease by Hematopoietic Stem Cell-Based Gene Therapy: Preliminary Results from a Phase I/II TrialPublication Number: 607Session: 801. Gene Therapy and Transfer: Gene Therapies for Non-Malignant DisordersDate and time:Monday, December 9, 7:00am ET

Investigators will present updated analyses from the ongoing proof-of-concept trial of OTL-203 for mucopolysaccharidosis type I (MPS-I).

About ADA-SCID and OTL-101Severe combined immune deficiency due to adenosine deaminase deficiency (ADA-SCID) is a rare, life-threatening, inherited disease of the immune system caused by mutations in the ADA gene resulting in a lack of, or minimal, immune system development.1-4The first symptoms of ADA-SCID typically manifest during infancy with recurrent severe bacterial, viral and fungal infections and overall failure to thrive, and without treatment the condition can be fatal within the first two years of life. The incidence of ADA-SCID is currently estimated to be one in 500,000 live births inthe United Statesand between one in 200,000 and one in 1 million inEurope.3OTL-101 is an autologous,ex vivo,hematopoietic stem cell-based gene therapy for the treatment of patients diagnosed with ADA-SCID being investigated in multiple clinical trials inthe United StatesandEurope, including a registrational trial at theUniversity of California, Los Angeles(UCLA). OTL-101 has received orphan drug designation from theU.S. Food and Drug Administration(FDA) and the European Medicines Agency (EMA) for the treatment of ADA-SCID, and Breakthrough Therapy Designation from theFDA.

About WAS and OTL-103Wiskott-Aldrich Syndrome (WAS) is a life-threatening inherited immune disorder characterized by autoimmunity and abnormal platelet function and manifests with recurrent, severe infections and severe bleeding episodes, which are the leading causes of death in this disease. Without treatment, the median survival for WAS patients is 14 years of age. Treatment with stem cell transplant carries significant risk of mortality and morbidities. OTL-103 is anex vivo,autologous, hematopoietic stem cell-based gene therapy developed for the treatment of WAS that Orchard acquired from GSK in April 2018 and has been developed at theSan Raffaele-Telethon Institute for Gene Therapy(SR-Tiget) inMilan, Italy. The global incidence of WAS is estimated to be about 100-260 births per year, with a global prevalence of 2,900-4,700 patients.

About MPS-I and OTL-203Mucopolysaccharidosis type I (MPS-I) is a rare inherited neurometabolic disease caused by a deficiency of the IDUA (alpha-L-iduronidase) lysosomal enzyme required to break down glycosaminoglycans (also known as GAGs or mucopolysaccharides). The accumulation of GAGs across multiple organ systems results in the symptoms of MPS-I including neurocognitive impairment, skeletal deformity, loss of vision and hearing, hydrocephalus, and cardiovascular and pulmonary complications. MPS-I occurs at an overall estimated frequency of one in every 100,000 live births.5There are three subtypes of MPS-I; approximately 60 percent of MPS-I patients have the severe Hurler subtype and, when untreated, these patients rarely live past the age of 10.IdTreatment options for MPS-I include hematopoietic stem cell transplant and chronic enzyme replacement therapy, both of which have significant limitations. Though early intervention with enzyme replacement therapy has been shown to delay or prevent some clinical features of the condition, it has only limited efficacy on neurological symptoms. OTL-203 is anex vivo, autologous, hematopoietic stem cell-based gene therapy being studied for the treatment of MPS-I. Orchard was granted an exclusive worldwide license to intellectual property rights to research, develop, manufacture and commercialize the gene therapy program for the treatment of MPS-I developed by theSan Raffaele-Telethon Institute for Gene TherapyinMilan, Italy.

About Orchard Orchard Therapeuticsis a fully integrated commercial-stage biopharmaceutical company dedicated to transforming the lives of patients with serious and life-threatening rare diseases through innovative gene therapies.

Orchards portfolio ofex vivo, autologous, hematopoietic stem cell (HSC) based gene therapies includes Strimvelis, a gammaretroviral vector-based gene therapy and the first such treatment approved by theEuropean Medicines Agencyfor severe combined immune deficiency due to adenosine deaminase deficiency (ADA-SCID). Additional programs for neurometabolic disorders, primary immune deficiencies and hemoglobinopathies are all based on lentiviral vector-based gene modification of autologous HSCs and include three advanced registrational studies for metachromatic leukodystrophy (MLD), ADA-SCID and Wiskott-Aldrich syndrome (WAS), clinical programs for X-linked chronic granulomatous disease (X-CGD), transfusion-dependent beta-thalassemia (TDT) and mucopolysaccharidosis type I (MPS-I), as well as an extensive preclinical pipeline. Strimvelis, as well as the programs in MLD, WAS and TDT were acquired by Orchard from GSK inApril 2018and originated from a pioneering collaboration between GSK and theSan Raffaele Telethon Institute for Gene TherapyinMilan, Italyinitiated in 2010.

Orchard currently has offices in the UK and the U.S., including London, San Francisco and Boston.

Forward-Looking StatementsThis press release contains certain forward-looking statements about Orchards strategy, future plans and prospects, which are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements may be identified by words such as anticipates, believes, expects, intends, projects, and future or similar expressions that are intended to identify forward-looking statements.Forward-looking statements include express or implied statements relating to, among other things, the therapeutic potential of Orchards product candidates, including the product candidate or candidates referred to in this release, Orchards expectations regarding the timing of regulatory submissions for approval of its product candidates, including the product candidate or candidates referred to in this release, the timing of announcement of clinical data for its product candidates and the likelihood that such data will be positive and support further clinical development and regulatory approval of these product candidates, including any cryopreserved formulations of such product candidates, and the likelihood of approval of such product candidates by the applicable regulatory authorities. These statements are neither promises nor guarantees and are subject to a variety of risks and uncertainties, many of which are beyond Orchards control, which could cause actual results to differ materially from those contemplated in these forward-looking statements. In particular, the risks and uncertainties include, without limitation: the risk that any one or more of Orchards product candidates, including the product candidate or candidates referred to in this release, will not be successfully developed or commercialized, the risk of cessation or delay of any of Orchards ongoing or planned clinical trials, the risk that prior results, such as signals of safety, activity or durability of effect, observed from preclinical studies or clinical trials will not be replicated or will not continue in ongoing or future studies or trials involving Orchards product candidates, the delay of any of Orchards regulatory submissions, the failure to obtain marketing approval from the applicable regulatory authorities for any of Orchards product candidates, the receipt of restricted marketing approvals, and the risk of delays in Orchards ability to commercialize its product candidates, if approved.Given these uncertainties, the reader is advised not to place any undue reliance on such forward-looking statements.

Other risks and uncertainties faced by Orchard include those identified under the heading "Risk Factors" in Orchards annual report on Form 20-F for the year endedDecember 31, 2018as filed with theU.S. Securities and Exchange Commission(SEC) onMarch 22, 2019, as well as subsequent filings and reports filed with theSEC. The forward-looking statements contained in this press release reflect Orchards views as of the date hereof, and Orchard does not assume and specifically disclaims any obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as may be required by law.

1Orphanet. SCID due to ADA deficiency.2Whitmore KV, Gaspar HB. Front Immunol. 2016;7:314.3Kwan A, et al. JAMA. 2014;312:729-738.4Sauer AV, et al. Front Immunol. 2012;3:265. 5Beck et al. The Natural History of MPS I: Global Perspectives from the MPS I Registry. Genetics in Medicine 2014, 16(10), 759.

Contacts

InvestorsRenee LeckDirector, Investor Relations+1 862-242-0764Renee.Leck@orchard-tx.com

MediaMolly CameronManager, Corporate Communications+1 978-339-3378media@orchard-tx.com

Original post:
Orchard Therapeutics to Present New Registrational Data of Investigational Gene Therapies at the 61st American Society of Hematology Annual Meeting -...

Recommendation and review posted by Bethany Smith

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Original post:
Insightful Growth of Cancer Gene Therapy Market 2019- 2025| Research Methodologies Offers High Business Outlook growth - Daily Watch Reports

Recommendation and review posted by Bethany Smith

SAN DIEGO Nov 10, 2019 (Thomson StreetEvents) -- Edited Transcript of Otonomy Inc earnings conference call or presentation Tuesday, November 5, 2019 at 9:30:00pm GMT

Otonomy, Inc. - President, CEO & Director

* Paul E. Cayer

Otonomy, Inc. - Chief Financial & Business Officer

H.C. Wainwright & Co, LLC, Research Division - MD & Senior Healthcare Analyst

* Tara A. Bancroft

Good afternoon, ladies and gentlemen, and welcome to the Q3 2019 Otonomy, Inc. Earnings Conference Call.

I would now like to turn the conference over to your host, Mr. Stephen Jasper from Westwicke Partners, please go ahead.

Good afternoon and welcome to Otonomy's Third Quarter 2019 Financial Results and Business Update Conference Call. Joining me on the call from Otonomy are Dr. David Weber, President and Chief Executive Officer; and Paul Cayer, Chief Financial and Business Officer.

Before I turn the call over to Dr. Weber, I would like to remind you that today's call will include forward-looking statements based on current expectations. Such statements represent management's judgment as of today and may involve risks and uncertainties that could cause actual results to differ materially from expected results. Such statements include but are not limited to timing of results, patient's recruitment and enrollment plans for and designing conduct of the Phase III clinical trial for OTIVIDEX, the Phase I/II clinical trial for OTO-313 and the Phase I/II clinical trial for OTO-413. Expectations regarding preclinical development, including but not limited to the potential benefits of activities under the collaboration agreement between AGTC and Otonomy, expectations regarding the benefits and value potential of Otonomy's programs, expectations regarding funding of clinical development program advancement and company operations into 2021 and expectations regarding financial guidance, including operating expenses for 2019 and 2020.

Please refer to Otonomy's filings with the SEC, which are available from the SEC or on the Otonomy website for information concerning the risk factors that could affect the company.

I will now turn the call over to Dave Weber, President and CEO of Otonomy.

David Allen Weber, Otonomy, Inc. - President, CEO & Director [3]

Thank you, Stephen. Good afternoon, everyone and thank you for joining us on this call to discuss Otonomy's business updates and third quarter 2019 financial results.

We made significant progress in the third quarter toward our goal of reporting results from 3 clinical trials in 2020. Most importantly, we advanced enrollment in the Phase III trial of OTIVIDEX in Mnire's disease with all participating countries actively enrolling patients. For OTO-313, we successfully completed the initial safety cohort and initiated enrollment in the exploratory efficacy cohort of the Phase I/II trial in tinnitus patients.

And finally, we received FDA clearance to initiate the Phase I/II trial of OTO-413 in patients with hearing loss, which was an important milestone for this innovative program. The successful completion of these trials is our highest priority and greatest focus. In parallel, we continue to advance multiple preclinical programs addressing important unmet needs in neurotology, including a recently announced gene therapy collaboration targeting the most common cause of congenital hearing loss. I'll provide an update on our clinical programs and an overview of this collaboration in my brief comments.

I will also highlight the financial results from the quarter and lower spending guidance for the year. It is important to note that our existing capital will fund the company through the 3 clinical catalysts next year and into 2021. I plan to keep my remarks brief, and we can then open up the call for any questions.

Beginning with the OTIVIDEX Phase III trial in Mnire's disease, we updated the timing in our earnings release today. We expect results in the third quarter of 2020, which is a slight adjustment from our original timing of data late in the first half of 2020. We are pleased with the progress we have made on enrollment of the trial and the timing reflects the care and methodical approach we've taken in site selection and patient recruitment. We have 60 sites enrolling patients across all participating countries. As a reminder, the conduct and design of this study is based on the successful AVERTS-2 trial, and we plan to enroll approximately 160 patients in the United States and Europe.

The next product candidate in our clinical development pipeline is OTO-313, a sustained exposure formulation of the NMDA receptor antagonist gacyclidine in development for the treatment of tinnitus. We have successfully completed the initial safety cohort of the Phase I/II trial and are now enrolling patients in the second cohort, which is the exploratory efficacy part of the study.

Cohort 2 will enroll approximately 50 patients with persistent tinnitus who will be assessed across a number of endpoints, including the Tinnitus Functional Index or TFI, which is a validated clinical instrument that measures tinnitus severity and its impact on patients. Importantly for entry into cohort 2, patients must have a TFI score that exceeds a specified level to ensure adequate disease severity at baseline.

Patients in cohort 2 receive a single intratympanic injection of OTO-313 or placebo, randomized 1:1 and are followed for 2 months. We expect results in the second quarter of 2020.

Our third clinical stage program is OTO-413, a sustained exposure formulation of brain-derived neurotrophic factor or BDNF that we are developing for the repair of cochlear synaptopathy. Recent research has identified damage to synaptic connections as the underlying pathology in noise and age-related hearing loss that manifests as speech-in-noise hearing difficulty. Neurotrophic factors, including BDNF have potential therapeutic effects in the cochlea by promoting the survival of spiral ganglion neurons, increasing neurite outgrowth and reconnecting neurons with cochlea hair cells after damage.

As I mentioned in my opening comments, we have recently initiated a Phase I/II clinical trial and expect to have results in the second half of 2020. This is an ascending dose safety and exploratory efficacy study that will enroll up to 40 patients with speech-in-noise hearing difficulty. Patients will receive a single intratympanic injection of OTO-413 or placebo and be followed for 3 months. A number of efficacy endpoints will be evaluated, including electrophysiological measurements of hearing function and speech-in-noise hearing test.

We are excited to be the first company conducting a clinical trial of a therapeutic for synaptopathy, which has been an active area of neurotology research during the past decade. We believe that OTO-413 will not only provide clinical benefits for the many patients with impaired hearing in a noisy environment but more generally for the large population of patients with loss of hearing function due to aging or noise exposure.

In addition to OTO-413 for synaptopathy, we have -- I have also have ongoing preclinical development for OTO-6XX, which is our hair cell regeneration program to treat patients with severe hearing loss. Cochlea hair cells play a central role in hearing by converting sound waves into electrical signals that are then transmitted to the brain via auditory nerves. It is well-established that damage to hair cells through aging, excessive noise or exposure to ototoxic chemicals leads to hearing loss. Unfortunately for humans, we cannot naturally regenerate hair cells like non-mammalian species, such as birds and chickens. However, it is possible to activate regenerative path waves via drug intervention, thereby providing an approach to treat this pathology.

We have demonstrated hair cell regeneration in a nonclinical proof-of-concept model using a class of small molecules and have identified a candidate for further development. Between our OTO-413 and OTO-6XX programs, we addressed 2 of the critical pathologies believed to underlie acquired forms of hearing loss, and with our recently announced strategic collaboration with AGTC, we extend the reach of our pipeline to now also include genetic hearing loss.

The goal of this program is to develop an AAV based gene therapy to restore hearing in patients with sensorineural hearing loss caused by mutation in the gap junction protein beta 2 gene, otherwise known as GJB2. Mutations in this gene are the most common cause of congenital hearing loss, accounting for approximately 30% of all genetic hearing loss cases. Patients born with this mutation can have severe to profound deafness in both ears as identified in screening test now performed routinely in newborns.

The collaboration leverages the expertise, technology and capabilities of each partner, allowing each of us to do what we do best. In addition, the structure is highly cost efficient by utilizing each partner's existing resources, sharing the workload and splitting the cost. We look forward to sharing more information about this program in the future.

Taken together, our clinical and preclinical programs comprise the broadest and most advanced product pipeline in the emerging field of neurotology, and we have the cash on hand to support the rich advancement. As you all know from our financial statements in the earnings release and 10-Q, we finished the third quarter with $68 million in cash and short-term investments. We continue to manage our spending levels carefully and are in fact lowering our non-GAAP operating expense guidance by $5 million for full year 2019.

We also expect as we previously stated that 2020 operating expenses will be lower than 2019 and that our current capital will fund the company's operation through the 3 clinical trial readouts and into 2021.

In summary, we have positioned Otonomy for a breakout year in 2020. The OTIVIDEX Phase III trial, OTO-313 Phase I/II trial and OTO-413 Phase I/II trial provide multiple value creation catalysts for the company, and we are laser focused on their successful completion. We look forward to bringing this message to investors through an expanded set of outreach activities beginning this quarter and continuing into 2020.

To this point, we will be attending the Piper Jaffray Health Care Conference on December 3 in New York and participating in a hearing loss panel at investor meetings at the Evercore ISI Conference in Boston on December 4.

Operator, we are now ready for questions.

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Questions and Answers

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Operator [1]

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(Operator Instructions) Your first question comes from line of Tyler Van Buren from Piper Jaffray.

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Tara A. Bancroft, Piper Jaffray Companies, Research Division - Research Analyst [2]

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This is Tara on for Tyler. So in thinking ahead to the OTIVIDEX Phase III readout, can you kind of set the bar for us as far as expectations and what are meaningful changes in these patients? Should we expect a similar vertigo day benefit like we saw on AVERTS-2? And what about percent of vertigo decrease?

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David Allen Weber, Otonomy, Inc. - President, CEO & Director [3]

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Thank you, Tara. Yes, what you can expect is similar to what we reported for AVERTS-2 and the Phase IIb trial that's in our corporate deck. We continue to focus in the primary outcome, is on definitive vertigo days, and change in definitive vertigo days. And importantly, achieving the p value that we've discussed with the agency. We have, as you know, one successful trial with AVERTS-2. So it really is duplicating that trial to provide two separate successful Phase III trials for submission of the NDA. So the data would be consistent with what we've shown previously, the trail design is the same, the endpoints are the same, and the data that we would expect to present both to investors and to the FDA are the same as AVERTS-2.

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Tara A. Bancroft, Piper Jaffray Companies, Research Division - Research Analyst [4]

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Okay. Can I ask then similarly for the Phase II and 313. Can you explain more about how the TFI questionnaire will maybe inform future registration endpoints and approval? Like what specifics are you looking for regarding changes in hearing quality there?

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David Allen Weber, Otonomy, Inc. - President, CEO & Director [5]

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Yes, thank you. So the TFI is a validated -- considered a validated instrument. It was actually developed by a consortium of researchers and it plays out in that testing, which is represented by 25 questions that cover things like intrusiveness of the tinnitus, a sense of control that the patients have, their cognition, their ability to sleep, their auditory function and more quality of life like their emotional state is in that TFI through those 25 questions. It's established through the validation of that work of what represents generally a meaningful change is 13 points and based on the work that has been done there, and we also understand the classification of patients. So patients that typically are less than 25 on the TFI score are considered mild, whereas 25 to 50 are moderate, and higher than that are 50 and severe. Generally, physicians consider any patient that has 25 and higher to be patients in need of treatment. That will be our primary outcome because we do believe that, as I've said, a very measurable and validated instrument, we are also assessing separately other types of rating scales, such as tentative loudness and annoyance and then also a patient global impression of change, basically where we are asking the patients of how they perceive their tinnitus since the beginning of the study to understand their overall perception of change.

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Tara A. Bancroft, Piper Jaffray Companies, Research Division - Research Analyst [6]

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Yes, that's super helpful. If I can ask one more question about the gene therapy pipeline?

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David Allen Weber, Otonomy, Inc. - President, CEO & Director [7]

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Sure.

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Tara A. Bancroft, Piper Jaffray Companies, Research Division - Research Analyst [8]

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Okay. So you mentioned in the press release regarding the AGTC collaboration that you are targeting the patients with GJB2 mutation that has been identified from the routine hearing screens in newborns. So I'm assuming your target population will include like newborns and infants with hearing loss due to that mutation, but we also know that the same genes that are responsible for homogenic deafness may also contribute to environmental hearing loss due to like drug exposure, noise and aging. So will those patient also be included in your target population for this gene therapy?

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David Allen Weber, Otonomy, Inc. - President, CEO & Director [9]

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No, not initially at least. This will be focused more on the pediatric population because they are the most severely threatened with hearing loss and progressive hearing loss. So typically, this can be picked up on newborn screening and patients will continue to progress from there. So it's very important to catch them at an early stage and so that will be our initial focus for the gene therapy.

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Operator [10]

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Your next question comes from the line of Oren Livnat from H.C. Wainwright.

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Oren Gabriel Livnat, H.C. Wainwright & Co, LLC, Research Division - MD & Senior Healthcare Analyst [11]

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I have a few. With the OTIVIDEX Phase III that's enrolling little bit slower than we had modeled, can you just remind us what you're doing differently in this trial maybe from AVERTS-1 such that a more deliberate enrollment speed is potentially an indicator of improved likelihood of success? And I have a couple of others.

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David Allen Weber, Otonomy, Inc. - President, CEO & Director [12]

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Yes, thanks Oren. I'm taking one at a time, that's fine. So great question, and that actually is the key, as we are very focused on being very careful here, and very deliberate in our enrollment. We think that its very key to the success of the trial based on our learnings from AVERTS-1. As we've discussed previously, the real learnings was around AVERTS-1 so as to control the placebo response and manage the patient expectation bias. And that was really kind of focused on 3 major areas and one of those was careful site selection. So we have gone through, obviously, now we have 60 centers enrolling across all participating countries, that took time. We needed to make sure we got it right, the right clinical centers, and right investigators, and we feel very confident in the group that we've assembled that are now all participating and enrolling. So that was the first.

From there it's really careful selection of the patients. In this case, there are no -- there is no advertising going on direct to patients, unlike with the AVERTS-1, where there were investigators who were reaching out in the general population. This is all very controlled and targeted patient enrollment and so it's very -- in that regard, it does take time and it is important that investigators are identifying these patients and carefully selecting them.

So we're not putting pressure on the investigators in terms of trying to advertise or increase the enrollment, we want to be very deliberate in that patient population. So we think that the few weeks to few months that we're talking about here in extending is just a safeguard to make sure we get -- ultimately are able to deliver a successful trial as well step.

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Oren Gabriel Livnat, H.C. Wainwright & Co, LLC, Research Division - MD & Senior Healthcare Analyst [13]

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All right. And just a follow-up on the tinnitus question. You mentioned that the TFI improvement of more than 13 is believed to be clinically meaningful. Is that what you're targeting? Are you expecting any statistical significance in this small study? Or are you just looking for any signal? And if so, if you do see a signal, what do you think the next steps are? Should we expect another Phase II before jumping into the more advanced?

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David Allen Weber, Otonomy, Inc. - President, CEO & Director [14]

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Well, let's take that one at a time there. In terms of Phase II to Phase III, but I think first of all, this is not size for power. It is the exploratory efficacy trial because it is the first of its kind. We have no prior clinical data to base sizing and powering on, it is what we consider exploratory and so we are looking for signals through these different endpoints, including the TFI. The TFI, as I mentioned, when the instrument was developed and validated by the consortium, they identified 13 point difference as being clinically meaningful, but I should point out that's in the absence of a therapeutic that really is through other types of both behavioral treatment of tinnitus and even some devices that have been tried in tinnitus. So I think it'll be up to -- as we look at the data to understand what do we see with the TFI but clearly that gives us the benchmark at least based on some prior work, even if it was in a pharmaceutical treatment. I think clearly the patient global impression of change and the other endpoints that I mentioned of loudness perception and annoyance perception are also very key to these patients given that it is the loudness and that annoyance that is the most debilitating for them in this disorder. So that's how we look at the study, and we would look to utilize the Phase I/II trial for then powering the future study. With regards to Phase II, additional Phase II, Phase III, I think that is something that we will consider based on that data.

One of the things -- so clearly with very strong signals, the opportunity is to do what I will call a larger Phase II type Phase III trial or obviously based on the data if we had confidence to go into a Phase III from there, I think one of the things that we also will want to look at, however, in addition to this patient population we are currently studying is to look at bilateral patients as well. So it's something that we're interested in because there are many patients that have bilateral tinnitus and that potentially be eligible, but that is something we want to look at probably in a separate study before including those patients.

Currently, we're focused on unilateral patients and that is because there has been concern clinically and working with our KOLs of whether patients can really tell the difference if they have bilateral, can they really talk and understand the difference in their tinnitus between one ear and the other or is there a confusion there because of both ears. And so that's why we're being very careful here using unilateral patients, but I think one of the things you can probably expect from us in future work is to also include some bilateral patients to look at the ability to detect changes in those patients as well. I'd say detect because I think that's the key. We and our KOLs all believe that showing an effect in a single ear will equate to treatment of both ears, ultimately that you'd be able to treat both ears mechanistically. It's more ability to differentiate the signaling for their patient reported outcome here. Can they report the outcome very carefully between one ear versus the other is something I think we have to look at clinically if that makes sense.

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Oren Gabriel Livnat, H.C. Wainwright & Co, LLC, Research Division - MD & Senior Healthcare Analyst [15]

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All right. And at the risk of abusing my time, it was lost to me that there was a recent IPO of Frequency Therapeutics and other therapeutic company working I think on hair cell regeneration, and I'm just curious, obviously you can't speak too much to what they're doing but maybe you can just highlight how similar or different your approaches are? And if you think that there will be any key learnings from what they are doing?

--------------------------------------------------------------------------------

Read this article:
Edited Transcript of OTIC earnings conference call or presentation 5-Nov-19 9:30pm GMT - Yahoo Finance

Recommendation and review posted by Bethany Smith

Editor's note: The following is Patch Field Editor Russ Crespolini's, hopefully, weekly column. It is reflective of his opinion alone.

"One slip, and you're toast."

A doctor said this to describe a test my endocrinologist said I needed to get more answers about my brain tumor.

For those of you who have been following along at home, I have been documenting in my column my ongoing medical issue that included a myriad of tests all leading to the conclusion that I have a pair of tumors. One in my brain, attached to my pituitary gland and one somewhere else in the body, most likely in my lungs.

It, or they, are causing a biochemical imbalance known as cushing syndrome or disease.

The next step for me is an inferior petrosal sinus sampling (IPSS). The IPSS is an invasive procedure in which adrenocorticotropic hormone (ACTH) levels are sampled from the veins that drain the pituitary gland. This is done through what is apparently a really painful catheterization process. So, good times. They send the probes up into the brain through the groin to grab the samples.

They then compare the ACTH levels in the peripheral blood to determine whether the pituitary tumor is causing my issues. If it is NOT the culprit and it is an incidental finding, then we begin a hunt for an ectopic (mostly benign) tumor...or a malignancy.

In the interim, I went to my primary care physician for a physical and they suggested that I get a second opinion. So I went to see a second endocrinologist who reviewed my results, and described the IPSS test to me and followed it up by telling me that the test is dangerous because one slip and I am toast.

As in dead.

Cool.

He said it with no malice, he was just trying to make a point of the seriousness of what I was facing. Which I appreciate. But what he didn't appreciate was one of the things that had kept me sane over the past few weeks was the thought I was heading towards some kind of consensus and some kind of a resolution. Having that questioned left me feeling more lost and hopeless than I can remember feeling in a very long time.

Because now I was being torn between two completely different schools of thought. One was saying I needed to undergo this test, which came with risks and the other was that I just needed to keep repeating more conservatives tests every month.

In neither plan, was a path to treating my symptoms.

So I spent the weekend trying to figure out what to do next. My first endocrinologist was trying to find me a place to get the IPSS and the second doctor had me second-guessing the wisdom of that decision. And not matter how hard I tried to rationalize and explain it away, "one slip and you're toast" still kept repeating over in my internal monologue.

And then I made an accidental discovery. One of my earlier columns, a couple in fact, had been picked up by the an organization called the Pituitary Network Association. The PNA is an international non-profit organization for patients with pituitary tumors and disorders, their families, loved ones, and the physicians and health care providers who treat them.

PNA was founded in 1992 by a group of acromegalic patients in order to communicate and share their experiences and concerns. PNA has rapidly grown to become the world's largest and fastest growing patient advocacy organization devoted to the treatment and cure of pituitary disorders. This was a nice discovery because my thoughts were being shared with other people who were going through something similar. It also showed me the power of this Patch network. But I also discovered that their network included experts.

I reached out to them and immediately got a response back that walked me through why I needed to find a specialist in this area and then gave me the name of one at Sloan Kettering in New York. The next morning, my doctor messaged me to tell me she found a specialist that can help me with this test and what comes after.

It was the same name.

So now I know where I am headed next. Sure, one slip and I might be toast. But I need to trust that these specialists won't slip.

Russ Crespolini is a Field Editor for Patch Media, adjunct professor and college newspaper advisor. His columns have won awards from the National Newspaper Association and the New Jersey Press Association.

He writes them in hopes of connecting with readers and engaging with them. And because it is cheaper than therapy. He can be reached at russ.crespolini@patch.com

More:
Russs Ravings: One Slip, And Youre Toast - Westfield, NJ Patch

Recommendation and review posted by Bethany Smith

Feeling a little heated? Its typically nothing to worry about especially if youre sick. However, other issues can cause your temperature to rise.

A normal body temp is typically around 98.6 degrees Fahrenheit (37 degrees Celsius) but can vary slightly for each individual, and even fluctuate depending on the time of day.

It can be lower in the morning and higher in the late afternoon and evening, said Michael Hall, a physician based in Miami. But when your temperature gets to 100.4 degrees Fahrenheit or higher, and lasts more than a few hours, youre getting into fever territory something that can be caused by a number of conditions.

Most of my patients understand that a fever is a common symptom of cold and flu, said Christopher Dietz, an area medical director at MedExpress Urgent Care. However, what some people might not realize is that a fever isnt always just a sign that youre coming down with something.

Heres what could also be at play, according to medical experts:

PhotoAlto/Frederic Cirou via Getty Images

Infections

If you are looking for the reason behind your elevated temperature, start here. Experts note that infections are commonly associated with a fever.

When the immune system detects a threat such as bacteria or virus, a substance known as pyrogens is released into the bloodstream to reach the hypothalamus, which regulates body temperature, said Diana Gall, a general practitioner with Doctor4U in the U.K. When the hypothalamus detects pyrogens, it raises body temperature and causes fever in an attempt to kill off bacteria and viruses.

She noted that a high fever is one of the ways your body is responding and fighting the infection but a body temperature that is too high can also be dangerous.

If the fever is persistent and isnt coming down with home remedies, you should see a doctor, particularly if the fever is accompanied by a severe headache, difficulty breathing, blood in your urine or stool, redness of the skin or rash, or vomiting, etc. The infection may be serious and your body temperature may not reduce without medical treatment, she said.

Overexerting yourself outdoors

Hot outdoor temperatures and internal heat generation from exercise and mechanical movement of the body can heat you up, said Phil Mitchell, national medical director at DispatchHealth.

Under normal circumstances, your body will function well enough to cool you down through sweating and dilation of blood vessels. But if these basic systems are overcome and you cannot cool down, your body will continue to increase in temperature.

This typically does not happen from exercise alone, but exertion in a hot environment can cause this under the right circumstances, Mitchell said. He noted that you should immediately remove yourself from the heat and try other methods to cool your body down if this is the case.

Heatstroke can occur if heat exhaustion is not treated promptly. You need immediate medical attention if you become confused, lose consciousness or if you have an elevated temperature in this situation, said Steven Reisman, a cardiologist and director of New York Cardiac Diagnostic Center.

Vaccinations

Vaccines to prevent a bacterial or viral infection prepare your body to come in contact with that infection later, said Erik A. Larsen, assistant director of EMS and emergency preparedness at White Plains Hospital in New Yorks Westchester County.

So when you get the vaccine, your bodys immune response is stimulated and the body says, Whoa, what is this? It then mounts a fever, he said.

Larsen added that when you get a vaccine, youre not really invaded by an active infection, but it tips your body off that sometime in the future you may come across this.

tommaso79 via Getty Images

Alcohol withdrawal

Low-grade fevers can occur during the first few days of alcohol withdrawal as the central nervous system, which has been suppressed by alcohol, readjusts, said Holly Phillips, a board-certified general internist in New York and a medical expert for RxSaver.

Alcohol withdrawal also causes tremors, which can affect your heat, Larsen said.

The body is reacting to the loss of not receiving alcohol, which creates muscle contractions. This makes the body shake like a tremor, and it raises the bodys temperature, he said.

Inflammatory conditions

Certain inflammatory conditions, like rheumatoid arthritis and lupus, can cause fevers, said Lisa Alex, a physician at Medical Offices of Manhattan. This also occurs because the body is producing pyrogens, which raises your temperature. So if you have underlying inflammatory conditions and have a flare-up of any sort, the result may be a fever.

Certain medications

Many medications like antibiotics [and] antimalarials can also cause drug-induced fever. Anticonvulsants and some herbal medications can also do the trick, said Soma Mandal, a New Jersey-based physician.

You should monitor your bodys reaction when taking any new medication.

Look for a fever that starts a week after starting a new medication and goes away once you stop taking the drug, said J. David Gatz, an assistant medical director of the emergency department at the University of Maryland Medical Center.

Blood clots

Blood clots are an under-discussed source of fevers, according to Nate Favini, medical lead at preventative primary care service Forward.

If youre experiencing fever along with pain, swelling and redness in your leg or shortness of breath, that could be a sign of a blood clot, he said.

Endometriosis

While rare, several of my patients have had fever and flu-like symptoms every month at the start of their periods, likely due to severe pelvic inflammation caused by chronic bleeding into the stomach from wide-spread endometriosis, said Kenneth Ward, director of Predictive Laboratories and a scientific advisor for Predictive Technology Group in Salt Lake City.

If you experience this, Ward suggested making an appointment with your physician to get screened for the condition. Additional symptoms can include debilitating cramps during your period or pain with sex, urination or bowel movements.

Recent surgery

If youve recently gone under the knife, especially for a chest or abdominal procedure, you may experience an elevation in temperature in the days to follow, known as postoperative fever.

The body produces inflammatory proteins in response to the trauma surgery ... This causes fever as a reaction for the first few days post-operatively, said Laurence Gerlis, CEO and lead clinician at SameDayDoctor in London.

Studies show that this is a common side effect from surgeries, with up to 90% of patients reporting elevated temperature after the fact. In most cases, this resolves on its own.

Fevers could also be a side effect to anesthesia, although thats more rare, said Erin Nance, an orthopedic surgeon and hand and upper extremity specialist in New York. This is called malignant hyperthermia.

When this happens, according to Nance, its because of your bodys response to common anesthetic agents used during surgery. This can present as a high fever, muscle rigidity and rapid heart rate. The condition can be fatal and is treated with a medication called Dantrolene and ice packs.

If you have a family history of malignant hyperthermia, it is critical to tell your anesthesiologist before proceeding with surgery, she said.

STIs

Rina Allawh, a board-certified dermatologist with Montgomery Dermatology LLC in Pennsylvania, said that certain sexually transmitted infections may cause a higher-than-normal temperature.

Initially, syphilis presents with a non-tender chancre (i.e. an ulcer). However, if left untreated, may result in high fevers, joint pain, lymph node enlargement and fatigue, he said.

Gonorrhea, if left untreated, may result in high fevers associated with a rash, Allawh said. To prevent life-threatening consequences, prompt recognition and treatment of the condition is essential, he said. Additionally, practicing safe sexual practices and sexual-transmitted disease testing is equally as important.

Traveling to another country

Depending on the area of travel, a rise in body temperature can often be attributed to tropical bacteria and protozoa not often seen in developed countries, said Amna Husain, a board certified pediatrician and founder of Pure Direct Pediatric in New Jersey.

For this reason, I recommend travelers consult with their physicians and refer to the (Centers for Disease Control) guidelines for safe food and water recommendations, she said.

laflor via Getty Images

Hormone disorders or changes

Hyperthyroidism itself does not cause a fever, but we can see a very dangerous and fatal disorder associated with a large influx of thyroid hormone into the body called a thyroid storm, which does have fever, along with rapid heartbeat, fluctuations in blood pressure, and tremors associated with it, Husain said.

She noted that thyroid storm can occur because of a major stressor such as trauma, heart attack, delivery of a baby or because of an infection in people with uncontrolled hyperthyroidism.

In rare cases, it can be caused by treatment of hyperthyroidism with radioactive iodine therapy for Graves disease, she said.

Hormonal changes that occur during menopause can also cause you to feel warmer than normal, which are typically known as hot flashes.

Cancer

Keep in mind that a fever isnt necessarily the first sign or a major sign of cancer. However, it could be one of many symptoms.

Several cancers are associated with fever, which are most commonly leukemias and lymphomas, although other cancers can cause this as well, said Timothy S. Pardee, chief medical officer at Rafael Pharmaceuticals and an oncologist and director of Leukemia Translational Research at Wake Forest Baptist Health in North Carolina.

Pardee said this occurs because, in some cases, cancer cells create an inflammatory response, which then causes the body to respond with a fever. In other cases, the cancer cells themselves secrete cytokines or substances in the body that can cause a fever. And, according to Pardee, cancers like leukemia can impair your bodys ability to fight off infections resulting in prolonged illnesses and fevers.

Additional symptoms to look for are unintended weight loss and drenching night sweats (where you have to change your shirt or sheets when you wake up). These symptoms should prompt a call to your doctor for further evaluation, he added.

When you should be concerned about a fever

A fever may not be cause for alarm, unless there are some specific situations, said David Cutler, a family medicine physician at Providence Saint Johns Health Center in Santa Monica, California.

He added that medication to reduce fever when there is an infection like a cold, flu or pneumonia can help minimize bothersome symptoms like headache, body aches and dehydration from excessive sweating.

But if the fever is caused by hormonal effects, such as menopausal hot flashes or muscular activity like strenuous exercise, these medications will not be effective. In these instances, Cutler said to use measures like cooling fans to lower the bodys temperature.

According to Amesh A. Adalja, senior scholar at Johns Hopkins Center for Health Security in Maryland, a person should be concerned for fever above 101 degrees Fahrenheit (38.3 degrees Celsius) when it is unremitting, when it is associated with other symptoms such as dehydration, extreme fatigue, shortness of breath and severe rash.

Additionally, someone suffering who has a compromised immune system should have a low threshold for seeking medical attention. Same goes for those who are pregnant, have heart or lung disease, or who are very young, he said.

That said, if youre ever concerned about a fever, its always worth it to call your doctor. Thats what theyre there for, after all.

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13 Unexpected Reasons Why You Might Have A Fever - HuffPost

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November is National Diabetes Month.

Diabetes is a serious condition that happens when your body cannot make enough of a hormone called insulin or cannot properly use the insulin it has. Insulin helps your body digest sugars that come from what you eat and drink. Without enough insulin, sugar builds up in your blood. Over time, having too much sugar or glucose in your blood can cause health problems.

More than 30.3 million Americans have diabetes, or about 9.4 percent of the population. About 1 in 4 people with diabetes do not know they have the disease. Another 84.1 million have pre-diabetes, a condition in which a persons blood sugar is high, but not high enough to trigger diabetes.

According to the National Heart, Lung and Blood Institute, adults with diabetes are nearly twice as likely to die from heart disease or stroke as people without diabetes. This is because over time, high blood glucose from diabetes can damage your blood vessels and the nerves that control your heart. The good news is that steps taken to manage diabetes can also help lower the risk of having heart disease or a stroke.

Manage your A1C, blood pressure and cholesterol levels. Ask your health care team what your goals should be.

Develop or maintain healthy lifestyle habits. Follow a healthy eating plan and make physical activity part of your routine. To reduce stress, try gardening, taking a walk or listening to favorite music.

Stop smoking or using other tobacco products. If you have diabetes and use tobacco, your risk of heart problems is even greater. Both tobacco use and diabetes narrow blood vessels, so your heart has to work harder.

Take medicine as directed. It is important that those with diabetes take any medicine as prescribed by a physician. Talk with your doctor if you have questions about your medicines and do not stop taking them without checking with your doctor first.

Skillet Zucchini and Mushrooms

In a large skillet, heat oil. Saut green pepper and onion. Add zucchini and cook, covered until tender. Add mushrooms and heat through.

Spoon into a 2-quart baking dish. Sprinkle with cheese. Cover and let stand for 5 minutes or until cheese is melted. Serve hot.

Makes 6 servings.

Nutrition information per serving: 70 calories, 4g fat, 60 mg sodium, 5 g carbohydrates 1 g fiber.

Cami Wells is an Extension Educator for Nebraska Extension in Hall County. Contact her at (308) 385-5088 or at cwells2@unl.edu. Visit the Hall County website at http://www.hall.unl.edu

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Nutrition Break: Take diabetes to heart | Advice - Grand Island Independent

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AUGUSTA As Maine compiles thousands of test results for soil and water contamination from an emerging class of toxic substances, consumers need look no further than their own homes for the most immediate and persistent exposure to these forever chemicals.

You wont find them listed on many labels, but the chemicals known as PFAS are literally everywhere in the modern household.

From the moment that we wake up in the morning to the moment we go to bed, we are encountering products that contain these chemicals, said Mike Schade, who tracks PFAS and other chemicals in consumer products for the nonprofit Safer Chemicals, Healthy Families Mind the Store campaign.

They are in cosmetics, shampoos and dental floss. Grabbing pizza, a burger or hot-and-ready dinner from a grocery store? Your food may come with a side order of PFAS-laced packaging.

From the Gore-Tex jacket or boots that keep you cozy in winter, to the stain-resistant couches and nonstick cookware that make life less messy, many of the modern products so common in American households are made with a diverse class of chemical now at the center of a growing health concern.

Studies have linked two specific types of the chemical PFOA and PFOS to cancer, kidney disease and other serious aliments. But while the chemical industry says newer varieties are safer, medical and public health experts say the developing science strongly suggests otherwise.

These are serious concerns about human health across the population, said Dr. Leonardo Trasande, director of New York University School of Medicines environmental pediatrics program and author of the book Sicker Fatter Poorer on hormone-disrupting chemicals. The reality is we always have gaps in our understanding, but at the same time there is enough data for us to take action.

WHAT ARE PFAS?

The term PFAS refers generally to a broad category of synthetic chemicals, per- and polyfluoroalkyl substances, the first of which were developed in the 1940s by companies such as Dupont and 3M.

The chemicals helped usher in a new era of consumer convenience, perhaps best illustrated by the revolutionary nonstick cookware coated by Teflon. Dubbed the slickest substance known to man, the key chemical component in Teflon, polytetrafluoroethylene or PTFE, and another chemical PFOA work by essentially preventing water and water-based substances from penetrating.

Those hydrophobic qualities have made the two chemicals and thousands of subsequent varieties extremely popular with manufacturers. In addition to creating nonstick surfaces on frying pans, types of PFAS make ski jackets water-repellent, help prevent spilled wine from immediately staining carpet or upholstery, and keep fast food wrappers or takeout containers from becoming soggy, greasy messes before you can finish the food.

But their function goes beyond consumer convenience. These chemicals also serve lifesaving roles.

A type of PFAS is the critical ingredient in the foam that airport and military firefighters use and are required by the Federal Aviation Administration to keep in supply to smother the ferociously hot fires created by burning jet fuel. Dozens of municipal fire departments in Maine as well as petroleum companies also keep PFAS foam on hand.

Fluoropolymers that are part of the PFAS family are also commonly used in lifesaving medical devices such as stents and pacemakers as well as some brands of dental floss.

EMERGING HEALTH CONCERNS

The complex and hardy chemical compounds that make PFAS so useful in consumer products also mean, however, that the chemicals do not easily break down in the environment or the body. Some compounds are believed to linger for decades centuries, even in soils and take years to exit the body after exposure, hence the nickname forever chemicals.

Concerns over the health effects of PFOA began surfacing in the 1980s among workers at a DuPont factory in West Virginia that produced Teflon products. But the company kept quiet about the growing evidence of PFOAs toxicity even after workers began being diagnosed with higher rates of leukemia and kidney cancer, as well as birth defects among the children of female workers.

Then in 1998, a neighboring farmer whose livestock were mysteriously dying sued the company in a landmark environmental lawsuit that showed DuPont knew for years about the health risks of the chemical. The farmer won that lawsuit, and a subsequent class-action case targeted the company for contaminating local drinking water.

Both PFOA and another toxic chemical cousin, PFOS, are no longer allowed to be manufactured in the U.S., Europe or Japan or used in products made here, although the compounds are still reportedly used in some foreign manufacturing.

The primary manufacturers of PFAS in the U.S. 3M, DuPont and its spinoff, Chemours are also facing dozens of lawsuits filed by plaintiffs claiming the chemicals have caused cancer or other health problems.

CHEMICAL WHACK-A-MOLE

Chemical companies have since switched to differently structured forms of PFAS (chemically speaking, six-chain compounds versus the eight-chain versions in PFOS and PFOA) that manufacturers say break down faster and avoid the toxicity problems of their predecessors.

The body of evidence reviewed shows they are not carcinogenic, they do not have developmental or reproductive concerns, the toxicity is much approved over the toxicity of PFOA and PFOS that weve spent a lot of time talking about, Renee Lani of FluoroCouncil told members of Maines PFAS task force in September. The dont bioaccumulate and an evidence analysis that was just published last year demonstrates that they are not an endocrine disruptor.

Environmental health groups and medical professionals strongly dispute industry claims that the next-generation, short-chain PFAS compounds are less problematic. And they point to the widespread development and use of new PFAS varieties as evidence of a federal regulatory system that they say is ill-equipped to keep up with industry and failing to protect public health.

This is chemical whack-a-mole in action, said Trasande, who is vice chairman for research in the NYU School of Medicines Pediatric Department. Just because the chemical has a short half-life, that helps if the exposure is a single point in time. But these are ongoing chemicals with consistent, ongoing exposure.

Trasande, who specializes in endocrine-disrupting chemicals in children, said evidence suggests that the newer, shorter-chain PFAS compounds stay in the body long enough to have health impacts. Laboratory animal studies have shown potential liver and kidney toxicity from some of the newer generation of compounds.

And he said there are serious gaps in our knowledge and toxicology in figuring out how PFAS interact with the hundreds of hormones in the body, particularly among children and adolescents.

There is what we know and what we havent studied, Trasande told Maine lawmakers in March during an appearance before the Legislatures Environment and Natural Resources Committee.

Industry representatives have urged Maine lawmakers as well as members of Congress not to group-label all PFAS as potentially hazardous substances. Companies that make PFAS say the newer, most common types of chemicals are safer and less forever than the now-banned versions definitely linked to cancer, kidney disease and other ailments.

My fear is that an overgeneralization is leading to a lot of misinformation, a lot of fear and a lot of confusion over a chemistry that is not even being used anymore, Brady Pitts, an application chemist for PFAS manufacturer Daikin America, told Maine lawmakers at the same March hearing.

And then there is the potential health threat posed by contamination from the legacy, now-banned versions.

Dr. Abby Fleisch, an attending physician in pediatric endocrinology and diabetes at Maine Medical Center, recently received a five-year, $2.2 million federal grant to study whether childhood or pre-birth exposure to PFAS can contribute to development of diabetes or lower bone densities.

Fleisch and her team is still in the earlier stages of that research, but initial findings suggest that children between the ages of 6 and 10 who had higher PFAS levels in the blood also had lower bone density. That is important because adolescence is peak bone-formation time, and low bone mineral density during teenage years may predispose those individuals to osteoporosis later in life, Fleisch said.

The research team also plans to follow up on earlier work examining the same group of women and children that suggested girls exposed to higher PFAS levels in utero could be predisposed to childhood obesity.

Research suggests that PFAS exposure may impact multiple health outcomes, Fleisch said in an interview. However, we dont have all of the answers and I believe it is important to continue exploring these fields.

REGULATORY ACTION AND INACTION

Theres been a flurry of activity at the state and federal level in recent years, spurred initially by the discovery of PFAS hotspots around military bases.

In Maine, high levels of PFAS have been found at the former Brunswick Naval Air Station, former Loring Air Force Base and around the Maine Air National Guard base at Bangor International Airport. But the chemicals have also turned up on an Arundel dairy farm, at former tanneries, near landfills and other industrial sites in Maine.

Congress and the federal government are exploring a variety of actions, ranging from adopting tighter health standards for contamination to adding PFAS to the list of chemicals eligible for federal cleanup under the Superfund program. There is also an effort to add at least some forms of PFAS to the list of chemicals that companies are required to report emitting or discharging under the federal Toxics Release Inventory.

Maines PFAS task force is expected to recommend a host of legislative or administrative actions. Those potential actions include expanded statewide tests for contamination, required reporting whenever a fire department uses PFAS-laden foam and mandatory screening for PFAS among all public water systems.

The Maine Department of Environmental Protection, meanwhile, is seeking legislative authority to order companies to clean up PFAS-contaminated sites, something it currently lacks because the federal government doesnt list PFAS as a hazardous material.

Maine is among the handful of states including Washington, Massachusetts, New Hampshire and Michigan that are leading the regulatory charge on PFAS. For instance, Maine lawmakers passed the nations first phase-out of PFAS in food packaging earlier this year, although the law only takes effect when safer alternatives are available.

We dont anticipate a lot of progress in Washington regulating PFAS in food packaging so it is really up to the states to step up, said Schade, of the Safer Chemicals, Healthy Families nonprofit.

THE CUSTOMER IS ALWAYS RIGHT

Schade is also a firm believer in the power of the consumer. And he says recent decisions by retailers to act on PFAS before the federal government is proof of that power.

Through its Mind the Store campaign, Safer Chemicals, Healthy Families, and like-minded organizations nationwide have tested consumer products and food packaging for the presence of PFAS. They then used those results to attempt to pressure manufacturers or retailers to remove PFAS from products.

For instance, a 2018 report from Mind the Store and the group Toxic-Free Future showed likely PFAS ingredients in many store-brand products and packaging from the major grocery store chains Ahold Delhaize, Whole Foods, Albertsons and Kroger.

Immediately after the report, Whole Foods announced plans to stop using takeout food packaging that contains PFAS. And in September of this year, the owner of Hannaford and Stop & Shop supermarket chains, Ahold Delhaize, announced that it plans to begin removing PFAS from packaging for grocery items, baby products and personal care products.

Both the Lowes and Home Depot home improvement chains also recently announced that they would stop selling carpeting and rugs that contain PFAS. And two weeks ago, Staples announced that it would work with suppliers to begin transitioning to safer alternatives to PFAS and other chemicals in products.

Additionally, the maker of the water-repellent fabric Gore-Tex has committed to eliminate PFAS varieties of environmental concern from 85 percent of its consumer products by the end of next year and from the remaining products by 2023.

So this is really a growing sustainability trend among major retailers and businesses, Schade said. At the same time, we have seen leadership from states such as Maine and Washington in recent years.

PROTECTING YOURSELF

According to the Agency for Toxic Substances and Disease Registry within the U.S. Centers for Disease Control and Prevention, exposure to PFOA and PFOS from todays consumer products is usually low, especially when compared to exposures to contaminated drinking water.

But PFAS awareness advocates say there are steps that consumers can take to educate and potentially protect themselves from exposure. They include:

Organizations such the Environmental Working Group, Safer Chemicals, Healthy Families and Toxic-Free Future recommend avoiding nonstick cookware altogether. Thats because even newer versions marketed as PFOA-free could contain the shorter-chain chemical cousins that they maintain have not been proved safe.

Many of those organizations recommend using cast-iron or stainless steel. But advice to consumers on such topics as nonstick cookware can be contradictory and confusing.

In a 2016 fact sheet on PFOA, the American Cancer Society stated: Other than the possible risk of flu-like symptoms from breathing in fumes from an overheated Teflon-coated pan, there are no known risks to humans from using Teflon-coated cookware. While PFOA is used in making Teflon, it is not present (or is present in extremely small amounts) in Teflon-coated products.

Finding out whether a product was made with PFAS is difficult. But Schade with the Mind the Store campaign said consumers should ask manufacturers or retailers such questions, in part to educate themselves and in part to send a message to businesses.

Consumers really need to be savvy and aware, but at the same time none of us should need to have a Ph.D. in chemistry, which is why we need governments to act, he said.

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Households are awash in 'forever chemicals' - Press Herald

Recommendation and review posted by Bethany Smith

COLUMBUS, Ohio The Ohio Senate Nov. 6 passed a bill that would require a child born alive following an abortion receives the same medical care accorded any newborn at the same gestational age.

A second measure OKd the same day would mandate that abortion facilities inform women that chemical abortions can possibly be reversed to save their unborn childs life.

The Born-Alive Infant Protection Act, or S.B. 208, passed with a 24-9 vote, and the Abortion Pill Reversal Act, or S.B. 155, passed with a 23-10 vote.

Called life-affirming by the Catholic Conference of Ohio, the public policy arm of the states Catholic bishops, the two bills will now be taken up by the Ohio House of Representatives. The conference commended the bills sponsors, Republican Sens. Terry Johnson and Peggy Lehner, respectively. Lehner also was a co-sponsor of the Born-Alive bill.

This legislation acknowledges, promotes and preserves the dignity of human life, Johnson said in a statement. Every new born infant deserves our compassion and care, no matter where we stand in the broader abortion debate.

In addition to the medical care provisions, this legislation creates reporting requirements and penalties for the attending physician who fails to report a born-alive baby. While individual cases will remain confidential, the Ohios Department of Health will publish annually the number of babies who survive abortions.

Current federal law recognizes that all infants born at any stage of development, regardless of the circumstances surrounding the birth, are persons. However, supporters of this legislation believe this recognition alone is insufficient to provide protections for infants born alive following an attempted abortion, said a news release from Johnsons office.

The Born-Alive Infant Protection Act is a vital protection of defenseless babies that survive failed abortions, said a statement from Stephanie Ranade Krider, vice president of Ohio Right to Life. This bill would stand ready to protect these helpless infants and require they are given proper medical attention at their most critical moment.

She added, These babies deserve protection under law like infants born under any other circumstance.

Regarding S.B. 155, Lehner said in a statement: Women who decide to take their babies to term should be celebrated and supported. This bill simply gives women more information about the option for a second chance to make an extremely emotional and difficult decision.

The bill would require doctors prescribing abortion-inducing drugs to also provide written information informing the patient of the possibility of reversing the effects of an abortion in the event she changes her mind within the first two days.

According to a news release from Lehners office, the Mifeprex chemical abortion procedure is a two-day regimen used to terminate early pregnancies by blocking the hormone progesterone needed to sustain pregnancy. A second drug, Misoprostol, stimulates uterine contraction to expel the dead baby.

Women who choose a chemical abortion and regret it within the first two days of taking the first drug have a chance to save their baby, as long as they have not taken the second drug, it said.

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Ohio Senate bills will 'give more babies a second chance,' say supporters - The Dialog

Recommendation and review posted by Bethany Smith

Hematopoietic stem cells (HSCs) are responsible for the constant replenishment of all blood cells throughout life. One of the major challenges in regenerative medicine is to produce tailor-made HSCs to replace the defective ones in patients suffering from blood related diseases. This would circumvent the shortage of donor HSCs available for the clinic. To achieve the controlled production of bona fide HSCs in vitro, in a dish, a better understanding is required of where, when and how HSCs are physiologically produced in vivo, in the living body. Researchers from the groups of Catherine Robin(Hubrecht Institute) and Thierry Jaffredo (UPMC, LBD IBPS, Paris) have found a previously unappreciated hematopoietic wave taking place in the bone marrow of late fetuses and young adults and producing HSCs from resident hemogenic endothelial cells of somite origin. This transient hematopoietic wave fills the gap between the completion of embryonic blood production and the beginning of adult bone marrow hematopoietic production in both chicken and mice.

Endothelial origin of hematopoietic stem cells

The constant production of short-lived blood cells, needed for proper oxygenation of tissues and protection against pathogens throughout life, relies on a small cohort of HSCs. The first HSCs derive from specialized endothelial cells, named hemogenic endothelial (HE) cells, via an endothelial to hematopoietic transition (EHT). EHT transiently occurs in the main arteries, such as the aorta, during the embryonic development of vertebrates. The pool of HSCs is then amplified before migrating to the bone marrow where HSCs will reside during adult life. Whether EHT occurs past the embryonic stage and in other organs, such as the bone marrow, was unknown until now.

Hemogenic endothelial cells in the bone marrow

To find out whether EHT occurs past the embryonic stage and in the bone marrow, the researchers used a combination of experimental embryology, genetic, transcriptomic and functional approaches on chicken and mouse models. By tracing bone marrow-forming endothelial cells through fluorescent genetic labelling and live imaging analyses, they found that the entire vascular network of the bone marrow derives from the somites. The somites are segments of the body that will progressively form important tissues of the organism as the embryo develops, including bones, muscles and skin. Unexpectedly, the researchers found that some somite-derived endothelial cells produce HSCs and multipotent progenitors in the late fetus and young adult bone marrow, through the same EHT process that was thus far only seen in the embryo. These cells are molecularly very similar to the cells undergoing EHT or recently emerged HSCs in the embryonic aorta, with a prominent Notch pathway, endothelial-specific genes and transcription factors involved in EHT. The results therefore demonstrate that HSCs are newly generated past embryonic stages, from hemogenic endothelial cells from somitic origin and via EHT, the same mechanism that occurs in the embryo.

A new wave of blood cell production

The yolk sac of the embryo produces two partially overlapping waves of hematopoiesis. The first (primitive) wave gives rise to hematopoietic cells that last only during embryonic development. The second (definitive) wave produces various progenitors that migrate to the fetal liver to produce the immediately needed blood cells. These progenitors are sufficient for the embryo to survive until birth, when the aorta-derived HSC-dependent wave will take over. The transient hematopoietic production discovered in the present study fills the gap between the end of the yolk sac hematopoiesis and the bone marrow HSC-dependent production of blood cells. Indeed, the pool of HSCs that expanded in the fetal liver starts to colonize the bone marrow only just before birth. HSCs are present in very low numbers and time is most likely required before they find their final adult-type niches and start to differentiate and proliferate into more committed progenitors and mature blood cells. The transient hematopoietic wave that the researchers describe in late fetal and young adult stages might also prepare the bone marrow niches for the HSCs coming from the fetal liver.

Stem cell therapies

Defects in HSCs lead to various blood-related disorders and cancers that are partly treated by HSC transplantations. The controlled production of bona fide HSCs from pluripotent precursors remains very difficult to achieve in vitro, in a petri dish, and therefore requires a better understanding of the HSC production as it occurs physiologically in vivo, in the living body. Identifying all steps of hematopoietic production and the molecular events controlling this process is of fundamental interest and should help to devise innovative stem cell therapies for hematopoietic disorders in the future.

Reference:Yvernogeau, L., Gautier, R., Petit, L., Khoury, H., Relaix, F., Ribes, V., Jaffredo, T. (2019). In vivo generation of haematopoietic stem/progenitor cells from bone marrow-derived haemogenic endothelium. Nature Cell Biology. https://doi.org/10.1038/s41556-019-0410-6

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Transient Wave of Hematopoietic Stem Cell Production in Late Fetuses and Young Adults - Technology Networks

Recommendation and review posted by Bethany Smith

Doris A. Taylors so-called replacement ghost heart suggests something otherworldly, but the eerie-looking form is far from an apparition. Its an innovative approach to organ transplantation that has inspired many in the medical community and at least one artist.

The Texas researchers process piggybacks on natures sophisticated design. Together she and a team of researchers strip cells off human and animal cadaver hearts with a soapy solution, leaving ghostly white protein shells that retain the form of the organ. They inject them with a patients blood or bone-marrow stem cells, and the ghost hearts act as scaffolding on which the newly introduced cells can slowly transform into a beating muscle.

What we said was, Wouldnt it be really cool if we could wash the sick cells out and put the healthy cells back in? said Taylor, director of Regenerative Medicine Research and director of the Center for Cell and Organ Biotechnology at the Texas Heart Institute, during a recent talk at the Radcliffe Institute for Advanced Study.

The hope is that one day these regenerated hearts will resolve the most challenging issues transplant patients currently face: the lack of a permanent artificial replacement, concerns about rejection, and the shortage of viable donor hearts.

Taylors efforts are driving what could become a revolution in organ transplants, and they have sparked the creativity of transdisciplinary artist Dario Robleto, whose latest work, on view at the Johnson-Kulukundis Family Gallery in Radcliffes Byerly Hall, recreates in images and sounds the original pulse wave of the heart first captured in visual form by scientists in the 1900s. Robleto and Taylor, longtime friends and Texas residents, explored those connections during Mondays Radcliffe discussion, which was moderated by Jennifer Roberts, Elizabeth Cary Agassiz Professor of the Humanities.

Robletos exhibit, Unknown and Solitary Seas, touches on the overlap between the medical mysteries and workings of the vascular pump, and the metaphor for the heart as the emotional center of the soul. It includes a video installation that features recreated sounds of a beating heart from the 19th century, reconstructed images of how the earliest pulse waves first appeared on the page, and a series of heart waveform sculptures in brass-plated stainless steel.

Roberts said that with his work, Robleto acknowledges the pulse waves promise, their profundity, their scientific value, but he also reclaims some of their ambiguity and asks us to wonder whether we can or should accept that these waveforms have escaped the realms of art, culture, and emotional communication.

Taylor similarly views her work as a blend of the scientific and the human. It transcends complicated, complex science, she says, in that her ghost hearts require a kind of passion, commitment, care, attention, and nurturing similar to whats required by a small child. Its really about building hearts at the emotional, mental, spiritual, and physical level that I think is going to get them to work, she said.

For Robleto, big ideas, like the creation of a new human heart, require multiple perspectives.

The artist called Taylors work one of the most fascinating and definitely one of the most emotional things Ive ever seen. As an object, he added, the ghost heart is stunningly beautiful but it also raises questions about the self, identity, emotion, the notions of form and where memory is truly held, questions he thinks artists can help address. He cited two of the nations earliest heart transplants, after which the patients wives asked their husbands, who had received donor hearts, if they still loved them.

Taylors work, Robleto said, is right at the edge of identity and materiality and so when the day comes when someone says the first ghost heart transplant I think we will have a similar moment where perhaps we will be forced to re-evaluate what we ask from our heart metaphor.

Dario Robletos Unknown and Solitary Seas is on view in Byerly Halls Johnson-Kulukundis Family Gallery through Jan. 18, 2020.

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An artist and a transplant researcher discuss the heart - Harvard Gazette

Recommendation and review posted by Bethany Smith

Scientists at Harvard-affiliated Massachusetts General Hospital (MGH) have identified a previously unknown biological pathway that promotes chronic inflammation and may help explain why sedentary people have an increased risk for heart disease and strokes.

In a study to be published in the November issue ofNature Medicine, MGH scientists and colleagues at several other institutions found that regular exercise blocks this pathway. This discovery could aid the development of new therapies to prevent cardiovascular disease.

Regular exercise protects the cardiovascular system by reducing risk factors such as cholesterol and blood pressure. But we believe there are certain risk factors for cardiovascular disease that are not fully understood, said Matthias Nahrendorf of the Center for Systems Biology at MGH. In particular, Nahrendorf and his team wanted to better understand the role of chronic inflammation, which contributes to the formation of artery-clogging blockages called plaques.

Nahrendorf and colleagues examined how physical activity affects the activity of bone marrow, specifically hematopoietic stem and progenitor cells (HSPCs). HSPCs can turn into any type of blood cell, including white blood cells called leukocytes, which promote inflammation. The body needs leukocytes to defend against infection and remove foreign bodies.

When these [white blood] cells become overzealous, they start inflammation in places where they shouldnt, including the walls of arteries.

Matthias Nahrendorf

But when these cells become overzealous, they start inflammation in places where they shouldnt, including the walls of arteries, said Nahrendorf.

Nahrendorf and his colleagues studied a group of laboratory mice that were housed in cages with treadmills. Some of the mice ran as much as six miles a night on the spinning wheels. Mice in a second group were housed in cages without treadmills. After six weeks, the running mice had significantly reduced HSPC activity and lower levels of inflammatory leukocytes than the mice that simply sat around their cages all day.

Nahrendorf explains that exercising caused the mice to produce less leptin, a hormone made by fat tissue that helps control appetite, but also signaled HSPCs to become more active and increase production of leukocytes. In two large studies, the team detected high levels of leptin and leukocytes in sedentary humans who have cardiovascular disease linked to chronic inflammation.

This study identifies a new molecular connection between exercise and inflammation that takes place in the bone marrow and highlights a previously unappreciated role of leptin in exercise-mediated cardiovascular protection, said Michelle Olive, program officer at the National Heart, Lung, and Blood Institute Division of Cardiovascular Sciences. This work adds a new piece to the puzzle of how sedentary lifestyles affect cardiovascular health and underscores the importance of following physical-activity guidelines.

Reassuringly, the study found that lowering leukocyte levels by exercising didnt make the running mice vulnerable to infection. This study underscores the importance of regular physical activity, but further focus on how exercise dampens inflammation could lead to novel strategies for preventing heart attacks and strokes. We hope this research will give rise to new therapeutics that approach cardiovascular disease from a completely new angle, said Nahrendorf.

The primary authors of theNature Medicinepaper are Nahrendorf, who is also a professor of radiology at Harvard Medical School; Vanessa Frodermann, a former postdoctoral fellow at MGH who is now a senior scientist at Novo Nordisk; David Rohde, a research fellow in the Department of Radiology at MGH; and Filip K. Swirski, an investigator in the Department of Radiology at MGH.

The work was funded bygrantsHL142494 andHL139598from the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health.

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Exercise found to block chronic inflammation in mice - Harvard Gazette

Recommendation and review posted by Bethany Smith

When Nicky Turkoz (aboveleft) was diagnosed with leukaemia, her only hope was an anonymous stem-cell donation. That donor was Annette Hamson (above right) and the two, once strangers, now share an unbreakable bond

I was wrestling the Christmas decorations down from the loft when I got the call. I can remember hearing the landline ring and telling my daughter, Meltem, who was steadying the ladder, to leave it. They can call back if its urgent, I said. My mobile rang and we left that too, but the landline went again. I better get it, Mum, said Meltem. Someone clearly wants to talk to you. She answered it as I was hauling the last of the decorations down. Its the surgery, she said, passing the phone to me.

That morning Id had a blood test. Id been feeling strange for months and had finally made an appointment to see the GP. I told her I was feeling lethargic and depressed, which was very unlike me, but Id put it down to ageing and a spot of empty-nest syndrome, as my youngest daughter Zeynep had just left home to work abroad. Odd things, such as a recurring gum infection, were making me wonder if something else was going on. My GP seemed unconcerned but sent me for blood tests anyway. A few hours later she was telling me to pack an overnight bag and get to hospital. Your results show youre very anaemic, she said. Theyll need to do some more tests. You might be there a while.

She never used the word cancer. Looking back, I think she knew then but was sugar- coating it for me. We left the decorations.

Three hours later, after more prodding and poking, a consultant told me I had acute myeloid leukaemia, a blood cancer. It seems unbelievable now but I can remember thinking, Well, thank goodness theyve found something wrong with me, I knew I wasnt feeling great. I had no idea, of course, what was coming down the track.

It was a Wednesday evening and I was told they would start my chemotherapy on the Friday, but Id need to stay in hospital in the meantime. So while I was being installed on a ward, my poor daughter was handed a leaflet about myeloid leukaemia and drove home to our undecorated tree.

The first round of chemo lasted 10 days, which meant I had to miss Meltems 23rd birthday on 21 December. Zeynep left Gran Canaria, where she had just started working as a holiday rep, and flew home to be with us. It has always been just the three of us, ever since they were tiny. Im a very can-do sort of person and have always just got on with life whatever it has thrown at us. I couldnt bear it when my girls suddenly had to look after me. It all just seemed so unfair. I suppose everyone feels like that though.

See the rest here:
'I've become best friends with the woman who saved my life' - Telegraph.co.uk

Recommendation and review posted by Bethany Smith

An unexpected early morning phone call from the hospital is never good news. When Joy Johnson answered, her first thought was that Sharon Birzer, her partner of 15 years, was dead. Her fears were amplified by the voice on the other end refusing to confirm or deny it. Just come in and talk to one of the doctors, she remembers the voice saying.

Johnson knew this was a real possibility. A few weeks earlier, she and Birzer sat in the exam room of a lymphoma specialist at Stanford University. Birzers cancer had grown, and fast first during one type of chemotherapy, then through a second. Out of standard options, Birzers local oncologist had referred her for a novel treatment called chimeric antigen receptor T-cell therapy or CAR-T. Birzer and Johnson knew the treatment was risky. They were warned there was a chance of death. There was also a chance of serious complications such as multi-organ failure and neurological impairment. But it was like warning a drowning person that her lifeboat could have problems. Without treatment, the chance of Birzers death was all but certain. She signed the consent form.

Johnson hung up the phone that early morning and sped to the hospital. She met with a doctor and two chaplains in a windowless room in the cancer ward, where happy photos of cancer alumni smiled down from the walls. This is getting worse and worse, Johnson thought. As she remembers it, the doctor went through the timeline of what happened for 10 minutes, explaining how Birzer became sicker and sicker, before Johnson interrupted with the thought splitting her world in two: I need you to tell me whether shes alive or dead.

Birzer wasnt dead. But she was far from okay. The ordeal began with Birzer speaking gibberish. Then came seizures so severe there was concern she wouldnt be able to breathe on her own. When it took a few different medications to stop Birzer from seizing, her doctors sedated her, put a breathing tube down her throat, and connected her to a ventilator. Now, she was unconscious and in the intensive care unit (ICU).

Birzer was one of the early patients to receive CAR-T, a radical new therapy to treat cancer. It involved removing Birzers own blood, filtering for immune cells called T-cells, and genetically engineering those cells to recognize and attack her lymphoma. CAR-T made history in 2017 as the first FDA-approved gene therapy to treat any disease. After three to six months of follow-up, the trials that led to approval showed response rates of 80 percent and above in aggressive leukemias and lymphomas that had resisted chemotherapy. Patients on the brink of death were coming back to life.

This is something I often dream of seeing but rarely do. As a doctor who treats cancer, I think a lot about how to frame new treatments to my patients. I never want to give false hope. But the uncertainty inherent to my field also cautions me against closing the door on optimism prematurely. We take it as a point of pride that no field of medicine evolves as rapidly as cancer the FDA approves dozens of new treatments a year. One of my biggest challenges is staying up to date on every development and teasing apart what should and shouldnt change my practice. I am often a mediator for my patients, tempering theoretical promises with everyday realism. To accept a research finding into medical practice, I prefer slow steps showing me proof of concept, safety, and efficacy.

CAR-T, nearly three decades in the making, systemically cleared these hurdles. Not only did the product work, its approach was also unique among cancer treatments. Unlike our usual advances, this wasnt a matter of prescribing an old drug for a new disease or remixing known medications. CAR-T isnt even a drug. This is a one-time infusion giving a person a better version of her own immune system. When the FDA approved its use, it wasnt a question of whether my hospital would be involved, but how we could stay ahead. We werent alone.

Today, two FDA-approved CAR-T products called Kymriah and Yescarta are available in more than 100 hospitals collectively across the U.S. Hundreds of clinical trials are tinkering with dosages, patient populations, and types of cancer. Some medical centers are manufacturing the cells on-site.

The FDA approved CAR-T with a drug safety program called a Risk Evaluation and Mitigation Strategy (REMS). As I cared for these patients, I quickly realized the FDAs concerns. Of the 10 or so patients Ive treated, more than half developed strange neurologic side effects ranging from headaches to difficulty speaking to seizures to falling unconscious. We scrambled to learn how to manage the side effects in real time.

Johnson and Birzer, who I didnt treat personally but spoke to at length for this essay, understood this better than most. Both had worked in quality control for a blood bank and were medically savvier than the average patient. They accepted a medical system with a learning curve. They were fine with hearing I dont know. Signing up for a trailblazing treatment meant going along for the ride. Twists and bumps were par for the course.

Cancer, by definition, means something has gone very wrong within a cell has malfunctioned and multiplied. The philosophy for fighting cancer has been, for the most part, creating and bringing in treatments from outside the body. Thats how we got to the most common modern approaches: Chemotherapy (administering drugs to kill cancer),radiation(using high energy beams to kill cancer), and surgery (cutting cancer out with a scalpel and other tools). Next came the genetics revolution, with a focus on creating drugs that target a precise genetic mutation separating a cancer cell from a normal one. But cancers are genetically complex, with legions of mutations and the talent to develop new ones. Its rare to have that one magic bullet.

Over the last decade or so, our approach shifted. Instead of fighting cancer from the outside, we are increasingly turning in. The human body is already marvelously equipped to recognize and attack invaders, from the common cold to food poisoning, even if the invaders are ones the body has never seen before. Cancer doesnt belong either. But since cancer cells come from normal ones, theyve developed clever camouflages to trick and evade the immune system. The 2018 Nobel Prize in Physiology or Medicine was jointly awarded to two researchers for their work in immunotherapy, a class of medications devoted to wiping out the camouflages and restoring the immune systems upper hand. As I once watched a fellow oncologist describe it to a patient: Im not treating you. You are treating you.

What if we could go one step further? What if we could genetically engineer a patients own immune cells to spot and fight cancer, as a sort of best hits of genetic therapy and immunotherapy?

Enter CAR-T. The technology uses T-cells, which are like the bouncers of the immune system. T-cells survey the body and make sure everything belongs. CAR-T involves removing a persons T-cells from her blood and using a disarmed virus to deliver new genetic material to the cells. The new genes given to the T-cells help them make two types of proteins. The first giving the technology its name is a CAR, which sits on the T-cells surface and binds to a protein on the tumor cells surface, like a lock and key. The second serves as the T-cells caffeine jolt, rousing it to activate. Once the genetic engineering part is done, the T-cells are prodded to multiply by being placed on a rocking device that feeds them nutrients while filtering their wastes. When the cells reach a high enough number a typical dose ranges from hundreds of thousands to hundreds of millions they are formidable enough to go back into the patient. Once inside, the cancer provokes the new cells to replicate even more. After one week, a typical expansion means multiplying by about another 1,000-fold.

Practically, it looks like this: A person comes in for an appointment. She has a catheter placed in a vein, perhaps in her arm or her chest, that connects to a large, whirring machine which pulls in her blood and separates it into its components. The medical team set the T-cells aside to freeze while the rest of the blood circulates back into the patient in a closed loop. Then, the hospital ships the cells frozen to the relevant pharmaceutical companys headquarters or transports them to a lab on-site, where thawing and manufacturing takes from a few days to a few weeks. When the cells are ready, the patient undergoes about three days of chemotherapy to kill both cancer and normal cells, making room for the millions of new cells and eradicating normal immune players that could jeopardize their existence. She then gets a day or two to rest. When the new cells are infused back into her blood, we call that Day 0.

I remember the first time I watched a patient get his Day 0 infusion. It felt anti-climactic. The entire process took about 15 minutes. The CAR-T cells are invisible to the naked eye, housed in a small plastic bag containing clear liquid.

Thats it? my patient asked when the nurse said it was over. The infusion part is easy. The hard part is everything that comes next.

Once the cells are in, they cant turn off. That this may cause collateral damage was evident from the start. In 2009 working in parallel with other researchers at Memorial Sloan Kettering Cancer Center in New York and the National Cancer Institute in Maryland oncologists at the University of Pennsylvania opened a clinical trial for CAR-T in human leukemia patients. (Carl June, who led the CAR-T development, did not respond to Undarks interview request.) Of the first three patients who got CAR-T infusions, two achieved complete remission but nearly died in the process. The first was a retired corrections officer named Bill Ludwig, who developed extremely high fevers and went into multi-organ failure requiring time in the ICU. At the time, the medical teams had no idea why it was happening or how to stop it. But time passed. Ludwig got better. Then came the truly incredible part: His cancer was gone.

With only philanthropic support, the trial ran out of funding. Of the eligible patients they intended to treat, the Penn doctors only treated three. So they published the results of one patient in the New England Journal of Medicine and presented the outcomes of all three patients, including Ludwig, at a cancer conference anyway. From there, the money poured in. Based on the results, the Swiss pharmaceutical company Novartis licensed the rights of the therapy.

The next year, six-year-old Emily Whitehead was on the brink of death when she became the first child to receive CAR-T. She also became extremely ill in the ICU, and her cancer was also eventually cured. Her media savvy parents helped bring her story public, making her the poster child for CAR-T. In 2014, the FDA granted CAR-T a breakthrough therapy designation to expedite the development of extremely promising therapies. By 2017, a larger trial gave the treatment to 75 children and young adults with a type of leukemia B-cell acute lymphoblastic leukemia that failed to respond to chemotherapy. Eighty-one percent had no sign of cancer after three months.

In August 2017, the FDA approved a CAR-T treatment as the first gene therapy in the U.S. The decision was unanimous. The Oncologic Drugs Advisory Committee, a branch of the FDA that reviews new cancer products, voted 10 to zero in favor of Kymriah. Committee members called the responses remarkable and potentially paradigm changing. When the announcement broke, a crowd formed in the medical education center of Penn Medicine, made up of ecstatic faculty and staff. There were banners and T-shirts. A remarkable thing happened was the tagline, above a cartoon image of a heroic T-cell. Two months later, in October 2017, the FDA approved a second CAR-T formulation called Yescarta from Kite Pharma, a subsidiary of Gilead Sciences, to treat an aggressive blood cancer in adults called diffuse large B-cell lymphoma, the trial of which had shown a 54 percent complete response rate, meaning all signs of cancer had disappeared. In May 2018, Kymriah was approved to treat adults with non-Hodgkin lymphoma.

That year, the American Society of Clinical Oncology named CAR-T the Advance of the Year, beating out immunotherapy, which had won two years in a row. When I attended the last American Society of Hematology meeting in December 2018, CAR-T stole the show. Trying to get into CAR-T talks felt like trying to get a photo with a celebrity. Running five minutes late to one session meant facing closed doors. Others were standing room only. With every slide, it became difficult to see over a sea of smartphones snapping photos. At one session I found a seat next to the oncologist from my hospital who treated Birzer. Look, she nudged me. Do you see all these non-member badges? I turned. Members were doctors like us who treated blood cancers. I couldnt imagine who else would want to be here. Who are they? I asked. Investors, she said. It felt obvious the moment she said it.

For patients, the dreaded c word is cancer. For oncologists, its cure. When patients ask, Ive noticed how we gently steer the conversation toward safer lingo. We talk about keeping the cancer in check. Cure is a dangerous word, used only when so much time has passed from her cancer diagnosis we can be reasonably certain its gone. But that line is arbitrary. We celebrate therapies that add weeks or months because the diseases are pugnacious, the biology diverse, and the threat of relapse looming. Oncologists are a tempered group, or so Ive learned, finding inspiration in slow, incremental change.

This was completely different. These were patients who would have otherwise died, and the trials were boasting that 54 to 81 percent were cancer-free upon initial follow-up. PET scans showed tumors that had speckled an entire body melt away. Bone marrow biopsies were clear, with even the most sensitive testing unable to detect disease.

The dreaded word was being tossed around could this be the cure weve always wanted?

When a new drug gets FDA approval, it makes its way into clinical practice, swiftly and often with little fanfare. Under the drug safety program REMS, hospitals offering CAR-T were obligated to undergo special training to monitor and manage side effects. As hospitals worked to create CAR-T programs, oncologists like me made the all too familiar transition from first-time user to expert.

It was May 2018 when I rotated through my hospitals unit and cared for my first patients on CAR-T. As I covered 24-hour shifts, I quickly learned that whether I would sleep that night depended on how many CAR-T patients I was covering. With each treatment, it felt like we were pouring gasoline on the fire of patients immune systems. Some developed high fevers and their blood pressures plummeted, mimicking a serious infection. But there was no infection to be found. When resuscitating with fluids couldnt maintain my patients blood pressures, I sent them to the ICU where they required intensive support to supply blood to their critical organs.

We now have a name for this effect cytokine release syndrome that occurs in more than half of patients who receive CAR-T, starting with Ludwig and Whitehead. The syndrome is the collateral damage of an immune system on the highest possible alert. This was first seen with other types of immunotherapy, but CAR-T took its severity to a new level. Usually starting the week after CAR-T, cytokine release syndrome can range from simple fevers to multi-organ failure affecting the liver, kidneys, heart, and more. The activated T-cells make and recruit other immune players called cytokines to join in the fight. Cytokines then recruit more immune cells. Unlike in the early trials at Penn, we now have two medicines to dampen the effect. Steroids calm the immune system in general, while a medication called tocilizumab, used to treat autoimmune disorders such as rheumatoid arthritis, blocks cytokines specifically.

Fortuity was behind the idea of tocilizumab: When Emily Whitehead, the first child to receive CAR-T, developed cytokine release syndrome, her medical team noted that her blood contained high levels of a cytokine called interleukin 6. Carl June thought of his own daughter, who had juvenile rheumatoid arthritis and was on a new FDA-approved medication that suppressed the same cytokine. The team tried the drug, tocilizumab, in Whitehead. It worked.

Still, we were cautious in our early treatments. The symptoms of cytokine release syndrome mimic the symptoms of severe infection. If this were infection, medicines that dampen a patients immune system would be the opposite of what youd want to give. There was another concern: Would these medications dampen the anti-cancer activity too? We didnt know. Whenever a CAR-T patient spiked a fever, I struggled with the question is it cytokine release syndrome, or is it infection? I often played it safe and covered all bases, starting antibiotics and steroids at the same time. It was counterintuitive, like pressing both heat and ice on a strain, or treating a patient simultaneously with fluids and diuretics.

The second side effect was even scarier: Patients stopped talking. Some, like Sharon Birzer spoke gibberish or had violent seizures.Some couldnt interact at all, unable to follow simple commands like squeeze my fingers. How? Why? At hospitals across the nation, perfectly cognitively intact people who had signed up to treat their cancer were unable to ask what was happening.

Our nurses learned to ask a standardized list of questions to catch the effect, which we called neurotoxicity: Where are we? Who is the president? What is 100 minus 10? When the patients scored too low on these quizzes, they called me to the bedside.

In turn, I relied heavily on alaminated booklet, made by other doctors who were using CAR-T, which we tacked to a bulletin board in our doctors workroom. It contained a short chart noting how to score severity and what to do next. I flipped through the brightly color-coded pages telling me when to order a head CT-scan to look for brain swelling and when to place scalp electrodes looking for seizures. Meanwhile, we formed new channels of communication. As I routinely called a handful of CAR-T specialists at my hospital in the middle of the night, national consortiums formed where specialists around the country shared their experiences. As we tweaked the instructions, we scribbled updates to the booklet in pen.

I wanted to know whether my experience was representative. I came across an abstract and conference talk that explored what happened to 277 patients who received CAR-T in the real world, so I emailed the lead author, Loretta Nastoupil, director of the Department of Lymphoma and Myeloma at the University of Texas MD Anderson Cancer Center in Houston. Fortuitously, she was planning a trip to my university to give a talk that month. We met at a caf and I asked what her research found. Compared to the earlier trials, the patients were much sicker, she said. Of the 277 patients, more than 40 percent wouldnt have been eligible for the very trials that got CAR-T approved. Was her team calling other centers for advice? They were calling us, she said.

Patients included in clinical trials are carefully selected. They tend not to have other major medical problems, as we want them to survive whatever rigorous new therapy we put them through. Nastoupil admits some of it is arbitrary. Many criteria in the CAR-T trials were based on criteria that had been used in chemotherapy trials. These become standard languages that apply to all studies, she said, listing benchmarks like a patients age, kidney function, and platelet count. But we have no idea whether criteria for chemotherapy would apply to cellular therapy.

Now, with a blanket FDA approval comes clinical judgment. Patients want a chance. Oncologists want to give their patients a chance. Young, old, prior cancer, heart disease, or liver disease without strict trial criteria, anyone is fair game.

When I was making rounds at my hospital, I never wandered too far from these patients rooms, medically prepared for them to crash at any moment. At the same time, early side effects made me optimistic. A bizarre truism in cancer is that side effects may bode well. They could mean the treatment is working. Cancer is usually a waiting game, requiring months to learn an answer. Patients and doctors alike seek clues, but the only real way to know is waiting: Will the next PET scan show anything? What are the biopsy results?

CAR-T was fundamentally different from other cancer treatments in that it worked fast. Birzers first clue came just a few hours after her infusion. She developed pain in her lower back. She described it as feeling like she had menstrual cramps. A heavy burden of lymphoma lay in her uterus. Could the pain mean that the CAR-T cells had migrated to the right spot and started to work? Her medical team didnt know, but the lead doctors instinct was that it was a good sign.

Two days later, her temperature shot up to 102. Her blood pressure dropped. The medical team diagnosed cytokine release syndrome, as though right on schedule, and gave her tocilizumab.

Every day, the nurses would ask her questions and have her write simple sentences on a slip of paper to monitor for neurotoxicity. By the fifth day, her answers changed. She started saying things that were crazy, Johnson explained.

One of Birzer's sentences was guinea pigs eat greens like hay and pizza. Birzer and Johnson owned two guinea pigs, so their diet would be something Birzer normally knew well. So Johnson tried to reason with her: They dont eat pizza. And Birzer replied, They do eat pizza, but only gluten-free.

Johnson remembers being struck by the certainty in her partners delirium. Not only was Birzer confused, she was confident she was not. She was doubling down on everything, Johnson described. She was absolutely sure she was right.

Johnson vividly remembers the evening before the frightening early-morning phone call that brought her rushing back to the hospital. Birzer had said there was no point in Johnson staying overnight; she would only watch her be in pain. So Johnson went home. After she did, the doctor came by multiple times to evaluate Birzer. She was deteriorating and fast. Her speech became more and more garbled. Soon she couldnt name simple objects and didnt know where she was. At 3 a.m., the doctor ordered a head CT to make sure Birzer wasnt bleeding into her brain.

Fortunately, she wasnt. But by 7 a.m. Birzer stopped speaking altogether. Then she seized. Birzers nurse was about to step out of the room when she noticed Birzers arms and legs shaking. Her eyes stared vacantly and she wet the bed. The nurse called a code blue, and a team of more doctors and nurses ran over. Birzer was loaded with high-dose anti-seizure medications through her IV. But she continued to seize. As nurses infused more medications into her IV, a doctor placed a breathing tube down her throat.

Birzers saga poses the big question: Why does CAR-T cause seizures and other neurologic problems? No one seemed to know. My search of the published scientific literature was thin, but one name kept cropping up. So I called her. Juliane Gust, a pediatric neurologist and scientist at Seattle Childrens Hospital, told me her investigations of how CAR-T affects the brain were motivated by her own experiences. When the early CAR-T trials opened at her hospital in 2014, she and her colleagues began getting calls from oncologists about brain toxicities they knew nothing about. Where are the papers? she remembered thinking. There was nothing.

Typically, the brain is protected by a collection of cells aptly named the blood-brain-barrier. But with severe CAR-T neurotoxicity, research suggests, this defense breaks down. Gust explained that spinal taps on these patients show high levels of cytokines floating in the fluid surrounding the spine and brain. Some CAR-T cells circulate in the fluid too, she said, but these numbers do not correlate with sicker patients. CAR-T cells are even seen in the spinal fluid of patients without any symptoms.

What does this mean? Gust interprets it as a patients symptoms having more to do with cytokines than the CAR-T cells. Cytokine release syndrome is the number one risk factor for developing neurotoxicity over the next few days, she said. The mainstay for neurotoxicity is starting steroids as soon as possible. In the beginning we didnt manage as aggressively. We were worried about impairing the function of the CAR-T, she added. Now we give steroids right away.

But the steroids dont always work. Several doses of steroids didnt prevent Birzer from seizing. The morning after Johnsons alarming phone call, after the meeting at the hospital when she learned what had happened, a chaplain walked her from the conference room to the ICU. The first day, Johnson sat by her partners bedside while Birzer remained unconscious. By the next evening, she woke up enough to breathe on her own. The doctors removed her breathing tube, and Birzer looked around. She had no idea who she was or where she was.

Birzer was like a newborn baby, confused and sometimes frightened by her surroundings. She frequently looked like she was about to say something, but she couldnt find the words despite the nurses and Johnsons encouragement. One day she spoke a few words. Eventually she learned her name. A few days later she recognized Johnson. Her life was coming back to her, though she was still suspicious of her reality. She accused the nurses of tricking her, for instance, when they told her Donald Trump was president.

She took cues from the adults around her on whether her actions were appropriate. The best example of this was her I love you phase. One day, she said it to Johnson in the hospital. A few nurses overheard it and commented on how sweet it was. Birzer was pleased with the reaction. So she turned to the nurse: I love you! And the person emptying the trash: I love you! Months later, she was having lunch with a friend who asked, Do you remember when you told me you loved me? Birzer said, Well, I stand by that one.

When she got home, she needed a walker to help with her shakiness on her feet. When recounting her everyday interactions, she would swap in the wrong people, substituting a friend for someone else. She saw bugs that didnt exist. She couldnt hold a spoon or a cup steady. Johnson would try to slow her down, but Birzer was adamant she could eat and drink without help. Then peas would fly in my face, Johnson said.

Patients who experience neurotoxicity fall into one of three categories. The majority are impaired but then return to normal without long-term damage. A devastating handful, less than 1 percent, develop severe brain swelling and die. The rest fall into a minority that have lingering problems even months out. These are usually struggles to think up the right word, trouble concentrating, and weakness, often requiring long courses of rehabilitation and extra help at home.

As Birzer told me about her months of rehab, I thought how she did seem to fall somewhere in the middle among the patients Ive treated. On one end of the spectrum was the rancher who remained profoundly weak a year after his infusion. Before CAR-T, he walked across his ranch without issue; six months later, he needed a walker. Even with it, he fell on a near weekly basis. On the other end was the retired teacher who couldnt speak for a week she would look around her ICU room and move her mouth as though trying her hardest and then woke up as though nothing happened. She left the hospital and instantly resumed her life, which included a recent trip across the country. In hindsight, I remember how we worried more about giving the therapy to the teacher than the rancher, as she seemed frailer. Outcomes like theirs leave me with a familiar humility I keep learning in new ways as a doctor: We often cant predict how a patient will do. Our instincts can be just plain wrong.

I asked Gust if we have data to predict who will land in which group. While we can point to some risk factors higher burdens of cancer, baseline cognitive problems before therapy the individual patient tells you nothing, she confirmed.

So we wait.

Doctors like me who specialize in cancer regularly field heart-wrenching questions from patients. They have read about CAR-T in the news, and now they want to know: What about me? What about my cancer?

So, who gets CAR-T? That leads to the tougher question who doesnt? That depends on the type of cancer and whether their insurance can pay.

CAR-T is approved to treat certain leukemias and lymphomas that come from the blood and bone marrow. Since the initial approval, researchers have also set up new CAR-T trials for all sorts of solid tumors from lung cancer to kidney cancer to sarcoma. But progress has been slow. While some promising findings are coming from the lab and in small numbers of patients on early phase trials, nothing is yet approved in humans. The remarkable responses occurring in blood cancers just werent happening in solid tumors.

Cancer is one word, but its not one disease. Its easier to prove why something works when it works than show why it doesnt work when it doesnt work, said Saar Gill, a hematologist and scientist at the University of Pennsylvania who co-founded a company called Carisma Therapeutics using CAR-T technology against solid tumors. That was his short answer, at least. The longer answer to why CAR-T hasnt worked in solid cancers involves what Gill believes are two main barriers. First, its a trafficking problem. Leukemia cells tend to be easier targets; they bob through the bloodstream like buoys in an ocean. Solid tumors are more like trash islands. The cancer cells stick together and grow an assortment of supporting structures to hold the mound together. The first problem for CAR-T is that the T-cells may not be able to penetrate the islands. Then, even if the T-cells make it in, theyre faced with a hostile environment and will likely die before they can work.

At Carisma, Gill and his colleagues look to get around these obstacles though a different immune cell called the macrophage. T-cells are not the only players of the immune system, after all. Macrophages are gluttonous cells that recognize invaders and engulf them for destruction. But studies have shown they cluster in solid tumors in a way T-cells dont. Gill hopes genetically engineered macrophages can be the stowaways that sneak into solid tumor and attack from the inside out.

Another big challenge, even for leukemias and lymphomas, is resistance, where the cancers learn to survive the CAR-T infusion. While many patients in the trials achieved remission after a month, we now have two years worth of data and the outlook isnt as rosy. For lymphoma, that number is closer to 40 percent. Patients celebrating cures initially are relapsing later. Why?

The CAR-T cells we use target a specific protein on cancer cells. But if the cancer no longer expresses that protein, that can be a big problem, and were finding thats exactly whats happening. Through blood testing, we see that many patients who relapse lose the target.

Researchers are trying to regain the upper hand by designing CAR-Ts to target more than one receptor. Its an old idea in a new frame: An arms race between our medicines and the illnesses that can evolve to evade them. Too much medical precision in these cases is actually not what we want, as it makes it easier for cancer to pinpoint whats after it and develop an escape route. So, the reasoning goes, target multiple pieces at once. Confuse the cancer.

Then theres the other dreaded c word: Cost. Novartis Kymriah runs up to $475,000 while Kite Pharmas Yescarta is $373,000. That covers manufacturing and infusion. Not included is the minimum one-week hospital stay or any complications.

They are daunting numbers. Some limitations on health care we accept maybe the patients are too sick; maybe they have the wrong disease. The wrong cost is not one we as a society look kindly upon. And drug companies shy away from that kind of attention.

Cost origins in medicine are notoriously murky. Novartis, confident in its technology, made an offer to offset the scrutiny in CAR-T. If the treatment didnt work after one month, the company said it wouldnt send a bill.

Not everyone agrees that cost is an issue. Gill, for example, believes the concern is over-hyped. Its not a major issue, he told me over the phone. Look, of course [with] health care in this country, if you dont have insurance, then youre screwed. That is no different when it comes to CAR-T as it is for anything else, he said. The cost conversation must also put CAR-T in context. Gill went on to list what these patients would be doing otherwise months of chemotherapy, bone marrow transplants, hospital stays for cancer-associated complications and the associated loss of income as patients and caregivers miss work. These could add up to far more than a one-time CAR-T infusion. A bone marrow transplant, for example, can cost from $100,000 to more than $300,000. The cancer-fighting drug blinatumomab, also used to treat relapsed leukemia, costs $178,000 a year. Any discussion of cost is completely irresponsible without weighing the other side of the equation, Gill said.

How the system will get on board is another question. Logistics will be an issue, Gill conceded. The first national Medicare policy for covering CAR-T was announced in August 2019, two years after the first product was approved. The Centers for Medicare and Medicaid Services has offered to reimburse a set rate for CAR T-cell infusion, and while this figure was recently raised, it remains less than the total cost. Despite the expansion of medical uses, at some centers referrals for CAR-T are dropping as hospitals worry its a net loss. And while most commercial insurers are covering CAR-T therapies, companies less accustomed to handling complex therapies can postpone approval. Ironically, the patients considering CAR-T are the ones for whom the window for treatment is narrowest. A delay of even a few weeks can mean the difference between a cure and hospice.

This, of course, poses a big problem. A breakthrough technology is only as good as its access. A major selling point of CAR-T besides the efficacy is its ease. Its a one-and-done treatment. Engineered T-cells are intended to live indefinitely, constantly on the alert if cancer tries to come back. Compare that to chemotherapy or immunotherapy, which is months of infusions or a pill taken indefinitely. CAR-T is more akin to surgery: Cut it out, pay the entire cost upfront, and youre done.

Birzer was lucky in this respect. I asked her and Johnson if cost had factored into their decision to try CAR-T. They looked at each other. It wasnt an issue, said Johnson. They remembered getting a statement in the mail for a large sum when they got home. But Birzer had good insurance. She didnt pay a cent.=

One year after Birzers infusion, I met her and Johnson at a coffee shop near their home in San Francisco. They had saved a table. Johnson had a newspaper open. Birzer already had her coffee, and I noticed her hand trembling as she brought it to her mouth. She described how she still struggles to find exactly the right words. She sometimes flings peas. But shes mostly back to normal, living her everyday life. She has even returned to her passion, performing stand-up comedy, though she admitted that at least for general audiences: My jokes about cancer didnt kill.

People handed a devastating diagnosis dont spend most of their time dying. They are living, but with a heightened awareness for a timeline the rest of us take for granted. They sip coffee, enjoy their hobbies, and read the news while also getting their affairs in order and staying on the lookout, constantly, for the next treatment that could save them.

Hoping for a miracle while preparing to die are mutually compatible ideas. Many of my patients have become accustomed to living somewhere in that limbo. It is humbling to witness. They hold out hope for a plan A, however unlikely it may be, while also adjusting to the reality of a plan B. They live their lives; and they live in uncertainty.

I see patients in various stages of this limbo. In clinic, I met a man with multiple myeloma six months after a CAR-T trial that supposedly cured him. He came in with a big smile but then quietly began praying when it was time to view PET results. He asked how the other patients on the trial were doing, and I shared the stats. While percentages dont say anything about an individual experience, theyre also all patients have to go on. When someone on the same treatment dies, its shattering for everyone. Was one person the exception, or a harbinger anothers fate? Who is the outlier?

I look at these patients and think a sober truth: Before CAR-T, all would likely die within six months. Now, imagine taking 40 percent and curing them. Sure, a naysayer might point out, its only 40 percent. Whats the hype if most still succumb to their cancer? But there was nothing close to that before CAR-T. I agree with how Gill described it: I think CAR-T cells are like chemotherapy in the 1950s. Theyre not better than chemotherapy theyre just different. For an adversary as tough as cancer, well take any tool we can get.

There remain many questions. Can we use CAR-T earlier in a cancers course? Lessen the side effects? Overcome resistance? Streamline manufacturing and reimbursement? Will it work in other cancers? Patients will sign up to answer.

For now, Birzer seems to be in the lucky 40 percent. Her one-year PET scan showed no cancer. I thought of our last coffee meeting, where I had asked if she ever worried she wouldnt return to normal. She didnt even pause. If youre not dead, she said, youre winning.

This article was originally published on Undark. Read the original article.

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Behind the Scenes of a Radical New Cancer Cure - Scientific American

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