Global Nebulizer Market Report 2019 Market Size, Share, Price, Trend and Forecast is a professional and in-depth study on the current state of the global Nebulizer industry.

The report also covers segment data, including: type segment, industry segment, channel segment etc. cover different segment market size, both volume and value. Also cover different industries clients information, which is very important for the manufacturers.

There are 4 key segments covered in this report: competitor segment, product type segment, end use/application segment and geography segment.

Make An EnquiryAbout This Report @ https://www.researchmoz.us/enquiry.php?type=E&repid=2527036&source=atm

For competitor segment, the report includes global key players of Nebulizer as well as some small players.

3A Health CareDeVilbiss HealthcarePHILIPSRossmax International Ltd.CareFusionOmronPARIGFAllied Healthcare Products

Segment by RegionsNorth AmericaEuropeChinaJapanSoutheast AsiaIndia

Segment by TypePneumatic NebulizersUltrasonic NebulizersMesh NebulizersOther

Segment by ApplicationCOPDCystic fibrosisAsthmaOther

Request Sample Report @ https://www.researchmoz.us/enquiry.php?type=S&repid=2527036&source=atm

Important Key questions answered in Nebulizer market report:

What will the market growth rate, Overview, and Analysis by Type of Nebulizer in 2024?

What are the key factors affecting market dynamics? What are the drivers, challenges, and business risks in Nebulizer market?

What is Dynamics, This Overview Includes Analysis of Scope and price analysis of top Manufacturers Profiles?

Who Are Opportunities, Risk and Driving Force of Nebulizer market? Knows Upstream Raw Materials Sourcing and Downstream Buyers.

Who are the key manufacturers in space? Business Overview by Type, Applications, Gross Margin, and Market Share

What are the opportunities and threats faced by manufacturers in the global market?

You can Buy This Report from Here @ https://www.researchmoz.com/checkout?rep_id=2527036&licType=S&source=atm

The content of the study subjects, includes a total of 15 chapters:

Chapter 1, to describe Nebulizer product scope, market overview, market opportunities, market driving force and market risks.

Chapter 2, to profile the top manufacturers of Nebulizer , with price, sales, revenue and global market share of Nebulizer in 2019 and 2015.

Chapter 3, the Nebulizer competitive situation, sales, revenue and global market share of top manufacturers are analyzed emphatically by landscape contrast.

Chapter 4, the Nebulizer breakdown data are shown at the regional level, to show the sales, revenue and growth by regions, from 2019 to 2025.

Chapter 5, 6, 7, 8 and 9, to break the sales data at the country level, with sales, revenue and market share for key countries in the world, from 2019 to 2025.

Chapter 10 and 11, to segment the sales by type and application, with sales market share and growth rate by type, application, from 2019 to 2025.

Chapter 12, Nebulizer market forecast, by regions, type and application, with sales and revenue, from 2019 to 2025.

Chapter 13, 14 and 15, to describe Nebulizer sales channel, distributors, customers, research findings and conclusion, appendix and data source.

Original post:
Mannequin-based Simulation Market Insights on Emerging Scope 2026 - Health News Office

Recommendation and review posted by Bethany Smith

Global Nebulizer Market Report 2019 Market Size, Share, Price, Trend and Forecast is a professional and in-depth study on the current state of the global Nebulizer industry.

The report also covers segment data, including: type segment, industry segment, channel segment etc. cover different segment market size, both volume and value. Also cover different industries clients information, which is very important for the manufacturers.

There are 4 key segments covered in this report: competitor segment, product type segment, end use/application segment and geography segment.

Make An EnquiryAbout This Report @ https://www.researchmoz.us/enquiry.php?type=E&repid=2527036&source=atm

For competitor segment, the report includes global key players of Nebulizer as well as some small players.

3A Health CareDeVilbiss HealthcarePHILIPSRossmax International Ltd.CareFusionOmronPARIGFAllied Healthcare Products

Segment by RegionsNorth AmericaEuropeChinaJapanSoutheast AsiaIndia

Segment by TypePneumatic NebulizersUltrasonic NebulizersMesh NebulizersOther

Segment by ApplicationCOPDCystic fibrosisAsthmaOther

Request Sample Report @ https://www.researchmoz.us/enquiry.php?type=S&repid=2527036&source=atm

Important Key questions answered in Nebulizer market report:

What will the market growth rate, Overview, and Analysis by Type of Nebulizer in 2024?

What are the key factors affecting market dynamics? What are the drivers, challenges, and business risks in Nebulizer market?

What is Dynamics, This Overview Includes Analysis of Scope and price analysis of top Manufacturers Profiles?

Who Are Opportunities, Risk and Driving Force of Nebulizer market? Knows Upstream Raw Materials Sourcing and Downstream Buyers.

Who are the key manufacturers in space? Business Overview by Type, Applications, Gross Margin, and Market Share

What are the opportunities and threats faced by manufacturers in the global market?

You can Buy This Report from Here @ https://www.researchmoz.com/checkout?rep_id=2527036&licType=S&source=atm

The content of the study subjects, includes a total of 15 chapters:

Chapter 1, to describe Nebulizer product scope, market overview, market opportunities, market driving force and market risks.

Chapter 2, to profile the top manufacturers of Nebulizer , with price, sales, revenue and global market share of Nebulizer in 2019 and 2015.

Chapter 3, the Nebulizer competitive situation, sales, revenue and global market share of top manufacturers are analyzed emphatically by landscape contrast.

Chapter 4, the Nebulizer breakdown data are shown at the regional level, to show the sales, revenue and growth by regions, from 2019 to 2025.

Chapter 5, 6, 7, 8 and 9, to break the sales data at the country level, with sales, revenue and market share for key countries in the world, from 2019 to 2025.

Chapter 10 and 11, to segment the sales by type and application, with sales market share and growth rate by type, application, from 2019 to 2025.

Chapter 12, Nebulizer market forecast, by regions, type and application, with sales and revenue, from 2019 to 2025.

Chapter 13, 14 and 15, to describe Nebulizer sales channel, distributors, customers, research findings and conclusion, appendix and data source.

More:
Serving numerous end-users, Cladding Panels market anticipated to continue to rise between 2019 2027 - Health News Office

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 recognise 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% and above in aggressive leukemias and lymphomas that had resisted chemotherapy. Patients on the brink of death were coming back to life.

Also read:Rwanda on Track to Become the First Country to Eliminate Cervical Cancer

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 US. Hundreds of clinical trials are tinkering with dosages, patient populations, and types of cancer. Some medical centres 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 realised the FDAs concerns. Of the 10 or so patients Ive treated, more than half developed strange neurological 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 marvellously equipped to recognise 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 tumour 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 jeopardise 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 Centre 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 leukaemia patients. (Carl June, who led the CAR-T development, did not respond to Undarks interview request.)

Also read:Explainer: What Is Soft Tissue Cancer?

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 leukaemia B-cell acute lymphoblastic leukaemia 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 US. The decision was unanimous. The Oncologic Drugs Advisory Committee, a branch of the FDA that reviews new cancer products, voted 10 to zero in favour of Kymriah. Committee members called the responses remarkable and potentially paradigm changing. When the announcement broke, a crowd formed in the medical education centre 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 tumours 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.

Also read:The DNA Detectives Hunting the Causes of Cancer

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 standardised 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 colour-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 centres 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 judgement. 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 Birzers 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.

Also read:Bankrupt, Poorly Educated Cancer Patients Forced to Live on Street Outside Mumbai Hospital

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 neurological 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 paediatric 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 defence 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 recognised 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.

Also read:Why Everyone Around You Seems to Be Getting Cancer

So we wait.

Doctors like me who specialise 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 leukaemias 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 tumours 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 tumours.

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 tumours. 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. Leukaemia cells tend to be easier targets; they bob through the bloodstream like buoys in an ocean. Solid tumours 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 recognise invaders and engulf them for destruction. But studies have shown they cluster in solid tumours in a way T-cells dont. Gill hopes genetically engineered macrophages can be the stowaways that sneak into solid tumour and attack from the inside out.

Another big challenge, even for leukaemias 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 leukaemia, costs $178,000 a year. Any discussion of cost is completely irresponsible without weighing the other side of the equation, Gill said.

Also read:Many Women With Breast Cancer May Not Need Chemo, But Beware Misleading Headlines

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 Centres 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 centres 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%. 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.

More:
Behind the Scenes of a Radical New Cancer Cure - The Wire

Recommendation and review posted by Bethany Smith

Global Nebulizer Market Report 2019 Market Size, Share, Price, Trend and Forecast is a professional and in-depth study on the current state of the global Nebulizer industry.

The report also covers segment data, including: type segment, industry segment, channel segment etc. cover different segment market size, both volume and value. Also cover different industries clients information, which is very important for the manufacturers.

There are 4 key segments covered in this report: competitor segment, product type segment, end use/application segment and geography segment.

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3A Health CareDeVilbiss HealthcarePHILIPSRossmax International Ltd.CareFusionOmronPARIGFAllied Healthcare Products

Segment by RegionsNorth AmericaEuropeChinaJapanSoutheast AsiaIndia

Segment by TypePneumatic NebulizersUltrasonic NebulizersMesh NebulizersOther

Segment by ApplicationCOPDCystic fibrosisAsthmaOther

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The content of the study subjects, includes a total of 15 chapters:

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Chapter 2, to profile the top manufacturers of Nebulizer , with price, sales, revenue and global market share of Nebulizer in 2019 and 2015.

Chapter 3, the Nebulizer competitive situation, sales, revenue and global market share of top manufacturers are analyzed emphatically by landscape contrast.

Chapter 4, the Nebulizer breakdown data are shown at the regional level, to show the sales, revenue and growth by regions, from 2019 to 2025.

Chapter 5, 6, 7, 8 and 9, to break the sales data at the country level, with sales, revenue and market share for key countries in the world, from 2019 to 2025.

Chapter 10 and 11, to segment the sales by type and application, with sales market share and growth rate by type, application, from 2019 to 2025.

Chapter 12, Nebulizer market forecast, by regions, type and application, with sales and revenue, from 2019 to 2025.

Chapter 13, 14 and 15, to describe Nebulizer sales channel, distributors, customers, research findings and conclusion, appendix and data source.

Read more:
Leading Manufacturers and their Strategies to see Distinctly Growth in Antidiuretic Drugs Market by 2025 - Health News Office

Recommendation and review posted by Bethany Smith

A two-time cancer survivor learns more about pancreatic cysts and discusses the value and cautions of genetic testing.

Barbara Tako is a breast cancer survivor (2010), melanoma survivor (2014) and author of Cancer Survivorship Coping ToolsWe'll Get You Through This. She is a cancer coping advocate, speaker and published writer for television, radio and other venues across the country. She lives, survives, and thrives in Minnesota with her husband, children and dog. See more at http://www.cancersurvivorshipcopingtools.com,or http://www.clutterclearingchoices.com.

Intraductal Papillary Mucosal Neoplasms in my pancreas are the latest "lovely" thing that cancer has brought into my life. Well, it is not my first time around - I have already had breast cancer and melanoma. My particular IPMNs may not be or ever become cancer, and yet they subject me to play the "wait and watch game" with one more cancer-type thing.

If you are a cancer survivor, you know how that gameworks - try to move forward with life while not pre-worrying too much. How were my IPMNs found? I had a screening MRI because of my PALB2 genetic cancer mutation. Sometimes IPMNs are found by accident when having an MRI for an unrelated reason. Gotta love technology!

The way one doctor worded it, I was fortunate to have the PALB2 genetic mutation that prompted the MRI that caught these three IPMNs so early and will result in continued monitoring. Cancer survivors all learn that cancers caught early often have better outcomes than cancers that have already grown and spread. Pancreatic cancer has a poor survival ratebecause it is often caught too late. There is a moral to that story that I want to shout from the rooftops: Please, please see a geneticist and have genetic testing done!

Still, there is a potential dark side to genetic testing. It sounds like if a person has a genetic finding and wants to have children, they may be able to screen out embryos that get the mutation before implanting them. Hm. Hey wait a minute:I would have been one of those screened-out embryos if the technology had existed back in that day and my parents had chosen that route. So, yes, genetic testing is a choice,but meeting with a genetic counselor before the testing is decided upon is also very important.

There are many questions to consider before even getting testing done. To test or not to test? How much do you want to know? What happens once that knowledge is out there?A person can't be discriminated against for health care due to genetic test results, but life or disability insurancecoverage, among others, may be a different story. Also, if you choose genetic testing, how often do you go back and get re-tested? Exciting advances are happening rapidly in this field. When I first got tested nine years ago, they only tested a couple of breast cancer genetic mutations. My latest genetic test looked for nineteen mutations - and found my PALB2!

Of course in my case, I GoogledIPMNs and learned lots of frightening stuff before I met with the pancreas specialist. For IPMNs, location and size matter, and I am fortunate that mine are very small and not in worrisome locations. They are also too small for fine needle aspiration or surgery. I will have another MRI in about a year to watch for changes. This means that if they do start to appear cancerous, I may have surgical options to consider which might, in my case, provide a better prognosis than usual for pancreatic cancer.

Genetic testing leaves me optimistic, grateful, and yes, cautious. Please be careful out there, make thoughtful choices, and be sure your sources of information are reliable.

Follow this link:
Things to Consider in Genetic Testing - Curetoday.com

Recommendation and review posted by Bethany Smith

If youre a dog owner, you can buy your pet bespoke treats, you can put them in a red vest and take them everywhere you go, and you can accessorize them to the hilt. Cats rarely get in on this fun (only a self-hating feline will allow the application of a costume), so the industry tends to leave them behindwhich is probably just what they want.

Look, we get it. Your dog loves you and is your proverbial best friend. Cats are cruel and soulless. And yet, millions of us simply prefer the company of felines, and its not just because your dog smells bad and drools all over the place. Its just in our DNA.

Speaking of which, while dog owners have scads of options for testing their pups DNA, cat owners have largely been left out in the cold by the genetic testing industry. And while most cat owners arent dying to get on the cloning bandwagon the way dog owners are, that doesnt mean we dont want to know more about our pets heritage and health, even if science could care less.

We have two cats, but when my wife and I talk about genetic questions, they revolve around Saffy, our 6-year-old specimen who most would charitably describe as a mix. Shes about eight different colors, with an orange splotch on her back and another on one ear. Equally charitably, one would say she is eccentric. Few believe me when I say that she spends all day in our bed, under the covers. I mean all day: She crawls in around 8 am and doesnt come out until 5 pm. And she is absolutely terrified of everything. If a delivery driver pulls into the driveway during her awake hours, she runs to the safety of the covers. The doorbell throws her into a full-on panic. My wife says shes a babe.

Photograph: Susanne Bergstrom Null

I write all of this because I have a lot of questions about Saffy. What kind of cat(s) is she? And why is she such a freak? Could it be a medical condition?

Enter Basepaws, one of a very small number of services that promise to sequence your kittys DNA, revealing information about both breed and ancestry as well as scanning for numerous markers that could indicate elevated risks for certain diseases. If youve ever taken a human DNA test, you know how this goes. You swab the inside of your cats mouthnot hard if you have a helperand drop the swab into a test tube. You then mail it off to Basepaws and wait for the results to come back.

We swabbed, mailed, and waited, and eventually I received Basepaws report in two pieces. First came the health results, then the genetic report was later appended to it. The report takes the form of a massive PDF34 pages long for lil Saffand it certainly feels full of information. The health data is weighty, including information on 17 diseases based on 39 genetic markers. I was surprised, but happy, to see that Saffy was in the clear on all of them, with no risks noted. She wasnt even a carrier of any genes that would put her at risk of disease, though Saffys clearly not meant for breeding. From polycystic kidney disease to mucopolysaccharidosis, Saffy appears to be free of major ailments and is destined to have a long and happy life ahead of her, safely tucked away in bed.

The breed report is somewhat more complex and is indicative of the general lack of available scientific information about cat breeds and ancestry. An introduction in the report notes that cats are comparably wild in comparison to dogs and other animals, that theyve not changed all that much in thousands of years. And while cat breeds are definitely a thing, by and large cats just arent bred nearly as much as dogs are. The result: 95 percent of cats in the world are of mixed breed, referred to in the report as polycat.

Polycat doesnt mean a mix of a couple of known breeds, it basically means a mix of all the breeds. Its the common part of the genome that the reference genome (felis_catus_9.0) doesnt really have enough information about. The genes in the polycat segment could relate to Russian Blue, or they could be Egyptian Mau. They just dont know yet. Sure enough, Saffys reportand I expect most reportspeg her at nearly 46 percent polycat.

The rest of the report is where the fun is, with Basepaws breaking down the breeds into four major groups: Western, Eastern, Persian, and Exotic. Saffys other 56 percent has traits related to all four of these groups, and her mix of those groups is roughly 37, nine, six, and three percent, respectively. Basepaws then breaks down those four breed groups by detailing three to seven cat breeds within each. These are ranked based on similarity to your cat, though you dont exactly get a specific breakdown like you do with, say, Ancestry.com. While Basepaws tells me Saffy is mostly Burmese within that 9 percent Eastern group, theres no estimate that shes, say, 6 percent Burmese overall, which would be a lot more fun.

Photograph: Basepaws

Basepaws does get to this information in a sort-of roundabout way in full-page descriptions of each of the top four sub-breeds under the four main categories. So for Saffy, that was American Shorthair (of course), Burmese, Bengal, and Exotic Shorthair. On the relevant page, Basepaws tells me that Saffy is more similar to the American Shorthair than 72.76 percent of all other cats in our database. Thats interesting, but it ultimately tells me more about the Basepaws database than Saffys genetics. Shes 54.67 percent more similar to a Burmese than all the other cats in the Basepaws database yet only 9 percent of her genetics are even in that family. In fact shes also more similar to both Bengal and Exotic Shorthair than more than 50 percent of cats in the database, which would seem to indicate shes got a lot of different cat types in her. Essentially shes the everything bagel of cats.

The Basepaws report can be a bit confusing, and it doesnt feel complete in large part because it cant be complete. Theres just not enough information about cat breeds available to make for a full picture. Basepaws notes that as it collects more data, it will be able to chip away at that polycat component, though some updates will cost extra (pricing is still being worked out).

As curious as the Basepaws report is, the company still seems to be having some growing pains. It took two months for the health report to come in, and nearly another month to receive Saffys genetic profile. Thats a long time. In cat years thats like 18 months.

At $99, Basepaws is priced the same as AncestryDNA (for people), though its still the least expensive and seemingly the most full-featured cat DNA testing product on the market. HomeDNAs Cat DNA kit runs $125; Optimal Selection has a $100 kit targeted mainly at breeders, and those are the only other options Ive been able to find. Any way you cut it, DNA testing your kitty is a pricey affair, though those concerned about hereditary diseases may find the added peace of mind more than worth it.

Your cat, of course, could not care less.

Basepaws' Cat DNA test is available directly from the company's website, or from Amazon.

See the original post:
Basepaws' $99 Cat DNA Test Tells You What's Truly Wrong With Your Cat - WIRED

Recommendation and review posted by Bethany Smith

DNA testing giant Ancestry.com LLC is entering the growing and potentially lucrative field of genetic health screenings with a strategy thats markedly different from that of its biggest competitor.

Ancestry said last Tuesday that its new consumer health tests an area the genealogy-focused company has been slow to embrace will require authorization by a physician.

Its main competitor, 23andMe Inc., went through the lengthy and expensive process of getting approval from the U.S. Food and Drug Administration so it can sell its tests directly to customers without a prescription.

The involvement of doctors in Ancestrys tests places it in the midst of a debate over whether physician-ordered genetic screening is merely a way for companies to avoid the regulatory scrutiny of the FDA. Several other DNA startups, including Color and Veritas, also require a doctor to order health tests.

The FDA hasnt intervened in the field of physician-ordered genetic tests, although it has signaled an intent to do so. So far, a doctors involvement has been considered enough protection for consumers, even if a patient has little interaction with the physician. Its unclear whether the entrance of a major player like Ancestry might change that.

I suspect that FDA is going to eventually do something as these tests begin to enter our world in a big way, said Robert Cook-Deegan, a professor at the University of Arizona who studies genome ethics and the law.

Ancestry Chief Executive Officer Margo Georgiadis said the company wanted to focus on providing ways for its tests to integrate easily into the care patients receive from their regular doctors.

Thats really why we chose a path that has a doctor, she said, so that the consumer not only can find out a risk factor, but they can seamlessly take a lab report with clinically recommended guidelines into the doctors office so that theres a clear next path for action.

After ordering a health DNA test from Ancestry, customers must fill out a brief medical history survey, which Ancestry then funnels to an outside network of doctors and genetic counselors employed by PWNHealth LLC to approve the test.

Once the results are in, those doctors review them and make sure that patients receive the appropriate educational materials alongside their results. For example, if results show a harmful variant of the BRCA 1 or 2 genes, a customer would receive a video explaining hereditary breast and ovarian cancer syndrome. Its a model similar to that followed by other genetic-testing companies.

Ancestrys health tests include free access to a genetic counselor. And before disclosing potentially troubling results, the company requires consumers to watch educational material about the condition. The reports also include clinical reports that a customer can share with their doctor.

If you have a finding thats important, you will have all the tools you need to learn more about it, said Catherine Ball, Ancestrys chief scientific officer.

But according to Cook-Deegan, the university professor, most consumers may not understand the limitations of the test.

A lot of whether this is a good thing or a bad thing depends on the quality of their testing, he said. It depends on the degree to which those physicians are really involved and the degree to which the genetic counseling is truly incorporated into the process.

Companies that offer genetic testing outside of the health-care system should be expected by regulators to show that their tests can successfully be integrated into that system in order to actually improve customers health, said Michael Murray, the director of clinical operations at Yale Universitys Center for Genomic Health.

I havent seen anything from a company thats doing this from outside of health care that demonstrates anything, he said.

Lehi, Utah-based Ancestry entered the genetic-testing market seven years ago, and with more than 15 million kits sold has become the dominant player in the ancestry DNA testing space.

In its move into health testing, it will introduce two products. Its less-expensive version, AncestryHealth Core, made its debut Tuesday. For $149, it delivers information about a handful of disease risks and health conditions, including breast cancer, as well as the original ancestry test.

A premium product, AncestryHealth Plus, which will launch early next year. It will decode the genome in far greater detail. It will cost $199, with a membership fee of $49 for six months of updates.

Georgiadis said the company didnt plan to seek FDA approval for its tests anytime soon.

Were a consumer-centric company, she said. And I truly believe that business models drive behavior. Our goal is to help people gain the preventative knowledge so that they personally can take action for their health.

See the original post:
Ancestry's DNA health screening to require a physician's order - The Union Leader

Recommendation and review posted by Bethany Smith

Genetic testing promises customers insights into ancestry and potential health risks. But for one Durango family, the testing also identified a new family member.

Lindsay Breed, 32, sent her saliva sample to 23andMe, a genomics and biotechnology company, two years ago to learn more about her predisposition to certain health conditions.

About a year later, in September 2018, Breed received a message through 23andMe from Jean Griffin, 62. Griffin reached out to Breed to say she thought she might be Breeds first cousin based on their DNA test results.

But the three-decades age difference between Griffin and Breed was too great. Breed and her mother, Lori Moss, looked deeper into the DNA match and family ancestry and determined Griffin must be Moss half sister.

A phone call settled the question.

I pretty much knew right away she was related to me, there were so many similarities, said Moss of Durango.

Griffin and Moss have the same height, shoe size, walk and sense of humor, she said. All qualities they inherited from their father, Clifford Carlson of Durango.

Griffin, Moss and their brother, Gregg Carlson, all clicked and still talk regularly. The three all grew up in the same area despite never knowing each other Moss and Gregg Carlson in Long Island and Griffin in Connecticut, where she still lives.

I feel like I hit the jackpot, Griffin said.

Clifford Carlson, 84, had no idea Griffin had been born as a result of a brief and casual relationship, Moss said. When Moss broke the news to her father, he was stunned, but the next day he called Moss back and asked for Griffins phone number.

Griffin and Carlson met for the first time this summer at Durango-La Plata County Airport.

It felt like an out-of-body experience, Griffin said.

Griffin knew she had been adopted and requested information about her birth parents 20 years ago through a TV show. But she didnt keep looking for information because her adoptive parents were still alive. She initially took a genetic test because she was interested in finding out more about her ancestry, but then she found her birth mother. She took the 23andMe test because she was interested in what more she could learn about her family history.

As genetic testing increases in popularity, its likely many other families are making similar discoveries all the time. At the beginning of the year, an estimated 26 million people had taken tests through four DNA testing companies, according to MIT Technology Review.

Moss advises those interested in taking a DNA test talk with family members about it.

Family members should reach out to other family members and say: I am about to do this. Are you going to be OK? Are you going to be OK if I find some hidden relatives that you didnt know about? Moss said.

If test-takers are hopeful about finding relatives, Griffin said they need to be ready for all kinds of outcomes.

It can be disappointing. ... There is a lot of not-so-good scenarios, she said.

Griffin said she approached her birth family just hoping to get to know them. She feels she got lucky.

They have been nothing but wonderful from the word go, she said.

Moss said when she first learned about Griffin she tried think about the situation from her sisters perspective.

If I was her, I would want to know my biological family, too, she said.

mshinn@durangoherald.com

Read more:
62-year-old woman meets Durango father for the first time - The Durango Herald

Recommendation and review posted by Bethany Smith

[He Jiankuis CRISPR babies] brought to the surface common misunderstandings even among scientists and ethicists thatreproductive usesof this genome-modifying tool have therapeutic value, will treat people with genetic disorders, will save lives, and will eradicate disease. None of those are true.

Imagine an individual or couple at high risk for creating a child with a serious genetic disease. They have the following simplified range of options:

Create a genetically related child in the time-honored fashion who will be at high risk for the genetic disease.

Create a genetically related child using CRISPR who will be at very low risk for the genetic disease.

Create no genetically related child.

The existence of option C undermines the claim that rCRISPR applications are lifesaving or curative.

Individuals have a choice in the matter of creating children at high risk of genetic disease: They can choose option C. Here is a different way of seeing the point that rCRISPR is not morally urgent because it does not involve a child whose existence, or illness, is inevitable.

Read full, original post: Using CRISPR to edit eggs, sperm, or embryos does not save lives

Read the original post:
Viewpoint: Why CRISPR embryo editing is not 'morally urgent': No one has to have a child - Genetic Literacy Project

Recommendation and review posted by Bethany Smith

Phenotypic screening is gaining new momentum in drug discovery with the hope that this approach will improve the success rate of drug approval.1 In this article we look at some of the latest screening tools and their applications.

This is illustrated by their recent study with Dr Ayman Zen where the team developed a high-content imaging screen using the endothelial tube formation assay, miniaturized to a 384-well plate format. Screening with an annotated chemical library of 1,280 bioactive small molecules identified a retinoid agonist, Tazarotene, that enhanced in vitro angiogenesis and wound healing in vivo. This high content screen identified an already FDA-approved small molecule that could be potentially exploited in regenerative medicine.3

Immuno-oncology: Pushing the Frontier of Discovery Through Advanced High Throughput Flow Cytometry

Immuno-oncology encompasses a number of approaches with one common thread: they harness the bodys own immune system against cancer.

Download this article to learn how advanced throughput flow cytometry overcomes these challenges to drive forward innovation in the immuno-oncology field.

Ebner is currently working in collaboration with recent Nobel-Prize winner Peter Ratcliffe, alongside scientists at Edinburgh University and MIT, to model hypoxia in glioblastoma. Hypoxia is a problem with some glioblastomas as it protects cells from radiotherapy treatment. Our aim is to use Peters expertise to help us set up an assay that mimics real tumor hypoxia. Then if we can identify small compounds that alter that hypoxic condition we can make the glioma cells more susceptible to either radiotherapy or temozolomide or some other treatment combination.

The labs main readout is high-content imaging, using fluorescent microscopy that can take many thousands of pictures. This approach utilizes different labels and harnesses software that automates the image analysis. The image analysis is set by the biologists but then it's applied across the entire screen. Its lower throughput than plate-based readout, but you get a lot more information out of the images, says Ebner. Increasingly, high content imaging is moving towards using AI and deep learning where you're trying to draw out even more information than the primary phenotype that you were looking at.

Indeed, a recent study using CRISPR-Cas9 mutagenesis showed that the proteins targeted by many cancer drugs currently in clinical development are non-essential for tumor growth, despite evidence to the contrary from previous studies using RNAi and small molecule inhibitors.4 In addition, the efficacy of the drugs tested was unaffected when CRISPR was used to knockout its assumed target suggesting that many are eliciting their anticancer activity through off-target effects.

The other benefit of CRISPR is that its extremely flexible, says Pettitt. This means you can expand the range of cell line models, for example, that you can screen in. The key reason why RNAi was such a popular technology, and now CRISPR is, is that you can basically knock out a gene by synthesizing just a short piece of RNA, he explains. CRISPR guides are very easy to synthesize, you can do it in a very high throughput setting, and you can design customized libraries to knock out every gene in the genome or a particular set of genes. As long as you can get the CRISPR machinery into your cells, it works very reliably.

The classic CRISPR (CRISPR-Cas9) system comprises a nuclease called Cas9 which you can program with a short RNA (20 nucleotides). The RNA will direct the nuclease to a certain site in the genome that matches and the nuclease will cleave the genome at that point. Repair of that double-strand break results in small insertions and deletions that result in knock out of a gene. But theres now more evolved applications of the technology emerging.

I think it's possible to be very creative with CRISPR in a way that it isnt with RNAi, says Pettitt. With RNAi you can really only shut genes off, but with CRISPR as well as making random mutations to knock out genes - you can also precisely edit genes if you provide a template region with a mutation with it. This can be incorporated into the target site for CRISPR so you can introduce the specific mutation youre interested in.

One such example is the problem with BRCA1 mutations: its important to be able to functionally classify whether these mutations are benign or pathogenic. A recent study used CRISPR to test 96.5% of all possible single-nucleotide variants (SNVs) in exons that encode functionally critical domains of BRCA1 and found over 400 non-functional missense SNVs were identified, as well as around 300 SNVs that disrupt expression. This knowledge will immediately aid clinical interpretation of BRCA1 genetic test results.5 In another study,6 Pettitt and colleagues used genome-wide CRISPR-Cas9 mutagenesis screens to identify the mutated forms of PARP that cause in vitro and in vivo PARP inhibitor resistance, and found that these mutations are also tolerated in cells with a pathogenic BRCA1 mutation resulting in a different profile of sensitivity to chemotherapy drugs compared with other types of PARP inhibitor resistance.

You couldnt screen at that level of detail using RNAi, where you design custom CRISPR that targets many different regions of the same gene and you can figure out which domains of the protein are important for your phenotype of interest, says Pettitt.

There are other evolutions of CRISPR now being developed as screens. For example, if you mutate the nuclease activity of Cas9, it still retains its ability to localize to the target site, so you can fuse Cas9 to transcriptional activators or repressors, and screen for transcriptional repression with CRISPR, as well as knock-out screens, says Pettitt. Theres also a whole range of CRISPR tools being developed that will edit bases by causing missense mutations rather than insertions or deletions, or causing methylation of DNA, or bringing in fluorescent proteins so you can visualize where the DNA sequences in the cells are. Its a measure of how flexible and useful CRISPR is in comparison to RNAi.

So will CRISPR be the one technology that everyone turns to for phenotypic screening in future? Im a firm believer that no technology answers every question, says Ebner. CRISPR is amazing, its use as a therapeutic or biologic is the stuff of science fiction. But as a tool for target identification, it comes with one important caveat. CRISPR knockout means exactly that it removes the potential protein that would otherwise be in the mix. Thats very different from a small compound inhibiting a protein that is still able to form a complex or that is just not active. Its the perfect example of a brilliant technology that is transformative, but it's not perfect. No technology is perfect.

References

1. Zheng W, Thorne N and McKew JC. Phenotypic screens as a renewed approach for drug discovery. Drug Discov. Today 2013; 18: 1067-1073.

2. Horvath P, Aulner N, Bickle M, et al. Screening out irrelevant cell-based models of disease. Nat Rev Drug Discov. 2016 Nov;15(11):751-769. doi: 10.1038/nrd.2016.175. Epub 2016 Sep 12.

3. Al Haj Zen A, Nawrot DA, Howarth A, et al. The Retinoid Agonist Tazarotene Promotes Angiogenesis and Wound Healing. Mol Ther. 2016 Oct;24(10):1745-1759. doi: 10.1038/mt.2016.153.

4.Lin et al. Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials. Science Translat Med. 2019; 11: (509). doi: 10.1126/scitranslmed.aaw8412

5.Findlay GM, Daza RM, Martin B et al. Accurate classification of BRCA1 variants with saturation genome editing. Nature. 2018 Oct; 562(7726): 217222. doi: 10.1038/s41586-018-0461-z

6.Pettitt et al. Genome-wide and high-density CRISPRCas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance. Nat Commun. 2018 May 10;9(1):1849. doi: 10.1038/s41467-018-03917-2.

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Phenotypic Screening Advances in Technologies and Techniques - Technology Networks

Recommendation and review posted by Bethany Smith

You probably know from experience that there is not as much information on small-cap companies as there is on large companies. Of course, this makes it really hard and difficult for individual investors to make proper and accurate analysis of certain small-cap companies. However, well-known and successful hedge fund managers like Jeff Ubben, George Soros and Seth Klarman hold the necessary resources and abilities to conduct an extensive stock analysis on small-cap stocks, which enable them to make millions of dollars by identifying potential winners within the small-cap galaxy of stocks. This represents the main reason why Insider Monkey takes notice of the hedge fund activity in these overlooked stocks.

CRISPR Therapeutics AG (NASDAQ:CRSP) was in 13 hedge funds' portfolios at the end of June. CRSP shareholders have witnessed a decrease in support from the world's most elite money managers of late. There were 14 hedge funds in our database with CRSP positions at the end of the previous quarter. Our calculations also showed that CRSP isn't among the 30 most popular stocks among hedge funds(view the video below). Video: Click the image to watch our video about the top 5 most popular hedge fund stocks.

5 Most Popular Stocks Among Hedge Funds

So, why do we pay attention to hedge fund sentiment before making any investment decisions? Our research has shown that hedge funds' small-cap stock picks managed to beat the market by double digits annually between 1999 and 2016, but the margin of outperformance has been declining in recent years. Nevertheless, we were still able to identify in advance a select group of hedge fund holdings that outperformed the market by 40 percentage points since May 2014 through May 30, 2019 (see the details here). We were also able to identify in advance a select group of hedge fund holdings that underperformed the market by 10 percentage points annually between 2006 and 2017. Interestingly the margin of underperformance of these stocks has been increasing in recent years. Investors who are long the market and short these stocks would have returned more than 27% annually between 2015 and 2017. We have been tracking and sharing the list of these stocks since February 2017 in our quarterly newsletter. Even if you aren't comfortable with shorting stocks, you should at least avoid initiating long positions in our short portfolio.

Oleg Nodelman EcoR1 Capital

Unlike former hedge manager, Dr. Steve Sjuggerud, who is convinced Dow will soar past 40000, our long-short investment strategy doesn't rely on bull markets to deliver double digit returns. We only rely on hedge fund buy/sell signals. We're going to take a look at the recent hedge fund action surrounding CRISPR Therapeutics AG (NASDAQ:CRSP).

Heading into the third quarter of 2019, a total of 13 of the hedge funds tracked by Insider Monkey held long positions in this stock, a change of -7% from the first quarter of 2019. By comparison, 17 hedge funds held shares or bullish call options in CRSP a year ago. With hedge funds' sentiment swirling, there exists a few noteworthy hedge fund managers who were boosting their holdings considerably (or already accumulated large positions).

No of Hedge Funds with CRSP Positions

Story continues

Among these funds, EcoR1 Capital held the most valuable stake in CRISPR Therapeutics AG (NASDAQ:CRSP), which was worth $75.8 million at the end of the second quarter. On the second spot was Cormorant Asset Management which amassed $33 million worth of shares. Moreover, Farallon Capital, Clough Capital Partners, and Valiant Capital were also bullish on CRISPR Therapeutics AG (NASDAQ:CRSP), allocating a large percentage of their portfolios to this stock.

Since CRISPR Therapeutics AG (NASDAQ:CRSP) has experienced declining sentiment from hedge fund managers, we can see that there exists a select few hedge funds that elected to cut their entire stakes in the second quarter. It's worth mentioning that Steven Boyd's Armistice Capital said goodbye to the biggest investment of the 750 funds monitored by Insider Monkey, comprising about $2.9 million in stock. Noam Gottesman's fund, GLG Partners, also said goodbye to its stock, about $1.8 million worth. These bearish behaviors are intriguing to say the least, as aggregate hedge fund interest fell by 1 funds in the second quarter.

Let's also examine hedge fund activity in other stocks similar to CRISPR Therapeutics AG (NASDAQ:CRSP). We will take a look at Box, Inc. (NYSE:BOX), MGE Energy, Inc. (NASDAQ:MGEE), Independent Bank Corp (NASDAQ:INDB), and AMN Healthcare Services Inc (NYSE:AMN). This group of stocks' market values are closest to CRSP's market value.

[table] Ticker, No of HFs with positions, Total Value of HF Positions (x1000), Change in HF Position BOX,27,395491,-5 MGEE,13,53798,4 INDB,11,16780,5 AMN,14,109685,3 Average,16.25,143939,1.75 [/table]

View table hereif you experience formatting issues.

As you can see these stocks had an average of 16.25 hedge funds with bullish positions and the average amount invested in these stocks was $144 million. That figure was $180 million in CRSP's case. Box, Inc. (NYSE:BOX) is the most popular stock in this table. On the other hand Independent Bank Corp (NASDAQ:INDB) is the least popular one with only 11 bullish hedge fund positions. CRISPR Therapeutics AG (NASDAQ:CRSP) is not the least popular stock in this group but hedge fund interest is still below average. This is a slightly negative signal and we'd rather spend our time researching stocks that hedge funds are piling on. Our calculations showed that top 20 most popular stocks among hedge funds returned 24.4% in 2019 through September 30th and outperformed the S&P 500 ETF (SPY) by 4 percentage points. Unfortunately CRSP wasn't nearly as popular as these 20 stocks (hedge fund sentiment was quite bearish); CRSP investors were disappointed as the stock returned -13% during the third quarter and underperformed the market. If you are interested in investing in large cap stocks with huge upside potential, you should check out the top 20 most popular stocks among hedge funds as many of these stocks already outperformed the market so far in 2019.

Disclosure: None. This article was originally published at Insider Monkey.

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Is CRISPR Therapeutics AG (CRSP) Going To Burn These Hedge Funds ? - Yahoo Finance

Recommendation and review posted by Bethany Smith

23 Oct 2019

A multi-institutional group, including members of the Tau Consortium, unveiled a stem cell tool kit for scientists studying primary tauopathies. In the November 12 issue of Stem Cell Reports, researchers co-led by Celeste Karch ofWashington University, St. Louis, and Alison Goate and Sally Temple of Icahn School of Medicine in New York, describe a collection of fibroblasts, induced pluripotent stem cells, and neural precursor cells. The cells come from 140 skin samples, some given by donors with richly documented clinical histories who carry pathogenic MAPT mutations or risk variants. Others come from noncarrier family members, patients with a sporadic tauopathy, and cognitively normal controls. The set includes induced pluripotent stem cell lines from 31 donors and 21 CRISPR-engineered isogenic lines. The cells are available to other researchers for study.

These types of high-quality repositories are becoming increasingly important for the scientific community, Clive Svendsen of the Cedars-Sinai Medical Center in Los Angeles wrote to Alzforum.

This is the way the field is going, agreed Lawrence Golbe of CurePSP, New York. Golbes organization funds research into progressive nuclear palsy (PSP) and related disorders, and collaborates with the Tau Consortium on other projects. Enthusiastic about the resources potential, Golbe hopes CurePSP grantees will get an automatic pass to use the cells.

Choice Mutations. Cells in the new iPSC collection carry some of the most common MAPT mutations, covering a wide range of clinical and neuropathological phenotypes of frontotemporal lobe dementia (FTLD)-Tau. [Courtesy of Karch et al., 2019.]

Tauopathies have proven difficult to study in animal models, in part because unlike other neuropathologies, they seem to afflict only humans (Heuer et al., 2012). Moreover, while adult human brains express approximately equal amounts of the tau spliced isoforms 3R and 4R, rodents produce almost exclusively 4R (Trabzuni et al., 2012). This is problematic. For example, leading proposals to explain how tau mutations cause disease point to abnormalities in splicing and microtubule binding, which differ between isoforms. The models we had been focusing on were not capturing the complexity of MAPT in human cells, said first author Karch. As a result, human induced pluripotent stem cells (iPSCs) have been gaining popularity in the field. The NINDS Human Cell and Data Repository is helping meet the demand by offering iPSC lines derived from 10 patients harboring MAPT mutations.

However, Karch and her collaborators think the field could benefit from a larger and more diverse collection of human cells, including isogenic iPSC lines. To accomplish this, they collected skin samples from 140 people carrying MAPT pathogenic mutations or risk variants, non-mutation carriers, and patients with sporadic PSP or corticobasal syndrome (CBS), most with comprehensive clinical histories. Although a few cells came from the NINDS repository, most came from patients participating in longitudinal studies at the Memory and Aging Center at the University of California, San Francisco, and the Knight Alzheimer Disease Research Center at WashU. The clinical records of most of these patients include detailed neurological and neuropathological workups, as well as fluid biomarkers and neuroimaging data collected from MRI, A-PET, and tau-PET studies.

To capture a broad range of phenotypes associated with some of the most common MAPT mutations, the authors created 36 fibroblast lines and 29 iPSC lines from individuals carrying the P301L, S305I,IVS10+16, V337M, G389R, and R406W mutations, as well as from carriers of the A152T variant, which increases the risk for both PSP and CBS (image above). The latter could be particularly useful for dissecting the mechanisms that underlie the phenotypic differences between the two diseases. The researchers also obtained iPSC lines from two noncarrier family members, and two people who suffered from autopsy-confirmed sporadic PSP. In addition, they stored fibroblast lines from 12 patients with sporadic PSP, five with CBS, 10 with a mixed PSP/CBS presentation, and 69 cognitively normal controls.

Biopsies are available for 27 of the 31 patients whose cells were used to generate iPSCs, and autopsy data for seven, including the two cases of sporadic PSP.

Importantly, the researchers edited 21 iPSC lines using CRISPR/Cas 9. They corrected cells with these mutations: MAPT IVS10+16,P301L, S305I, R406W, and V337M. Conversely, they inserted into control iPSCs these mutations: R5H, P301L,G389R, S305I, or S305S.

The authors also created a stem cell line carrying MAPT P301S,a mutation commonly overexpressed in tauopathy mouse models but not present in the available donors, by editing the P301L line. Isogenic lines are so powerful, particularly in these diseases which are so variable in their onset and progression, even within the same family, said Karch. Gnter Hglinger and Tabea Strauss at the German Center for Neurodegenerative Disease (DZNE) in Munich agreed. Having a pool of cell lines with different disease-linked mutations and risk variants from several individuals and their isogenic control cells is an excellent resource for the research community to enlighten disease mechanisms, they wrote (full comment below).

Several of the reported lines have already starred in recent studies of tauopathy mechanisms and candidate therapies (e.g., Sep 2019 conference news; Nakamura et al., 2019; Hernandez et al., 2019; Silva et al., 2019).

Karch and colleagues have partially differentiated some of the iPSCs and stored them as neural progenitor cells (NPCs), so that researchers can relatively easily thaw, expand, and differentiate them into neurons. These NPCs have proved useful for large-scale functional-genomics studies, proteomics, and genetic modifier screens (e.g., Cheng et al., 2017; Boselli et al., 2017;Tian et al., 2019).

In addition, the authors inserted a neurogenin-2 transgene into two healthy controls and two MAPT mutant stem cells, P301L and R406W. Neurogenin-2 enables low-cost, large-scale differentiation of stem cells into homogenous excitatory neurons. These transgenic cells are particularly useful for high-throughput drug screens (Wang et al., 2017; Sohn et al., 2019).

Researchers can request all the reported cells online at http://neuralsci.org/tau. They must provide a summary of experimental plans, an institutional material transfer agreement, and a nominal fee to cover maintenance and distribution costs. Karch said the process resembles that of the Coriell Institute and the NINDS repository. Our goal is to share with as few hurdles as possible, she said.

While the authors are still reprogramming fibroblasts they have already collected, they also plan to add more causative mutations, generate more isogenic lines, and obtain more cells from members of the same families to help shed light on phenotypic variability. In addition, Karch said, she hopes repository users will resubmit lines with new modifications they generate.

Jeffrey Rothstein, Johns Hopkins University, Baltimore, welcomed the new resource. I think it is great they have assembled this collection, he said. Rothstein founded and co-directs the Answer ALS research project, which has amassed 600 iPSC lines from controls and patients with amyotrophic lateral sclerosis (ALS).

Rothstein suggested the tauopathy collection may want to prioritize adding cells from donors with the most common form of disease, that is, sporadic. His group aims to generate 1,000 iPSC lines, with a large fraction representing sporadic diseasealso the most common form of ALSto identify the most prevalent disease subtypes. One strategy that has helped his group build their collection, he said, is using peripheral blood mononuclear cells instead of fibroblasts to create iPSCs. More donors are willing to donate blood than have a piece of skin punched out. In addition, iPSCs derived from blood cells are genetically more stable, he noted.

Rothstein emphasized the importance of assembling a large collection of healthy controls. Although isogenic controls are of great value, he cautioned they can be subject to artifacts. One problem is that the cell population can change due to selective pressures during CRISPR editing (Budde et al., 2017). To address this, Karch and colleagues are collecting not only modified iPSC clones, but also control clones that have gone through the editing pipeline but remain unmodified.

Stem-cell users studying tauopathies face another challenge: iPSC-derived neurons express primarily the fetal isoform of tau, 3R0N. However, citing a study that shows three-dimensional neuronal cultures switch to the adult profile relatively quickly (Miguel et al., 2019), Hglinger and Strauss wrote, [It] allows us to be optimistic that current challenges of this model system can be overcome in the future.Marina Chicurel

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Introducing: iPSC Collection from Tauopathy Patients - Alzforum

Recommendation and review posted by Bethany Smith

A gene therapy for a rare blood disorder has shown what the manufacturer calls the first evidence of long-term improvement associated with the disease.

New York-based Rocket Pharmaceuticals said Thursday that it had presented long-term follow-up data from the Phase I/II study of RP-L102, its gene therapy for Fanconi anemia, at the annual congress of the European Society of Cell and Gene Therapy in Barcelona, Spain. The company said it represented the first evidence of long-term improvement and stabilization in blood counts and durable mosaicism among patients who received the therapy without the use of the conditioning regimens normally used for allogeneic stem cell transplants, which the company calls Process A.

Shares of Rocket were up slightly on the Nasdaq following the news. RP-L102 is a lentiviral vector-based gene therapy. Most other gene therapies in development, and both of the currently marketed ones Spark Therapeutics Luxturna (voretigene neparvovec-rzyl) and Novartis Zolgensma (onasemnogene abeparvovec-xioi) are adeno-associated viral vector-based.

According to the data, representing four of nine patients, there were improved blood counts and long-term bone marrow mitomycin C (MMC) resistance, thereby indicating durable phenotypic correction. The data met or exceeded a 10 percent threshold that the company said the Food and Drug Administration and European Medicines Agency had agreed to for its upcoming Phase II registration study, for which it plans to start enrolling patients by the end of the year.

FA is a rare, genetic bone marrow failure disorder, half of whose patients are diagnosed before the age of 10, while about 10 percent of patients are diagnosed as adults, according to the National Organization for Rare Disorders. It is often associated with progressive deficiency of production of red and white blood cells and platelets in the bone marrow and can eventually lead to certain solid and liquid tumor cancers. It occurs in 1-in-136,000 births and is more common among Ashkenazi Jews, Spanish Roma and black South Africans.

These results indicate the feasibility of engraftment in FA patients using autologous, gene corrected [hematopoietic stem cells] in the absence of any conditioning regimen, said Dr. Juan Bueren, scientific director of the FA gene therapy program at Spains Center for Energy, Environmental and Technological Research, in a statement. This indicates the potential of this therapeutic approach as a definitive hematologic treatment, while avoiding the burdensome side effects associated with allogeneic transplant, including the risk of post-transplant mortality and a substantially higher risk of head and neck cancer.

Photo: virusowy, Getty Images

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Rocket's gene therapy shows long-term efficacy in rare blood disorder - MedCity News

Recommendation and review posted by Bethany Smith

The National Institutes of Health and the Bill and Melinda Gates Foundation will together invest at least $200 million over the next four years to develop gene-based cures for sickle cell disease and HIV with an attribute even rarer in the world of genetic medicine than efficacy, the groups announced on Wednesday: The cures, they vowed, will be affordable and available in the resource-poor countries hit hardest by the two diseases, particularly in Africa.

The effort reflects growing concerns that scientific advances in genetic medicine, both traditional gene therapies and genome-editing approaches such as CRISPR, are and will continue to be prohibitively expensive and therefore beyond the reach of the vast majority of patients. Spark Therapeutics Luxturna, a gene therapy for a rare form of blindness, costs $425,000 per eye, for instance, and genetically engineered T cells (CAR-Ts) to treat some blood cancers cost about the same.

With CRISPR-based treatments already being tested in clinical trials for sickle cell disease, the blood disorder beta thalassemia, and another form of blindness, and with additional CRISPR treatments in development, scientists, ethicists, and health policy experts have grown increasingly concerned that the divide between haves and have-nots will grow ever-wider.

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Gene-based treatments are largely inaccessible to most of the world by virtue of the complexity and cost of treatment requirements, which currently limit their administration to hospitals in wealthy countries, the NIH said in a statement. To help right that, its collaboration with the Gates Foundation aims to develop curative therapies that can be delivered safely, effectively and affordably in low-resource settings.

Scientists whose research focuses on gene-based cures welcomed the infusion of funding and the recognition that genetic cures are on track to be unaffordable to the majority of patients. But they noted one irony. The most effective sickle cell drug, hydroxyurea, has hardly even been studied in sub-Saharan Africa, let alone made widely available. Yet a 2019 study found that giving children the drug cut their death rate by two-thirds and halved the pain crises that are common in sickle cell disease, caused by misshapen red blood cells that cannot flow through blood vessels.

The NIH-Gates collaboration is tremendously exciting and has the potential to have a great impact on sickle cell disease in sub-Saharan Africa, said Dr. Vijay Sankaran of the Dana-Farber/Boston Childrens Cancer and Blood Disorders Center, who has done pioneering research on genetic cures for the disease. But my hesitation is that even the inexpensive therapies we have today, such as hydroxyurea, are largely unavailable there. The question is, how do we best approach this disease, with therapies that are working today or with genetic therapies that might work?

The same concerns surround HIV. Very inexpensive less than $100 per year in the U.S. antiretroviral drugs can keep the virus in check, but only 67% of HIV-positive adults and 62% of HIV-positive in children in east and southern Africa are estimated to be on antiretroviral treatment.

The new collaboration aims to move gene-based cures into clinical trials in the U.S. and countries in sub-Saharan Africa within the next seven to 10 years, and to eventually make such treatments available in areas hardest hit by sickle cell disease and HIV/AIDS. The idea is to focus on access, scalability, and affordability to make sure everybody, everywhere has the opportunity to be cured, not just those in high-income countries, NIH Director Francis Collins said in a statement. We aim to go big or go home. But the challenge is enormous, he told reporters on Wednesday: Im not going to lie. This is a bold goal.

An estimated 95% of the 38 million people with HIV live in the developing world, with 67% in sub-Saharan Africa. Up to 90% of children with sickle cell disease in low-income countries die before they are 5 years old. In the U.S., the life expectancy for people with sickle cell disease is in the low 40s.

The NIH and the Gates Foundation will fund research to identify potential gene-based cures for sickle cell and HIV, and also work with groups in Africa to test those cures in clinical trials.

The science of genetic cures for both diseases is within reach, experts say. CRISPR Therapeutics and Vertex (VRTX) are already running a clinical trial for sickle cell disease, using the CRISPR genome editor to do an end-run around the disease-causing mutation in the hemoglobin gene: The therapy releases the brake on red blood cells production of fetal hemoglobin, whose production shuts off in infancy but which does not have the sickling damage of adult hemoglobin.

Developing effective, safe genetic cures for sickle cell and HIV would be only a first step, however. As currently conceived, such therapies require advanced medical facilities to draw blood from patients, alter their cells genomes in a lab, give the patients chemotherapy to kill diseased blood-making cells, and then perform whats essentially a bone marrow transplant, followed by monitoring patients in a hospital for days to prevent infection and provide intensive medical support, said Dr. Dan Bauer, a sickle cell expert at Boston Childrens.

He called the NIH-Gates effort terrific, but cautioned that delivering advanced gene therapies requires tremendous effort, extended hospitalization, and large supplies of blood products. All of those requirements mean that even if a CRISPR-based cure for sickle cell disease or HIV were provided at cost, there will still be barriers to access.

Recognizing that, Collins said, a genetic cure would have to be given directly into patients (in vivo), presumably through an infusion, rather than by treating blood or other cells removed from patients and genetically transformed in a lab (ex vivo). That could avoid the resources needed for and the complications that can occur with ex vivo therapies, said Sankaran, who has discussed the approach with Gates officials.

This story has been updated with additional comments.

Continue reading here:
NIH, Gates Foundation aim to bring genetic cures to the poor - STAT

Recommendation and review posted by Bethany Smith

Assessing the challenges

As part of the CRA analysis, the team reached out to a range of industry stakeholders including experts in drug development and commercialisation, academic researchers, investors and payers for insights about emerging annuity pricing models and the challenges they can present.

Research also included a global review of launch dates and regulatory information related to several cell and gene therapies.

Input from industry insiders and experts identified a range of concerns associated with annuity payment models, including a potentially significant impact on cost of capital and company valuations, costs and burden of long-term patient monitoring, the need to make reimbursement decisions based on very limited long-term clinical data, and the need to consider entirely new business models and forecasting strategies based on extended payment schedules.

Despite the challenges, some cell and gene therapy companies have already launched products based on annuity pricing models. GlaxoSmithKline (GSK) launched its gene therapy STRIMVELIS, a one dose treatment for severe combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID), in Europe in 2016 with an outcomes-based annuity pricing model.

Under the terms of this model, payments to GSK by payers are spread out over a pre-determined timeline for each treated patient. The model confirms that GSK must return a portion of the reimbursement to the Italian Medicines Agency if the drug does not demonstrate a sufficient level of efficacy based on pre-determined outcomes measures.

In their assessment, based on the mutually determined outcomes measures, GSK projected that aboutone in six treatments on average might need to be partially refunded.

The financial impact of annuity payment models

Annuity models require manufacturers to consider several factors that can increase their own operational costs as well as the cost of capital. With annuity models, the risk that a payer might not be a viable long-term business entity or may contest a payment schedule could mean a potentially devastating disruption in revenue fora manufacturer.

While the use of insurer-backed annuity payments as collateral for secured loans can help mitigate this risk, in considering this option manufacturers need to carefully consider multiple factors, including trends in interest rates and the duration of the annuity contract, the cost of capital based on a lenders fees, operational repayment milestones and the expected costs of goods.

Both manufacturers and payers must also complete risk assessments based on available data, which will often be more limited than data used in traditional outcomes and risk assessments.

Banks and other lenders will also likely complete their own due diligence in evaluating many factors, including levels of payer interest, patient outcomes measures and the terms of annuity contracts to determine their own acceptable level of risk, often with limited relevant experience. In many cases, lenders will also require drug developers to provide audited cash flow statements.

Optimal strategies for mitigating risk

As progress in the development of cell and gene therapies continues to advance, payers andhealth systems can anticipate the introduction of many new high-priced drugs in the near future.

While annuity pricing models are already a widely considered option to address the unique reimbursement issues associated with cell and gene therapies, developing and implementing these plans successfully will require careful analysis and successful efforts in building consensus among all stakeholders.

The risks may be especially acute among biotechnology companies with only one drug on the market. Manufacturers will need to bring together the full range of resources and expertise necessary to assess the impact these models will have on capacity, cash flow and long-term business planning.

To achieve this goal, drug developers will need to reach out to a broad set of stakeholders for guidance and expertise.

They may need to work closely with finance providers such as banks and other lenders and seek collaborations with consultants in market access early in a development programme to begin what is likely to be a long-term initiative in planning and programme execution.

It is likely that there will not be one simple solution. Effective approaches in reimbursement of cell and gene therapies may need to include elements from several potential models including, but not limited to, annuity-based models.

But the progress in research means that development of innovative pricing models that optimise benefits and balance risks for manufacturers, payers and health systems will become increasingly time sensitive as more paradigm-changing cell and gene therapies advance toward commercialisation.

The views expressed herein are the authors and not those of Charles River Associates (CRA) or any of the organisations with which the author is affiliated.

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Assessing the risks in annuity pricing models - PMLiVE

Recommendation and review posted by Bethany Smith

October 25, 2019

Researchers working to find a cure for malignant mesothelioma are acutely aware of the need for speed: the disease is always considered fatal, and more people are diagnosed with and die of the condition every day. Still, there is a process that must be followed: theories need to be tested in the laboratory before people, and this slows everything down. Recently, researchers at the University of Pennsylvania had the opportunity to see the human results of a protocol that had shown promise with lab animals but is not yet ready for patient testing. They reported a significant positive outcome.

Previous animal research had combined radiotherapy with immune-gene therapy in the treatment of mice with malignant pleural mesothelioma, and had revealed both disease regression and what is called an abscopal effect the combination not only affected tumors that were targeted by radiation but also those that were outside of the range of the therapy.

The researchers from thePerelman School of Medicine at the University of Pennsylvaniadid not intend to test the effect on humans, but ended up doing so with a 67-year-old male patient with malignant pleural mesothelioma who signed on for a clinical trial of immuno-gene therapy. Though his tumor responded positively he needed to stop the treatment due to complications from his tumor for which he was given palliative radiation therapy followed by a standard course of chemotherapy.

Two months after having completed the course of palliative radiotherapy, the man had a CT scan of his chest that revealed that the targeted mesothelioma tumor had shrunk. Remarkably, the treatment had also shrunk tumors that were outside of the irradiated field. This is the first report of a patient having an abscopal effect following radiotherapy and immune-gene therapy. Writing of his results, lead researcher Andrew R. Barsky said, The patients response to immuno-gene therapy, palliative radiotherapy and subsequent chemotherapy, both in-field and out-of-field, was dramatic, and notably more pronounced than what is generally achievable for even well-responding malignant pleural mesothelioma patients In fact, his exaggerated response was far greater than would be expected based upon the volume of disease irradiated and radiation dose employed. The researchers plan to pursue further study of this dynamic.

If you or someone you love has been diagnosed with malignant mesothelioma, positive outcomes like these offer reason for hope. For more information on treatment protocols available to you, contact the Patient Advocates at Mesothelioma.net at1-800-692-8608.

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Let's play a game of word association. I'll go first.

Cell Therapy

What words spring to mind? CRISPR? Medicine? Genetic disorders? Cancer? Gene therapy?

What about green tea? Unlikely, I imagine.

But in a new study published today in Science Advances, researchers from East China Normal University have created an elegant system for activating genetically edited cells using green tea.1Realizing the promise of cell therapiesEngineered cell therapies, deemed the "next frontier" in modern medicine, contain specific cellular material that triggers a desired effect in vitro or in vivo. Such therapies are in development in laboratories across the globe for an array of different conditions, including acute myocardial infarction (heart attack), brain cancer, breast cancer, diabetes and liver diseases. They offer a novel avenue of therapeutics for patients suffering from diseases for which treatment options are limited.For their efficacious and safe use in the clinic, scientists need to be able to regulate the activity of these cells in vivo. Essentially, they require a "remote control". This has proven a major barrier for the delivery of cell therapies to patients. Initial work in this field has adopted antibiotics such as doxycycline or tetracycline as remote-control triggers for gene expression in the cells. However, regular use of antibiotics may result in antibiotic resistance and other adverse side effects.So, what alternatives exist?Haifeng Ye, Professor at East China Normal University, says "Ideal trigger molecules for clinical biomedical applications would be natural, non-toxic, highly soluble, inexpensive, and perhaps even beneficial to health."Previous studies have reported that remote control switches can be activated through the use of food or cosmetic preservatives, vanillic acid, benzoate and phloretin for example. These molecules do not naturally occur in food however, and the safety implications of their long-term use is not well known.A green solution?Nothing beats a good cup of tea. It is the second most popular beverage on the planet (following water) and can be found in the household cupboards of 80% of Americans. Tea is available in a variety of forms, including but not limited to black tea, oolong tea, white tea and green tea. A plethora of research studies have documented the numerous health benefits of green tea consumption, including anticarcinogenic, anti-inflammatory, antimicrobial, and antioxidant effects.The components of green tea most heavily researched with regards to health are the polyphenols, of which the most pertinent are flavonoids, and the most pertinent flavonoids are the catechins.2Post green-tea consumption, the tea catechins and phenolic acids undergo metabolic processing to form the antioxidant protocatechuic acid (PCA). In their latest study, Ye and team have utilized this antioxidant as a "remote control" for activating gene switches in cells. "PCA is a major tea catechin compound produced by humans following green tea consumption that has powerful antioxidant activity. Therefore, in this study, we showed the use of protocatechuic acid (we call it PCA), a metabolite after tea drinking, as a trigger molecule," Ye told Technology Networks.PCA-inducible gene switchesIn the study, the scientists engineered PCA-inducible gene switches in mammalian cells. Initially, they explored the potential for using PCA to monitor cell-based long-term therapies in vivo by integrating the genetic switch into HEK-293 cells and found that the cell line demonstrated reversible and tunable induction kinetics, which the authors regard as "excellent switching performance". This was characterized by negligible basal expression and nonsaturating increases in the transgene output over the course of a 15-day trial.Next, they microencapsulated and implanted the HEK cells into mice. Ye tells us, "The alginate-poly (L-lysine)-alginate-based encapsulation technology was used in our study for cell therapy. This clinically validated implant technology enables the free diffusion of metabolites, nutrients and proteins of lower molecular weights (<72 kDa) across the biocompatible capsule membrane while shielding their cellular content from physical contact with the hosts immune system. The implant technology has been successfully validated in human clinical trials and the performance of the material is continuously improved for clinical applications."The researchers found that, regardless of delivery method (intraperitoneal, oral intake from water, or oral intake from concentrated green tea), PCA could control the secretion of a reporter protein, SEAP, in a dose-dependent manner.Making CRISPR more crisp?CRISPR gene-editing shows promise in revolutionizing personalized medicine. A notable key issue with CRISPR, however, is the "off target" effects that limit its specificity. In this study, the scientists used the PCA-responsive cells to perform more targeted CRISPR gene editing: "By applying newly-designed fusion-protein-based PCA-controlled gene switches to Pol III promoters, we created trigger-inducible expression systems for gRNAs to program PCA-mediated CRISPR/Cas9-activity," says Ye.Exploring diabetes treatment with PCA-induced cell therapyYe and colleagues next tested the potential of the PCA remote control system for treating experimental diabetes using a mouse model. Using the switch, they engineered two different cell lines: one that enabled PCA-inducible expression of the reporter protein SEAP and insulin, and the other producing a short variant of human glucagon-like peptide 1 and SEAP. Implantation of these cells into mouse models of type 1 diabetes and type 2 diabetes mellitus resulted in restored homeostatic fasting blood glucose concentrations and glucose tolerance upon PCA injection.Recognizing that the translation of research findings from mouse models to humans in the clinic can be problematic, the scientists then decided to explore the PCA remote control switch efficacy in non-human primate models of diabetes. In parallel to the treatment efficacy observed in the type 2 diabetic mice, daily oral administration of PCA rapidly increased the expression of glucagon-like peptide 1 and restored glucose homeostasis in diabetic monkeys.In terms of safety, blood biochemical analyses related to inflammatory responses found that white blood cell count, lymphocytes, monocytes, eosinophils, and basophils, did not increase at any point during the treatment when compared with pre-treatment.The study findings certainly excite the authors, "Although there have not yet been preclinical studies for the application of engineered cellbased therapies in humans, this first-in-monkey study demonstrates the feasibility of safely and successfully scaling up a treatment strategy by controlling microencapsulated engineered cells to release therapeutic outputs from animals such as mice to larger NHPs. Therefore, this study substantiates the medical utility of concepts developed in synthetic biology," they note in the discussion of the paper.How much tea is too much tea?Hypothetically, if this therapy was to reach the clinic, I ponder over the possibility of an individual consuming "too much" green tea, and how this might impact the therapy. Ye is quick to inform me that this would not be an issue, "Only custom prepared concentrated green tea can activated the implanted designer cells. The normal green tea drinks cannot activate the implanted cells because of low concentration," he says.The future looks greenThe study is comprehensive, assessing the PCA "switch" in a variety of cell lines and mammalian models with a variety of control measures in place.Thus, in which direction will this research go next? I ask Ye, who tells me, " We will next focus on solving the following limitations:(1) The PCAON-switch was stably integrated into [the] genome by a "Sleeping Beauty" transposon system. Due to a random integration, unwanted insertional mutagenesis might occur. We will next consider using gene editing tools, such as CRISPR, to enable facile and permanent integration of the switch into the targeted genomic sequences in human cells without insertional mutagenesis;(2) The chassis of the HEK-293 cells are easily handled, transfected, and compatible to the PCAON-switch. For translational applications, they must also be safe (no side effects) in humans. Hence, we will test the therapeutic efficiency of the PCAON-switch in autologous parental cells from patients own mesenchymal stem cells, which may provide immunocompatible and noncarcinogenic autologous or allogeneic cell sources;(3) The lifespan of the designer cells inside the alginate microcapsules is an imperative issue. To realize long-term cell therapy, we will further improve the encapsulation technology."Haifeng Ye, Professor at East China Normal University, was speaking with Molly Campbell, Science Writer, Technology Networks.References:1. A green teatriggered genetic control system for treating diabetes in mice and monkeys," by J. Yin; L. Yang; K. Dong; J. Jiang; S. Xue; Y. Xu; X. Wang; H. Ye at East China Normal University in Shanghai, China; L. Mou; Y. Lu at First Affiliated Hospital of Shenzhen University in Shenzhen, China.2. Reygaert. 2018. Green Tea Catechins: Their Use in Treating and Preventing Infectious Diseases. Biomed Research International. doi: 10.1155/2018/9105261.

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Green Tea Acts as a "Remote Control" To Switch on Cell Therapy - Technology Networks

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 a laminated 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 of 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.

* * *

Ilana Yurkiewicz, M.D., is a physician at Stanford University and a medical journalist. She is a former Scientific American Blog Network columnist and AAAS Mass Media Fellow. Her writing has also appeared in Aeon Magazine, Health Affairs, and STAT News, and has been featured in "The Best American Science and Nature Writing."

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

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The Possibilities and Risks of Genetically Altering Immune Cells to Fight Cancer - Smithsonian.com

Recommendation and review posted by Bethany Smith

MENLO PARK, Calif., Oct. 24, 2019 (GLOBE NEWSWIRE) -- Adverum Biotechnologies, Inc.,(Nasdaq: ADVM), a clinical-stage gene therapy company targeting unmet medical needs in ocular and rare diseases, today announced that the first patient was dosed in the third cohort (n=9) of the ongoing OPTIC phase 1 clinical trial for ADVM-022 for the treatment of neovascular or wet age-related macular degeneration (wet AMD). Patients in this cohort are receiving a single intravitreal injection of gene therapy candidate ADVM-022 at a dose of 2 x 10 ^11 vg/eye.

We are excited to report dosing the first patient in the third cohort of OPTIC. This expansion of OPTIC will generate important clinical data to support the further development of ADVM-022, said Aaron Osborne, MBBS, chief medical officer of Adverum. Based on the recently presented data from the first cohort of OPTIC, which demonstrated a sustained response to a single injection of ADVM-022 out to a median of 34 weeks, with no patient in the first cohort requiring anti-VEGF rescue therapy, we believe that ADVM-022 has the potential to be a transformative treatment option for patients with wet AMD.

Dante Pieramici, M.D., co-director of the California Retina Research Foundation, Managing Partner of The California Retina Consultants and investigator in the OPTIC trial, said, An intravitreal gene therapy that can significantly reduce the number of injections required to maintain vision would be welcomed by patients with wet AMD as well as their caregivers and physicians. Im encouraged by the recently presented clinical data from the first cohort of the OPTIC trial showing that the therapy was safe and well tolerated with no rescue injections required in patients who previously required frequent anti-VEGF injections to control their wet AMD.

About the OPTIC Phase 1 Trial of ADVM-022 in Wet AMDThe multi-center, open-label, phase 1 trial is designed to assess the safety and tolerability of a single intravitreal (IVT) administration of ADVM-022 in patients with wet AMD who are responsive to anti-vascular endothelial growth factor (VEGF) treatment. In the first cohort, patients (n=6) received ADVM-022 at a dose of 6 x 10^11 vg/eye and in the second cohort (n=6) patients received ADVM-022 at a dose of 2 x 10^11 vg/eye. In the third cohort (n=9), patients are receiving ADVM-022 at a dose of 2 x 10^11 vg/eye and in the fourth cohort (n=9), patients will receive ADVM-022 at a dose of 6 x 10^11 vg/eye. Patients in the first and second cohorts received prophylactic oral steroids, while patients in the third and fourth cohorts will receive prophylactic steroid eye drops. The primary endpoint of the trial is the safety and tolerability of ADVM-022 after a single IVT administration. Secondary endpoints include change in best-corrected visual acuity (BCVA), change in central subfield thickness (CST) and macular volume, as well as mean number of anti-VEGF rescue injections and percentage of patients needing anti-VEGF rescue injections. Each patient enrolled in the study will be followed for a total of two years.

Eight leading retinal centers acrossthe United Statesare participating in the OPTIC phase 1 trial for ADVM-022. For more information on the OPTIC phase 1 clinical trial of ADVM-022 in wet AMD, please visithttps://clinicaltrials.gov/ct2/show/NCT03748784.

About ADVM-022 Gene TherapyADVM-022 utilizes a propriety vector capsid, AAV.7m8, carrying an aflibercept coding sequence under the control of a proprietary expression cassette. ADVM-022 is administered as a one-time intravitreal injection, designed to deliver long-term efficacy, reduce the burden of frequent anti-VEGF injections, optimize patient compliance, and to improve vision outcomes for wet AMD and diabetic retinopathy patients.

In recognition of the need for new treatment options for wet AMD, the U.S. Food and Drug Administration granted Fast Track designation for ADVM-022 for the treatment of this disease.

Adverum is currently evaluating ADVM-022 in the OPTIC study, a phase 1 clinical trial in patients 50 years and older with wet AMD. Additionally, Adverum plans to submit an Investigational New Drug Application for ADVM-022 for the treatment of diabetic retinopathy to the U.S. Food and Drug Administration in the first half of 2020.

About Adverum Biotechnologies, Inc.Adverum Biotechnologies (Nasdaq: ADVM) is a clinical-stage gene therapy company targeting unmet medical needs for serious ocular and rare diseases. Adverum is evaluating its novel gene therapy candidate, ADVM-022, as a one-time, intravitreal injection for the treatment of its lead indication, wet age-related macular degeneration. For more information, please visit http://www.adverum.com

Forward-looking StatementsStatements contained in this press release regarding events or results that may occur in the future are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Such statements include, but are not limited to statements regarding: Adverums plans for advancing ADVM-022; the potential benefits of ADVM-022: the expected timing of submitting an IND for diabetic retinopathy, all of which are based on certain assumptions made by Adverum on current conditions, expected future developments and other factors Adverum believes are appropriate in the circumstances. Adverum may not achieve any of these in a timely manner, or at all, or otherwise carry out the intentions or meet the expectations disclosed in its forward-looking statements, and you should not place undue reliance on these forward-looking statements. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, which include risks inherent to, without limitation: Adverums novel technology, which makes it difficult to predict the time and cost of product candidate development and obtaining regulatory approval; the results of early clinical trials not always being predictive of future results; the potential for future complications or side effects in connection with use of ADVM-022; obtaining regulatory approval for gene therapy product candidates; enrolling patients in clinical trials; reliance on third parties for conducting the OPTIC trial and vector production; and ability to fund operations through completion of the OPTIC trial and thereafter. Risks and uncertainties facing Adverum are described more fully in Adverums Form 10-Q filed with the SEC on August 8, 2019 under the heading Risk Factors. All forward-looking statements contained in this press release speak only as of the date on which they were made. Adverum undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.

Investor and Media Inquiries:

Investors:Myesha LacyAdverum BiotechnologiesVice President, Investor Relations and Corporate Communicationsmlacy@adverum.com1-650-304-3892

Media:Cherilyn Cecchini, M.D.Account Supervisorccecchini@lifescipublicrelations.com1-646-876-5196

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Adverum Biotechnologies Doses First Patient in Third Cohort of OPTIC Phase 1 Clinical Trial of ADVM-022 Intravitreal Gene Therapy for Wet AMDPatients...

Recommendation and review posted by Bethany Smith

NIH launches new collaboration to develop gene-based cures for sickle cell disease and HIV on global scale

The National Institutes of Health plans to invest at least $100 million over the next four years toward an audacious goal: develop affordable, gene-based cures for sickle cell disease (SCD) and HIV. The Bill & Melinda Gates Foundation will also invest $100 million toward this goal. The intention is for these cures to be made globally available, including in low-resource settings.

This initiative follows a bold announcement made earlier this year by President Donald J. Trump during the State of the Union Address to end the HIV epidemic in the United States in the next 10 years.Ending the HIV Epidemic: A Plan for Americaaims to leverage the powerful data and tools now available to reduce new HIV diagnoses in the United States by 75% in five years and by 90% by 2030.The Trump Administration has also elevated the attention paid to sickle cell disease, identifying it as an intractable health challenge with the potential for dramatic advances in the coming years.

Dramatic advances in genetics over the last decade have made effective gene-based treatments a reality, including new treatments for blindness and certain types of leukemia. Yet these breakthroughs are largely inaccessible to most of the world by virtue of the complexity and cost of treatment requirements, which currently limit their administration to hospitals in wealthy countries. To make these treatments effective and available for SCD and HIV, which disproportionately affect populations living in Africa or of African descent, new investment is needed to focus research on the development of curative therapies that can be delivered safely, effectively and affordably in low-resource settings.

The collaboration between the NIH and the Gates Foundation sets out a bold goal of advancing safe, effective and durable gene-based cures to clinical trials in the United States and relevant countries in sub-Saharan Africa within the next seven to 10 years. The ultimate goal is to scale and implement these treatments globally in areas hardest hit by these diseases.

This unprecedented collaboration focuses from the get-go on access, scalability and affordability of advanced gene-based strategies for sickle cell disease and HIV to make sure everybody, everywhere has the opportunity to be cured, not just those in high-income countries, said NIH Director Francis S. Collins, M.D., Ph.D.We aim to go big or go home.

The collaboration will align aggressive, high-reward research efforts to accelerate progress on shared gene-based strategies to cure SCD and HIV. Both organizations also will continue to invest in other parallel research efforts on cures for SCD and HIV outside of this collaboration.

In recent years, gene-based treatments have been groundbreaking for rare genetic disorders and infectious diseases, said Trevor Mundel, M.D., Ph.D., President, Global Health Program, Bill & Melinda Gates Foundation. While these treatments are exciting, people in low- and middle-income countries do not have access to these breakthroughs. By working with the NIH and scientists across Africa, we aim to ensure these approaches will improve the lives of those most in need and bring the incredible promise of gene-based treatments to the world of public health.

SCD and HIV are major burdens on health in low-resource communities around the world. Approximately 95% of the 38 million people living with HIV globally are in the developing world, with 67% in sub-Saharan Africa, half of whom are living untreated. Fifteen million babies will be born with SCD globally over the next 30 years, with about 75% of those births occurring in sub-Saharan Africa. An estimated 50-90% of infants born with SCD in low-income countries will die before their 5th birthday and SCD is identified as the underlying cause of about 1 in 12 newborn deaths in sub-Saharan Africa.

Collaboration Details

The collaboration will focus on two areas of coordination:

Though SCD, a genetically inherited disease, and HIV, an acquired infectious disease, present significantly different scientific challenges, gene-based treatments hold promise for both, and many of the technical challenges for gene-based cures are expected to be common to both diseases.

To achieve the goals of the collaboration, both projects will require new delivery systems that can get prospective therapies to the right places in the body and optimize treatments to target the cells involved in the respective diseases efficiently and specifically. For SCD, that would mean repairing or compensating for the mutations in hemoglobin that cause SCD in hematopoietic stem cells. For HIV, that would mean targeting the reservoir of proviral DNA that continues to lurk inside a small number of cells, even after many years of effective antiviral treatment.

Such treatments that happen entirely within the body, known asin vivotreatments, would be a major step forward from current treatments, which apply genetic therapies to cells taken outside the body (ex vivo) and then reinfused.

We are losing too much of Africas future to sickle cell disease and HIV, said Matshidiso Rebecca Moeti, M.B.B.S., Regional Director for Africa, World Health Organization. Beating these diseases will take new thinking and long-term commitment. Im very pleased to see the innovative collaboration announced today, which has a chance to help tackle two of Africas greatest public health challenges.

The collaborations goal for SCD is to develop an easy-to-administer, gene-based intervention to either correct the SCD gene mutations or promote fetal hemoglobin gene expression to achieve normal hemoglobin function. The path to a cure will rely in part on the development of gene-based delivery systems capable of selectively targetinghematopoietic stem cells. This will result in the precise correction of gene mutations or addition of a gene to promote sufficient levels of normal hemoglobin expression and function.

Our excitement around this partnership rests not only in its ability to leverage the expertise in two organizations to reduce childhood mortality rates in low-resource countries, but to bring curative therapies for sickle cell disease and HIV to communities that have been severely burdened by these diseases for generations, said Gary H. Gibbons, M.D., Director, National Heart, Lung, and Blood Institute (NHLBI), part of the NIH.A persons health should not be limited by their geographic location, whether rural America or sub-Saharan Africa; harnessing the power of science is needed to transcend borders to improve health for all.

In addition, more needs to be done to understand the burden of SCD in sub-Saharan Africa and to screen newborns for SCD in high-risk geographic areas. NHLBI has already begun to establish a clinical research infrastructure in sub-Saharan Africa. However, additional clinical research and capacity-building efforts are needed to deliver point-of-care screening, such as at the time of infant vaccinations, and to initiate a standard of care. These activities will be undertaken by NIH and Gates Foundation outside of the collaboration, but will support collaboration efforts.

Nearly 38 million people worldwide are living with HIV, with 770,000 deaths due to AIDS in 2018 alone. Like SCD, people in sub-Saharan Africa face a disproportionate risk of HIV. Antiretroviral therapy is highly effective and has made it possible for people with HIV to live long, healthy lives without transmitting the disease to sexual partners. However, treatment must be maintained for a lifetime. A low-cost, safe, effective and durable cure that also prevents reinfection upon sexual exposure has long been a goal to curb the HIV global pandemic.

A number of approaches will be considered to meet the goal of a scalable HIV cure. Both the Gates Foundation and National Institute of Allergy and Infectious Diseases (NIAID), part of NIH, are already funding cure research, exploring gene-based treatments in concert with long-acting therapeutics, monoclonal antibodies and other immune-based targets. This collaboration will allow the partners to intensify and better coordinate ongoing research efforts on these strategies, accelerating studies into early phase clinical trials to safely test promising tools and interventions.A particularly appealing approach is to identify the location of the reservoir of infected cells that still harbor integrated HIV genomes after treatment and target those DNA sequences with gene editing technology.

This collaboration is an ambitious step forward, harnessing the most cutting-edge scientific tools and NIHs sizable global HIV research infrastructure to one day deliver a cure and end the global HIV pandemic, said NIAID Director Anthony S. Fauci, M.D. We are taking into account those with the greatest need at the foundation of this effort, to ensure that, if realized, this exceptional public health achievement will be made accessible to all.

Originally posted here:
NIH, Gates Foundation partner for gene-based cures - BSA bureau

Recommendation and review posted by Bethany Smith

LONDON--(BUSINESS WIRE)--The report, global age-related macular degeneration (AMD) therapeutics market has been added to Technavios catalog. It provides a comprehensive analysis of the market, including its global and regional market share as well as market segmentation based on type and geography for the forecast period 2019-2023.

To learn more about the global trends impacting the future of market research: Download Free Sample Report

This report on the age-related macular degeneration (AMD) therapeutics market includes:

Age-related macular degeneration (AMD) therapeutics market analysis and forecast 2019-2023: Features

Age-Related Macular Degeneration (AMD) Therapeutics Market 2019-2023: Competitive Landscape

Age-Related Macular Degeneration (AMD) Therapeutics Market 2019-2023: Geographic Landscape

Age-Related Macular Degeneration (AMD) Therapeutics Market 2019-2023: Type Landscape

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High prevalence of AMD will drive the age-related macular degeneration (AMD) therapeutics market

The prevalence of AMD is increasing significantly, owing to the presence of high-risk factors such as aging, smoking, high cholesterol, and high blood pressure. Moreover, despite the high prevalence of AMD, no approved therapies are available in the market for the treatment of the condition. Thus, the high prevalence coupled with the huge unmet medical need of dry AMD are expected to drive market growth during the forecast period.

Development of gene therapy for AMD An emerging trend in the osteoporosis market

At present, only a few drugs are approved for the treatment of AMD. However, the side effects associated with them are very severe, and the majority of them act against VEGF only. Hence, there is a huge unmet need for safe and novel drugs to treat AMD. The currently available anti-VEGF therapies require repetitive and inconvenient intraocular injections. Hence, several companies are working on novel drugs to combat AMD, among which gene therapy is expected to cure the disease effectively. Hence, the development of gene therapy is expected to be a positive trend for the global AMD therapeutics market.

Other Key Topics Covered in the Report are:

MARKET LANDSCAPE

MARKET SIZING

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Growth of Age-Related Macular Degeneration (AMD) Therapeutics Market to be Impacted by the Development of Gene Therapy for AMD | Technavio - Business...

Recommendation and review posted by Bethany Smith

NOVATO Oct 24, 2019 (Thomson StreetEvents) -- Edited Transcript of Biomarin Pharmaceutical Inc earnings conference call or presentation Wednesday, October 23, 2019 at 8:30:00pm GMT

* Daniel K. Spiegelman

BioMarin Pharmaceutical Inc. - Executive VP & CFO

* Henry J. Fuchs

BioMarin Pharmaceutical Inc. - President of Worldwide Research & Development

BioMarin Pharmaceutical Inc. - Chairman & CEO

BioMarin Pharmaceutical Inc. - Executive VP & Chief Commercial Officer

BioMarin Pharmaceutical Inc. - VP of IR

SVB Leerink LLC, Research Division - MD of Rare Diseases & Senior Research Analyst

* Philip M. Nadeau

William Blair & Company L.L.C., Research Division - Co-Group Head of Biopharma Equity Research

Welcome to the BioMarin's Third Quarter 2019 Financial Results Conference Call. Hosting the conference call today from BioMarin is Traci McCarty, Vice President, Investor relations. Please go ahead, Traci.

Traci McCarty, BioMarin Pharmaceutical Inc. - VP of IR [2]

Thank you, Grace. Thank you, everyone, for joining us today. To remind you, this nonconfidential presentation contains forward-looking statements about the business prospects of BioMarin Pharmaceutical Inc., including expectations regarding BioMarin's financial performance, commercial products and potential future products in different areas of therapeutic research and development. Results may differ materially depending on the progress of BioMarin's product programs, actions of regulatory authorities, availability of capital, future actions in the pharmaceutical market and developments by competitors, and those factors are detailed in BioMarin's filings with the Securities and Exchange Commission such as 10-Q, 10-K and 8-K reports.

On the call today from BioMarin's management team are J.J. Bienaim, Chairman and Chief Executive Officer; Henry Fuchs, President of Worldwide Research and Development; Dan Spiegelman, Executive Vice President and Chief Financial Officer; Robert Baffi, President of Global Manufacturing and Technical Operations; and Jeff Ajer, Executive Vice President and Chief Commercial Officer. Consistent with the last 2 quarterly calls, we intend to keep this call to 1 hour in length. If we do not get to your question, please send me an e-mail or give me a call and we'll get right back to. Thank you for your understanding. Now I'd like to turn the call over to our Chairman and CEO, J.J. Bienaim.

Jean-Jacques Bienaim, BioMarin Pharmaceutical Inc. - Chairman & CEO [3]

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

Thank you, Traci. Good afternoon, and thank you for joining us on today's call. We are proud to share our highest quarterly revenue results to date at BioMarin, a record $461 million in revenues in the third quarter, which represents an 18% growth over the third quarter of last year and demonstrates the increasing strength of our base business. And while we are excited about our next-generation products valrox and vosoritide, we never lose sight of the importance of our existing products to both the people who rely on them to improve their health and to the financial health of our business. In these unpredictable times, this is reassuring that between our strong balance sheet and excellent commercial business, we are not reliant on the financial markets.

As we round out 2019, confidence in our base business combined with R&D expense management, we've also been tightening our both GAAP and non-GAAP guidance to the top of the range for the full year. Our continued commitment to grow our profitability was demonstrated by cash generated in the third quarter, which was just over [$30] million. In addition to our strong base business, the potential returns from our investments in valrox and vosoritide are on the horizon. Approximately 3 years ago, we laid out a 5-year plan for financial success of the business, and we remain on track. We said that R&D expenses as a percentage of revenues would peak and then come down. Over the last 3 years, it has come down from 60% to 43% of revenues and on its way to our long-term goal of 25%, all while preserving a high level of productivity from our R&D engine. Our top line has grown 15% or more year-over-year with a $2 billion revenue target for 2020. And valrox and vosoritide should see growth well beyond that after 2020.

And of course, we have been focusing on the bottom line as well. In 2016, we said that we would be non-GAAP positive starting in 2017. We were non-GAAP positive in 2017, and we have continued to grow each year. Our next target is GAAP profitability, and from here, with the success we anticipate from valrox and vosoritide profit and significantly profitable growth is on the horizon. We are all aware of recent market volatility and the negative impacts it has had on our shareholders in the short term.

However, with a potential business payoff of our strategies in full view, we remain steadfast in our focus to get valrox and vosoritide approved and launched. And with over $1 billion in cash and investments, our 2 potential blockbusters on the horizon and a third already on the market which is Palynziq, we are poised to leverage the R&D, commercial and manufacturing expertise and capabilities established over the last several years.

At the heart of our business and what creates our growth opportunities is our R&D engine. And with that in mind, we look forward to hosting you at our Annual R&D day in New York on November 14, where we will provide updates on our late-stage programs as well as shine a light on the next potential growth drivers beyond valrox and vosoritide. We will also have an interesting lineup of preclinical candidates to share with you. As we can see, the lease programs will be added next to our development pipeline. Please email the IR team for further details, and we hope you will be able to join us. Now I would like to turn the call over to Jeff who will provide more details on the commercial business in the quarter and our expectations for the remainder of the year. Jeff?

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Jeffrey Robert Ajer, BioMarin Pharmaceutical Inc. - Executive VP & Chief Commercial Officer [4]

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Thank you, J.J. As J.J. mentioned, the third quarter was record-breaking in terms of revenue for BioMarin driven by a strong revenue quarter for Vimizim and $30 million in revenue growth from our newest brands, Palynziq and Brineura. Globally, BioMarin's commercial brands contributed $428 million, a 19% increase quarter-over-quarter and $1.2 billion year-to-date or 14% year-over-year growth. I will detail the breakdown of individual product contributions, but we'll start with a positive development in Brazil, a major market for our MPS brands. In the third quarter, we recognized the first installment of a 12-month supply agreement with the Brazilian Ministry of Health for both Vimizim and Naglazyme, which combined for a total contribution of $45 million. This new 1-year supply agreement should result in more revenue predictability through Q2 of 2020, although there will still be uneven order patterns quarter-to-quarter. Importantly, under this new arrangement with the Brazilian Ministry of Health, we would expect the majority of the roughly $90 million contract to be applied in 2019.

And now a little more detail on Vimizim globally. Quarterly revenue of $164 million represented the year-over-year increase of 33%. While a large Brazil order was a major factor in the quarter, patient growth of 11% globally also contributed to the increased and will support long-term additional revenue growth. For the full year, we are tightening our guidance to between $540 million and $570 million. For Naglazyme, the revenues driven from Brazil were offset by decreases due to ordering patterns in the EUMEA region, and thus, Q3 revenue totaling $94 million was down 4% versus Q2. Despite the neutralizing effect of both the favorable and unfavorable ordering in this quarter, overall patient growth remained steady, and we expect consistent annual revenue growth will continue. For the full year, we see revenues tightening to between $360 million and $380 million tightening the range.

Turning now to the PKU brands and starting with Palynziq. In the U.S., July marked the 1-year milestone of drug availability post FDA approval and the trajectory of patient referrals and correlating revenues are meeting expectations across all metrics. Q3 revenues of $24 million, essentially all of which came from U.S. sales, were driven by a combination of the growing number of patients, who have now achieved once-daily dosing and new patients initiating therapy. A reminder that it takes, on average, 5 months for a patient referral to get to commercial therapy and then to daily dosing, at which point, that patient is a material revenue driver.

At the end of Q3 in the United States, there were 670 patients on Palynziq commercial therapy, 142 of those patients from clinical studies and 528 patients formally naive to Palynziq. There were an additional 153 enrolled naive patients who have not yet received their first commercial dispense. A total of 823 adult PKU patients therefore either already being treated with commercial Palynziq or well on their way to their first shipment.

Turning our attention now to the EU launch. In May 2019, we announced approval for Palynziq by the EMA, and since that time, have engaged in very active education efforts, preparation of reimbursement dossiers and promotional activities in first-priority markets. I'm happy to share that physicians are treating patients now in Germany, the first EU country to market. Without the benefit of patients transitioning from clinical trial, in combination with the timing required to achieve reimbursement approvals, we expect that it will take time to realize material revenue contributions from Europe. We're very happy with the progress that we've made to date, and we've reaffirmed revenue guidance for Palynziq tightening range.

Shifting now to Kuvan. Global revenues in the third quarter totaled $121 million, representing a 6% increase year-over-year. The majority of this was due to patient growth in the United States and achieved in parallel through changing patient demographics as more adult PKU patients now have the option to treat with Palynziq. We are adjusting up our full year guidance for Kuvan.

Finally, an update on Brineura. Net product revenues were $20 million in Q3 driven by patient uptake in diverse global market across all 4 regions. Our teams continue to focus their efforts on driving early diagnosis and identifying new patients who will benefit from therapy, coupled with unlocking reimbursement in countries around the world. As a result of these efforts, Brineura has exhibited steady growth over time and now is reaching the level of material revenue contributions on a quarterly basis. We expect continued growth going forward and reaffirm our guidance for Brineura.

In conclusion, I'm very pleased with the commercial team's execution and performance in the third quarter of 2019 in all 4 regions and excited to track and report the progress of the launch of Palynziq in EU. For the remainder of the year, with our established commercial base business, we are confident in our ability to achieve full year revenue guidance of approximately $1.7 billion. So thank you. And now I'd like to turn the call over to Hank.

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Henry J. Fuchs, BioMarin Pharmaceutical Inc. - President of Worldwide Research & Development [5]

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Thanks, Jeff, and congratulations to you and your team. Starting with valrox for adults with severe hemophilia A, an exciting new regulatory development has been announced today. We are pleased to share that the European Medicines Agency has recently granted our request for accelerated assessment of valrox. In their assessment report, the European Medicines Agency acknowledged valrox's potential to address the existing unmet need by providing patients with a treatment option that only requires a single intravenous administration and then subsequently is expected to provide steady levels of endogenously produced coagulation factor VIII for a substantial amount of time. This decision is particularly important because it shows that based on the data the EMA has already received, EMA recognizes valrox's potential as a product of major interest for public health and therapeutic innovation. This decision is also important as the accelerated assessment procedure reduces the timeframe for the European Medicine Agency commitment -- Committee for Medicinal Products for Human Use (CHMP) to review our planned marketing authorization application for valrox on track for later this year. Needless to say, we are gratified to accept this recognition of valrox given the impact it could have for patients with severe hemophilia A.

Another positive development we want to share is the news that our Shanbally facility has been successfully inspected by the Irish HPRA for testing and release of gene therapy products. These newly constructed laboratories are part of our overall strategy for meeting worldwide regulatory requirements for product distribution. This added capability prepares us to meet in-country testing requirements for the release of commercial product in the EU region.

We continue to expect to submit marketing applications in both the United States and Europe in this quarter based on recent meetings with the FDA and EMA as we announced earlier in this quarter. These submissions were based on the recently completed Phase III interim analysis and the updated 3-year Phase I/II data of patients treated with valoctocogene roxaparvovec. Enrollment in the generate I Phase III open-label study is expected to complete mid-November, with the 52-week results anticipated in that study at the end of 2020. As we have said previously, although the trial is open-label, we have a data access plan in place, which is designed to significantly mirror a blinded trial. This precludes anyone not directly monitoring the trial to access any emerging data from this study, and we are not updating any of our prior analyses. As for the ongoing Phase II study, we intend to share a 4-year update with a 6e13 dose as well as a 3-year update on a 4e13 dose at the middle of next year at an appropriate medical conference.

Turning to our next late-stage program, vosoritide for children with achondroplasia is finished -- nearing the finish line. Our global multipronged program has been designed to achieve maximum clinical benefit for infants and children with achondroplasia from newborns through growth plate closure. Beginning with the Phase III program, results from the large global study that includes children from ages 5 to 18 are -- the data are expected by the end of the year. Needless to say, we look forward to sharing all these top line results with you at that time. Another key component of our global program in achondroplasia is the Phase II, 0-5 year old study. Given our conviction and the opinion stated at the achon AdCom meeting that the FDA held earlier in the year and last year, treatment with vosoritide started as early as possible may translate into the best results for children with achondroplasia. We're thrilled with the progress of this ongoing study. We have completed enrollment in the first cohort of the study, which includes children from 2 to 5 years of age. The second cohort, which includes children from 6 months of age through 2 years of age, is expected to complete by the year end and the last cohort of the study, which includes newborns through 6 months of age, began earlier enrolling this month. Needless to say, the level of interest from families seeking treatment for their very young children is very consistent with our belief in starting treatment as early as possible. We hope to provide more insight and detail in this program at R&D day.

Turning to BMN 307, our investigational gene therapy for PKU, we are pleased to have received orphan designation for BMN 307 this past Monday from the FDA. As you likely saw in our recent press release, we submitted a clinical trial application, or CTA, with the Medicines and Healthcare Product Regulatory Agency in the United Kingdom, or the HPRA -- sorry, the MHRA for BMN 307. We expect to start enrolling patients with material manufactured with a commercial-ready process to derisk the program to facilitate rapid clinical development in the Phase I/II trial in early 2020, and we are actively preparing regulatory submissions for other countries. We are excited about the prospect of BMN 307 as it represents a potential third PKU treatment option in our PKU franchise and a second gene-therapy development program, leveraging our learnings and capabilities from valrox.

And finally, on pipeline changes. We announced today that we have entered into a licensing agreement with Allievex for Tralesinidase Alfa, formally BMN 250, an investigational enzyme-replacement therapy for the treatment of Sanfilippo Syndrome Type B. As we've stated previously, our focus is shifting to larger indications where we can have an impact with our highly integrated products so we are thrilled to have Allievex now shepherding the continued development of Tralesinidase Alfa. We couldn't be happier for patients and their families as we expect they will benefit tremendously from Allievex's focus on treatments for rare neurogenerative diseases. We look forward to hosting you at our upcoming R&D day on November 14 in New York, where we will showcase our next potential commercial products, namely valrox and vosoritide including some baseline data never shared before. Another highlight will include an updated look at the natural history information, including trends of vosoritide treatment through 54 months as well as evaluation of untreated patients with achondroplasia. With our earlier-stage pipeline, we look forward to sharing a preview of the next potential INDs we are considering for development. We hope you will attend, so please reach out to our IR department should you need more information. Thank you for continued support, and I'll now call -- turn the call over to Dan to review the financial quarters. Dan?

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Daniel K. Spiegelman, BioMarin Pharmaceutical Inc. - Executive VP & CFO [6]

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Thank you Hank. Please refer to today's press release summarizing our financial results for full details on the third quarter. First, with respect to revenues, we reported total revenues in the quarter of $461 million and are on track for full year 2019 revenues of approximately $1.7 billion, being in the expected range of $1.69 billion to $1.72 billion. In addition to tracking towards the middle of the range for full year total product revenues, as J.J. mentioned, we expect both GAAP and non-GAAP results to be at the top end of the ranges due to continued R&D expense management as we continue to improve overall margins. An important item of note for the quarter is the impact of foreign exchange on our financial results. Over the past year, the dollar has strengthened materially against the Euro and the British pound and even more significantly against several of the Latin American currencies. Overall, net of our hedging, full year revenue is projected to be negatively affected by approximately $20 million to $25 million such that our full year revenue would have been at the high end of our guidance instead of the midrange without these negative FX impacts. Thanks to our hedging contracts, which offset more than half of the potential revenue impact from the strengthening dollar and natural expense hedge offsets, full year bottom line forecasted results are not materially impacted this year by exchange rates.

One specific revenue item that Jeff did not discuss was Aldurazyme revenue in the quarter. It increased by $17 million versus 2Q due to delays in that quarter with Sinofi's QA release that has since been resolved. Year-to-date, Aldurazyme is down $44 million due to a onetime (inaudible) of revenue in Q1 2018 though patients on therapy, as reported by Genzyme, continue to grow in 2019 versus 2018.

Moving to operating expenses. Both R&D and SG&A expenses in the third quarter roughly track to previously provided full year guidance. SG&A is expected to come in at the upper end of the range between $670 million and $690 million. SG&A expenses in the third quarter were impacted by the expansion of sales and marketing capabilities as we launched Palynziq in Europe and continue to prepare for valrox and vosoritide approvals and launch.

In the third quarter, R&D expenses reflect the continued enrollment of additional patients in the global Phase III Generate I study, the manufacturing of BMN 307, our PKU gene therapy product, ahead of clinical trials early next year and the children in the 0 to 5-year-old study with vosoritide.

However, despite the progress of these later-stage development programs, with the decision not to pursue development of both BMN 270 for Frie -- 290, I'm sorry, for Friedreich's ataxia and BMN 250, we now expect R&D expense for the full year to be lower than previously guided. For the full year, we now expect R&D expenses of between $710 million and $740 million.

Turning to BioMarin results. GAAP net income in the third quarter was $55 million as compared to a GAAP net loss of $12.6 million in the third quarter of 2018. GAAP net income in the third quarter increased primarily due to a net profit from operations and a benefit from income taxes of approximately $45 million. For the full year, we expect GAAP loss to come in at the low end of our initial guidance range and now expect the loss of between $65 million and $45 million.

As you know, we also measure our performance on a non-GAAP basis, which is based on EBITDA and also excludes stock compensation, contingent consideration and certain other specified items. Our non-GAAP income in the third quarter was $78 million compared to non-GAAP income of $61 million in the third quarter of 2018. We are now narrowing the range of full year non-GAAP income to be between $150 million and $170 million. The use of cash, cash equivalents and investments as of September 30, 2019, we have $1.15 billion as compared to $1.1 billion on June 30, 2019.

And finally, a note on our cash flows for the third quarter. Year-to-date cash used for operational activities totaled just about $9 million, whereas cash generated by operating activities for the third quarter were just over $70 million. GAAP profitability and continued cash flow growth are expected as our revenues increase. Our P&L structure is expected to be similar to our larger biotech peers we aspire to follow.

In closing, BioMarin's current commercial business remains on track to deliver roughly $1.7 billion in revenues this year and close to $2 billion next year, with increasing GAAP and non-GAAP bottom line profitability. Over the next 18 months, we also expect to accelerate into the next phase of higher revenue and growth through potential approvals of valrox and vosoritide, which could lead to approvals and revenue contributions starting before the end of 2020.

Thanks for your support, and I will now open it to your questions. Operator?

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Questions and Answers

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Operator [1]

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(Operator Instructions) Your first question comes from the line of Salveen Richter from Goldman Sachs.

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Salveen Jaswal Richter, Goldman Sachs Group Inc., Research Division - VP [2]

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So for vosoritide, how should we think about the clinical meaningfulness of the Phase III data? So while you showed about a 2-centimeter a year benefit at the same dose in the Phase II, clearly, there is a range for various stratification measures that adds up here or gets you on a normal growth curve. So if you can give us any clarity there, and I have a follow-up.

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Henry J. Fuchs, BioMarin Pharmaceutical Inc. - President of Worldwide Research & Development [3]

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Salveen, the clinical meaningfulness of just the Phase III study I don't think can be considered in isolation because the Phase III study is a relatively short duration of 1 year, in that, it's placebo-controlled, and that was what we and our investigators agreed was feasible to study and generate high-quality data. I think the way to think about clinical meaningfulness of vosoritide is in terms of cumulative effect over chronic therapy. And to remind you, we reported last year the accumulated benefit of vosoritide through 42 months of chronic therapy in our Phase I/II cohort of 10 patients. This year, we'll be giving you another update on that, which will now carry patients through 54 months of therapy. And as I mentioned in my talking points, we are now in a position to start addressing what the height gain over untreated patients can be expected to be given that we're now coming online with our own contemporaneous natural history study. So all that taken together says the value of the Phase III trial is to prove that vosoritide is effective compared to placebo. But the magnitude of the benefit should be weighed in the context of longer-term therapy.

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Salveen Jaswal Richter, Goldman Sachs Group Inc., Research Division - VP [4]

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That was helpful. And then can you discuss the forward trajectory and dynamics for Kuvan? Do you expect the majority of patients here to transition over to Palynziq prior to IP expiration?

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Jeffrey Robert Ajer, BioMarin Pharmaceutical Inc. - Executive VP & Chief Commercial Officer [5]

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Salveen, it is certainly our goal to transition as many adult Kuvan patients to Palynziq as possible before loss of exclusivity in a year, and we are making a lot of progress. 38% of our Palynziq referrals, our naive Palynziq patient referrals, are Kuvan transitions, so making a lot of progress there. It is also true that though there remain a smaller now number of new adult patients that are being referred in for Kuvan treatment, and it is also true, particularly in the United States, that our pediatric population is growing on Kuvan. So the trajectory, I would think, would be similar to what we are reporting year-to-date with patient growth of about 6% tied to continued revenue growth. Our focus, both in Europe and the United States, is overwhelmingly now on adult patients gaining access to, and benefiting from, Palynziq therapy.

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Jean-Jacques Bienaim, BioMarin Pharmaceutical Inc. - Chairman & CEO [6]

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Salveen, I'm sorry, just want to remind you on the line that the loss of exclusivity in Q4 of next year is only in the U.S. In Europe, in ex U.S. we have protection until 2024. I'd also give you one point that maybe it's no different from your traditional generic modeling is that when you've a small molecule, you lose protection of market exclusivity. When you lose a patient to a generic they very rarely come back to the brand, if ever. In our case, what in the case we do starting in Q4 2020, October, November 2020. If we do lose a Kuvan patient to a generic, they are not lost forever to our business in the sense that they can always go to Palynziq down the road, so they are not lost forever.

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Operator [7]

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Your next question comes from the line of Phil Nadeau from Cowen and Company.

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Philip M. Nadeau, Cowen and Company, LLC, Research Division - MD & Senior Research Analyst [8]

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One on vosoritide for me also. In the Phase II data, we saw at month 12, just below a 50% increase in annualized growth velocity. Hank, is there any reason why we shouldn't expect that in the Phase III? Are there any notable differences in the patient populations who are enrolled that could change the expected results?

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Henry J. Fuchs, BioMarin Pharmaceutical Inc. - President of Worldwide Research & Development [9]

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Not really, no. We purposely kept the eligibility criteria fairly consistent and also the outcome measures, between the outcome measure and the dose and regimen are the same so we should expect a fairly similar result. Now the one thing that we've pointed out is that we've been doing those calculations compared to the baseline run in. But as you -- as people have pointed out and as you noticed from (inaudible) achondroplasia growth studies, there is a gentle negative slope so at 1 year, there could be some negative placebo effects, such that we underestimated that 1 year the magnitude in treatment benefit of vosoritide. And I think that's going to get to be more and more important as you go out farther and farther in time because those declines will start to add up. And I was suggesting that at the R&D day, we'll have an opportunity to look at those, both of those phenomena, the chemo derived benefit from product treatment as well as contrast that to similar populations of patients who have not been treated with vosoritide.

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Philip M. Nadeau, Cowen and Company, LLC, Research Division - MD & Senior Research Analyst [10]

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Got it. Okay. And even though the age 5 to 14 is exactly the same between Phase II and Phase III, do you know whether the people who are actually enrolled have a similar age characteristic? So was the Phase II weighted towards younger patients and Phase III is getting older patients or as far as you know, the ages in the trial are also identical?

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Henry J. Fuchs, BioMarin Pharmaceutical Inc. - President of Worldwide Research & Development [11]

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Read the original:
Edited Transcript of BMRN earnings conference call or presentation 23-Oct-19 8:30pm GMT - Yahoo Finance

Recommendation and review posted by Bethany Smith

Regeneron will lose out on hundreds of millions of dollars if a rival to its top-selling drug performs the way Wall Street expects. Even more would be at risk if recently proposed changes to government insurance become a reality.

In these situations, when a drugmaker's biggest product is under fire, acquisitions can look like an attractive way to put out the flames. AbbVie's $63 billion bid to acquire Allergan stems almost entirely from the buyer trying to find new revenue streams before generics start eating away at its mega-blockbuster drug, Humira.

But Regeneron isn't like other drugmakers. In the 30 years since its founding, it has never acquired another company. Though Regeneron isn't completely shut off to the idea of doing M&A, there's little to indicate the biotech is actively trying to change its deal track record.

Regeneron maintains that it doesn't need to buy drugs because of its R&D skills. Under the direction of CEO Len Schleifer and Chief Scientific Officer George Yancopoulos, the biotech has brought seven new medicines to market, including five from a long-standing partnership with Sanofi.

"When I look at Gilead, for example, or even Biogen [there is] a lot of investor pressure to buy something," Evan Seigerman, a Credit Suisse analyst, told BioPharma Dive. "Regeneron is still good at telling the narrative that 'we can develop our own assets and we have the best capabilities, so we're not going to buy anything.'"

The biggest of those assets is Eylea, a drug for multiple eye diseases that hit $6.75 billion in global sales last year.

For 2019, the average Wall Street estimate has Eylea reaching $7.43 billion in sales. For 2020 and beyond, however, analysts are torn about how it will fare in light of a new competitor.

*Selection of four investment bank forecasts for global Eylea sales

Earlier this month, Novartis began selling in the U.S. a drug for wet AMD, an age-related vision loss disease for which Eylea is also approved. Novartis on its third quarter earnings call touted how the drug, Beovu, is off to a strong launch, though the company didn't provide sales numbers.

While some analysts initially viewed Beovu's label as weaker than expected Christopher Raymond of Piper Jaffray called the drug "little more than an also-ran" it is still poised to steal market share from Eylea. Just how much share is the big question facing Regeneron.

RBC Capital Markets' research team said it recently spoke with an eye specialist who plans on switching one-third of her Eylea-treated wet AMD patients to Beovu. On a broader scale, the American Society of Retina Specialists found in a recent survey of 1,009 people from ophthalmology organizations that 50% plan on prescribing Beovu for wet AMD patients who don't adequately respond to drugs like Eylea or Roche's Lucentis.

Beovu may not be the only challenge to Eylea, either. President Donald Trump and Democrats in the House of Representatives have pitched different plans that would affect how Medicare pays for certain drugs. Medicare Part B spends more on Eylea than any other drug, leaving it particularly exposed if changes to government insurance take shape.

Amid these uncertainties, Regeneron's share price has fallen 16% since the beginning of the year. By contrast, the Nasdaq Biotechnology Index, which includes Regeneron, rose 13% over the period.

"They really do have quite a successful R&D engine," Kennen MacKay of RBC said. "But with the stock trading where it is, maybe there's a feeling that's no longer enough."

Jacob Bell / BioPharma Dive, market data

Regeneron's success is tied to its prowess in developing monoclonal antibodies a type of drug that, while a novelty in the past, is now a mainstay of many drugmakers' pipelines.

Some on Wall Street fret that Regeneron's competitive edge may have weakened as more companies entered this space. Last month, Geoffrey Porges of SVB Leerink went so far as to pose the provocative question: "Is Regeneron becoming the TiVo of biopharma?"

Whether or not those worries are valid, analysts can't envision Regeneron buying anything because that would be so out of character.

"These companies really do have a certain genetic makeup of what they're about, especially Regeneron," Cowen & Co.'s Yaron Werber told BioPharma Dive. "Doing M&A is not something that's in their DNA."

The threats to Eylea are therefore unlikely big enough or realized enough to push Regeneron toward acquisitions. According to consensus figures provided by Credit Suisse, analysts envision sales of the eye drug growing over the next year in spite of Beovu, as it takes greater market share in areas like diabetic macular edema.

Investors also have other bright spots to keep their attention off M&A. Dupixent, a treatment for eczema and asthma, achieved triple-digit growth over the last year and could help offset future hits to Eylea.

Regeneron's pipeline drugs, meanwhile, face significant competition.Roche and Amgen are working on rival cancer agents, while Merck & Co., Bristol-Myers Squibb and Alexion Pharmaceuticals already market blockbuster drugs for diseases that Regeneron is targeting.

"There's a deep pipeline, but it's lacking that one disruptive product that investors always want to see," Werber said. "It's a pipeline that still is getting defined."

Regeneron could find that disruptive product through bets on newer technologies. The company entered a gene editing deal with Intellia Therapeutics in 2016, a cell therapy deal with Bluebird bio in 2018, and an RNA-focused deal with Alnylam Pharmaceuticals this April.

"There's nothing inherently good about doing M&A."

Nouhad Husseini

Head of Business Development, Regeneron

While Regeneron has favored partnerships to acquisitions, it could do the latter if it wanted. By the end of June, the company held just over $1 billion in cash and cash equivalents and another $4.5 billion in marketable securities.

"The deal we did with Alnylam, or Intellia, or any of our partners where we're accessing external innovation, we could have just as easily decided to acquire one of those companies," Nouhad Husseini, Regeneron's head of business development, said in an interview.

Husseini holds reservations about outright acquisitions, though he said he could see Regeneron buying something in the short- or medium-term. Collaborations have worked out well, he notes, because both sides can stay focused on the science without getting distracted by the upheaval that often comes from M&A.

"The way I look at it is: M&A and doing a partnering deal, it's shades of gray and there are pros and cons. It's a way of structuring the deal, nothing more than that," Husseini said. "We really value these companies who have this independent entrepreneurial spirit, and I've seen firsthand what happens when big companies come in and acquire these little companies."

Scientific independence is a value shared by other biotech dealmakers as well.

Gilead and Galapagos structured their $5.1 billion research deal so the smaller company would remain a motivated partner, according to Gilead CEO Daniel O'Day. Gilead also announced in May that it will keep separate its cell therapy subsidiary, Kite Pharma, which O'Day reasoned would improve efficiency.

Jeffrey Leiden, the CEO of Boston-based Vertex, told BioPharma Dive earlier this year that he planned on letting Semma Therapeutics, which Vertex had just acquired for $1 billion, operate with more autonomy because of the target company's leadership team and expertise in stem cell-derived therapies.

Follow this link:
Pharmacquired: Eylea could be in trouble, but that doesn't make Regeneron a buyer - BioPharma Dive

Recommendation and review posted by Bethany Smith

The Gene Therapy Market report presents and displays a vigorous vision of the global scenario in terms of market size, market potentials, and competitive environment. A new professional intelligence report published by stats and reports has the ability to help the decision-makers in the most important market in the world that has played a significantly important role in making a progressive impact on the global economy. The study is derived from primary and secondary statistical data and consists of qualitative and quantitative analysis of the industry and key players.

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Read this article:
Global Gene Therapy Market New Innovation| Size, Share, Application, Revenue, And Sales Till 2022 - Sino News Daily

Recommendation and review posted by Bethany Smith

New York City, NY: October 25, 2019 Published via (Wired Release) Excellent growth of Cryonics Technology Market|Comprehensive study by Global Innovations, New Business Developments,SWOT Analysis with key players, Capital Investment, Technological Innovation and Emerging Trends of Outlook To 2029

Global Cryonics Technology Market 2020 report contains wide-extending measurable details of Cryonics Technology Market, which enables the customer to separate the future maneuver and anticipate right execution.Cryonics Technology market reveals dynamics in many geographic segments for this business landscape and future state of affairs over the forecast amount.cryonics technology market research report 2020 is a comprehensive, professional report delivering market research data that is suitable for new market participants or established players. The Research report presents a full evaluation of the Market and has current growth factors, future trends, facts, attentive views, and market data approved by the industry.

The research report gives an in-depth explanation of the trends and consumer behavior patterns that are likely to govern the evolution of the global cryonics technology market. The research covers a crucial market segmentation analysis that is a rich source of all essential segments including Cryonics Technology types, applications, technologies, end-users, and regions. The study provides an idea of what condition the market will face, what will be the growth rate and which type of failure will occur. The comprehensive valuation of the market is presented in the report entailing facts, existing growth factors, attentive outlooks, coming trends, and industry-confirmed market data forecast until 2029.

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Market Segmentation:

Some of the Major Cryonics Technology Market Players Are:

PraxairCellulisCryologicsCryothermKrioRusVWRThermo Fisher ScientificCustom Biogenic SystemsOregon CryonicsAlcor Life Extension FoundationOsiris CryonicsSigma-AldrichSouthern Cryonics

Cryonics Technology Market Segment by Type, covers:

Slow freezingVitrificationUltra-rapid

Cryonics Technology Market Segment by Application, covers:

Animal husbandryFishery scienceMedical sciencePreservation of microbiology cultureConserving plant biodiversity

Cryonics Technology Market: Region-wise Outlook

Middle East & Africa (Egypt, Saudi Arabia, Turkey, South Africa)

Southeast Asia (Japan, Korea, India, China)

Europe (Germany, France, United Kingdom, Italy, Russia)

North America (United States, Canada, Mexico)

South America (Brazil, Chile, Peru, Argentina )

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This report provides Complete overview of cryonics technology market

Developing market dynamics of the cryonics technology market

In-depth analysis Of cryonics technology Market segmentation by Type, by Application, key players

The report provides past data, current and predicted cryonics technology market from 2020 to 2029 share and volume in terms of size and cost.

The Present cryonics technology Market opportunities and industry challenges

Major competitors and porter analysis of Cryonics Technology market

Business strategies of cryonics technology market top key players and product offerings

Reasons to buy this report:

The latest progress in the cryonics technology industry and details of the manufacturing leaders along with their business plan

and share.

The reports contains very valuable information about growth, size, leading opponents and segments of the market.

Explain the Present and future of the cryonics technology in both improved and developing markets.

The report assists in realigning the marketing strategies by highlighting the cryonics technology business advantages.

This report throws light on the segment expected to manage the cryonics technology industry and market.

Estimates the regions demanded to observe the quickest growth of cryonics technology market

To share specific information about the key factors affecting the growth of the market.

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Latest Research report on Cryonics Technology Market Size predicts favorable growth and forecast - TheLoop21

Recommendation and review posted by Bethany Smith