Until the day she dies, Sandy Morris is hunting for a comma and a clause.

In May 2018, the 53-year-old mother of three learned she has ALS, a diagnosis made even more devastating by a somber directive to get her affairs in order period. The finality speaks to the absence of an effective treatment, yet alone a cure, for the neurodegenerative disease also known as Lou Gehrig's disease.

Since the diagnosis, Morris has sought to give future ALS patients some measure of optimism, amending the 'get your affairs in order' instruction to add 'but, there's something worth looking into.' While medical advances in areas like gene therapy show potential to change the course of other potentially fatal diseases, a disease-modifying treatment in ALS has proved elusive.

"In cancer, you have a shot," Morris said in an interview. "Not always a great shot, but you have one. In this land, everybody is just like, 'We don't have anything.'"

But now, Morris said she has reason for hope, stemming from a first-of-its-kind study in ALS that will test five experimental drugs simultaneously in a platform trial. Five drugmakers selected for the trial were announced last week.

After years of work, the broader promise of these adaptive trials, which allow more flexibility to make changes throughout, is beginning to be put into action. This trial aims to accelerate the pace of ALS research and may prove to be a template for other rare diseases as well, experts said.

The design offers advantages for each key stakeholder in drug development: patients have a lower probability of receiving placebo due to the study's shared control arm; companies get quicker topline results at lower cost; and researchers talk of the study as an "endpoint engine" that could advance their scientific understanding of the disease.

Formidable challenges remain in the way of broader adoption, particularly among leaders of the drug industry. The ALS study uses experimental treatments from small biotechs instead of industry giants, which can afford to prioritize control and pay for their own studies instead.

Even so, it's an exciting advancement in ALS research. Morris, who is also a leader of the patient group I Am ALS, said the trial can bring hope to future patients, even if it comes too late to help her.

"It's not going to save me. I'm not in time for any of this," Morris said. "But, dammit, we have to make it better for the rest."

Merit Cudkowicz understands speed. After 25 years specializing in ALS research, Cudkowicz is fully aware of how ALS changes a patient's life, shortening their life expectancy from decades to just years. The disease has a roughly three-year median survival.

Merit Cudkowicz

Massachusetts General Hospital

That life-changing diagnosis came in May 2018 for Sean Healey, then the CEO of an asset management firm worth more than $8 billion. After resigning from that post, Healey connected with Cudkowicz as he searched for treatment options and realized there was an opportunity to accelerate the pace of research.

Just six months from his diagnosis, Healey raised $40 million to launch a research center at Massachusetts General Hospital. Now, slightly less than a year after being established, the Sean M. Healey & AMG Center for ALS Research is aiming to start the platform trial in the first few months of 2020.

And earlier this month, the Healey Center announced the first five therapies to be tested in the study, including drugs from Biohaven Pharmaceutical and Ra Pharmaceuticals.

Cudkowicz, who leads the study, as well as the Healey Center and Mass General's neurology department, said in an interview the trial aims to have 160 patients for each of five treatments. The primary outcome will be whether or not the drug boosted a functional rating score for ALS after six months. One placebo group will be shared for all treatment arms, and more drugs can be added as the study continues. (Cudkowicz cautioned the plan is nearing finalization with the Food and Drug Administration, so specifics could still change.)

Moving quickly is the trial's aim. Cudkowicz called the study "an endpoint engine" that can help create better outcome measurements, including future surrogate markets, pushing ALS research forward. She estimated topline results to come 12 to 18 months after the study begins, depending on enrollment speed.

But those goals are steps toward the actual mission: developing a cure, Healey wrote in an email to BioPharma Dive.

"Of course, we all understand that the most meaningful measure of success will be the development of effective treatments and ultimately a cure," Healey wrote. "I am convinced that the Platform Trial, along with other initiatives we are supporting, will substantially accelerate the achievement of this ultimate goal."

For the first five biotechs, the decision to participate was a no-brainer. The center and other groups are footing the majority of the cost, leaving the companies' primary expense to simply provide their drug.

Out of about 30 applicants, the Healey Center selected five drugs for the study, most notably Biohaven's verdiperstat and Ra Pharma's zilucoplan. The trial also will test therapies from Implicit Bioscience, Prilenia Therapeutics and Clene Nanomedicine.

Cudkowicz said the typical applicants were small biotechs that "have great ideas but not deep pockets."

The expense of clinical trials limits the ability for biotechs to run multiple studies simultaneously across a range of indications. Instead, companies typically focus on a lead indication, with others following in succession.

"As a small company, we live and die by being able to run efficiently and test our hypotheses," said Irfan Qureshi, Biohaven's vice president of neurology.

For instance, Biohaven's verdiperstat is in Phase 3 testing for multiple system atrophy, and Ra Pharma's zilucoplan is focused on a different neuromuscular disorder called generalized myasthenia gravis.

"We wanted to do the study anyway, but to be honest, we probably wouldn't have gotten to it for years if this had not come along," Ra Pharma CEO Doug Treco said in an interview.

While smaller biotechs have bought into the platform trial and its efficiencies, missing from the list of initial participants are industry leaders. With a market value of about $2 billion, Biohaven is the largest company involved.

Cudkowicz noted larger drugmakers have shown interest in roundtable discussions that shaped the trial's design, and there's always potential to add additional therapies after the trial starts.

"We're talking to the other ones like Biogen and Sanofi," she said. "They are interested and came to these meetings, but they have the money to do it on their own."

But the main hang-up for these companies is ceding control, said Scott Berry, a senior statistical scientist and co-founder of Berry Consultants, which worked on the ALS platform trial.

"All these companies have people that this is what they do for a living they run trials, and they know how to do it," Berry said. "To hand your drug to somebody else and you don't have control over making sure that happens is uncomfortable for companies, and it's different than what they usually do."

Additionally, with lengthy protocols and many moving parts, the trials are complex and typically require extensive consulting to get off the ground. Running a multi-arm study also brings statistical pitfalls that can make it harder to interpret results.

Beyond ALS, adaptive trials have been started in breast cancer, Alzheimer's disease and glioblastoma. Experts say they anticipate other rare diseases as logical future targets for these studies.

"As these start to get developed and people see them, in most rare diseases there will be people jumping on board," predicted Berry.

Biohaven's Qureshi added that once companies are willing to experiment beyond typical drug development, these trials could be particularly attractive for rare diseases by easing enrollment concerns where there are "not patients growing on trees," he said.

But the ultimate test to get the industry's full attention, Qureshi said, would be such a study yielding an approved drug.

In the meantime, platform trials appear here to stay. Janet Woodcock, the long-time leader of the FDA's drug review center, has been an influential supporter for these study designs. Just this month, the agency finalized guidance on ALS research that advised companies to consider adaptive trial designs.

Earlier this year, Woodcock told BioPharma Dive she believes these types of studies will gain ground as patients become more vocal about how trials are conducted.

Morris said the platform trial has struck her with its compassion. While no patient wants to be put on placebo, it's of particular importance in a disease that progresses as rapidly and severely as ALS, leaving most patients the time to try one study in their life.

She already took her shot, enrolling in a clinical trial that required a three-month observation period before receiving treatment, which then carried a 50% chance of being placebo. "We are humans," she said. "We aren't zebrafish."

Now, she wants to take the baton from "the voices in the graveyard" and pass it onto the next generation. Platform trials may allow her to cover a bit more ground before that hand-off, eventually reaching a day when people might be able to live with ALS, like HIV.

"ALS's day is coming," Morris said.

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First-of-its-kind trial in ALS spurs hope for brutal disease - BioPharma Dive

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