Until the final moments of her life, Sandy Morris has been searching for a comma and a clause.

In May 2018, the 53-year-old mother of three learned she had amyotrophic lateral sclerosis (ALS), a diagnosis made heavier by a heartbreaking directive from her doctor: "Get your affairs in order. Period." The bluntness reflected the lack of effective treatments, let alone a cure, for the neurodegenerative disease, also known as Lou Gehrig's disease.

Since her diagnosis, Morris has tried to offer some optimism for future ALS patients, amending the "get your affairs in order" directive to "but, there are things worth studying." While medical advances in areas like gene therapy show potential to alter the course of other potentially fatal diseases, disease-modifying therapies for ALS have remained elusive.

"In cancer, you at least have a chance," Morris said in an interview. "Not necessarily a good one, but you have one. And here, everyone just says, 'We have nothing.'"

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

After years of effort, the broader promise of such adaptive trials, which allow for more flexible adjustments during the course of research, is beginning to be put into practice. Experts say the trial aims to accelerate the pace of ALS research and could serve as a template for research into other rare diseases.

The design offers advantages to every key stakeholder in drug development: patients have a lower chance of receiving a placebo because of the shared control group; companies can get preliminary results faster and at lower cost; and researchers view the study as an "endpoint engine" that could advance scientific understanding of the disease.

Significant challenges remain on the road to broader adoption, especially among the leaders of the pharmaceutical industry. The ALS study uses experimental therapies from small biotech companies, not industry giants—the latter having the ability to prioritize autonomy and fund their own research.

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

"It won't save me. I won't catch up to all this," Morris said. "But, damn it, we have to make things better for those who come after."

Speed born of necessity

Merit Cudkowicz knows the importance of speed. After 25 years in ALS research, she fully understands how ALS changes a patient's life—shortening life expectancy from decades to just a few years. The disease'smedian survival is about three years。

In May 2018, Sean Healey—then CEO of a company with over $8 billion in assets under management—received this life-changing diagnosis. After stepping down from his role, Healey contacted Cudkowicz in his search for treatment options and realized there was an opportunity to accelerate research.

Just six months after his diagnosis, Healey raised $40 million to establish a research center at Massachusetts General Hospital. Now, less than a year after the founding of the Sean M. Healey & AMG ALS Center, plans are underway to launch this platform trial in the first few months of 2020.

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

Cudkowicz leads the study and also serves as head of the Healey Center and the neurology department at Mass General. In an interview, she said the trial aims to enroll 160 patients for each of the five treatments. The primary endpoint is whether the drug improves ALS functional scores after six months. All treatment groups will share a single placebo control group, and more drugs can be added as the study progresses. (Cudkowicz cautioned that the plan is being finalized with the U.S. Food and Drug Administration, and details may still change.)

Moving quickly is the goal of this trial. Cudkowicz called the study an "endpoint engine" that will help create better outcome measures, including future surrogate markers, to advance ALS research. She estimates that, depending on enrollment speed, initial results will be available 12 to 18 months after the study begins.

But these goals are just steps toward the real 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 therapies and ultimately a cure," Healey wrote. "I believe the platform trial and other initiatives we support will greatly accelerate this ultimate goal."

Initial industry participation

For the first five biotech companies, the decision to participate was clear. The Healey Center and other institutions cover most of the costs, with the companies' main expense being simply providing the drugs.

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 will also test therapies from Implicit Bioscience, Prilenia Therapeutics, and Clene Nanomedicine.

Cudkowicz said the typical applicant is a small biotech company that "has a great idea but not much funding."

The cost of clinical trials limits the ability of biotech companies to conduct multiple studies across a range of indications simultaneously. Instead, companies typically focus on one primary indication, with others following in sequence.

"As a small company, our survival depends on operating efficiently and validating our hypotheses," said Irfan Qureshi, vice president of neurology at Biohaven.

For example, Biohaven's verdiperstat is in Phase 3 testing for multiple system atrophy, while Ra Pharma's zilucoplan is focused on another neuromuscular disease—generalized myasthenia gravis.

"We wanted to do this study anyway, but honestly, without this opportunity, we might not have started it for years," Ra Pharma CEO Doug Treco said in an interview.

Although small biotech companies have embraced platform trials and their efficiency advantages, the initial list of participants lacks industry leaders. Biohaven, with a market cap of about $2 billion, is the largest company participating.

Cudkowicz noted that large pharmaceutical companies have shown interest in the roundtable discussions shaping the trial design, and there is always the possibility of adding additional therapies once the trial is underway.

"We are in communication with other companies like Biogen and Sanofi," she said. "They are interested and attended these meetings, but they have the funding to conduct their own research."

But the main concern for these companies is giving up control, said Scott Berry, senior statistical scientist and co-founder of Berry Consultants, which helped design the ALS platform trial.

"These companies have professionals who do this for a living—they run trials and know how to do it," Berry said. "Handing your drug to someone else and not being able to control the process is uncomfortable for companies and different from their usual approach."

Additionally, because protocols are lengthy and involve many components, these trials are complex and typically require extensive consultation to launch. Conducting multi-arm studies also introduces statistical pitfalls that can make interpreting results more difficult.

A template for rare diseases?

Beyond ALS, adaptive trials have been launched in breast cancer, Alzheimer's disease, and glioblastoma. Experts say they expect other rare diseases to be logical future targets for such studies.

"As these trials begin to develop and gain visibility, there will be people eager to join in most rare disease areas," Berry predicted.

Biohaven's Qureshi added that once companies are willing to go beyond the typical drug development model, such trials could be especially attractive for rare diseases because they can alleviate enrollment challenges—"patients aren't just hanging from trees like fruit," he said.

But Qureshi said that for the industry to fully pay attention, the ultimate test is whether such studies can produce an approved drug.

Meanwhile, platform trials appear to be here to stay. Janet Woodcock, who has long led the FDA's drug evaluation center, has been an influential advocate for such study designs. Just this month, the agencyissued final guidance on ALS researchrecommending that companies consider adaptive trial designs.

Earlier this year, Woodcock told BioPharma Dive that she believes such studies will gain greater traction as patients have more say in how trials are conducted.

Morris said the empathetic design of the platform trial resonated with her. While no patient wants to receive a placebo, it is especially important in a disease like ALS that progresses so rapidly and severely—most patients only have time to participate in one study in their lifetime.

She has already used her chance, participating in a clinical trial that required a three-month observation period before treatment, after which there was still a 50% chance of being assigned to the placebo group. "We are human beings," she said, "not zebrafish."

Now, she wants to take the baton from the "voices in the graveyard" and pass it to the next generation. The platform trial might allow her to walk a bit further before handing it over, eventually reaching the day when people can live with ALS as they do with HIV.

"That day for ALS will come," Morris said.