Access in ALS: patients want expanded access ramped up, now

Patient advocates calling on FDA, Congress to create pathways that broaden access to therapies in the clinic

ALS patients and advocates are injecting the urgency of their disease to their fight for more and better treatments. Alongside calls for FDA to show flexibility on standards for new therapies, they are demanding the agency and Congress create pathways to expand access to therapies in the clinic.

ALS patient groups are extremely vocal, and their voices have significant weight among members of Congress, where the House Energy & Commerce’s health subcommittee voted unanimously Thursday to advance The Act for ALS to the full committee.  

Time is short for patients diagnosed with amyotrophic lateral sclerosis; according to NIH, most people with ALS die from respiratory failure, usually within three to five years from when symptoms first appear.

While patients and advocates want to see FDA allow more compounds to reach the market, even where efficacy is in doubt, they are calling for more access to potential treatments sooner, by broadening the existing expanded access and compassionate use pathways. 

Most ALS patients don’t qualify for clinical trials because standard inclusion criteria prevent participation when the disease has progressed beyond the earliest stages. According to I AM ALS co-founder Brian Wallach, that proportion is 50-90% of people living with the disease.

Sandra Abrevaya, who is Wallach’s wife and a co-founder of the organization, told BioCentury that most clinical trials are looking for patients who are no more than 18-24 months from diagnosis.

There are as yet no stratifying biomarkers for the highly heterogeneous disease, at least none that have panned out in the clinic. The most recent attempt at enhancing efficacy by matching a therapeutic mechanism to a genetically defined patient subset — the testing of SOD1 antisense therapy tofersen in SOD1 mutation carriers — failed to meet its Phase III endpoint last month. 

Without biomarkers that can select responsive subsets, the diversity of biological processes that contribute to ALS means therapies that could work in specific phenotypes may continue to show little or no benefit in clinical trials.

“What patients want is access to therapies that have proven to be safe and somewhat effective because the reality is ALS is an incredibly heterogeneous disease,” Wallach told BioCentury.

“If it’s safe, and it’s proving effective for some patients,” Abrevaya said, “That’s what leads patients to say, ‘If I’m not going to have subtype efficacy data, I’m interested in having an opportunity to take it.’”

For these reasons, Wallach and Abrevaya have been pushing for more therapies to be available via pathways such as expanded access and compassionate use. They argue this could provide researchers and companies new avenues for collecting data while at the same time satisfying the demands of a patient group with high tolerance for risk.

If products are approved for early stage patients, the information could help doctors decide when to use a therapy off label in late-stage cases.

“In addition to what we will learn when we give patients who don’t qualify for clinical trials access, you just get a whole new subset of data that is extremely relevant and valuable,” Abrevaya said.

Political action

Wallach believes that excluding more advanced patients from ALS trials is a missed opportunity to collect data on a much broader group of patients.

“Right now, when FDA looks at a dataset and is trying to decide whether to approve a therapy, they don’t have any data on the therapy’s efficacy for a patient who is three, four, five, six years into their fight,” Wallach said.

Legislation that is already moving through Congress, he says, could provide “an easy fix for that,” in part by lowering the hurdles faced by smaller companies who would like to provide their therapies under expanded access programs but lack the resources to do so.

The Act for ALS, formally, the Accelerating Access to Critical Therapies for ALS Act (H.R. 3537; S. 1813), would make $100 million available each fiscal year during 2022-26 to fund early access to ALS therapies in the clinic, accelerate ALS and neurodegenerative disease therapy development through a public-private partnership among NIH, FDA and an academic research center or non-profit, and increase R&D on treatments for rare neurodegenerative diseases through a newly created research grant program.

In a sign of the influence wielded in Congress by I AM ALS and other advocacy groups, the legislation has 326 co-sponsors in the House of Representatives, where, during Thursday’s markup, Health Subcommittee Chair Anna Eshoo (D-Calif.) called the legislation “the most popular bill” in the House thanks to its co-sponsors’ tenacity and the ALS advocates “who will not allow Congress to ignore their suffering.” 

The act also has 40 co-sponsors in the Senate, where it has been referred to the Committee on Health, Education, Labor, and Pensions (HELP).

Another priority for I AM ALS is establishing an Advanced Research Projects Administration for Health (ARPA-H), which would aim to use nimble contracting authorities and hands-on project management to achieve biomedical breakthroughs across many diseases.

It’s a high priority for the Biden administration, which asked Congress to create ARPA-H in the White House’s FY22 spending proposal. Rep. Eshoo has introduced an ARPA-H bill, and sponsors have said it will be a central component of the 21st Century Cures 2.0 legislation.

At a May 25 congressional hearing, Rep. Rosa DeLauro (D-Conn.) asked NIH Director Francis Collins if ARPA-H would target the development of ALS therapies. Collins responded by saying that “cancer, Alzheimer’s and diabetes were put forward as examples of common diseases that ARPA-H could work on,” but he also cited ALS as “a great example” of a disease for which the model could be applied.

Collins added that he had spoken with NIH scientists about “creating an ARPA-H project specifically focused on ALS, recognizing that we are learning some fundamental things about what happens to the motor neurons in the spinal cord that could, with a crash program, be advanced much more quickly to understand the pathogenesis and new approaches to therapy using such things as RNA approaches. It is a great example of what we could do that we currently cannot quite do.”