With ALS action plan, FDA aims for patient engagement

But ALS advocates note that the agency’s timeline exceeds the life expectancy of most current patients

FDA’s five-year action plan for rare neurodegenerative diseases, including amyotrophic lateral sclerosis, laid out how the agency wants to support translational research, engage with patients, and explore innovative clinical trial designs, but ALS patient advocates said any benefits will come too late for the current cohort of patients who have an immediate, unmet need for accelerated drug approvals.

Published June 23, the five-year plan said FDA will establish a task force and public-private partnership, develop “disease specific science strategies” and leverage the agency’s regulatory science initiatives. It was developed to meet the requirements of the Accelerating Access to Critical Therapies (ACT) for ALS Act, which President Biden signed in December.

The plan also described an ALS science strategy with three main areas of focus: improving characterization of disease pathogenesis and natural history; facilitating patient access to new therapies; and improving clinical trial infrastructure agility.

That agility means to “enable early selection of promising therapeutic candidates for further development, optimize clinical trial design, improve access to the trials, streamline clinical trial operations, and reduce the time and cost of drug development,” the plan said. 

The plan does not state how much money FDA will invest to carry out the plan, though does note that ACT for ALS authorizes the appropriation of $100 million for each of fiscal years 2022 to 2026. 

NIH’s budget for ALS in FY22 is $25 million, with a further $1 million for a National Academy of Sciences Assessment ALS study. FDA’s specific competencies include trial infrastructure, in contrast to NIH’s. The agency published the guidance document Amyotrophic Lateral Sclerosis: Developing Drugs for Treatment in 2019. 

Frank Sasinowski, attorney at Hyman, Phelps & McNamara and former regulatory counsel in FDA’s Center for Drugs and Biologics, told BioCentury he thought the plan could benefit all rare disease patients, not just those with a rare neurodegenerative disease or even ALS — even though the plan came to be in large part due to the advocacy of the ALS community. 

He said FDA has experience executing on the strategies laid out in the action plan for mitochondrial diseases, and the agency should clarify what “confirmatory evidence” means in the context of neurodegenerative diseases and how it can be acquired, as this would be a “game changer” for all rare diseases. “A rising tide lifts all boats,” he said. Sasinowski represents  Amylyx Pharmaceuticals Inc. (NASDAQ:AMLX), which is developing AMX0035 (Albrioza – Canada) to treat ALS, and is vice chairman of non-profit EveryLife Foundation for Rare Diseases. 

But patient advocates including I AM ALS’s Brian Wallach and Voices for ALS’s Michelle Lorenz argue ALS companies and FDA could do more to help patients in the short term than is detailed in the neurodegenerative diseases action plan. 

“Drug developers have a lot of flexibility under FDA’s 2019 guidance,” said Wallach. “They can use remote monitoring, reduce the number of patients on placebo, and add an open label extension to every trial, so any patient who feels they are seeing a benefit can stay on treatment.”

He added that drug developers could establish an expanded access program (EAP) for each Phase III trial, which would allow any ALS patient access to a drug at the discretion of the study sponsor, regardless of whether they qualified under the trial inclusion criteria.

“In the past, ALS trials have excluded patients who are more than two years past diagnosis,” he said. “I’m five years in, and can’t quality for any clinical trial. The action plan discusses how expanded access programs can be integrated into clinical trials, but it doesn’t take the position of requiring them.”

EAP programs can add considerably to the cost of trials, but Wallach said that Act for ALS made funds available for smaller companies that couldn’t otherwise afford them. 

Lorenz said FDA should move more quickly to help ALS patients using existing tools such as accelerated approval and the “regulatory flexibility” the agency stressed in the 2019 guidance document.

“We’re grateful they’re partnering with us in the plan,” said Lorenz, “But the frustration of patients is that they won’t be alive in time to see a five-year plan implemented.”

Wallach agreed. “The action plan recognizes the failure of past clinical trials and proposes a task force to look into it, which means that we’ll have an actual recommendation in probably two years. That’s way too long for patients.”

Lorenz said FDA should immediately change its approach to the regulation of ALS treatments and rely much more on real-world evidence than it does currently.

ALS’s rarity and heterogeneity — both in terms of underlying pathophysiology and rates of progression — make it challenging for treatments to achieve persuasive p values in clinical trials.

Albrioza, NurOwn from BrainStorm Cell Therapeutics Inc. (NASDAQ:BCLI), and tofersen from Biogen Inc. (NASDAQ:BIIB) should all be approved under accelerated approval, Lorenz said.

“ALS is going to require a cocktail of drugs, just like HIV,” she added. “Our concern is that FDA requires one drug to work on everybody.”

Calls for rapid approval of these therapies by the ALS community demands raise questions about the regulatory bar they would have to overcome. 

In March, members of FDA’s Peripheral and Central Nervous System Drug Advisory Committee voted 6-4 against AMX0035’s effectiveness. All agreed the results of the company’s Phase II CENTAUR study held promise, and that the need for regulatory flexibility was exceptionally acute given ALS’s 100% fatality rate. However, deeming the data sufficient to support approval seemed to most committee members to bend FDA’s statutory requirements beyond the breaking point.

NurOwn, which comprises mesenchymal stem cells induced to secrete a variety of trophic factors, did not meet the endpoint in a Phase III study of ALS patients last year. “It has become clear that data do not support the proposed clinical benefit of this therapy,” the agency said. Tofersen missed its primary endpoint in the six-month Phase III VALOR study last year, although 12-month data from the open-label follow-up suggests longer treatment with the antisense therapy in SOD1-mutant ALS may reduce disease progression; Biogen said it was “engaging with FDA and regulators around the world.” 

The Peripheral and Central Nervous System Drug panel will reconvene to discuss AMX0035, which comprises sodium phenylbutrate and tauroursodeoxycholic acid, on Sept. 7; the drug’s PDUFA date was extended from June 29 to Sept 29 to give the agency time to consider additional data. Wallach pointed out that Health Canada approved the therapy in June “without any issues.”