New ALS Treatments Face Regulatory Uncertainty

ALS regulatory uncertainty

Pictured: An illustration of a maze leading to a human brain/Taylor Tiden for BioSpace

The past two years have seen a pair of new treatments approved for a particularly intractable neurodegenerative disease—amyotrophic lateral sclerosis. But while Amylyx’s Relyvrio and Biogen’s Qalsody have crossed the FDA finish line, others have stumbled in a regulatory space that experts say is still evolving.

The FDA put out new guidance in 2019 that sought to clarify the clinical outcome measures required for traditional approval of an ALS therapy. But with conflicting data regarding the importance a key biomarker, neurofilament light chain (NfL), and with the disease’s heterogenous nature challenging the interpretation of clinical trial results, a lot is still up in the air.

Merit Cudkowicz, chair of the neurology department at Massachusetts General Hospital who helped run trials for both Relvrio and Qalsody, told BioSpace that the recent leadership changes within the FDA’s neurology division—Billy Dunn stepped down as head of the neuroscience office a year ago—are an opportunity to dialogue with regulators in order to understand the standard for approval of an ALS drug.

What the FDA Is Looking For

The 2019 guidance outlines clinical outcome measures that can be used as endpoints in ALS trials to support traditional approval, with a focus on “measures that assess function in daily activities, muscle strength, respiratory function and mortality,” the neurology division’s new director, Teresa Buracchio, told BioSpace in an email.

Relyvrio was approved in September 2022 after an unprecedented second adcomm. The drug hit its primary outcome measure in the Phase II CENTAUR trial, and long-term survival data from the open-label extension trial also supported its approval, said Cudkowicz, one of the trial’s co-principal investigators. Relyvrio is composed of two repurposed drugs—sodium phenylbutyrate and taurursodiol—with a lot of safety data behind them, she added. Amylyx is expecting topline data from the Phase III PHOENIX trial during or before the second quarter of 2024.

For accelerated approval, Buracchio said, surrogate endpoints or intermediate clinical endpoints that are “determined to be ‘reasonably likely’ to predict clinical benefit” can be used.

Qalsody, approved in April 2023 under the accelerated approval pathway for patients with ALS associated with a mutation in the superoxide dismutase 1 (SOD1) gene, capitalized on this provision. Despite missing its primary Phase III endpoint, the antisense therapy “had really outstanding data in the open label extension, with some people stopping progression and getting better,” said Cudkowicz, a co-principal investigator on the trial, adding that there was also a large biomarker effect. Indeed, the approval was based on reductions in plasma levels of NfL, a marker of nerve injury and neurodegeneration—changes that were determined to be reasonably likely to predict clinical benefit.

For ALS therapies still seeking approval, it remains to be seen how to best demonstrate efficacy. “The appropriate design of a clinical trial for ALS will depend on the mechanism of the drug and population of patients that will be enrolled in a trial,” Buracchio said.

Take BrainStorm Cell Therapeutics’ NurOwn, which failed to impress a panel of FDA advisers during a September 2023 adcomm, with panelists citing a “lack of efficacy” in terms of survival and statistical evidence that didn’t meet the regulatory requirement. While acknowledging that a small group of people might have benefited from the treatment, “others did not or may have done worse,” said Cudkowicz, who served as the trial’s principal investigator. “There were many learnings from the trial, and the next step would be to consider a study in the population more likely to respond.”

Neurofilament as an ALS Biomarker

While much attention has been given to NfL as an important biomarker for neurodegenerative diseases, Cudkowicz said she wouldn’t yet consider it a standard requirement in ALS. “I think it’s helpful when it changes, but we don’t know if it doesn’t change what that means.” Three of the ALS drugs currently on the market, Riluzole, Relyvrio and Radacava, “did not change neurofilament but had a clinical effect,” she said.

Cudkowicz added that the upcoming PHOENIX trial readout for Relyvrio will be informative. “If it’s positive and still doesn’t have an effect on NfL, that really tells us that it’s good when it changes but it doesn’t mean that a drug isn’t effective when it doesn’t change.”

Amylyx co-CEO and co-founder Josh Cohen said the company will be more focused on the clinical evidence from the PHOENIX trial but will look at NfL as well. “I think the ALS field is really eager for a biomarker,” he told BioSpace. “Personally, I think the jury’s very much out [on] whether neurofilament is a helpful tool or is more than that.”

Asked what a win would be when the PHOENIX topline data read out, Justin Klee, the company’s other co-CEO and co-founder, said, “ALS is largely looked at still as an untreatable disease, so showing twice with a treatment that you can fundamentally impact the progression of the disease, I think would be an enormous milestone.”

Meanwhile, Salt Lake City–based Clene received FDA feedback in December 2023 that initial biomarker data from the Phase II trials of its investigational gold nanocrystal suspension CNM-Au8 were “insufficient to support accelerated approval.” CNM-Au8, which is part of the Healey ALS Platform trial on which Cudkowicz is a sponsor and principal investigator, elicited a “statistically significant” reduction in NfL levels compared to placebo after 24 weeks of treatment. On average, patients treated with CNM-Au8 saw a 10% decline from baseline in NfL over the 24-week double-blind treatment period of the HEALEY trial compared to placebo and a 16% decline from baseline versus placebo in the OLE through 76 weeks, Clene reported in December 2023. But Cudkowicz said the effect was “small [and] nothing like Qalsody,” which lowered NfL levels by more than 50% in participants on active treatment. 

She added that it was a very good study “that identified the right dose and had a clinically important signal” and noted that a larger Phase III trial is a critical next step. Clene anticipates launching a Phase III trial in 2024, CEO Rob Etherington said in a press release announcing the meeting’s outcome.

Patient Heterogeneity Challenges NurOwn’s Path to Market

For Bob Hebron, co-head of the I AM ALS Clinical Trials committee whose daughter was diagnosed with ALS more than a decade ago, much of the challenge lays in the heterogeneity of the disease. “No two patients progress at the same rate, and progression even within a single patient changes over time,” he told BioSpace. Thus, a treatment can appear to work for some patients but not in others. “It’s very hard with certain patients to discern progression,” he said, pointing to NurOwn as an example.

BrainStorm reported in November 2020 that the Phase III trial of NurOwn failed to meet statistical significance in the primary efficacy endpoint. The 34.7% response rate was only a little better than the 27.7% placebo response, which exceeded others observed in contemporary ALS trials. However, in a pre-specified subgroup of patients with early-stage disease, the difference was much larger, with 34.6% of NurOwn recipients having a clinically significant response compared with 15.6% in the placebo group.

BrainStorm executives have consistently pointed to a “floor effect,” which occurs when the scale of measurement is unable to capture the patient’s progression at the bottom end of the scale, to explain the overall result. Essentially, patients declining more rapidly reach the end of the scale’s ability to measure progression. If such rapidly declining patients are unevenly distributed between the treatment and placebo groups, this could skew the results.

BrainStorm co-CEO Stacy Lindborg confirmed that this challenge would be addressed in the company’s second Phase III trial, for which it submitted a Special Protocol Assessment request to the FDA on February 23. “One of the most critical aspects that any sponsor has to think about is inclusion criteria,” she told BioSpace. “That is an important learning and is central to how we’re designing the trial, to ensure we have the right patients.”

Ultimately, Lindborg said that with a number of ALS products having now gone through the regulatory process, questions about how to best measure functional benefit in ALS have begun to be answered. “There is more and more of a standard,” she said. However, because biomarkers and clinical trial design continue to be the subject of much discussion, the path to bringing new ALS therapies to market is still uncertain.

Heather McKenzie is a senior editor at BioSpace. You can reach her at Also follow her on LinkedIn.

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