The FDA provided briefing documents ahead of Amylyx’s rare second adcomm for AMX0035, an investigational treatment for ALS. The regulator does not appear to be convinced.
From left: Amylyx Co-founders and Co-CEOs Justin Klee and Josh Cohen/Courtesy Amylyx
Wednesday offers a rare opportunity for Amylyx Pharmaceuticals, which will go before the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee in a second attempt to win recommendation for its amyotrophic lateral sclerosis (ALS) drug, AMX0035.
The FDA provided briefing documents Friday, and despite the unusual second adcomm, it does not appear to be convinced. To be approved, AMX0035 must meet substantial evidence of effectiveness, which “may be derived by either a single very persuasive trial or a single adequate and well-controlled study plus confirmatory evidence,” the documents state.
In March, the PCNSDAC voted 6-4 that the Phase II CENTAUR trial was not sufficient to prove efficacy in ALS. This trial, made up of 137 participants, showed a median overall survival (mOS) rate of 4.8 months compared to placebo.
Amylyx subsequently submitted additional analyses of the survival data from this trial and an open-label extension study. The agency considered this new data a “major amendment” and extended the drug’s review time by three months. Recognizing the “substantial unmet medical need in ALS,” it again convened the PCNSDAC and here we are.
Wednesday’s vote carries a higher burden for Amylyx to prove - that the data supporting AMX0035 is sufficient to “support approval”.
The Case
Amylyx will present new analysis using the Rank Preserving Structural Failure Time Model (RPSFTM) to adjust for the effect of treatment crossover. This refers to patients who swtiched from treatment to placebo following the Phase II trial. In this analysis, the mOS in the intent-to-treat (ITT) population is 9.7 months.
The company also submitted analyses using natural history as a control to estimate survival time, as well as biomarker evidence from the Phase II PEGASUS trial of AMX0035 in Alzheimer’s disease (AD).
While Amylyx is presenting the above as confirmatory evidence, the FDA wrote, “The presented RPSFTM analysis is not independent data and is simply a new method for analyzing the same survival data presented in the original NDA submission.”
Of the biomarker analysis, the regulator said, “The submitted biomarker data are not clear evidence of a CNS effect or a potential clinical benefit in patients with ALS.”
AMX0035 is currently being assessed in a Phase III trial and the FDA expressed an inclination to wait until its completion, which is expected late next year or in early 2024. The PHOENIX trial will enroll approximately 600 individuals across the United States and Europe.
“This places the Agency in a challenging situation of potentially making a regulatory decision that may not be subsequently aligned with the results of the ongoing study,” the FDA stated.
For its part, Amylyx released the following statement Friday: “AMX0035 is the first drug candidate to show benefit on function and survival in ALS in a randomized, placebo-controlled clinical trial, as a standalone therapy or when added to existing approved treatments.”
Thought Leaders Weigh In
In ALS, which carries a typical death sentence of 3-5 years after diagnosis, any survival increase is enticing, particularly in a space that has seen little progress in recent years. BioSpace reached out to ALS thought leaders and drug developers prior to the adcomm for their perspectives.
“Based on the data presented from their phase II trial, the Amylyx drug appears to offer a benefit in terms of slowing of disease progression and a possible survival benefit,” said Stan E. Abel, CEO of ProJenX Inc., in an email.
ProJenX is in Phase I development with Prosetin, a mitogen-activated protein kinase (MAP4K) inhibitor targeting endoplasmic reticulum (ER) stress, a common feature in sporadic and familiar forms of ALS.
“Given the benign safety profile, it is encouraging to see the FDA take a careful look at all the data…,” Abel continued. This was an area of consensus between Amylyx and the FDA in March, with both concluding AMX0035 did not pose a safety risk to patients.
There is another potential wrinkle in the case of AMX0035. In June, Amylyx notched its first regulatory approval when Health Canada approved the drug, now known as Albrioza, conditional on the results of the PHOENIX trial.
If AMX0035 does not receive approval in the U.S. or other countries, Abel noted it “would add uncertainty and confusion to an already challenging clinical trial environment.” He added that “people living with ALS would likely seek treatment across borders which adds a significant burden to managing their care and [would put] more strain on the drug importation phenomenon.”
Dr. Merit Cudkowicz, director of the Sean M. Healey & AMG Center for ALS and chief of neurology at Massachusetts General Hospital, shared her thoughts in an email.
“A positive phase II study like Centaur – where there is slowing of loss of function, prolongation of life - a survival benefit - and no safety issues – is something we need to be able to get to our patients in the U.S.,” Cudkowicz said.
With recent breakthroughs in the space, there is a sense of momentum right now. If AMX0035 is ultimately approved, “it will provide much needed positive news in the space and encourage further investment in other new promising therapies,” Abel said.
Regulatory Flexibility for ALS
The ALS community has been calling for regulatory flexibility since the FDA approved Biogen’s Aduhelm for Alzheimer’s in June 2021.
Of the Sept. 7 adcomm, Stacy Lindborg, Ph.D., EVP and chief development officer at BrainStorm Cell Therapeutics said, “We hope that a positive…recommendation would encourage the FDA to exercise regulatory flexibility.”
BrainStorm is in the final stages of completing a BLA for NurOwn, an ALS candidate made up of autologous mesenchymal stem cells (MSCs) and neurotrophic factors (NTFs). Lindborg noted that the totality of evidence for NurOwn “[brings] to light valuable insights on the nature of ALS research and biomarkers as predictors of clinical response.”
In June, the FDA unveiled its Action Plan for Rare Neurodegenerative Diseases including ALS. The five-year strategy intends to improve and extend the lives of people living with rare neurodegenerative diseases by “advancing the development of safe and effective medical products and facilitating patient access to novel treatments.”
Cudkowicz made a comparison to the FDA’s approval process for drugs in serious cancer indications.
“The oncology branch of FDA approves drugs with smaller effects on survival based on a single study, and it would be a huge step forward in ALS if single studies like this could be approved conditional on future studies,” she wrote in the same email.
Abel shared his thoughts on both the adcomm and the Action Plan.
“The action plan for rare neurodegenerative diseases and this second Amylyx adcomm are both important steps that signal the FDA’s willingness to apply thoughtful regulatory standards which take disease-specific considerations into account,” he said.
Lindborg concurred, stating, “FDA’s release of the plan is an important step in adopting an outlook that prioritizes action to move potential therapies forward.”
SVB Senior Research Analyst Marc Goodman provided a summary of his most recent note on Amylyx.
“Significant unmet need in ALS with only two existing SOC (standard of care) agents that don’t work very well should drive expedited regulatory approvals of AMX0035 and strong uptake, in combination with SOC agents,” he wrote.
If AMX0035 does receive FDA approval, Cudkowicz said, “It would strongly encourage more trials of other therapeutic approaches in ALS and would be a huge positive for the field.” A negative opinion, she said, “…would be hugely disappointing for people living with ALS today and for ALS clinicians. It could risk putting the field back with less interest from industry.”
BioSpace will have continued coverage of the Amylyx adcomm this week.
