A Historic Day in Drug Development: FDA Approves Amylyx’s Drug to Treat ALS, Demonstrating FDA’s Application of Appropriate Flexibility in Rare Diseases

September 30, 2022By Frank J. Sasinowski & James E. Valentine

On September 29, 2022, FDA approved Amylyx’s NDA for its drug, Relyvrio (sodium phenylbutyrate/taurursodiol), for treatment of patients with amyotrophic lateral sclerosis (ALS) (see FDA announcement here).  This approval decision charts a path for the exercise of appropriate flexibility in regulatory decisions for other rare conditions where there is a serious and/or life-threatening unmet medical need, as is very often the case.  As articulated by Dr. Billy Dunn, the Director of CDER’s Office of Neuroscience, at the September 7, 2022 meeting of the Peripheral and Central Nervous System Drugs Advisory Committee, applying the statutory standard in approval decisions in these clinical contexts warrants the “broadest possible” flexibility.  These remarks by Dr. Dunn and his Summary Review offer insights into the practical application of the FDA’s December 2019 draft guidance on substantial evidence of effectiveness (as we will discuss further below).  Hyman, Phelps & McNamara, P.C.’s Frank Sasinowski and James Valentine are honored to have aided Amylyx in this development program and approval.

This approval is a testament to FDA drug officials in the Office of Neuroscience and Division of Neurology 1 (see their Summary Review here).  We would like to acknowledge FDA for its efforts on this devastating condition, ALS.  The Office and Division have paid special attention to the Voice of the ALS Patient as witnessed by the historic engagement with the ALS community to craft disease-specific drug development guidance, ongoing engagement through FDA-hosted and community-led meetings (see, e.g., ALS Association We Can’t Wait Action Meeting), and efforts to understand patients’ continued unmet medical needs (see ALS Voice of the Patient Report).  This is evidence of FDA’s embrace of patient-focused drug development.

However, this approval has implication for the development and review of drugs for all rare diseases, not just ALS.  While the concept of “flexibility” has been in FDA regulations for decades, the Agency’s first fulsome articulation of how this should be manifested when reviewing evidence of effectiveness came in 2019, when FDA issued draft guidance on the substantial evidence of effectiveness standard.  This guidance, for the first time, offered insights into where and how a single adequate and well-controlled (A&WC) study with confirmatory evidence could meet this standard.  The guidance went further to describe how, in certain circumstances, less traditional study designs that introduce greater uncertainty (e.g., due to being historically-controlled) can still be considered an A&WC study.  Yet, in our view, Dr. Dunn’s opening presentation at the September 7th Advisory Committee meeting is FDA’s most eloquent description of how to apply appropriate regulatory “flexibility,” which we know can be like asking regulators to color outside of the lines.  In these remarks, notably, Dr. Dunn suggested that we look to FDA’s previous approval decisions to understand just how much uncertainty can be accepted, sighting in ALS to previous approval decisions that did not provide traditional efficacy evidence. This is what these authors worked to do in 2010 and 2015 when we catalogued and characterized the application of appropriate flexibility in FDA approvals of orphan drugs, shedding light on these important issues (see coverage of here).

This flexibility by FDA manifested itself ultimately in the approval of Relyvrio, where FDA in its Summary Review concluded:

Overall, Study AMX3500 demonstrated a statistically significant treatment benefit of AMX0035 compared to placebo on the prespecified primary endpoint, the rate of decline of ALSFRS-R. In post hoc long-term analyses, an overall survival benefit was observed for those patients who were originally randomized to AMX0035 compared to those originally randomized to placebo. Supplemental post hoc exploratory analyses comparing the overall survival to natural history databases provided consistent results. There are limitations to these findings that result in a degree of residual uncertainty about the evidence of effectiveness that exceeds that which might typically remain following a conclusion that substantial evidence of effectiveness has been demonstrated; however, given the serious and life-threatening nature of ALS and the substantial unmet need, this level of uncertainty is acceptable in this instance and consideration of these results in the context of regulatory flexibility is appropriate. Exercising regulatory flexibility, the single study with positive results on a clinically meaningful primary outcome accompanied by confirmatory evidence of an observed survival benefit provides substantial evidence of effectiveness. (emphasis added)