Patients, sponsors, and regulators have often been at odds over the best way to run clinical trials in amyotrophic lateral sclerosis (ALS). The FDA’s upcoming regulatory decision for Amylyx’s AMX-0035 in ALS could add needed clarity to the debate.
The FDA will finally decide whether to grant accelerated approval for AMX-0035 by September 29, following multiple about-faces from the agency and its outside advisory committee (AdCom). Last week, an FDA AdCom voted 7–2 in favor of an accelerated approval for AMX-0035, just six months after voting 6–4 against the ALS drug.
Amylyx’s Phase II CENTAUR trial (NCT03127514) met its primary endpoint along ALS Functional Rating Scale-Revised (ALSFRS-R), which many sponsors and patients say is the most sensitive ALS endpoint. However, the FDA prefers a greater focus on ALS survival rate and has argued that CENTAUR does not adequately account for missing data along the ALSFRS-R endpoint.
Nevertheless, the FDA is under growing pressure to give AMX-0035 an accelerated approval nod, particularly after Health Canada’s decision to conditionally approve AMX-0035 in June. Meanwhile, continued backlash against the FDA’s decision to grant Aduhelm (aducanumab) accelerate approval in Alzheimer’s disease in 2020 only raises the regulatory stakes.
Tensions over ALS primary endpoints
Though ALSFRS-R is among the most common endpoints in ALS clinical studies, the FDA has said it prefers a joint assessment that looks at both function and survival. The 137-patient, placebo-controlled CENTAUR trial met its primary endpoint of ALSFRS-R over 24 weeks, but it did not include any survival endpoints.
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However, Amylyx has already initiated the 600-patient Phase III PHEONIX trial (NCT05021536), which uses a joint assessment of ALSFRS-R and survival over 48 weeks as a primary endpoint. The trial has an estimated primary completion date of November 2023 and completion date of March 2024, according to ClinicalTrials.gov.
In both Amylyx AdComs, FDA officials stressed the need for PHEONIX data prior to any approval, citing concerns with CENTAUR’s randomization and statistical analysis of missing data. Meanwhile, Amylyx and patient advocates argued that the high unmet need for ALS treatments, along with encouraging Phase II AMX-0035 data, warrant a conditional approval.
Previously, Clinical Trials Arena broke down the challenges of designing an ALS study that meets the complex demands of patients, regulators, and payers. Experts say stratifying patients based on disease severity and integrating ALS biomarkers could make it more feasible to incorporate survival endpoints in trials.
Upcoming ALS clinical trials to watch
While the ALS field eagerly awaits the FDA’s decision on AMX-0035, several other key ALS candidates have upcoming trial readouts, according to a Clinical Trials Arena analysis of ALS drug trials. The Phase II/III HEALEY study (NCT04297683) in ALS, which utilizes an innovative platform trial design, headlines the field with three expected readouts this year.
Among the HEALEY trial arms, Biohaven’s verdiperstat (NCT04436510) and Prilenia’s pridopidine (NCT04615923) use ALSFRS-R as a primary endpoint and survival as a secondary outcome. Meanwhile, Clene Nanomedicine’s CNM-Au8 (NCT04414345) also uses ALSFRS-R as the primary endpoint, with a joint assessment of survival and function and a standalone measure of survival as secondary outcomes.
Overall, there has been a steady increase in new drug trials initiated in ALS over the past decade, according to GlobalData’s Clinical Trials Database. The increase amounted to 70% when measured as a percentage of total trials in the central nervous system (CNS) space. GlobalData is the parent company of Clinical Trials Arena.
Looking ahead, Clene Nanomedicine and NeuroSense Therapeutics executives have previewed late-stage trial plans in ALS with Clinical Trials Arena. Clene plans to run a 300-patient Phase III trial of CNM-Au8 in ALS, and NeuroSense has its sights set on a 70-patient Phase IIb trial of PrimeC in fast-progressing ALS. Meanwhile, the FDA recently announced plans to accelerate research efforts for rare neurodegenerative diseases, including ALS.
But despite these new investments in ALS clinical research, patients are still desperately awaiting new treatments for the devastating neurodegenerative disease. In the meantime, all eyes are on the pending Amylyx decision as questions continue to swirl over the optimal endpoint choice in ALS clinical studies.