Long-term survival outcomes of AMX0035 for ALS

AMX0035 significantly reduced the risk of death in ALS patients compared with placebo, regardless of concomitant riluzole and/or edaravone use. This is the result of the long-term survival analysis of the phase 2 CENTAUR trial. Of note, the study used a novel approach of collecting survival data, which could be useful in future ALS trials.

AMX0035 is a fixed-dose combination of 2 compounds (sodium phenylbutyrate and taurursodiol), is orally administered, and aims to decrease neuronal cell death. The phase 2 CENTAUR trial (NCT03127514) included 137 patients, who where randomised 2:1 to the AMX0035 group (n=89) or placebo group (n=48). After a short randomisation period of 6 months, the primary safety, tolerability, and efficacy endpoints (ALSFRS-R slope reduction of 2.32 points) were met. Subsequently, all participants (placebo group included) were invited to enter the open-label extension and get exposure to AMX0035; 92% of the original population did so. Long-term survival data was collected through a participant locating service, a method well known to oncology research, but new to ALS trials. In this way, survival data could be retrieved from all original participants.

Long-term survival analysis, presented by Dr Sabrina Paganoni (Massachusetts General Hospital, Massachusetts, USA), showed that participants originally randomised to the AMX0035 group had a 44% lower risk of death than participants in the placebo group, with corresponding median survival (25.0 vs 18.5 months) and median duration of exposure (8.8 vs 1.9 months) data. Dr Paganoni emphasised that these results were obtained despite the fact that all participants were on riluzole and/or edaravone at baseline. Analysis of the adverse events over long-term follow up showed that participants in the AMX0035 survived longer without tracheostomy, permanent assisted ventilation, and first hospitalisation.

Dr Paganoni mentioned that the true survival effect of AMX0035 might be underestimated, because many participants in the original placebo group had exposure to AMX0035 in the open-label extension study. An exploratory analysis using the ENCALS survival prediction model demonstrated that the placebo group had a 6.4 months longer median survival than predicted by the model, suggesting an underestimation of the long-term survival outcomes.

The patient-centred study design of the CENTAUR trial used a relatively short randomisation period, but meaningful survival information was presented nonetheless. The participant locating service, a novel approach to ALS research, could prove useful in other future ALS trials to collect survival data.

1. Paganoni S, et al. Long-Term Survival of Participants in the CENTAUR Trial of AMX0035 for ALS. AAN 2021 Virtual Congress, 17-22 April.

Posted on 22 April 202117 June 2021