Treatment with AMX0035 significantly extended the median survival of amyotrophic lateral sclerosis (ALS) patients by more than 10 months compared with a placebo, a new analysis of the Phase 2/3 CENTAUR clinical trial indicates.
That survival difference was even greater in patients who continued to receive AMX0035 in the open-label extension phase, compared with patients who never received the investigational treatment.
“The results of these long-term analyses of the CENTAUR trial provide further evidence that AMX0035 may offer a survival benefit in people with ALS and provide insights into potential new approaches to analyze survival data in ALS trials,” Sabrina Paganoni, MD, PhD, principal investigator of the CENTAUR trial and lead author of the study, said in a press release.
Results were detailed in the study, “Survival Analyses From the CENTAUR Trial in Amyotrophic Lateral Sclerosis: Evaluating the Impact of Treatment Crossover on Outcomes,” published in Muscle & Nerve. The analysis was funded by Amylyx Pharmaceuticals, the company developing AMX0035.
AMX0035 contains a fixed-dosed combination of two orally available small molecules, tauroursodeoxycholic acid and sodium phenylbutyrate, that are thought to protect nerve cells from damage caused by cellular stress. The therapy is currently being considered for approval in the U.S., and also in Canada and Europe.
Applications for AMX0035’s approval are supported by data from the Phase 2/3 CENTAUR clinical trial (NCT03127514). The study enrolled 137 people with rapidly progressing ALS, who were assigned randomly to receive AMX0035 or a placebo every day for six months.
At the end of the six-month placebo-controlled study, 90 of 98 eligible participants elected to continue into an open-label extension study (NCT03488524), where all were given AMX0035.
Previously announced results from CENTAUR and its extension showed that patients given AMX0035 throughout the studies lived a mean of 6.5 months longer than those initially assigned to a placebo.
Having an initial placebo-controlled trial, followed by an open-label extension, is common practice for serious conditions such as ALS, where giving patients a placebo for a long time is ethically dubious. However, this study design also means it’s difficult to make direct comparisons about how the therapy affected survival, since even participants who were given placebo in the initial trial then received AMX0035 during the open-label extension.
Here, scientists at Amylyx and other institutions used a statistical method called “rank-preserving structural failure time model” (RPSFTM) to analyze survival data from the CENTAUR study. This method has been employed frequently in clinical trials testing experimental cancer treatments. It basically works to estimate what the survival difference would have been if participants initially given placebo had stayed on placebo throughout the study, instead of switching to active treatment during the open-label extension.
“Trials that incorporate placebo-to-active treatment crossover are critically important in rapidly fatal diseases like ALS, however, this design may underestimate the clinical effect of investigational therapies. Fortunately, statistical models, like the RPSFTM, allow us to adjust results for treatment crossover,” said Machelle Manuel, PhD, head of global medical affairs at Amylyx and study co-author.
Without any statistical adjustment, the median survival time was 25.8 months for participants who started on AMX0035 in CENTAUR, and 18.9 months for those who initially were given placebo — a difference of 6.9 months, indicating a 43% lower risk of death.
After applying RPSFTM, median survival duration for those originally given AMX0035 remained at 25.8 months, while the estimated survival for participants on placebo was 15.2 months — a difference of 10.6 months, which translates to a 61% lower risk of death.
“We observed a significant survival benefit for AMX0035 in the survival analyses adjusting for treatment crossover, potentially offering those living with ALS and their families hope of sharing more memories and milestones together,” Manuel said.
Additional analyses showed that participants who had been on AMX0035 throughout the trial and open-label part lived a median of 18.8 months longer (33.6 months vs. 14.8 months) than those who had started on placebo and not switched to active treatment in the open-label extension.
Median survival times also were longer for participants who originally received placebo, but then started on AMX0035 in the open-label extension, compared to participants originally given AMX0035 who chose not to enter the open-label extension. That likely is because the first group had a longer duration of AMX0035 treatment.
The researchers stressed these analyses were limited by the small number of participants, but still noted that the data overall suggest better survival outcomes for participants who had been on AMX0035 for longer.
“By adjusting survival estimates in the presence of treatment switching, methods such as RPSFTM and subgroup analyses may provide additional clinical context beyond the observed survival outcomes in ALS trials incorporating this critical crossover design that may be informative for patients and other stakeholders,” the scientists concluded. “In post hoc analyses of the CENTAUR trial, these two methods yielded a 10.6- and 18.8-month adjusted survival benefit of [AMX0035], respectively.”