#MDA2021 – Long-term Use of AMX0035 of Aid in Rapidly Advancing Disease
Long-term treatment with AMX0035 significantly lowers the risk of death, and the need for permanent ventilation and hospitalization in amyotrophic lateral sclerosis (ALS) patients with rapidly progressing disease, according to three-year data from the CENTAUR trial and its extension study.
These findings add to previous data from both studies showing that the therapy safely and effectively slowed functional decline and prolonged the long-term survival in adults with rapidly progressing ALS.
“These new findings support our continued hopes to bring a safe and effective treatment to our patients with ALS,” Merit Cudkowicz, MD, co-principal investigator of the trial and the director of the Healey & AMG Center for ALS at the Massachusetts General Hospital, said in a press release.
Justin Klee, co-CEO and co-founder of Amylyx Pharmaceuticals, the therapy’s developer, said that “these data will help support our continued efforts to bring AMX0035 to the ALS community.”
The company recently announced plans to submit an application to Health Canada seeking the therapy’s approval for ALS. It also plans to make the treatment available earlier in that country via a special access program, anticipated to be finalized by June.
Meanwhile, Amylyx continues “to work collaboratively with global regulatory agencies to find the most efficient path forward,” Klee added.
The results were presented by Sabrina Paganoni, MD, PhD, the trial’s principal investigator with the Healey & AMG Center for ALS at Mass General, in an oral address at the 2021 MDA Virtual Clinical and Scientific Conference. Paganoni is also an assistant professor at Harvard Medical School and Spaulding Rehabilitation Hospital.
AMX0035 is a fixed-dose combination of two small, orally available molecules, tauroursodeoxycholic acid and sodium phenylbutyrate, both in clinical use and proven to be safe and well tolerated.
The combo works to prevent nerve cell death by blocking stress signals within mitochondria — the cells’ powerhouses — and the endoplasmic reticulum, a cellular organelle involved in protein production, modification, and transport.
The therapy, dissolved in water and taken by mouth or via feeding tube, is administered twice a day.
It received orphan drug designation in both the U.S. and in Europe, which helps to speed its development by providing regulatory support and financial benefits, as well as a marketing exclusivity period (of seven years in the U.S. and 10 in Europe) upon regulatory approval.
The CENTAUR Phase 2/3 trial (NCT03127514) evaluated the safety and effectiveness of six months of treatment with AMX0035 against a placebo in 137 adults newly diagnosed with sporadic or familial ALS and evidence of rapidly progressing disease.
CENTAUR, a collaboration between Amylyx, the ALS Finding a Cure Foundation, The ALS Association, the Northeast ALS Consortium, and the MGH Neurology Clinical Research Institute, concluded in November 2019.
Participants were recruited at 25 sites across the U.S., had a mean age of about 57, and experienced first symptoms at a mean of 13.5 months before trial enrollment. Most (77%) were on or had previously been treated with riluzole (marketed as Rilutek and Tiglutik) and/or Radicava (edaravone).
Top-line data showed that the study met its main goal, with AMX0035 safely and significantly slowing patients’ functional decline compared with a placebo, as assessed using the ALS functional rating scale-revised.
Notably, these functional benefits were found to be independent of the use and duration of approved ALS therapies.
In addition, the cumulative risk for death, tracheostomy, and hospitalization was lower among AMX0035-treated patients, compared with those given a placebo, but these differences did not reach statistical significance. (Tracheostomy is a surgical procedure to create an opening in the windpipe for mechanical ventilation.)
Newly presented data concerned a long-term analysis of patients’ risk of death, tracheostomy and permanent assisted ventilation, and first hospitalization throughout the trial’s open-label extension study (NCT03488524).
A total of 90 patients who completed CENTAUR (56 in the AMX0035 group and 34 in the placebo group) chose to enter the extension trial, where all were given AMX0035 for up to two and a half years (totaling nearly three years of treatment among those on AMX0035 in the main study).
Time to death was assessed through a search of public records for all participants, including those “who discontinued [treatment], who were lost to follow-up, or did not enroll in the open-label extension,” Paganoni said. The other two events were recorded prospectively via clinical reports.
She also noted that the period of observation was shorter for permanent ventilation and hospitalization than for time to death, so that data might be missing for those two events.
Patients continuously treated with AMX0035 in the main and extension trial received the therapy for a median of 8.8 months (range, 0.1 to 33 months), while those initially assigned to placebo were treated for a median of 1.9 months (range, 0 to 22.5 months).
Results at almost three years showed early and continuous use of AMX0035 was associated with a 44% lower risk of any event — death, tracheostomy or permanent assisted ventilation, or first hospitalization — compared with a placebo.
Notably, patients always on AMX0035 had a 6.5-month longer median survival than did those initially given a placebo — representing a 44% lower risk of death. They were also 44% less likely to be hospitalized, and more than half had not yet experienced their first hospitalization after nearly three years.
Continuous-treatment patients also lived significantly longer without the need for permanent ventilation or tracheostomy than those originally assigned to placebo (23.8 months vs. 18.5 months), reflecting a 42% lower combined risk.
All these results “are statistically significant and, I might add, clinically meaningful for people with a fatal disease,” Paganoni said.
Overall, “the long-term risk of all these events was significantly lower among participants originally randomized to AMX0035 versus placebo,” she concluded.