AMX0035 Significantly Extends ALS Patients’ Lives, Long-term Data Show

Treatment with AMX0035, Amylyx’s experimental oral therapy, significantly extends the lives of amyotrophic lateral sclerosis (ALS) patients with rapidly progressing disease, according to a long-term survival analysis of the CENTAUR Phase 2/3 trial.

The new data were reported in a study titled “Long‐Term Survival of Participants in the CENTAUR Trial of Sodium Phenylbutyrate‐Taurursodiol in ALS,” published in the journal Muscle & Nerve.

These findings add to previous CENTAUR top-line data, which showed that the therapy safely and effectively slowed functional decline in people with ALS. Together, “the results support that AMX0035 has functional and long-term survival benefits,” Merit Cudkowicz, MD, the study’s senior author and director of the Sean M. Healey & AMG Center for ALS at Mass General, in Boston, said in a press release.

“We have shown that AMX0035 may provide patients hope and the chance to function better and live longer lives,” added Cudkowicz, also the chief of neurology at Mass General, the chief medical officer of the ALS Finding a Cure Foundation, and a professor of neurology at Harvard Medical School.

“These results were seen on top of baseline use of approved ALS therapies,” said Sabrina Paganoni, MD, PhD, the study’s first author, who said she is “so excited about the potential of this [therapy] for the people living with ALS.” Pagoni also is the trial’s principal investigator and an assistant professor at Harvard Medical School and Spaulding Rehabilitation Hospital, in Boston.

AMX0035 is a combination of two small molecules, tauroursodeoxycholic acid and sodium phenylbutyrate, used in the clinic 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 received orphan drug designation for ALS in the U.S. in 2017, and earlier this year in the European Union, after a branch of the European Medicines Agency issued a positive recommendation for that indication.

CENTAUR (NCT03127514), completed in November 2019, had evaluated AMX0035’s safety and effectiveness in 137 adults who had recently been diagnosed with sporadic or familial ALS and had evidence of rapidly progressing disease — a stringent enrollment criteria meant to provide the most powerful results possible.

Participants were randomly assigned to receive an oral liquid of either AMX0035 (89 patients) or a placebo (48 patients) twice daily for 24 weeks (about six months).

Top-line data showed that the trial met its main goal, with the therapy significantly slowing patients’ functional decline, compared with a placebo, as assessed with the ALS functional rating scale-revised.

Notably, these functional benefits were found to be independent of the use and duration of other established ALS therapies, including riluzole (marketed as Rilutek and Tiglutik) and Radicava (edaravone).

AMX0035-treated patients also showed a trend toward slower decline in muscle strength and lung function and fewer hospitalizations, compared with the placebo group. However, except for upper limb strength, these differences did not reach statistical significance.

A total of 90 patients completing CENTAUR (56 in the AMX0035 group and 34 in the placebo group) chose to enter its open-label extension study (NCT03488524), in which all would receive AMX0035 for up to 30 months (about two and a half years).

The newly published study reports the results of a nearly three-year survival analysis of all CENTAUR participants, regardless of whether or not they enrolled in the trial’s extension study.

Results showed that participants originally assigned to AMX0035 lived significantly longer than those initially on placebo — specifically, a median of 25 months vs. 18.5 months in the placebo group — reflecting a 44% lower risk of death.

At two years, 51.6% of those receiving AMX0035 were estimated to be alive, compared with 33.9% for those originally assigned to a placebo.

Notably, this survival benefit was associated with a seven-month median difference in AMX0035 exposure between the two groups and independent of the use of other ALS therapies.

“The group originally randomized to [AMX0035] had a median overall survival that was 6.5 months longer than the group originally randomized to placebo,” the researchers wrote, adding that this “suggests a neuroprotective effect of [AMX0035] in ALS.”

Interim results from the ongoing extension study are expected to be presented this year, while long-term functional and safety data from CENTAUR and its extension study are being submitted for publication in a peer-reviewed journal.

CENTAUR was a collaboration between Amylyx, the ALS Finding a Cure Foundation, The ALS Association, the Northeast ALS Consortium, and the Massachusetts General Hospital Neurology Clinical Research Institute.

“The commitment of so many people with ALS to this research over the course of nearly three years, especially when weighing just how valuable time is for this patient community, has led us to this critical development milestone where we can now reimagine outcomes for ALS,” said Justin Klee, Amylyx’s co-CEO and co-founder.

“We know there is nothing more valuable than time to these and other patients, so we hope to share updates on our progress with AMX0035 with the ALS community as soon as possible,” he added.

“We will continue to work collaboratively and expeditiously with global regulatory agencies to bring this potential treatment to people living with ALS in accordance with the applicable regulatory approval processes,” said Josh Cohen, Amylyx’ co-founder, co-CEO, and chairman.