Amylyx to Seek AMX0035’s Approval in Europe

Amylyx Pharmaceuticals is planning to file an application by the end of this year requesting that the European Medicines Agency (EMA) approve AMX0035 as an oral treatment for amyotrophic lateral sclerosis (ALS).

This follows a recent announcement that a similar application will be submitted to Health Canada in the second half of the year.

“We are thrilled to plan our submissions in Europe and Canada and will continue working closely with regulators and the ALS community worldwide to determine the most expeditious and responsible pathways to advance AMX0035 through the clinical development process,” Joshua Cohen, co-CEO, chairman and co-founder of Amylyx, said in a press release.

Meanwhile, the U.S. Food and Drug Administration (FDA) has requested data from an additional controlled clinical trial before considering AMX0035 for approval. The company now plans to launch a Phase 3 trial in the coming months to investigate AMX0035 versus a placebo in ALS patients at sites in the U.S. and Europe. The FDA and Amylyx will continue to discuss the next steps.

“We appreciate all of the advice and guidance from the regulators worldwide and will continue to act with haste and to keep the community updated,” said Cohen.

“After decades of ALS trial failures, AMX0035 has given us the hope that a new potential treatment option may be on the horizon for those living with ALS. We remain highly encouraged as AMX0035 continues to move through the regulatory review process, and are excited for the Phase 3 clinical trial,” said Leonard H. van den Berg, MD, PhD, who serves as chairman of the Treatment Research Initiative to Cure ALS (TRICALS), a large European trial network fostering a cure for ALS.

“The pivotal Phase 3 clinical trial will catalyze a global collaboration between Amylyx, European and US ALS experts, advocacy groups, and clinical trial networks. We hope this is just the beginning of providing new options to people living with ALS,” said Merit Cudkowicz, MD, director of the Healey & AMG Center for ALS, and chair of neurology at Massachusetts General Hospital in Boston.

AMX0035 combines two small molecules, tauroursodeoxycholic acid and sodium phenylbutyrate, that have been used in the clinic and are known to be safe and well-tolerated.

The treatment is expected 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 submissions to regulatory authorities in Europe and Canada will be based on data from the completed CENTAUR Phase 2/3 trial (NCT03127514), which investigated AMX0035 in people with ALS.

A total of 137 patients recently diagnosed with sporadic or familial ALS were enrolled. All had rapidly progressing disease — a stringent enrollment criteria meant to provide the most powerful results possible — and were assigned randomly to receive twice daily AMX0035, or a placebo, for 24 weeks (almost six months).

Patients then could enter the trial’s open-label extension study (NCT03488524), and start or continue receiving the therapy for up to 30 months. Most patients (92%) chose to enter this part of the study.

The study met its main efficacy goal, with AMX0035 slowing patients’ functional decline — measured with the ALS Functional Rating Scale-Revised — in a clinically meaningful and statistically significant manner, compared with a placebo.

While 77% of participants in CENTAUR were taking, or had been treated previously, with approved ALS medications, the benefits of AMX0035 on disease progression were found to be independent of the use and duration of such therapies.

Long-term results spanning CENTAUR and its extension study also found that patients initially assigned AMX0035 lived about 6.6 months longer than those originally given a placebo, representing a 44% lower risk of death.

Of note, an exploratory analysis comparing participants’ predicted and observed survival also found a survival benefit among patients who were first on a placebo (18.4 months observed vs. 12 months predicted), though the benefits were greater for patients who started AMX0035 earlier (25 months vs. 13.5 months).

AMX0035 “is the first to show a combination of both functional and survival benefits for people living with ALS,” Sabrina Paganoni MD, PhD, said at the 2021 American Academy of Neurology (AAN) Annual Meeting Top Science Press Conference. Paganoni is the trial’s principal investigator with the Healey & AMG Center for ALS at Mass General.

“With the results from CENTAUR, we showed that AMX0035 may provide people living with ALS hope and the chance to function better and live longer lives,” Paganoni said in the release.

Additional long-term results also showed that early and continuous use of AMX0035 was associated with a 44% lower risk of first hospitalization and a 42% lower risk of permanent ventilation or tracheostomy, compared with patients originally on a placebo.

Patients on early AMX0035 also were 44% less likely to experience either death, tracheostomy or permanent assisted ventilation, or first hospitalization. Tracheostomy is a surgical procedure to create an opening in the windpipe for mechanical ventilation.

“Every single day matters for people living with ALS and we will continue to work with the U.S. FDA and global regulatory agencies to meet their requests so that we can advance AMX0035 through the clinical development process as quickly as possible. We will share updates on our progress with the community as we have them,” said Justin Klee, co-CEO and co-founder of Amylyx.