A combination therapy for amyotrophic lateral sclerosis (ALS), AMX0035, was marketed under the brand name Relyvrio. Its path to approval by the U.S. Food and Drug Administration (FDA) was unconventional, sparking debate among clinicians and regulators. The journey of this treatment provides a look into the complexities of drug development for severe neurodegenerative diseases.
The Science Behind AMX0035
AMX0035 combines two compounds: sodium phenylbutyrate (PB) and taurursodiol (TURSO), also known as TUDCA. While not new to medicine, they were combined in a novel formulation as an oral powder dissolved in water. The rationale for this combination lies in their complementary effects on the cellular processes implicated in ALS progression.
The progression of ALS involves the death of motor neurons, partly due to stress in two cellular structures: the endoplasmic reticulum (ER) and mitochondria. ER stress leads to misfolded proteins, while mitochondrial stress causes energy deficits, both contributing to neuron death. AMX0035 was designed to target both pathways simultaneously to protect motor neurons. Sodium phenylbutyrate works by reducing ER stress, while taurursodiol supports mitochondrial function, aiming to be more effective together than either compound alone.
Clinical Trial Findings
The primary evidence for AMX0035 came from CENTAUR, a Phase 2 clinical trial. The study evaluated the drug’s safety and efficacy in 137 participants with ALS. In the randomized, placebo-controlled trial, one group received AMX0035 and another received a placebo for 24 weeks, with the main goal of measuring the rate of functional decline.
Researchers used the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) to assess daily activities like speaking, swallowing, and walking. Over 24 weeks, patients receiving AMX0035 had a slower rate of decline than the placebo group. The treated group’s scores declined by 1.24 points per month versus 1.66 for the placebo group, a statistically significant difference.
After the main trial, an open-label extension where all participants received AMX0035 showed a survival benefit. An analysis suggested that patients originally on AMX0035 lived a median of 6.5 months longer than those from the placebo group. This survival data, combined with the functional findings, formed the basis of the company’s FDA application.
A Contentious Path to Approval
The regulatory journey of AMX0035 was contentious. After Amylyx submitted its New Drug Application based on the CENTAUR trial, the FDA expressed initial reservations. The agency’s primary concern was the sufficiency of data from a single Phase 2 trial, as approval often requires results from at least two large-scale Phase 3 trials.
This led to the first Peripheral and Central Nervous System Drugs Advisory Committee (PCNSDAC) meeting in March 2022. These committees of external experts provide independent advice to the FDA. Despite testimony from patients and advocates about the need for new treatments, the committee voted 6-to-4 against recommending approval. Members cited concerns about the trial’s design and the robustness of the results.
The FDA did not immediately issue a decision, which is an unusual step. It allowed Amylyx to submit additional analyses from the CENTAUR data and scheduled a second advisory committee meeting for September 2022. This provided another opportunity to discuss the evidence, including new analyses on survival.
At the September meeting, the dynamic shifted. While some panelists still had reservations about the data’s strength, the discussion was influenced by the context of ALS as a fatal disease with no cure. The new analyses and continued patient advocacy appeared to sway the committee. The panel reversed its earlier stance and voted 7-to-2 in favor of approval.
The Final FDA Decision and Its Implications
On September 29, 2022, the FDA approved AMX0035, to be marketed as Relyvrio. In its reasoning, the FDA cited the seriousness of ALS and the high unmet medical need. The agency stated it was exercising “regulatory flexibility,” an approach that allows for a different standard of evidence for life-threatening diseases with few treatment options.
A factor in the approval was a commitment from the manufacturer, Amylyx. The company was already conducting a larger Phase 3 trial, PHOENIX, to confirm the drug’s benefits. Amylyx pledged that if the PHOENIX trial failed to show effectiveness, it would voluntarily withdraw Relyvrio from the market. This promise acted as a safeguard, allowing patient access while more data was collected.
The approval offered a new option for people with ALS. However, in March 2024, Amylyx announced the Phase 3 PHOENIX trial did not meet its primary endpoint, failing to confirm the benefits seen in the earlier study. Fulfilling its promise, the company began withdrawing Relyvrio from the U.S. and Canadian markets in April 2024, transitioning patients to a free drug program.