Left to right: Amylyx Co-Founders and Co-CEOs Justin Klee and Josh Cohen/Courtesy of Amylyx Pharmaceuticals
Shares of Amylyx Pharmaceuticals are down again, although the company announced positive long-term survival analysis data for AMX0035, its investigational treatment for amyotrophic lateral sclerosis (ALS) which is pending U.S. approval Food and drug administration next month.
A a posteriori data analysis from the Phase II CENTAUR study that uses the grade-preserving structural failure time model, often used in oncology studies to account for crossover with placebo, showed a longer median survival time of 10.6 months for AMX0035 participants, Amylyx announced Thursday.
Additionally, trial participants who received the drug Amylyx and continued into an open-label extension demonstrated a median survival time of 18.8 months longer than participants who never received AMX0035 in a subgroup analysis, the company said. Altogether, the latest CENTAUR analysis suggested a greater survival benefit for AMX0035 when doing this cross-fit with placebo. Amylyx reported that these latest data show a median survival time of 10.6 to 18.8 months compared to the 6.9 months seen in the initial pre-specified intent-to-treat analysis in ALS patients.
Amylyx also noted that as of the March 2021 cut-off date, there was a lower risk of death and a longer median survival time of 4.8 months among those initially randomized to AMX0035 compared to those initially randomized to the placebo.
What impact this will have on the FDA’s decision next month is unknown. In late March, the regulatory agency’s Peripheral and Central Nervous System Drugs Advisory Committee voted 6 to 4 against the recommendation for approval experimental drug. As BioSpace previously reported, the committee members who opposed approval did so primarily on the design of the Phase II CENTAUR trial. The committee also questioned the initially shown 6.9 month survival benefit and suggested that the difference in decline measured on the ALSFRS-R scale between the placebo group and the treatment group was not sufficient. important.
Justin Klee and Joshua Cohen, co-CEOs of Amylyx, expressed enthusiasm for the post-hoc analysis and said they hoped the FDA would take this data into consideration before making a decision on AMX0035 next month.
“What we think is important is that this data highlights a treatment that can slow disease progression and increase lifespan. This is an important thing for the FDA and other agencies to consider,” Klee told BioSpace.
The latest survival data offers additional hope to an ALS community that currently faces only a bleak future. Cohen said most ALS patients who enter a clinical trial usually only have one chance to possibly receive an experimental drug that could slow their disease and extend their life. He noted that the company wanted to use the trial structure it had chosen for the CENTAUR study because it believed it was unethical to conduct a survival study in ALS where some patients are kept on placebo all the time. They wanted to ensure that patients on placebo would have the opportunity to cross over and receive the active treatment of AMX0035.
“We have a very clear clinical advantage. If you can see it has a functional benefit, it’s cruel to deny it to patients,” he said.
Amylyx’s AMX0035 is a fixed-dose combination of two small molecules, sodium phenylbutyrate and taurursodiol. It is designed to target the endoplasmic reticulum and mitochondria-dependent neuronal degeneration pathways in ALS and other neurodegenerative diseases.
If the FDA chooses to greenlight AMX0035 in June, Cohen said Amylyx would be able to manufacture the drug for market.
While the updated CENTAUR data may not move the needle on the FDA regarding potential approval, it does add depth to the understanding of how AMX0035 may impact the devastating disease as the company continues its Phase III PHOENIX study. The primary endpoint of the PHOENIX trial will include safety and efficacy, as well as the potential impact of AMX0035 on disease progression over 38 weeks. This will be determined after baseline ALSFRS-R readings and survival. Amylyx noted that additional measures critical for ALS patients, including slow vital capacity (SVC), serial assessments of patient-reported outcomes, and ventilation-free survival rates, will also be assessed in the study.
The PHOENIX trial is expected to include 600 patients with definite or clinically probable ALS within 24 months of symptom onset. The PHOENIX trial will have broader inclusion criteria than CENTAUR.
ALS, also known as Lou Gehrig’s disease, is a progressive neurodegenerative disease that negatively affects neurons in the brain and spinal cord. ALS patients lose the ability to control muscle movement. This eventually leads to total paralysis and then death. It is estimated that approximately 12,000 to 15,000 Americans have ALS, with approximately 5,000 to 6,000 new cases diagnosed each year.
Currently, the reference treatment is Riluzole, a glutamate inhibitor. In addition to Riluzole, which was approved in 1995, is the most recently approved rootcave, developed by Mitsubishi Tanabe. Other drugs in development for ALS include NeuroSense Therapeutics’ PrimeCa sustained-release formulation of two FDA-approved drugs, ciprofloxacin and celecoxib, and complementary therapy from Clene Inc., CLN-Au8, an experimental gold bioenergetic nanocatalyst that showed positive data in a mid-stage study in ALS. WAVE Life Sciences is developing WVE-004 for ALS. Last month, WAVE released positive data of a Phase Ib/IIa study.
If Amylyx is successful with AMX0035, the company intends to begin evaluating the therapeutic in other indications “where the science makes sense,” Cohen said. “If we are lucky enough to succeed, we consider it our responsibility to triple our efforts in this area.”
The PDUFA date for AMX0035 is June 29.