BACKGROUND
Amylyx Pharmaceuticals Inc. is a company that started in 2013 with the aim of testing a combination product called AMX0035 as a potential treatment for ALS and other neurodegenerative disorders. AMX0035 is an oral drug combining two compounds called sodium phenylbutyrate (PB) and tauroursodeoxycholic acid (TUDCA). TUDCA is also commonly referred to as taurursodiol (TURSO) or ursodoxicoltaurine, to learn more about TUDCA, please see here.
TRIAL DESIGN & RESULTS
AMX0035 was tested in a Phase 2/3 clinical trial called CENTAUR, which consisted of 137 participants recruited across 25 sites in the United States through the Northeast ALS (NEALS) Consortium. The trial was randomized, double-blind and placebo-controlled, and participants were assessed over a 24-week period for both safety and potential effect of AMX0035 on disease progression. The placebo-controlled trial was followed by an open label extension to collect further data from those that opted to participate.
The clinical trial had financial support from multiple key organizations in the ALS/MND field including The ALS Association, ALS Finding a Cure and the Northeast ALS Consortium (NEALS).
Results of the trial are published in The New England Journal of Medicine here. A press release delineated the key findings of the publication as follows:
- Patients retained function longer on AMX0035 versus placebo; the study achieved its primary outcome of a difference on the Revised ALS Functional Rating Scale (ALSFRS-R).
- AMX0035 demonstrated statistically significant benefit vs. placebo on the prespecified primary outcome (ALSFRS-R).
- AMX0035 showed numerical benefits on secondary outcomes including measures of muscle strength, breathing, and hospitalizations.
- AMX0035 was generally well tolerated with similar rates of adverse events recorded in the AMX0035 and placebo groups.
The publication further indicates that the effects were seen in addition to those provided by riluzole and edaravone use, though a better understanding of this additive value observation would benefit from further study. While the treatment was considered reasonably safe and tolerable, the publication also outlines that early gastrointestinal adverse events were notable and will need monitoring in future use.
An academic editorial was published (available here), outlining a cautious approach to interpreting the data while balancing that these results were indeed promising. The key points of the editorial are as follows:
- Well-designed, multi-center trial with “tantalizing preliminary data.”
- Trial was enriched for individuals with more rapidly progressive disease, making interpretation difficult for the wider population of people living with ALS/MND.
- Secondary outcome measures were not convincingly aligned with the effect on ALSFRS-R.
- Recommendation to proceed to a confirmatory phase 3 trial with wider eligibility criteria.
All participants in the trial (active drug and placebo) were also provided an option to enroll in an open-label extension where they would receive AMX0035. Data from this extension study was published in October 2020 in the journal Muscle & Nerve and demonstrated that individuals initially treated with AMX0035 lived an average of 6.5 months longer than those originally on placebo. This survival data was considered by some to strengthen the overall data. Two additional manuscripts on evaluation of survival were published here and here.
In 2021, Amylyx launched a 48-week, randomized placebo-controlled, confirmatory Phase 3 clinical trial called PHOENIX, which enrolled 664 participants across 55 sites in the first collaborative effort between TRICALS (Europe) and NEALS (US).
In March 2024, the company published a press release stating that this larger phase 3 trial confirmed that AMX0035 is generally safe. However, the study failed to confirm the results of the Phase 2/3 trial and did not meet its primary endpoint, defined as change from baseline in ALS Functional Rating ScaleRevised (ALSFRS-R) total score at 48 weeks. Additionally, no difference between the treated and placebo groups was observed when looking at the secondary outcome measures including slow vital capacity measured both in clinic and remotely, and patient-reported outcomes and others. Amylyx also informed that when taking into consideration only those trial participants that had similar characteristics to the ones that took part in the CENTAUR trial, the results did not change.
REGULATORY SUBMISSIONS
On November 2, 2021, following the positive results of the Phase 2/3 CENTAUR trial, Amylyx announced it had submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for AMX0035 and on December 29 it was announced as accepted for priority review. On March 30, 2022 an FDA Advisory Committee was convened to discuss and vote on whether they believed the current data established a conclusion that AMX0035 was effective in ALS; the result was a 6 – 4 ‘no’ vote. On July 5, the FDA announced it would reconvene the same Peripheral and Central Nervous System Drugs Advisory Committee (PCNDSAC) on September 7 for further discussion. Discussions focused on the additional analyses from the company’s clinical studies that were determined by the FDA to constitute a major amendment to the NDA. The second PCNDSAC vote was 7-2 in favor of sufficient evidence to support FDA approval. Of note, the ongoing Phase 3 clinical trial was cited throughout this discussion as an opportunity to seek confirmation of AMX0035 benefit in ALS and Amylyx verbally committed to removing the drug from market if approved and the second trial was negative. On September 29, 2022, the FDA approved AMX0035 as RELYVRIO based on the results of the Phase 2/3 trial and analyses from the open label extension.
On February 25, 2022, it was announced that the European Medicines Agency (EMA) agreed to review AMX0035 for potential approval. On May 30, 2023, it was shared by Amylyx that the Committee for Medicinal Products for Human Use (CHMP) was trending toward a negative opinion on a conditional Marketing Authorization for AMX0035. In June 2023 the European Medicine Agency (EMA) gave a negative opinion on AMX0035 based on the CENTAUR results. Amylyx asked for reconsideration and EMA gave a second negative opinion in October 2023, expressing concerns regarding effective slowing of disease shown by AMX0035.
On June 13, 2022, it was announced that Health Canada approved AMX0035 as ALBRIOZA through the Notice of Compliance with Conditions (NOC/c) pathway where one of the conditions includes confirmation of safety and efficacy in the ongoing PHOENIX Phase 3 clinical trial. Canada became the first country anywhere in the world with regulatory approval of AMX0035.
In April 2024, given the PHOENIX topline results, Amylyx announced to be voluntarily discontinuing the marketing authorizations for RELYVRIO/ALBRIOZA in those countries where the drug had been approved (USA and Canada). The removal of the drug from the market, meant that RELYVRIO/ALBRIOZA would not be available for people affected by ALS, however, those who were taking the drug and wished to stay on it could still access it for free or through the open label extension phase of PHOENIX.
ADDITIONAL INFORMATION
a) TUDCA clinical trial: One of the compounds in AMX0035, TUDCA, was also evaluated in a phase 3 clinical trial alone with 336 participants across 9 sites in Europe supported by the TRICALS initiative. Results from this trial were released in March 2024. The study ran for 18 months and showed that TUDCA was safe and well tolerated but failed to meet its primary endpoint. Additionally, no difference was observed between the placebo or TUDCA treated groups in any of the secondary outcome measures. To learn more about TUDCA, please see here.
b) Sodium phenylbutyrate clinical trial: Sodium phenylbutyrate was evaluated in a small clinical trial by the NEALS consortium and published here in 2009. It was considered safe and tolerable but was not designed to determine an effect on disease progression. Both compounds have demonstrated some success at modifying disease course in preclinical animal models.
SUMMARY
It is the opinion of the SAC that there is sufficient evidence to conclude that at the studied dosage, AMX0035 did not show overall clinical benefit in individuals living with ALS. Furthermore, both sodium phenylbutyrate and TUDCA, while available by prescription and over-the-counter, respectively, also did not show clinical benefit in ALS.
International Alliance of ALS/MND Associations
September 2024
The original language of communication is English and any translation cannot be guaranteed for accuracy of messaging.