On March 30, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee (AdCom) voted against granting a New Drug Application (NDA) for Amylyx’s AMX0035 for the treatment of amyotrophic lateral sclerosis (ALS) patients. The vote was almost split, with six members voting for the rejection of AMX0035 on the grounds of data insufficiency and four members voting in favor of the drug’s approval.

While extremely disappointing for the ALS community, this vote is not entirely surprising as the FDA had released briefing documents prior to the AdCom meeting signaling concerns about the results of AMX0035’s Phase II CENTAUR study (NCT03127514) and the open label extension (OLE) CENTAUR-OLE study (NCT03488524). GlobalData believes that even though this vote has narrowed AMX0035’s chances to get FDA approval by the target Prescription Drug User Fee Act date of June 2022, it has left the door open for AMX0035 to potentially present more robust data in the near future.

Although AMX0035 met the primary endpoint of change in ALS Functional Rating Scale-Revised (ALSFRS-R) in the CENTAUR study, which enrolled 137 patients with ALS over a period of 24 weeks, concerns remained over the modest benefits of the drug. During the meeting, the main concerns raised about the results of this study were related to the lack of substantial evidence of the benefits of AMX0035 over placebo. This was attributed to the marginally significant P-value used in the analysis of the ALSFRS-R over time, compounded with the small sample size of the study. Similarly, survival endpoints from the CENTAUR-OLE were deemed statistically unpersuasive. These concerns align with the FDA’s briefing document. The trial data continued to show that AMX0035 has a relatively good safety and tolerability profile.

Acknowledging the huge unmet needs in the ALS market, the FDA had accepted a filing for AMX0035’s NDA in October 2021 based only on data from the small Phase II CENTAUR study. At that time, this move was embraced as a sign of the agency showing more flexibility in assessing drugs for the treatment of severely debilitating neurological conditions, particularly drugs with huge community and physician advocacy.

AMX0035 is an orally administered combination of tauroursodeoxycholic acid (TUDCA) and sodium phenylbutyrate. AMX0035’s mechanism of action is seen as a promising addition to the treatment of ALS, which currently consists of just two modestly effective drugs: generic riluzole and Mitsubishi Tanabe Pharma’s Radicava (edaravone). The drug has a role in the downregulation of endoplasmic reticulum (ER) stress and mitochondrial dysfunction involved in ALS, thus reducing inflammation and neuronal cell death. Furthermore, the drug is being regarded as safe and well-tolerated, supposedly because its two active constituents have been prescribed for a long time in other indications without serious side effects. Key opinion leaders (KOLs) previously interviewed by GlobalData expressed concerns that some of their patients were already gaining access to one of the drug’s constituents, TUDCA, which is available online as a dietary supplement.

As such, KOLs noted that given the huge unmet needs and the devastating nature of ALS, there is a strong public pressure to get more drugs approved for this disease despite AMX0035 showing modest benefits on survival and slowing disease progression. As such, GlobalData expects that if AMX0035 ultimately does get FDA approval, it will likely have a strong impact on the ALS market.

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With the FDA facing mounting scrutiny over its controversial approval of Biogen’s Aduhelm (aducanumab) for Alzheimer’s disease following an AdCom rejection, it is highly likely that Amylyx will need to address a number of concerns in the design of its new Phase III PHOENIX trial (NCT05021536) before it can reassure the regulatory authorities and gain approval. The topline results of the PHOENIX trial are expected to readout in H1 2024, as mentioned by Amylyx’s representatives in the meeting.