AMX0035, developed by Amylyx, is a combination of two compounds — sodium phenylbutyrate (PB) and tauroursodeoxycholic acid (TUDCA) — that work together to minimize cellular mechanisms linked to cell death in amyotrophic lateral sclerosis (ALS). 

Amylyx has announced plans to seek regulatory approval of AMX0035 this year to treat ALS in Canada. The company also is working to make the medication available in Canada before an official approval, via a special access program expected to be finalized by June.

The ALS Association and I AM ALS filed a petition with Amylyx and the U.S. Food and Drug Administration (FDA), calling for the medication to be made available to ALS patients as soon as possible. The petition had over 50,000 signatures.

AMX0035 has received orphan drug designation in both the U.S. and Europe, meant to provide financial and other incentives that accelerate the therapy’s development.

How AMX0035 works

AMX0035 is designed to reduce nerve cell death by blocking cell death pathways that originate in the mitochondria and endoplasmic reticulum, two cellular compartments. Mitochondria are the energy production factories of cells, and the endoplasmic reticulum is involved in protein production, modification, and transport.

Both are in constant communication and are vital for cell survival. When one of the two compartments fails to function properly, the resulting stress can kill the cell or lead to inflammation. Brain cells are particularly sensitive to this stress, which has been implicated in the development of neurodegenerative diseases such as ALS.

AMX0035 was designed to target both the mitochondria and endoplasmic reticulum simultaneously. While TUDCA improves mitochondria energy production, PB helps proteins acquire their normal shape, thereby preventing the formation of protein clumps that cause nerve cell death.

AMX0035 in clinical trials

Both compounds in AMX0035, PB and TUDCA, have been used individually in ALS patients and shown to be safe.

A Phase 2/3 clinical trial (NCT03127514) called CENTAUR evaluated the safety and efficacy of AMX0035 in 137 adults recently diagnosed with sporadic or familial ALS.

All of the participants had rapidly progressing disease, a stringent enrollment criteria meant to provide the most statistically powerful results possible, and most (77%) were on or had previously been given other ALS treatments, namely riluzole (marketed as Rilutek, Tiglutik, and Exservan) and/or Radicava (edaravone).

Participants in CENTAUR were given either AMX0035 (89 participants) or a placebo (48 participants), taken by mouth twice daily for 24 weeks (about six months). At the end of this period, most eligible patients (92%) who completed the trial enrolled in its open-label extension study (NCT03488524). In that extension study, all participants are receiving AMX0035 for up to 30 months (about two and a half years).

Full results from CENTAUR showed that treatment with AMX0035 resulted in a clinically meaningful and statistically significant slowing of functional decline, measured by the ALS Functional Rating Scale-Revised (ALSFRS-R), independent of the use or duration of other ALS therapies. 

The mean rate of decline on ALSFRS-R was 1.24 points per month with AMX0035, as compared with 1.66 points per month with placebo. After 24 weeks of treatment (nearly six months), mean ALSFRS-R scores were significantly higher – by 2.92 points – among participants given AMX0035, compared with a placebo. 

Further findings from CENTAUR and its extension showed that participants originally given AMX0035 had a 44% decreased risk of death, and were also less likely to require permanent assisted ventilation or being hospitalized. 

AMX0035 was generally safe and well-tolerated in the CENTAUR trial. The most common side effects related to treatment were digestive issues such as diarrhea. Serious adverse events were more frequent among participants given a placebo than AMX0035 (19% vs. 12%), although participants on AMX0035 were more likely to discontinue treatment due to adverse events (19% vs. 8%).

Last updated: March 29, 2021

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