AMX0035

AMX0035, being 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 announced plans to seek regulatory approval of AMX0035 to treat ALS in Canada and in Europe by the close of 2021. The company also is working to make the medication available in Canada in advance of a regulatory decision, 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) in late 2020, calling for the medication to be made available to ALS patients in this country as soon as possible. The petition had over 50,000 signatures.

However, the FDA requested that data be available from an additional controlled Phase 3 clinical trial, which the company is planning to initiate. The trial is expected to enroll at sites in the U.S. and Europe.

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 mitochondria and in the 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 these two compartments fails to function properly, the resulting stress can kill a 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 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).

People in CENTAUR were assigned to 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 of the patients (92%) who completed the trial enrolled in its open-label extension study (NCT03488524). All in this study were treated with 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 each month with placebo. After 24 weeks of treatment, mean ALSFRS-R scores were significantly higher — by 2.92 points — among AMX0035-treated patients than those on placebo. 

Further findings from CENTAUR and its extension study showed that patients initially assigned to AMX0035 had a 44% lesser 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 patients on AMX0035 were more likely to discontinue treatment due to side effects (19% vs. 8%).

Last updated: April 15, 2021

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