A combination drug that targets cellular stress nudged, ever so slightly, progression of amyotrophic lateral sclerosis in a Phase 2 trial. Researchers led by Sabrina Paganoni at Massachusetts General Hospital, Boston, reported the findings in the September 3 New England Journal of Medicine. In the six-month trial, Amylyx Pharmaceutical’s AMX0035 slowed functional decline by about a quarter compared with a placebo. Many participants were taking the approved ALS drugs riluzole and edaravone as well, and AMX0035 appeared to confer a small independent benefit on top of this standard of care.

  • The combo drug AMX0035 slowed ALS progression in a Phase 2 trial.
  • Secondary outcome measures trended toward a benefit.
  • AMX0035 may offer benefit on top of approved ALS drugs.

The three treatments are believed to have different mechanisms of action. “We think we’re going to need a cocktail of drugs to have an impact on the multiple disease pathways implicated in ALS. These results give us hope we are making progress,” Paganoni told Alzforum.

In an NEJM editorial, Michael Benatar at the University of Miami and Michael McDermott at the University of Rochester Medical Center, New York, agreed that even small incremental gains for patients on AMX0035 were encouraging. “We hope that the sponsors and investigators will follow up on these tantalizing preliminary data with a confirmatory Phase 3 trial,” they wrote.

For many drugs, promising results in small Phase 2 studies have failed to replicate in larger Phase 3 trials, but news reports on this trial noted efforts to push the FDA to approve AMX0035 even now (ALS Association statement; STAT News; The New York Times). Paganoni said Amylyx Pharmaceuticals is in discussions with regulatory authorities to decide on next steps.

ALS destroys motor neurons, leading to paralysis and death within two to five years on average. Riluzole, approved in 1995, blocks glutamate release and lowers excitotoxicity in the brain. It extends patients’ life by only a few months. Edaravone, approved in 2017, is a free-radical scavenger that counteracts oxidative damage and somewhat slows functional decline but has not been shown to extend life (Jan 2016 conference news; May 2017 news). 

AMX0035 formulates two compounds together. Sodium phenylbutyrate, aka Buphenyl, is a prescription drug used to treat urea cycle disorders. It acts as a chemical chaperone on misfolded proteins to relieve stress on the endoplasmic reticulum. Taurursodiol, also known as tauroursodeoxycholic acid or TUDCA, is a bile acid derivative that is widely available as a liver support supplement. It reportedly promotes the health of mitochondria by protecting the integrity of their membranes and preventing release of cytochrome C, which triggers cellular apoptosis. In preclinical studies, either compound alone protected neurons (Ryu et al., 2005Thams et al., 2019). 

The ALS trial, dubbed CENTAUR, enrolled 137 people who had developed symptoms of the disease within the prior 18 months. Two-thirds, or 89 participants, received the combo drug, consisting of 3 grams of sodium phenylbutyrate and 1 gram of taurursodiol, taken orally as a powder dissolved in water. The remaining 48 participants got placebo.

Over 24 weeks, participants on drug declined by 1.24 points per month, and those on placebo by 1.66 points per month, on the primary outcome measure, the ALS Functional Rating Scale-Revised. The ALSFRS-R scale assesses motor abilities, speech, and breathing, and is a standard, validated outcome measure for ALS trials. The scale ranges from zero (worst) to 48 (best). By the end of the trial, the treatment group had an average ALSFRS-R of 29.06, compared with 26.73 for placebo, a difference of 2.33 points. The authors noted that it is unclear what amount of change constitutes a clinically meaningful difference on this scale.

On secondary measures of muscle strength and lung capacity, participants on drug fared numerically better than those on placebo, though the differences fell short of statistical significance. Participants taking AMX0035 were about half as likely as those on placebo to need hospitalization or tracheostomy, but again this was not significant. Paganoni said these measures tend to be more variable than the ALSFRS-R.

The researchers also measured plasma levels of phosphorylated neurofilament H, a marker of motor neuron damage. They found no significant difference with treatment. Cerebrospinal fluid levels of neurofilament H have been found to correlate better with disease progression than do plasma levels, but CSF was not measured (Li et al., 2016). 

About half of participants were taking either riluzole or edaravone; one-quarter were taking both. Overall, 68 percent of the treatment group and 77 percent of controls were on riluzole, while 25 percent of the treatment group and 50 percent of controls were on edaravone. A sensitivity analysis found that AMX0035 likely worked independently of these medications. Correcting for riluzole use did not significantly change the outcome, with the AMX0035 group sliding by 2.34 points less than placebo on the ALSFRS-R. Correcting for edaravone use shrank this difference to 2.15 points, which was no longer statistically significant.

Michael Weiss at the University of Washington, Seattle, noted that the reported benefit from AMX0035 is comparable in size to that seen with edaravone alone (full comment below). In the Phase 3 edaravone trial, patients on drug ended up 2.5 points higher on the ALSFRS-R than controls after six months. “An additional larger longitudinal study could be of value to corroborate the effect of the medication on slowing disease progression and more accurately determine any impact on survival,” Weiss wrote.

Koji Abe at Okayama University, Japan, who led edaravone trials there, pointed out that like that drug, sodium phenylbutyrate and taurursodiol are also believed to have antioxidant effects. “This report confirms the potential of anti-oxidative stress therapy for ALS,” he wrote to Alzforum.

Discontinuations from the trial amounted to 25 percent of those on drug and 21 percent of those on placebo. “This is typical of what we see in ALS trials,” senior author Merit Cudkowicz at Mass. General told Alzforum. In the treatment group, some of these dropouts were due to diarrhea and abdominal pain, the main side effect of AMX0035. About 5 percent of participants developed these symptoms, which typically abated with time. The researchers believe this problem might be ameliorated by titrating up the drug dose more slowly.

Trial participants continue to have access to the drug through an open-label extension trial and a compassionate use protocol.

Meanwhile, AMX0035 is being tested in the Phase 2 PEGASUS study of 96 AD patients. This trial’s primary outcome is safety, with cognition, psychiatric symptoms, and volumetric and functional MRI as secondary outcomes. It is fully enrolled and expected to read out in December. Rudy Tanzi, also from Mass. General and a co-author on the paper, noted that AMX0035 may indirectly soothe neuroinflammation. “I believe that if we therapeutically hit neuroinflammation, we have a chance of improving cognition,” he wrote to Alzforum.

Academic, industry, and clinical groups collaborated to complete this trial, which was partly funded with funds from the ice-bucket challenge (Jul 2015 news). There are 59 authors on the paper. “It’s an example of the collaborative spirit of the ALS scientific community,” Paganoni said.—Madolyn Bowman Rogers


  1. This study showed a significant impact of sodium phenylbutyrate/taurursodiol on ALS, based on slowing of the rate of decline in subjects versus controls as measured by the ALSFRS-R, a primary assessment tool for measuring functional change.

    Overall, there was a reduction over 24 weeks of the rate of decline using this metric that was comparable to the effects seen with edaravone, recently approved by the FDA for ALS. While this was a relatively large study (given the patient population), as the authors suggest, an additional larger longitudinal study could be of value to corroborate the effect of the medication on slowing disease progression and more accurately determine any impact on survival.

    To date, only riluzole has shown an impact on survival, albeit modest. Joshua Cohen and Justin Klee, the founders of Amylyx, are to be commended for their extraordinary focus, determination, and leadership in studying the neuroprotective properties of sodium phenylbutyrate/taurursodiol and then creating their company, while still undergraduates, to allow this compound to be studied successfully in patients with ALS.

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Therapeutics Citations

  1. Albrioza

News Citations

  1. Does Free Radical Scavenger Edaravone Slow ALS?
  2. FDA Approves Edaravone for Treatment of ALS
  3. Divvying Up the Ice-Bucket Dollars: Challenge Speeds Trials, Research

Paper Citations

  1. . Sodium phenylbutyrate prolongs survival and regulates expression of anti-apoptotic genes in transgenic amyotrophic lateral sclerosis mice. J Neurochem. 2005 Oct 21; PubMed.
  2. . A Stem Cell-Based Screening Platform Identifies Compounds that Desensitize Motor Neurons to Endoplasmic Reticulum Stress. Mol Ther. 2019 Jan 2;27(1):87-101. Epub 2018 Oct 19 PubMed.
  3. . Phosphorylated neurofilament heavy chain levels in paired plasma and CSF of amyotrophic lateral sclerosis. J Neurol Sci. 2016 Aug 15;367:269-74. Epub 2016 Jun 1 PubMed.

External Citations

  1. Phase 2
  2. ALS Association statement
  3. STAT News
  4. The New York Times
  5. open-label extension
  6. compassionate use protocol
  7. Phase 2 PEGASUS

Further Reading

Primary Papers

  1. . Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis. N Engl J Med. 2020 Sep 3;383(10):919-930. PubMed.
  2. . Incremental Gains in the Battle against ALS. N Engl J Med. 2020 Sep 3;383(10):979-980. PubMed.