Taurursodiol-Phenylbutryate Investigational Treatment for Amyotrophic Lateral Sclerosis Targets Neurodegeneration

Earlier this month, in the double-blind randomized placebo-controlled CENTAUR clinical trial (NCT03127514) the last-enrolled participant completed treatment. In CENTAUR, 137 participants with amyotrophic lateral sclerosis (ALS) were randomly assigned 2:1 to receive a combination of taurursodiol (TURSO) and sodium phenylbutyrate (PB) (AMX0035; Amylyx, Cambridge, MA) or placebo for 24 weeks. 

Notably, of the participants who completed the 6-month double-blind study, approximately 90% have continued into the open-label extension trial (NCT03488524), switching from placebo to TURSO-PB or continuing TURSO-PB. Some trial participants have now taken TURSO-PB for as long as 25 months. 

A full data readout is expected in the coming weeks. Data gathered during the trial include change from baseline on the ALS Functional Rating Scale-Revised (ALSFRS-R), Accurate Testing of Limb Isometric Strength (ATLIS), and blood levels of neurofilament heavy (p-NfH).

Enrollment criteria for CENTAUR were developed using data from over 10,000 participants in previous clinical trials based on statistical modeling to find ALS patients with a more homogenous progression rate. To enroll, participants had to have a confirmed diagnosis of diffuse ALS with initial onset of symptoms no more than 18 months prior to enrollment. Participants were allowed to continue using other treatments for ALS during the trial.

Sabrina Paganoni, MD, assistant professor at the Massachusetts General Hospital and Harvard University Medical School and lead investigator for CENTAUR said, “In this trial, partnership between industry and academia was used not just to test the new drug but also to learn things from this trial that will be of benefit in future trials. Using 2 databases of collectively over 10,000 people who have participated in ALS clinical trials, we created novel inclusion/exclusion criteria and targeted a specific population predicted to have fast progression of disease to maximize trial efficiency.” 

Justin Klee, president and co-founder of Amylyx said, “If efficacy is proven, we intend to drive the product forward as quickly as possible for people with ALS. At Amylyx we want to remain true to our mission of improving the lives of people with neurodegenerative diseases and do right by patients if this trial is a success.” 

The TURSO-PBA combination is taken orally and can also be administered via a gastrointestinal tube. The most common adverse events observed to date have been gastrointestinal discomfort or nausea generally described as mild. 

In preclinical trials, TURSO-PBA significantly reduced cell death from oxidative stress induced by hydrogen peroxide. At the cellular level, both oxidative stress at both mitochondria and the endoplasmic reticulum that are implicated in neurodegeneration are inhibited by both TURSO and PB. The agent is also being studied for use in other neurodegenerative diseases, including Alzheimer’s disease.