AMX0035 Meets Primary Safety and Tolerability End Point in Alzheimer Disease


A higher incidence of gastrointestinal events was observed in the treatment group compared with placebo, similar to what was seen in clinical trials of AMX0035 in amyotrophic lateral sclerosis.

Steven E. Arnold, MD, professor of neurology, Harvard Medical School, and managing director and translational neurology head, Interdisciplinary Brain Center, Massachusetts General Hospital

Steven E. Arnold, MD

Clinical data from the phase 2 AMX-8000 PEGASUS trial (NCT03533257) of AMX0035, a combination of sodium phenylbutyrate (PB) and taurursodiol (TURSO), in patients with Alzheimer disease (AD) were presented at the 14th Clinical Trials on Alzheimer’s Disease Conference (CTAD), November 9-12, confirming the treatment met its primary end point of safety and tolerability.1 Similar to previous clinical trial findings in amyotrophic lateral sclerosis (ALS), treatment with AMX0035 was found to be associated with a higher incidence of gastrointestinal events when compared with placebo. 

A total of 133 patients with dementia or mild cognitive impairment (MCI) because of AD were screened, with a total of 95 patients eventually included in the double-blind, placebo-controlled, multicenter trial. Participants had an average age of 70.7 years and were randomized to receive an oral, fixed dose coformulation of AMX0035 (n = 51) or placebo (n = 44) over the course of 24 weeks. 

Similar to results in the phase 2/3 CENTAUR trial of AMX0035 in patients with ALS, gastrointestinal (GI) events occurred more frequently in patients receiving treatment, compared with placebo in the PEGASUS trial. Thirty-six (67%) patients in the AMX0035 group reported treatment-emergent adverse events (TEAEs), compared with 26 (59%) patients in the placebo group. The greatest proportion of TEAEs in the treatment group were GI events, primarily diarrhea, occurring in 20 (39%) patients, compared with 6 (14%) patients in the placebo group. Within the AMX0035 group, 10 of 51 participants discontinued the study, and in the placebo group, 2 of 44 participants discontinued.

Investigators, led by Steven E. Arnold, MD, professor of neurology, Harvard Medical School, and managing director and translational neurology head, Interdisciplinary Brain Center, Massachusetts General Hospital, noted that the study was not designed to evaluate differences between placebo and treatment groups in terms of efficacy outcomes, and there were no differences found. Additionally, the safety profile of AMX0035 was consistent with previous data, and no new safety concerns arose. 

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Also noted was the possibility of AMX0035 activity improving certain biomarkers of AD pathology, namely amyloid beta species (Aß1-42 and Aß1-40), total tau (t-tau), and phospho-tau 181 (p-tau) in the cerebrospinal fluid (CSF). When compared with placebo, significant reductions were seen in CSF t-tau (P = .0005) and p-tau (P = .0008) in patients treated with AMX0035, as well as an increase in both Aß1-42 and Aß1-40 (P = .017). 

To be included, patients were required to have probably AD or MCI with biomarkers supporting AD pathology, as well as a baseline Montreal Cognitive Assessment (MoCA) score of 8 points or higher. Approximately 80% of patients were taking concomitant acetylcholinesterase inhibitors, and 42% were receiving concomitant memantine. A higher baseline level of cognitive impairment in the AMX0035 group was indicated by mean cognitive assessment scores, compared with placebo (14-item Alzheimer’s Disease Assessment Scale–Cognitive Subscale, MoCA, and Mild/Moderate Alzheimer’s Disease Composite Scale, all P <.01). The percentage of apolipoprotein ε4 carriers was also higher compared with placebo, at rates of 77.1% vs 61.4%, respectively (P = .12). 

AMX0035 has previously shown success in slowing functional decline and prolonging survival in ALS in the CENTAUR trial. PEGASUS in the first trial to evaluate the safety and efficacy of AMX0035 in AD. 

“Preclinical evidence suggests potential activity of PB and TURSO individually in AD,” Arnold et al wrote in their presentation abstract.2 “PB has been shown to reduce hippocampal neurodegeneration and amyloid plaque burden in murine AD models, with concordant improvements in spatial memory tasks. TURSO ameliorated amyloid deposition, reduced glial activation, and prevented cognitive decline in a double-transgenic murine model expressing chimeric mouse/human amyloid precursor protein and mutant human presenilin 1 (APP/PS1).”

Future research will include evaluation of additional CSF biomarkers, as well as imaging sequences. Earlier this year, Arnold spoke with NeurologyLive to discuss the design of the PEGASUS trial, as well as anticipated outcomes and goals for ongoing analyses. 

1. Amylyx Pharmaceuticals announces results from PEGASUS trial of AMX0035 in Alzheiemr’s Disease at the Clinical Trials on Alzheimer’s Disease (CTAD) Conference. News release. Amylx. November 9, 2021. Accessed November 16, 2021.
2. Arnold SE, Hendrix S, Nicodemus-Johnson J, et al. Safety and biological activity of a fixed-dose conformuliation of sodium phenylbutyrate/taurursodiol for the treatment of Alzheimer’s Disease. Presented at: CTAD; November 9-12, 2021; Virtual & Boston, MA. Poster/Abstract LP15. 
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