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Exploratory PEGASUS Data Reveal AMX0035’s Impact on Neurodegeneration, Tau
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The published data provided preliminary evidence that AMX0035 engages Alzheimer disease pathology and pathways of neurodegeneration, synaptic function, gliosis, and oxidative stress.
Steven E. Arnold, MD
Newly published exploratory data from the phase 2 PEGASUS study of patients with early-stage Alzheimer disease (AD) showed that treatment with AMX0035 (Relyvrio), a previously approved drug for amyotrophic lateral sclerosis (ALS), resulted in changes to multiple pathological pathways related to neurodegeneration, including reduced levels of phosphorylated tau 181 (p-tau) and total tau. Overall, these data further support the therapy’s potential to treat neurodegenerative diseases associated with tau dysfunction and tau aggregation, such as progressive supranuclear palsy (PSP).1,2
PEGASUS was a previously completed trial comprised of 95 participants with early-stage AD who were randomly assigned to AMX0035 (n = 51), a coformulation of phenylbutyrate and taurursodiol, or placebo (n = 44), for a 24-week period. Between the 2 groups, there were no differences in clinical efficacy outcomes on the primary end point of change in GST (between-group difference, 0.07; 95% CI, –0.08 to 0.21; P = .36); however, investigators concluded this was likely due to the small sample size and relatively short treatment duration.
Of the intent-to-treat cohort, 67 patients had cerebrospinal fluid (CSF) samples at baseline and week 24. Among AMX0035-treated patients, investigators observed reductions in core AD biomarkers p-tau181 (P <.0001) and total tau (P <.0001), neurodegeneration biomarkers neurogranin (P <.0001) and FABP3 (P = .0004), and gliosis biomarker YKL-40 (P = .0005). Furthermore, within this group, there were trends of increasing amyloid-ß42/40 ratio (P = .07) and increases in 8-OHdG (P = .007), a marker of oxidative stress.
"Alzheimer’s disease is defined by amyloid plaques and tau tangles, but it’s now understood that these pathologies are accompanied by alterations in multiple cell and molecular pathways, including neuronal dysfunction, neurodegeneration, and oxidative stress, driving the progression of this relentless disease,” lead investigator Steven E. Arnold, MD, a professor of neurology at Harvard Medical School, and managing director of the Interdisciplinary Brain Center at Massachusetts General Hospital, said in a statement.1 "The results from this exploratory analysis suggest that AMX0035 engages important pathways implicated in the pathogenesis of Alzheimer’s disease and other neurodegenerative diseases."
AMX0035 was approved as a treatment for ALS by the FDA in 2022; however, it was discontinued earlier this year after phase 3 data failed to confirm its benefit.3 Using preclinical evidence and data from PEGASUS, the company announced a phase 3 trial, dubbed ORION, that evaluates AMX0035 as a potential treatment for PSP, a fatal tauopathy. The ongoing study is expected to include 600 adults with PSP who will be assessed over a 52-week double-blind period, followed by an optional 52-week open-label extension.
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On a regression model, additional data from the exploratory analysis revealed between-group differences on Aß42/40 ratio (P = .004), p-tau181 (P = .0002), total tau (P <.0001), neurogranin (P = .0004), FABP3 (P = .0007), YKL-40 (P = .004), interleukin-15 (P = .028), and 8-OHdG (P = .005). Investigators also performed a sensitivity analysis where age, sex, Montreal Cognitive Assessment score, and apolipoprotein e4 genotype were separately added to the regression models for the 7 biomarkers for which between-group differences were observed. At the conclusion of this analysis, none of the variables attenuated the effects of AMX0035 treatment on the 7 identified biomarkers.2
"These data lend further support to the preclinical and clinical evidence that AMX0035 has the potential to treat neurodegenerative diseases associated with tau dysfunction and tau aggregation. One such disease is progressive supranuclear palsy, also known as PSP. Our ORION trial studying AMX0035 in PSP remains ongoing," Camille L. Bedrosian, MD, chief medical officer at Amylyx, said in a statement.1 "There is a pressing unmet need for new and effective treatments in PSP, and we are encouraged by our findings that further support the potential of AMX0035."
In 2021, Amylyx announced that AMX0035 met its primary end point of safety and tolerability in PEGASUS. Overall, 36 (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 gastrointestinal events, primarily diarrhea, occurring in 20 (39%) patients, compared with 6 (14%) patients in the placebo group.4
ORION, the more recently announced trial of AMX0035 in PSP, will use change in Total Progressive Supranuclear Palsy Rating Scale, a 28-item assessment, as the primary end point of the study, with other additional end points of brain atrophy, quality of life, overall survival, and relevant biomarkers. In late 2023, Gunter Hoglinger, MD, principal investigator of the study, sat down with NeurologyLive® to discuss the outline of the study, including the reasons behind inclusion criteria and outcomes used. In the clip below, Hoglinger, who also serves as a professor of neurology and translational neuroscientist at Ludwig-Maximillian’s University Munich, discussed the importance of identifying patients with PSP without other underlying disease pathologies.
