Abstract Details

Title Safety of a Fixed-Dose Coformulation of Sodium Phenylbutyrate and Taurursodiol in Amyotrophic Lateral Sclerosis and Alzheimer’s Disease: Integrated Clinical Trials Experience

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) S11 - ALS and Motor Neuron Disorders (1:48 PM-2:00 PM)

Poster/Presentation
Number 005

Background

PB/TURSO was designed to reduce neurodegeneration by targeting endoplasmic reticulum and mitochondrial stress, both implicated in the pathophysiology of ALS and AD.

Objective Safety and tolerability of an oral, fixed-dose sodium phenylbutyrate/taurursodiol (PB/TURSO) coformulation were assessed in phase 2 trials in amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD).

Design/Methods In the AMX-3500 Study (CENTAUR) in ALS, participants (PB/TURSO, n=89; placebo, n=48) completing the 24-week randomized phase (NCT03127514) were eligible to enroll in an open-label extension (OLE) phase (NCT03488524) and receive PB/TURSO (≤132 weeks, week 24 reported). Study AMX-8000 (PEGASUS; NCT03533257) was a 24-week randomized trial in adults with AD or mild cognitive impairment (PB/TURSO, n=51; placebo, n=44). PB/TURSO safety and tolerability was the primary objective of both trials.

Results Mean (SD) ages were 57.7 (9.6) and 70.7 (7.5) years in CENTAUR and PEGASUS, respectively. Treatment-emergent adverse event (TEAE) incidence was similar between groups in the CENTAUR randomized phase (PB/TURSO, 97%; placebo, 96%); 77% reported ≥1 TEAEs in the OLE phase. In PEGASUS, TEAEs occurred in 67% and 59% of the PB/TURSO and placebo groups, respectively. Gastrointestinal TEAEs were more frequent during initial PB/TURSO exposure (week ≤3) in CENTAUR and accounted for the predominance of PB/TURSO-related TEAEs in PEGASUS. Incidence of cardiac events with PB/TURSO was low (CENTAUR, 8%; PEGASUS, 4%), and in both studies, electrocardiographic findings were similar between groups at baseline, with no clinically meaningful changes observed over the course of treatment.

Conclusions These findings support the PB/TURSO safety profile in ALS and AD. TEAE incidence was generally similar between PB/TURSO and placebo in both trials. PB/TURSO-associated TEAEs were mostly gastrointestinal, consistent with the known profiles for PB and TURSO. Findings in AD further elucidate the PB/TURSO safety profile, as TEAEs in CENTAUR appear to have been largely disease driven. An updated safety analysis (pooled and OLE data) will be presented.

Authors/Disclosures
Sabrina Paganoni, MD, PhD PRESENTER	Dr. Paganoni has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cytokinetics. Dr. Paganoni has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Jannsen. Dr. Paganoni has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Arrowhead. Dr. Paganoni has received personal compensation in the range of $0-$499 for serving as a Consultant for Sola. Dr. Paganoni has received personal compensation in the range of $0-$499 for serving as a Consultant for Frequency Therapeutics. The institution of Dr. Paganoni has received research support from Amylyx. The institution of Dr. Paganoni has received research support from Revalesio. The institution of Dr. Paganoni has received research support from Alector. The institution of Dr. Paganoni has received research support from UCB. The institution of Dr. Paganoni has received research support from Biohaven. The institution of Dr. Paganoni has received research support from Clene. The institution of Dr. Paganoni has received research support from Prilenia. The institution of Dr. Paganoni has received research support from Seelos. The institution of Dr. Paganoni has received research support from Calico. The institution of Dr. Paganoni has received research support from Denali. The institution of Dr. Paganoni has received research support from Anelixis. The institution of Dr. Paganoni has received research support from Cytokinetics.
Steven E. Arnold, MD (Massachusetts General Hospital)	Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for EIP Pharma. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eisai. Dr. Arnold has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sage Therapeutics. Dr. Arnold has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Cortexyme. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Boyle Shaughnessy Law. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Wolf Greenfield. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as a Advisory Board Member with Bob's Last Marathon.
Suzanne Hendrix, PhD	Dr. Hendrix has received personal compensation for serving as an employee of Pentara Corporation. Dr. Hendrix has received personal compensation in the range of $50,000-$99,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pentara Corporation. Dr. Hendrix has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Pentara Corporation. The institution of Dr. Hendrix has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Pentara Corporation. Dr. Hendrix has stock in Pentara.
	No disclosure on file
Samuel Dickson (Pentara)	No disclosure on file
	No disclosure on file
	No disclosure on file
Jamie Timmons, MD (Amylyx Pharmaceuticals)	Dr. Timmons has received personal compensation for serving as an employee of Amylyx Pharmaceuticals. Dr. Timmons has stock in Amylyx Pharmaceuticals.
Machelle Manuel, PhD (Amylyx Pharmaceuticals, Inc.)	Dr. Manuel has received personal compensation for serving as an employee of Amylyx Pharmaceuticals.
	No disclosure on file
Patrick Yeramian	Patrick Yeramian has received personal compensation for serving as an employee of Amylyx Pharmaceuticals.
Merit E. Cudkowicz, MD, MSC, FAAN (Massachusetts General Hospital)	Dr. Cudkowicz has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for biogen. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for cytokinetics. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for immunitypharm. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for denali. The institution of Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for wave. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for transposon. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Quralis. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Regeneron. Dr. Cudkowicz has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Neurosense. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for vectorY. Dr. Cudkowicz has received personal compensation in the range of $0-$499 for serving as a Consultant for Arrowhead. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Servier. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eledon. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for inflectis. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for roche. Dr. Cudkowicz has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for novartis. Dr. Cudkowicz has received personal compensation in the range of $0-$499 for serving as a Consultant for ono. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for otsuka. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for coya. Dr. Cudkowicz has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Locust Walk. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pasithea. Dr. Cudkowicz has received personal compensation in the range of $50,000-$99,999 for serving as an officer or member of the Board of Directors for Praxis Precision Medicine. Dr. Cudkowicz has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Annals of Neurology . An immediate family member of Dr. Cudkowicz has stock in Sqz. The institution of Dr. Cudkowicz has received research support from NINDS. The institution of Dr. Cudkowicz has received research support from ALSA . The institution of Dr. Cudkowicz has received research support from ALSFAC. The institution of Dr. Cudkowicz has received research support from UCB ra. The institution of Dr. Cudkowicz has received research support from Biohaven. The institution of Dr. Cudkowicz has received research support from Clene nanomedicine. The institution of Dr. Cudkowicz has received research support from prilenia. The institution of Dr. Cudkowicz has received research support from ALS one. The institution of Dr. Cudkowicz has received research support from Seelos. The institution of Dr. Cudkowicz has received research support from Calico. The institution of Dr. Cudkowicz has received research support from denali. The institution of Dr. Cudkowicz has received research support from ITB. Dr. Cudkowicz has received publishing royalties from a publication relating to health care.