Abstract Details

Title Design of a Phase 3, Randomized, Placebo-controlled Trial of Tofersen Initiated in Clinically Pre-symptomatic SOD1 Mutation Carriers with a Longitudinal Natural History Run-in

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) S20 - Motor Neuron Disease/Amyotrophic Lateral Sclerosis (2:00 PM-2:08 PM)

Poster/Presentation
Number 001

Background

There is increasing evidence of a pre-symptomatic phase of disease in ALS and other neurodegenerative diseases such as Alzheimer’s, frontotemporal dementia, Parkinson’s, Huntington’s, and spinal muscular atrophy. Data from the Pre-symptomatic Familial ALS study (Pre-fALS) indicate serum and plasma neurofilament light (NfL) and heavy (pNfH) levels increase prior to the emergence of clinical signs/symptoms of ALS in SOD1 mutation carriers, supporting the utility of neurofilaments as potential biomarkers of pre-symptomatic ALS.

Tofersen, an antisense oligonucleotide targeting SOD1 mRNA to inhibit synthesis of toxic SOD1 protein, is currently being evaluated for the treatment of SOD1-ALS.

Objective To discuss a Phase 3 trial to evaluate whether tofersen, initiated in clinically pre-symptomatic carriers of a superoxide dismutase-1 (SOD1) mutation, delays emergence of clinically manifest ALS and/or slows disease progression.

Design/Methods The proposed study design is a 3-part Phase 3 trial of tofersen in clinically pre-symptomatic carriers of SOD1 mutations associated with rapidly progressive disease. Part A is a longitudinal natural history run-in, during which plasma NfL is monitored until NfL exceeds the protocol-defined threshold for enrollment in Part B. During Part B, pre-symptomatic participants with elevated NfL are randomized 1:1 to monthly intrathecal bolus injections of tofersen 100 mg or placebo for up to 2 years. Upon emergence of clinical signs/symptoms that definitely indicate ALS (defined by clinical signs of upper/lower motor neuron degeneration, supported as needed by EMG abnormalities), participants may receive open-label tofersen in Part C.

Results The proposed primary endpoint is the proportion of participants in Part B with emergence of clinically manifest ALS by month 12.

Conclusions

This study is designed to evaluate the effect of tofersen in delaying emergence of clinically manifest ALS. Combined with results of the ongoing trial in symptomatic SOD1-ALS, these data will inform the optimal timing of tofersen administration.

Study Supported by: Biogen

Authors/Disclosures
Michael G. Benatar, MBChB, DPhil, FAAN (University of Miami) PRESENTER	Dr. Benatar has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. The institution of Dr. Benatar has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Arrowhead. Dr. Benatar has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Alexion. Dr. Benatar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Annexon. Dr. Benatar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB. Dr. Benatar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UniQure. Dr. Benatar has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Immunovant. Dr. Benatar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cartesian. Dr. Benatar has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Horizon. Dr. Benatar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen. Dr. Benatar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eli Lilly. Dr. Benatar has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alector. Dr. Benatar has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Dr. Benatar has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Benatar has received intellectual property interests from a discovery or technology relating to health care.
Joanne Wuu, SCM (Univ of Miami, Dept Of Neurology)	The institution of Ms. Wuu has received research support from NIH NINDS. The institution of Ms. Wuu has received research support from NIH NCATS/NINDS. The institution of Ms. Wuu has received research support from CDC. The institution of Ms. Wuu has received research support from Target ALS. The institution of Ms. Wuu has received research support from ALS Recovery Fund. The institution of Ms. Wuu has received research support from NIH/NINDS. The institution of Ms. Wuu has received research support from NIH NINDS. The institution of an immediate family member of Ms. Wuu has received research support from NIH NINDS.
Peter Munch Andersen, MD (Dept. of Neurology, Umea University Hospital)	Prof. Andersen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Prof. Andersen has received personal compensation in the range of $0-$499 for serving as a Consultant for Orphazyme A/S. Prof. Andersen has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Prof. Andersen has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Orphazyme A/S. The institution of Prof. Andersen has received research support from Swedish Research Council. The institution of Prof. Andersen has received research support from Swedish Brain Foundation. The institution of Prof. Andersen has received research support from KAW. The institution of Prof. Andersen has received research support from The Ulla-Carin Lindquist patient organization. The institution of Prof. Andersen has received research support from Umea University Research Foundation. The institution of Prof. Andersen has received research support from Swedish Neuro Patient Organization.
Jinsy Andrews, MD, FAAN (Columbia University Medical Center)	Dr. Andrews has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Andrews has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Wave Life Sciences. Dr. Andrews has received personal compensation in the range of $0-$499 for serving as a Consultant for Cytokinetics. Dr. Andrews has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Apellis . Dr. Andrews has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Revalasio . Dr. Andrews has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amylyx. Dr. Andrews has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for AL-S Pharma. Dr. Andrews has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Dr. Andrews has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Quralis . Dr. Andrews has received personal compensation in the range of $500-$4,999 for serving as an officer or member of the Board of Directors for Neurosense. Dr. Andrews has received personal compensation in the range of $0-$499 for serving as an officer or member of the Board of Directors for Akava. The institution of Dr. Andrews has received research support from Amylyx. The institution of Dr. Andrews has received research support from Biogen . The institution of Dr. Andrews has received research support from Cytokinetics . The institution of Dr. Andrews has received research support from NIH . The institution of Dr. Andrews has received research support from Biohaven/Platform Trial. The institution of Dr. Andrews has received research support from Clene/Platform Trial . The institution of Dr. Andrews has received research support from Ra Pharma/Platform Trial . The institution of Dr. Andrews has received research support from Prilenia/Platform Trial . Dr. Andrews has received research support from ALS Association . Dr. Andrews has a non-compensated relationship as a Board of Trustee Member with ALS Association that is relevant to AAN interests or activities.
Bob Bucelli, MD, PhD (Washington University)	Dr. Bucelli has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen . Dr. Bucelli has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Bucelli has stock in Neuroquestions.com. An immediate family member of Dr. Bucelli has stock in Neuroquestions.com. The institution of Dr. Bucelli has received research support from Biogen. The institution of Dr. Bucelli has received research support from Ionis.
	No disclosure on file
Toby A. Ferguson, MD (Biogen)	Dr. Ferguson has received personal compensation for serving as an employee of Biogen. Dr. Ferguson has received stock or an ownership interest from Biogen.
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Janice Wong, MD	Dr. Wong has received personal compensation for serving as an employee of Janssen Research & Development. Dr. Wong has received personal compensation for serving as an employee of Biogen. Dr. Wong has stock in Biogen. Dr. Wong has stock in Janssen Research & Development.
Stephanie Fradette	Stephanie Fradette has received personal compensation for serving as an employee of Biogen. Stephanie Fradette has received stock or an ownership interest from Biogen.