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
Michael Benatar1, Joanne Wuu1, Peter M. Andersen2, Jinsy Andrews3, Robert C. Bucelli4, Markus Otto5, Toby A. Ferguson6, Weiping Chen6, Laura Fanning6, Danielle Graham6, Peng Sun6, Yingying Liu6, Janice Wong6, Stephanie Fradette6
1Department of Neurology, University of Miami, 2Department of Clinical Science, Neuroscience, UmeƄ University, 3Department of Neurology, Columbia University, 4Washington University School of Medicine, 5Department of Neurology, University of Ulm, 6Biogen
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.

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.

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

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