Background: Progressive supranuclear palsy is a rare neurodegenerative disease associated with dysfunctional tau protein. BIIB092 is a humanised monoclonal antibody that binds to N-terminal tau and is thus being assessed as a potential novel treatment for progressive supranuclear palsy. We aimed to investigate the safety and tolerability of BIIB092 in individuals with progressive supranuclear palsy. Methods: This 12-week, double-blind, randomised, placebo-controlled, multiple ascending dose, phase 1b trial was done at 13 outpatient sites in the USA. Participants aged 41–86 years with probable or possible progressive supranuclear palsy with a score of 20 or greater on the Mini-Mental State Examination (MMSE) were enrolled. Three BIIB092 dose escalation cohorts (150 mg, 700 mg, or 2100 mg; eight participants per cohort) were tested sequentially. For each dose cohort, the first two participants were randomly assigned by a computer-generated scheme to receive either BIIB092 or placebo intravenously every 4 weeks for 57 days. After 2 days, the six remaining participants in each cohort were randomly assigned (5:1) to receive BIIB092 or placebo for 57 days. An additional expansion panel of 24 patients was randomly assigned (3:1) to receive 2100 mg or placebo every 4 weeks for 57 days. All participants were followed up to day 85. The primary outcome was safety, which was analysed in the treated population (all enrolled participants who received at least one dose of the study drug). This trial is registered with ClinicalTrials.gov, NCT02460094. Findings: Between Oct 2, 2015, and Oct 19, 2016, 48 participants were enrolled and randomly assigned to the BIIB092 (n=36) and placebo (n=12) groups. No apparent demographic differences were observed between the two groups at baseline. All 48 participants completed the treatment phase of the study. Adverse events were generally mild to moderate in severity; the most common in the placebo and BIIB092 groups were falls (in two [17%] of 12 patients and in ten [28%] of 36 patients), urinary tract infections (in one [8%] of 12 and in six [17%] of 36), contusions (in one [8%] of 12 and in five [14%] of 36), and headaches (in none and in five [14%] of 36). Four serious adverse events resulting in admission to hospital were reported in three participants who received BIIB092 2100 mg: two severe adverse events of urinary tract infection, one severe adverse event of change in mental status, and one moderate adverse event of aspiration pneumonia. None was considered to be related to the study drug, all were resolved, and no deaths were reported. Interpretation: Repeated administration of the anti-tau monoclonal antibody BIIB092, at doses of up to 2100 mg, appears to be well tolerated in participants with progressive supranuclear palsy. Results of this phase 1b trial have informed the design of the ongoing phase 2 PASSPORT (NCT03068468) study to examine the efficacy and safety of BIIB092. Funding: Bristol-Myers Squibb, Biogen.
Bibliographical noteFunding Information:
ALB reports research support from the Alzheimer's Association, Association for Frontotemporal Degeneration, Bluefield Project to Cure Frontotemporal Dementia, Corticobasal Degeneration Solutions, Tau Research Consortium, and the National Institutes of Health (grants: U54NS092089, R01AG031278, R01AG038791, R01AG032306, and R01AG022983). ALB has served as a consultant for AbbVie, Aeton, Alector, Amgen, Arkuda, Celgene, Eisai, Ionis, Iperian, Janssen, Merck, Novartis, Toyama, UCB, and Wave, and received research support from Avid, Biogen, Bristol-Myers Squibb, C2N, Cortice, Eli Lilly, Forum, Genentech, Janssen, Pfizer, Roche, and TauRx. IQ is a former employee of Bristol-Myers Squibb and current employee of Biohaven Pharmaceuticals. MA is a former employee of Bristol-Myers Squibb, a paid employee of FORMA Therapeutics (cash and equity compensation) and Pinteon Therapeutics (cash and equity compensation), and president and sole employee of Ani Consulting, LLC (and as such, consults for and receives cash and some equity compensation from several companies and non-profit institutions including Acumen Therapeutics, BioHaven Therapeutics, Harrington Discovery Institute, the Michael J. Fox Foundation, Orthogonal Therapeutics, and Target ALS). MGru reports personal fees from Biogen and Bristol-Myers Squibb during the conduct of the study. LIG reports consulting fees from AbbVie, Bristol-Myers Squibb, and UCB; and research support from Biogen and Bristol-Myers Squibb. IL is an advisory board member for AbbVie; consultant for Toyama; medical advisory board member for the Biotie/Parkinson Study Group; and reports grants from Avid Pharmaceuticals, Bristol-Myers Squibb/Biogen, C2N Diagnostics/AbbVie, International Parkinson and Movement Disorder Society, Michael J. Fox Foundation, National Institutes of Health (grants: 5P50 AG005131-31, 5T35HL007491, 1U01NS086659, and 1U54NS092089-01), Parkinson's Foundation, and Parkinson Study Group. IL also receives a salary from the University of California, San Diego, and is chief editor of Frontiers in Neurology . LSH is a webinar presenter for Miller Medical Communications and reports grants from AbbVie, Axovant, Biogen, Bristol-Myers Squibb, Eli Lilly, Genentech, Lundbeck, Roche, TauRx, and vTv Therapeutics, and fees from Bristol-Myers Squibb, Eisai, and Eli Lilly. PT declares no competing interests outside of the submitted work. NRM reports personal fees from AbbVie, grants from the National Institutes of Health–National Institute of Neurological Disorders and Stroke, and grants from the Michael J. Fox Foundation, outside of the submitted work. PO'S reports grants from Biogen and Bristol-Myers Squibb, during the conduct of the study; and grants from Biohaven Pharmaceuticals, BlackThorn Therapeutics, and Pharma 2 B Ltd, outside of the submitted work. TX declares no competing interests outside of the submitted work. GST is an employee of and holds stock or stock options, or both, in Bristol-Myers Squibb, and has a patent titled “COMPOSITIONS AND METHODS FOR TREATING TAUOPATHIES” licensed to Biogen. CB is a former employee of Bristol-Myers Squibb. YB declares no competing interests outside of the submitted work. DSG reports research support from AbbVie, Avanir, Biogen, Bristol-Myers Squibb, Eisai, Eli Lilly, Janssen, and Neurim and personal fees from Grifols. MGro reports research support from Biogen and Bristol-Myers Squibb. SI reports receiving honoraria for CME, consulting fees, and research grants from, and/or serving as a promotional speaker on behalf of AbbVie, Acadia, Acorda, Adamas, Addex, Allergan, Amarantus, Axovant, Benevolent, Biogen, Britannia, Cerecor, Eli Lilly, Enterin, GE Healthcare, Global Kinetics, Impax, Intec Pharma, Ipsen, Jazz, Kyowa, Lundbeck, Michael J. Fox Foundation, Neurocrine, Neuroderm, Parkinson Study Group, Pharma2B, Roche, Sanofi, Sunovion, Teva, Theravance, UCB, US World Meds, and Zambon. TZ declares no competing interests outside of the submitted work. TO, KKM, DLG, JO'G, SBH, and TD are employees of and stockholders in Biogen.