Randomized phase I clinical trial of anti-α-synuclein antibody BIIB054.

BACKGROUND: Pathological and genetic evidence implicates toxic effects of aggregated α-synuclein in the pathophysiology of neuronal dysfunction and degeneration in Parkinson's disease. Immunotherapy targeting aggregated α-synuclein is a promising strategy for delaying disease progression. OBJECTIVE: This study (NCT02459886) evaluated the safety, tolerability, and pharmacokinetics of BIIB054, a human-derived monoclonal antibody that preferentially binds to aggregated α-synuclein, in healthy volunteers and participants with Parkinson's disease. METHODS: A total of 48 healthy volunteers (age 40-65, 19 women) and 18 Parkinson's disease participants (age 47-75, 5 women, Hoehn and Yahr stage ≤2.5) were in the study. Volunteers were enrolled into 6 single-dose cohorts of BIIB054 (range 1-135 mg/kg) or placebo, administered intravenously; Parkinson's disease participants received a single dose of BIIB054 (15 or 45 mg/kg) or placebo. All participants were evaluated for 16 weeks with clinical, neuroimaging, electrocardiogram, and laboratory assessments. Serum and cerebrospinal fluid BIIB054 concentrations were measured. BIIB054/α-synuclein complexes were measured in plasma. RESULTS: Most adverse events were mild and assessed by investigators as unrelated to the study drug. Pharmacokinetic parameters for volunteers and the Parkinson's disease participants were similar. BIIB054 serum exposure and maximum concentrations were dose proportional during the dose range studied. In volunteers and the Parkinson's disease participants, the serum half-life of BIIB054 was 28 to 35 days; the cerebrospinal fluid-to-serum ratio ranged from 0.13% to 0.56%. The presence of BIIB054/α-synuclein complexes in plasma was confirmed; all Parkinson's disease participants showed almost complete saturation of the BIIB054/α-synuclein complex formation. CONCLUSIONS: BIIB054 has favorable safety, tolerability, and pharmacokinetic profiles in volunteers and Parkinson's disease participants, supporting further clinical development. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Outcomes of natalizumab treatment within 3 years of relapsing-remitting multiple sclerosis diagnosis: a prespecified 2-year interim analysis of STRIVE.

BACKGROUND: STRIVE is a multicenter, observational, open-label, single-arm study of natalizumab in anti-JC virus (JCV) seronegative patients with early relapsing-remitting multiple sclerosis (RRMS). The objective of this prespecified 2-year interim analysis was to determine the effectiveness of natalizumab in establishing and maintaining no evidence of disease activity (NEDA) in early RRMS. METHODS: Patients aged 18-65 years had an RRMS diagnosis < 3 years prior to screening, an Expanded Disability Status Scale (EDSS) score ≤ 4.0, and anti-JCV antibody negative status. Magnetic resonance imaging was performed at baseline and yearly thereafter. Cumulative probabilities of 24-week-confirmed EDSS worsening and improvement were evaluated at 2 years. NEDA (no 24-week-confirmed EDSS worsening, no relapses, no gadolinium-enhancing lesions, and no new/newly enlarging T2-hyperintense lesions) was evaluated over 2 years. The Symbol Digit Modalities Test (SDMT) and Multiple Sclerosis Impact Score (MSIS-29) were assessed at baseline and 1 and 2 years. Statistical analysis used summary statistics and frequency distributions. RESULTS: The study population (N = 222) had early RRMS, with mean (standard deviation [SD]) time since diagnosis of 1.6 (0.77) years and mean (SD) baseline EDSS score of 2.0 (1.13). NEDA was achieved in 105 of 187 patients (56.1%) during year 1 and 120 of 163 (73.6%) during year 2. Over 2 years, 76 of 171 patients (44.4%) attained overall NEDA. Probabilities of 24-week-confirmed EDSS worsening and improvement were 14.1% and 28.4%, respectively. After 2 years, patients exhibited significant improvements from baseline in SDMT (n = 158; mean [SD]: 4.3 [11.8]; p < 0.001) and MSIS-29 physical (n = 153; mean [SD]: - 3.9 [14.7]; p = 0.001), psychological (n = 152; mean [SD]: - 2.0 [7.9]; p < 0.001), and quality-of-life (n = 153; mean [SD]: - 6.0 [21.3]; p < 0.001) scores. CONCLUSIONS: These results support natalizumab's effectiveness over 2 years, during which nearly half of early RRMS patients achieved NEDA. During year 2, nearly 75% of patients exhibited NEDA. Over 2 years, patients continued to experience significant cognitive and quality-of-life benefits. These results are limited by the lack of a comparator group to determine the extent of a placebo effect. TRIAL REGISTRATION: clinicaltrials.gov, NCT01485003 , registered 5 December 2011.