Safety, Tolerability and Pharmacokinetics of the Anti-LINGO-1 Monoclonal Antibody BIIB033 in Healthy Volunteers and Subjects with Multiple Sclerosis (P02.021)

Objective: To evaluate the safety, tolerability, and pharmacokinetics (PK) of the anti-LINGO-1 monoclonal antibody BIIB033 in healthy volunteers and subjects with multiple sclerosis (MS). Background LINGO-1 antagonism enhances remyelination and functional recovery in diverse rodent models. Biogen Idec is developing the anti-LINGO-1 monoclonal antibody, BIIB033, as a potential therapy to promote remyelination and functional recovery in MS. Design/Methods: In two separate randomized, placebo-controlled Phase 1 studies, single ascending doses (0.1 to 100 mg/kg) and multiple ascending doses (0.3 to 100 mg/kg; 2 doses separated by 14 days) of BIIB033 or placebo were administered via intravenous infusion to 64 healthy adult volunteers and 42 subjects with RRMS or SPMS, respectively. Safety was assessed by adverse event (AE) monitoring, vital signs, ECGs, laboratory tests, physical and neurological examinations, brain MRIs, VEP, SSEP, OCT, and retinal examination. Serum and cerebrospinal fluid (CSF) samples were collected to measure BIIB033 concentrations. All subjects were followed for 12-16 weeks after the last dose. Results: BIIB033 infusions were well tolerated. The frequency of AEs was similar between BIIB033 and placebo, with headache being the most frequently reported AE. There were no serious AEs or deaths. No clinically significant changes in any of the safety parameters were observed. BIIB033 PK was similar between healthy adults and MS subjects. Both Cmax and AUC increased in an approximately dose-proportional manner. The mean terminal half-life (t1/2) was approximately 15-21 days. Doses at 10 mg/kg or higher resulted in BIIB033 concentrations similar to or higher than concentration associated with 90% of the maximum remyelination effect in rats (EC90). The mean CSF/serum ratio of BIIB033 was approximately 0.06-0.09% which is similar to that observed in rat models. Conclusions: BIIB033 exhibits favorable safety profile, desirable PK and predicted brain penetration as suggested from CSF levels. These findings support advancing its development into proof-of-concept studies in MS. Supported by: Biogen Idec. Disclosure: Dr. Tran has received personal compensation for activities with Biogen Idec as an employee. Dr. Tran holds stock and/or stock options in Biogen Idec, which sponsored research in which Dr. Tran was involved as an investigator. Dr. Tran has received research support from Biogen Idec. Dr. Palaparthy has received personal compensation for activities with Biogen Idec as an employee.Dr. Palaparthy holds stock and/or stock options in Biogen Idec, which sponsored research in which Dr. Palaparthy was involved as an investigator.Dr. Palaparthy has received research support from Biogen Idec. Dr. Zhao has received personal compensation for activities with Biogen Idec as an employee. Dr. Zhao holds stock and/or stock options in Biogen Idec, which sponsored research in which Dr. Zhao was involved as an investigator. Dr. Zhao has received research support from Biogen Idec. Dr. Brosofsky has received personal compensation for activities with ALG Partners Inc. Dr. Brosofsky has received research support from ALG Partners Inc. Dr. Ray has received personal compensation for activities with Biogen Idec as an employee.Dr. Ray holds stock and/or stock options in Biogen Idec.Dr. Ray has received research support from Biogen Idec. Dr. Rana has received personal compensation for activities with Biogen Idec as an employee.Dr. Rana holds stock and/or stock options in Biogen Idec, which sponsored research in which Dr. Rana was involved in as an investigator.Dr. Rana has received research support from Biogen Idec. Dr. Cadavid has received personal compensation for activities with Biogen Idec as an employee. Dr. Cadavid holds stock and/or stock options in Biogen Idec, which sponsored research in which Dr. Cadavid was involved as an investigator. Dr. Cadavid has received research support from Biogen Idec.