PT  - JOURNAL ARTICLE
AU  - Tran, Jonathan Q.
AU  - Rana, Jitesh
AU  - Barkhof, Frederik
AU  - Melamed, Isaac
AU  - Gevorkyan, Hakop
AU  - Wattjes, Mike P.
AU  - de Jong, Remko
AU  - Brosofsky, Kristin
AU  - Ray, Soma
AU  - Xu, Lei
AU  - Zhao, Jim
AU  - Parr, Edward
AU  - Cadavid, Diego
TI  - Randomized phase I trials of the safety/tolerability of anti-LINGO-1 monoclonal antibody BIIB033
AID  - 10.1212/NXI.0000000000000018
DP  - 2014 Aug 01
TA  - Neurology - Neuroimmunology Neuroinflammation
PG  - e18
VI  - 1
IP  - 2
4099  - http://nn.neurology.org/content/1/2/e18.short
4100  - http://nn.neurology.org/content/1/2/e18.full
SO  - Neurol Neuroimmunol Neuroinflamm2014 Aug 01; 1
AB  - Objective: To evaluate the safety, tolerability, and pharmacokinetics (PK) of BIIB033 (anti-LINGO-1 monoclonal antibody) in healthy volunteers and participants with multiple sclerosis (MS).Methods: In 2 separate randomized, placebo-controlled studies, single ascending doses (SAD; 0.1–100 mg/kg) of BIIB033 or placebo were administered via IV infusion or subcutaneous injection to 72 healthy volunteers, and multiple ascending doses (MAD; 0.3–100 mg/kg; 2 doses separated by 14 days) of BIIB033 or placebo were administered via IV infusion to 47 participants with relapsing-remitting or secondary progressive MS. Safety assessments included adverse event (AE) monitoring, neurologic examinations, conventional and nonconventional MRI, EEG, optical coherence tomography, retinal examinations, and evoked potentials. Serum and CSF PK as well as the immunogenicity of BIIB033 were also evaluated.Results: All 72 healthy volunteers and 47 participants with MS were included in the safety analyses. BIIB033 infusions were well tolerated. The frequency of AEs was similar between BIIB033 and placebo. There were no serious AEs or deaths. No clinically significant changes in any of the safety measures were observed. BIIB033 PK was similar between healthy volunteers and participants with MS. Doses of ≥10 mg/kg resulted in BIIB033 concentrations similar to or higher than the concentration associated with 90% of the maximum remyelination effect in rat remyelination studies. The incidence of anti-drug antibody production was low.Conclusions: The emerging safety, tolerability, and PK of BIIB033 support advancing BIIB033 into phase II clinical development as a potential treatment for CNS demyelination disorders.Classification of evidence: This study provides Class I evidence that BIIB033 is well tolerated and safe (serious adverse event rate 0%, 95% confidence interval 0–7.6%).AE=adverse event; AUC=area under the time-concentration curve; Cmax=maximum serum concentration; DTI=diffusion tensor imaging; Gd=gadolinium; Ig=immunoglobulin; mAb=monoclonal antibody; MAD=multiple ascending dose; MS=multiple sclerosis; MT=magnetization transfer; MTR=magnetization transfer ratio; NAWM=normal-appearing white matter; PK=pharmacokinetics; RRMS=relapsing-remitting MS; SAD=single ascending dose; SC=subcutaneous; SPMS=secondary progressive MS; SSEP=somatosensory evoked potential; t1/2=half-life; Tmax=time to maximum serum concentration; VEP=visual evoked potential; VSS=steady-state volume of distribution