RT Journal Article
SR Electronic
T1 Randomized phase I trials of the safety/tolerability of anti-LINGO-1 monoclonal antibody BIIB033
JF Neurology - Neuroimmunology Neuroinflammation
JO Neurol Neuroimmunol Neuroinflamm
FD Lippincott Williams & Wilkins
SP e18
DO 10.1212/NXI.0000000000000018
VO 1
IS 2
A1 Tran, Jonathan Q.
A1 Rana, Jitesh
A1 Barkhof, Frederik
A1 Melamed, Isaac
A1 Gevorkyan, Hakop
A1 Wattjes, Mike P.
A1 de Jong, Remko
A1 Brosofsky, Kristin
A1 Ray, Soma
A1 Xu, Lei
A1 Zhao, Jim
A1 Parr, Edward
A1 Cadavid, Diego
YR 2014
UL http://nn.neurology.org/content/1/2/e18.abstract
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