Efficacy, Safety, and Pharmacokinetics of Natalizumab in Japanese Multiple Sclerosis Patients: A Double-blind, Randomized Controlled Trial and Open-label Pharmacokinetic Study

• Published in: Multiple sclerosis and related disorders Vol. 11; pp. 25 - 31
• Main Authors: Saida, Takahiko, Kira, Jun-ichi, Kishida, Shuji, Yamamura, Takashi, Sudo, Yukiko, Ogiwara, Kazutaka, Tibung, JT, Lucas, Nisha, Subramanyam, Meena
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2017
• Subjects: Adult; Disability Evaluation; Double-Blind Method; Female; Humans; Immunologic Factors - adverse effects; Immunologic Factors - pharmacokinetics; Immunologic Factors - therapeutic use; Japan; Japanese; Male; Middle Aged; Multiple sclerosis; Multiple Sclerosis, Relapsing-Remitting - drug therapy; Natalizumab; Natalizumab - adverse effects; Natalizumab - pharmacokinetics; Natalizumab - therapeutic use; Neurology; Pharmacokinetics; Randomized clinical trial; Treatment Outcome; Young Adult; AUC 0–last; time to maximum concentration; volume of distribution; pharmacodynamics; VAS; AUC; area under the curve to infinity; systemic clearance; area under the curve to the last measurable concentration of a dosing interval; EDSS; IFNβ; AE; not assessed; annualized relapse rate; area under the concentration time curve; T 1/2; adverse event; IVIG; randomized clinical trial; area under the curve for dosing interval; IV; standard error; half-life; Japanese; NMOSD; progressive multifocal leukoencephalopathy; T max; maximum concentration; JCV; ELISA; gadolinium; standard deviation; RRMS; ARR; N/A; John Cunningham virus; very late antigen-4; AUC 0–672; C max; intravenously; Expanded Disability Status Scale; Vd; SD; SE; pharmacokinetics; intravenous immunoglobulin; natalizumab; C trough; interferon beta; AUC 0; CI; multiple sclerosis; neuromyelitis optica; CL; visual analog scale; VLA-4; PML; relapsing-remitting multiple sclerosis; NMO; PD; neuromyelitis optica spectrum disorder; enzyme-linked immunosorbent assay; confidence interval; PK; Gd; trough concentration; Multiple sclerosis; Randomized clinical trial; Natalizumab; AUC0; Cmax; Ctrough; T1/2; AUC0–672; AUC0–last; Tmax; Pharmacokinetics
• ISSN: 2211-0348; 2211-0356
• DOI: 10.1016/j.msard.2016.11.002

Abstract Background Natalizumab, an anti-α4 integrin monoclonal antibody, has demonstrated efficacy in phase 2 and 3 studies of predominantly Caucasian patients with relapsing-remitting multiple sclerosis (RRMS). Objective To evaluate the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of natalizumab in Japanese RRMS patients. Methods This multicenter, phase 2 study included an open-label PK/PD study in 12 patients (part A) and a double-blind, placebo-controlled, randomized (computer-generated sequence) study in 94 patients (part B). For part B, patients received intravenous natalizumab 300 mg (n = 47) or placebo (n = 47) every 4 weeks. The primary efficacy endpoint was the rate of development of new active lesions (gadolinium-enhancing or new/enlarging T2 lesions) over 24 weeks. Clinical relapses and safety were also assessed. Results New active lesions developed at a significantly lower mean rate in natalizumab-treated patients (0.06 lesions/24 weeks) than in placebo-treated patients (0.35 lesions/24 weeks) ( p <0.001). The annualized relapse rate was 0.53 for natalizumab and 1.73 for placebo (w p <0.001). Twice as many natalizumab-treated patients (79%) as placebo-treated patients (38%) were relapse-free ( p <0.001). The safety, PK, and PD profiles of natalizumab in this study were consistent with data in Caucasian RRMS patients. Conclusions In Japanese RRMS patients, natalizumab treatment every 4 weeks for 24 weeks was well tolerated and reduced the development of new brain lesions and relapses (Funded by Biogen; ClinicalTrials.gov identifier: NCT01440101).