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Efficacy, safety, and pharmacokinetics of natalizumab in Japanese multiple sclerosis patients: A double-blind, randomized controlled trial and open-label pharmacokinetic study

Multiple Sclerosis and Related Disorders, Voluma 11, January 2017, Pages 25 - 31

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 (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).

Highlights

  • Natalizumab is an antibody treatment for relapsing-remitting multiple sclerosis.
  • This study investigated natalizumab efficacy and safety in Japanese patients.
  • New brain lesion development rate was lower with natalizumab than placebo (p<0.001).
  • Annualized relapse rate was 0.53 for natalizumab and 1.73 for placebo (p<0.001).
  • Natalizumab had a favorable safety and tolerability profile in Japanese patients.

Abbreviations: AE - adverse event, ARR - annualized relapse rate, AUC - area under the concentration time curve, AUC0–last - area under the curve to the last measurable concentration of a dosing interval, AUC0–∞ - area under the curve to infinity, AUC0–672 - area under the curve for dosing interval, CI - confidence interval, CL - systemic clearance, Cmax - maximum concentration, Ctrough - trough concentration, EDSS - Expanded Disability Status Scale, ELISA - enzyme-linked immunosorbent assay, Gd - gadolinium, IFNβ - interferon beta, IV - intravenously, IVIG - intravenous immunoglobulin, JCV - John Cunningham virus, N/A - not assessed, NMO - neuromyelitis optica, NMOSD - neuromyelitis optica spectrum disorder, PD - pharmacodynamics, PK - pharmacokinetics, PML - progressive multifocal leukoencephalopathy, RRMS - relapsing-remitting multiple sclerosis, SD - standard deviation, SE - standard error, T1/2 - half-life, Tmax - time to maximum concentration, VAS - visual analog scale, Vd - volume of distribution, VLA-4 - very late antigen-4.

Keywords: Multiple sclerosis, Japanese, Natalizumab, Randomized clinical trial, Pharmacokinetics.

Footnotes

a Kansai Multiple Sclerosis Center and Kyoto Min-iren Central Hospital, Kyoto, Japan

b Department of Neurology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

c Hakusuikai Hatsuishi Hospital, Chiba, Japan

d National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan

e Biogen Japan, Tokyo, Japan

f Biogen, Cambridge, MA, USA

Correspondence to: Kansai Multiple Sclerosis Center, Nishinokyo-Kasuga-cho 16-44-409, Nakakyo-ku, Kyoto 604-8453, Japan.