Natalizumab versus placebo in patients with secondary progressive multiple sclerosis (SPMS): results from ASCEND, a multicenter, double-blind, placebo-controlled, randomized phase 3 clinical trial

Authors: Deborah Steiner; Douglas Arnold, MD; Mark Freedman, MD, FAAN; Myla Goldman, MD; Hans-Peter Hartung, MD, FAAN; Eva Havrdova, MD; Douglas Jeffery, MD, PhD; Raj Kapoor; Aaron Miller, MD, FAAN; Finn Sellebjerg; Diogo Amarante, MD; Diego Cadavid, MD, FAAN; Bei Yu; Fiona Forrestal; Kezhen Liu

Objective: To investigate whether natalizumab slows disability progression unrelated to relapses in SPMS patients. Background: Natalizumab is highly efficacious in relapsing multiple sclerosis (RMS). However, no pharmacotherapeutics have been shown to reduce disability progression unrelated to relapses in SPMS patients. Design/Methods: ASCEND enrolled natalizumab-naive patients with SPMS for ≥2 years and disability progression unrelated to clinical relapses in the prior year. The primary endpoint (designed to capture treatment effects on key aspects of disability progression in SPMS) was a binary outcome of confirmed disability progressors or nonprogressors on a composite endpoint (Expanded Disability Status Scale [EDSS], Timed 25-Foot Walk [T25FW], and 9-Hole Peg Test [9HPT]).
Results: Participants received 300-mg IV natalizumab (n=439) or placebo (n=448) every 4 weeks for 96 weeks. At baseline, most patients had advanced disability; 71% had no relapses within 2 years pre-enrollment. While 63% presented with EDSS scores of 6.0-6.5 (walking aid required), median 9HPT time was 28.6 seconds, suggesting greater lower-limb than upper-limb impairment. ASCEND did not meet the primary endpoint; a slightly smaller percent of patients treated with natalizumab were progressors (44%) compared with placebo (48%) [adjusted odds ratio [OR]: 0.86, 95% CI:0.66-1.13; P=0.29]. Natalizumab showed a statistically significant treatment effect on reducing upper-limb disability progression unrelated to relapse (measured by 9HPT, a pre-specified component of the primary endpoint; 15% natalizumab vs 23% placebo; OR: 0.56; P=0.0012). A significant treatment effect was also observed on reducing annualized relapse rate and MRI activity. Natalizumab was generally well tolerated, with adverse events consistent with its known safety profile.
Conclusions: While natalizumab did not delay progression of ambulatory disability in this SPMS population, it was associated with significant slowing of upper-extremity disability progression and reduction of relapses and MRI activity. The lack of treatment effects on ambulatory function underscores the importance of treating MS early with effective therapies like natalizumab.

CoI None