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
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.