EXPAND

Siponimod

EXPAND showed that siponimod modestly delayed confirmed disability progression in secondary progressive multiple sclerosis.

Phase
Phase III
Population
Secondary progressive multiple sclerosis (SPMS)
Controlled period
Dec 20, 2012 — Apr 29, 2016

What was compared

Randomized 2:1Double-blindPlacebo-controlledEvent-driven
Intervention

Siponimod

2 mg orally once daily after dose titration

n=1,105 randomized
Comparator

Placebo

Matching oral tablet once daily

n=546
1,651 randomized; 1,645 analyzedUp to 3 years controlled phase

Primary endpoint

Prespecified outcome

3-month confirmed disability progression

Event-driven follow-up, up to 3 years

Outcome figure

Primary endpoint results

Intervention Comparator or reference

3-month confirmed disability progression

Participants with progression (%)

Event-driven follow-up, up to 3 years
Siponimod
26%
Placebo
32%

21% relative risk reduction; HR 0.79 (95% CI 0.65–0.95; P=0.013).

Selected secondary outcomes

Timed 25-foot walk

The key walking outcome did not show a significant treatment effect.

MRI

T2 lesion-volume and inflammatory lesion outcomes favored siponimod.

Who was studied

Key inclusion criteria

  • Age 18–60 years
  • SPMS with a history of RRMS diagnosis based on McDonald criteria 2010
  • Baseline EDSS 3.0–6.5
  • Documented EDSS progression in the previous 2 years
  • No relapse in the 3 months before randomization

Key exclusion criteria

  • Substantial immunological, cardiac, or pulmonary disease
  • Ongoing macular edema or uncontrolled diabetes
  • CYP2C9*3/*3 genotype
  • Negative varicella-zoster antibody status

Participants at baseline

CharacteristicSiponimodN=1105PlaceboN=546
Age, years — mean ± SD48.0 ± 7.848.1 ± 7.9
Female sex — n (%)669 (61%)323 (59%)
Time since MS symptom onset, years — mean ± SD17.1 ± 8.416.2 ± 8.2
Time since conversion to SPMS, years — mean ± SD3.9 ± 3.63.6 ± 3.3
EDSS — mean ± SD5.4 ± 1.15.4 ± 1.0
No previous DMT use — n (%)245 (22%)114 (21%)
No relapses in the 2 years before screening — n (%)712 (64%)343 (63%)
Gadolinium-enhancing T1 lesions present — n (%)237 (21%)114 (21%)

SD: standard deviation; EDSS: Expanded Disability Status Scale; DMT: disease-modifying therapy; SPMS: secondary progressive multiple sclerosis.

Source: Kappos et al., Lancet 2018, Table 1

Safety signal

  • Lymphopenia, liver-enzyme elevation, bradyarrhythmia, macular edema, hypertension, zoster reactivation, and convulsions were more frequent with siponimod than placebo.
  • Serious adverse events occurred in 18% with siponimod and 15% with placebo.

Why it mattered

EXPAND demonstrated a reduction in confirmed disability progression with siponimod in a selected SPMS population. It advanced pivotal evidence beyond relapse-centered trials, while the negative walking endpoint and mixed disease activity limited broad conclusions about progressive MS.

Important limitation

The absolute difference in 3-month progression was modest, the walking endpoint was negative, and eligibility selected a narrower population than the full clinical spectrum of SPMS.

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