HERCULES

Tolebrutinib

HERCULES showed that tolebrutinib delayed confirmed disability progression versus placebo in non-relapsing secondary progressive multiple sclerosis.

Phase
Phase III
Population
Non-relapsing secondary progressive multiple sclerosis (nrSPMS)
Controlled period
Sep 24, 2020 — Aug 29, 2024

What was compared

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

Tolebrutinib

60 mg orally once daily

n=754
Comparator

Placebo

Matching oral placebo once daily

n=377
1,131 randomizedMedian follow-up 133 weeks controlled phase

Primary endpoint

Prespecified outcome

6-month confirmed disability progression

Event-driven follow-up; median 133 weeks

Outcome figure

Primary endpoint results

Intervention Comparator or reference

6-month confirmed disability progression

Participants with progression (%)

Median follow-up 133 weeks
Tolebrutinib
22.6%
Placebo
30.7%

HR 0.69 (95% CI 0.55–0.88; P=0.003), a 31% relative risk reduction.

Selected secondary outcomes

New or enlarging T2 lesions

The adjusted annualized lesion count was 38% lower with tolebrutinib.

Confirmed disability improvement

A greater proportion achieved protocol-defined confirmed disability improvement.

Study population

Randomized
1,131 randomized
Age
18–60 years eligible
Disability
EDSS 3.0–6.5
Disease definition
Non-relapsing SPMS with recent progression and no relapse for at least 24 months

Who entered the trial

Key inclusion criteria

  • Defined based on McDonald criteria 2017
  • Documented disability progression during the preceding 12 months
  • No clinical relapse for at least 24 months and baseline EDSS 3.0–6.5

Key exclusion criteria

  • Relapse during the preceding 24 months
  • Active infection or clinically important hepatic abnormality
  • Medical condition or concomitant treatment that could confound disability assessment

Safety signal

  • Serious adverse events occurred in 15.0% with tolebrutinib and 10.4% with placebo.
  • ALT elevations above three times the upper limit of normal occurred in 4.0% and 1.6%, respectively.
  • Before intensified liver monitoring, one tolebrutinib-treated participant required liver transplantation and died from postoperative complications.

Why it mattered

HERCULES supplied the pivotal evidence for EU authorization of Cenrifki for adults with SPMS without relapses in the previous two years.

Important limitation

The result applies to a selected non-relapsing SPMS population and does not establish efficacy in relapsing MS or PPMS. Drug-induced liver injury requires structured monitoring.

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