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.

Who was studied

Key inclusion criteria

  • Age 18–60 years
  • SPMS diagnosis 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

Participants at baseline

CharacteristicTolebrutinibN=754PlaceboN=377
Age, years — mean ± SD48.9 ± 8.048.9 ± 8.0
Female sex — n (%)454 (60.2%)242 (64.2%)
Time since RRMS symptom onset, years — mean ± SD17.1 ± 8.317.6 ± 8.4
Time since SPMS diagnosis, years — mean ± SD7.9 ± 7.38.4 ± 7.8
EDSS — mean ± SD5.5 ± 1.05.6 ± 0.9
Time since last clinical relapse, years — mean ± SD7.4 ± 5.37.6 ± 5.5
No previous DMT use — n (%)205 (27.2%)89 (23.6%)
Gadolinium-enhancing T1 lesions present — n/N (%)93/742 (12.5%)49/373 (13.1%)

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

Source: Fox et al., NEJM 2025, Table 1

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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