PERSEUS

Tolebrutinib

PERSEUS found that tolebrutinib did not delay composite confirmed disability progression versus placebo in primary progressive multiple sclerosis.

Phase
Phase III
Population
Primary progressive multiple sclerosis (PPMS)
Controlled period
Aug 13, 2020 — Nov 14, 2025

What was compared

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

Tolebrutinib

60 mg orally once daily

n=515
Comparator

Placebo

Matching oral placebo once daily

n=252
767 randomizedUp to approximately 60 months controlled phase

Primary endpoint

Prespecified outcome

Time to 6-month composite confirmed disability progression

Up to approximately 60 months

Outcome figure

Primary endpoint results

Intervention Comparator or reference

6-month composite confirmed disability progression

Hazard ratio (95% CI)

Up to approximately 60 months
Tolebrutinib vs placebo1.01 (0.81–1.26)

The primary endpoint was not met: HR 1.01 (95% CI 0.81–1.26; P=0.94).

Selected secondary outcomes

Composite components

The distribution of qualifying EDSS, walking, and upper-limb progression events did not yield an overall treatment effect.

Regulatory consequence

Sanofi stated that it would not pursue a PPMS indication based on PERSEUS.

Who was studied

Key inclusion criteria

  • Age 18–55 years
  • PPMS diagnosis based on McDonald criteria 2017
  • Baseline EDSS 2.0–6.5
  • Positive cerebrospinal-fluid oligoclonal bands or elevated IgG index
  • No access to ocrelizumab, or prior intolerance or perceived inadequate efficacy with ocrelizumab

Key exclusion criteria

  • Active infection or clinically important hepatic abnormality
  • Recent MS treatment within protocol-specified washout periods
  • Medical condition or treatment that could confound disability assessment

Participants at baseline

CharacteristicAll participantsN=767
Age, years — mean ± SD45.3 ± 7.4
Male sex — n (%)416 (54.2%)
Time since MS symptom onset, years — mean ± SD7.8 ± 5.0
Time since PPMS diagnosis, years — mean ± SD4.2 ± 4.4
EDSS — mean ± SD4.9 ± 1.3
No previous DMT use — n (%)449 (58.5%)
Gadolinium-enhancing T1 lesions present — n (%)86 (11.3%)

SD: standard deviation; EDSS: Expanded Disability Status Scale; DMT: disease-modifying therapy.

Source: Fox et al., CMSC 2025 poster, Baseline demographics and disease characteristics

Safety signal

  • The sponsor reported a preliminary safety profile consistent with previous tolebrutinib studies.
  • Drug-induced liver injury remained an identified risk requiring early and regular liver monitoring.

Why it mattered

PERSEUS is an important negative pivotal study: tolebrutinib did not improve composite confirmed disability progression in its PPMS population. It showed that the positive nonrelapsing-SPMS result in HERCULES could not simply be extended to a different progressive MS course.

Important limitation

The efficacy and safety values currently come from a 2026 scientific-congress presentation and sponsor reporting; no peer-reviewed primary paper was verified.

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