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.

Study population

Randomized: 767 randomized
Age: 18–55 years eligible
Disability: EDSS 2.0–6.5
Disease definition: 2017 McDonald-defined PPMS with supportive cerebrospinal-fluid findings

Who entered the trial

Key inclusion criteria

Defined 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

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: it showed that the HERCULES disability result in non-relapsing SPMS did not extend to this PPMS population.

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.