GEMINI 1 & 2

Tolebrutinib

The parallel GEMINI trials found that tolebrutinib did not reduce annualized relapse rates more than teriflunomide in relapsing multiple sclerosis.

Phase
Phase III
Population
Relapsing multiple sclerosis (RMS)
Controlled period
Jun 11, 2020 — Jul 16, 2024

What was compared

Two parallel trialsRandomized 1:1Triple-maskedDouble-dummy
Intervention

Tolebrutinib

60 mg orally once daily with matching placebo

Comparator

Teriflunomide

14 mg orally once daily with matching placebo

1,873 randomized across two trialsEvent-driven; median follow-up 139 weeks controlled phase

Primary endpoint

Prespecified outcome

Annualized relapse rate

Event-driven follow-up in each trial

Outcome figure

Primary endpoint results

Intervention Comparator or reference

GEMINI 1 — annualized relapse rate

Adjusted relapses per participant-year

Event-driven follow-up
Tolebrutinib
0.130
Teriflunomide
0.122

GEMINI 2 — annualized relapse rate

Adjusted relapses per participant-year

Event-driven follow-up
Tolebrutinib
0.108
Teriflunomide
0.109

Neither trial demonstrated superiority: rate ratio 1.06 (P=0.67) in GEMINI 1 and 1.00 (P=0.98) in GEMINI 2.

Selected secondary outcomes

6-month confirmed disability worsening

The pooled analysis favored tolebrutinib (8.3% versus 11.3%; HR 0.71; 95% CI 0.53–0.95), but formal testing was precluded by the failed hierarchical primary endpoint.

MRI lesion activity

Focal inflammatory MRI lesion measures did not show a consistent advantage for tolebrutinib.

Study population

Randomized
1,873 randomized across two trials
Age
Mean 36.5 years; eligible 18–55
Sex
Approximately 67% women
Disability
EDSS 0–5.5 eligible
Disease definition
2017 McDonald-defined relapsing multiple sclerosis with recent activity

Who entered the trial

Key inclusion criteria

  • Defined based on McDonald criteria 2017
  • Baseline EDSS no higher than 5.5
  • Recent relapse or gadolinium-enhancing MRI activity

Key exclusion criteria

  • Primary progressive MS or non-relapsing secondary progressive MS
  • Active infection or clinically important hepatic abnormality
  • Bleeding disorder, platelet dysfunction, or prohibited anticoagulant therapy

Safety signal

  • Overall adverse-event incidence was similar between treatment groups.
  • Minor bleeding events were more frequent with tolebrutinib, including petechiae and heavy menstrual bleeding.
  • Liver-enzyme monitoring remained important because rare marked elevations occurred with tolebrutinib.

Why it mattered

The negative relapse results, alongside a hypothesis-generating pooled disability signal, helped separate effects on focal inflammatory activity from possible effects on disability biology.

Important limitation

Because both primary endpoints were negative, the pooled disability result was not formally tested under the prespecified hierarchy and cannot overturn the primary conclusion.

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