Trial results for the GEMINI 2 study (NCT04410991) investigating tolebrutinib for relapsing forms of multiple sclerosis (RMS) were posted on ClinicalTrials.gov on 2025-06-18. The Phase 3 trial showed that tolebrutinib significantly delayed the time to onset of 6-month confirmed disability worsening compared to teriflunomide, with a Hazard Ratio of 0.582 (95% CI: 0.38 to 0.891; p=0.0114).
Background
Tolebrutinib is an investigational Bruton's Tyrosine Kinase (BTK) inhibitor. The GEMINI 2 study aimed to assess the efficacy, safety, and tolerability of daily tolebrutinib in participants with relapsing forms of multiple sclerosis. The primary objective was to compare tolebrutinib to a daily dose of 14 mg teriflunomide (Aubagio) measured by annualized adjudicated relapse rate (ARR) in participants with relapsing forms of MS.
Trial design
The GEMINI 2 study (NCT04410991) was a Phase 3, randomized clinical trial that enrolled 899 participants with relapsing multiple sclerosis. Participants were randomized to receive either tolebrutinib 60 mg or teriflunomide 14 mg, with corresponding placebos to maintain blinding. The primary endpoint was the annualized adjudicated relapse rate (ARR). Secondary objectives included assessing efficacy on disability progression, MRI lesions, cognitive performance, and quality of life.
Key results
The trial evaluated several key outcomes comparing tolebrutinib 60 mg to teriflunomide 14 mg:
- Annualized Relapse Rate (ARR): The ARR was 0.108 relapses per participant year for tolebrutinib and 0.109 relapses per participant year for teriflunomide. Analysis showed a relative risk of 0.996 (95% Confidence Interval: 0.754 to 1.315; p=0.9758), indicating no statistically significant difference.
- Time to Onset of 6-Month Confirmed Disability Worsening: The median time to onset was 15.12 months for tolebrutinib and 12.14 months for teriflunomide. Analysis showed a Hazard Ratio (HR) of 0.582 (95% Confidence Interval: 0.38 to 0.891; p=0.0114), indicating a statistically significant delay with tolebrutinib.
- Time to Onset of 3-Month Confirmed Disability Worsening: The median time to onset was 12.11 months for both tolebrutinib and teriflunomide. Analysis showed a Hazard Ratio (HR) of 0.641 (95% Confidence Interval: 0.444 to 0.925; p=0.0181), indicating a statistically significant delay with tolebrutinib.
- Mean Number of New and/or Enlarging T2-Hyperintense Lesions Per Year: The mean was 5.092 for tolebrutinib and 4.369 for teriflunomide. Analysis showed a relative risk of 1.165 (95% Confidence Interval: 0.905 to 1.502; p=0.2362), indicating no statistically significant difference.
- Mean Number of New Gadolinium-Enhancing T1-Hyperintense Lesions Per Scan: The mean was 0.460 for tolebrutinib and 0.217 for teriflunomide. Analysis showed a relative risk of 2.118 (95% Confidence Interval: 1.502 to 2.987; p=0.0001), suggesting a significantly higher number of new Gd-enhancing T1 lesions with tolebrutinib.
- Change From Baseline in Cognitive Function (SDMT): The least squares mean change was 0.374 for tolebrutinib and 0.428 for teriflunomide. Analysis showed a least square mean difference of -0.053 (95% Confidence Interval: -0.156 to 0.05; p=0.31), indicating no statistically significant difference.
What this means
The results of the GEMINI 2 trial indicate that tolebrutinib demonstrated a statistically significant benefit in delaying both 3-month and 6-month confirmed disability worsening in patients with relapsing multiple sclerosis compared to teriflunomide. However, tolebrutinib did not show superiority over teriflunomide in annualized relapse rate, T2-hyperintense lesions, or cognitive function. Furthermore, tolebrutinib was associated with a significantly higher number of new gadolinium-enhancing T1-hyperintense lesions. These mixed results suggest a complex efficacy profile for tolebrutinib in RMS, with a notable positive impact on disability progression but areas where it did not outperform or performed worse than the comparator.
Source
The information regarding these trial results was obtained from ClinicalTrials.gov, a public database of clinical studies. The results for study NCT04410991, titled "Relapsing Forms of Multiple Sclerosis (RMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (GEMINI 2)," were posted on 2025-06-18 on clinicaltrials.gov.