Effects of Tolebrutinib on Progression Independent of Relapse Activity in the Phase Three GEMINI Relapsing MS Trials
Jiwon Oh1, Bruce A.C. Cree2, Douglas L. Arnold3, Ho Jin kim4, Maria Pia Sormani5, Sana Syed6, Yixin Chen6, Christina R. Maxwell6, Timothy J. Turner6, Heinz Wiendl7
1St. Michael’s Hospital, University of Toronto, Toronto, Canada, 2UCSF Weill Institute for Neurosciences, University of California San Francisco, Department of Neurology, San Francisco, United States, 3McGill University, Montréal, Canada; NeuroRx Research, Montréal, Canada, 4National Cancer Center, Department of Neurology, Goyang, South Korea, 5University of Genoa, Department of Health Sciences, Genoa, Italy; IRCCS Ospedale Policlinico San Martino, Genoa, Italy, 6Sanofi, Cambridge, United States, 7Department of Neurology and Neurophysiology, University of Freiburg, Freiburg, Germany; Brain and Mind Center, University of Sydney, Sydney, Australia
Objective:
To evaluate the effects of tolebrutinib versus teriflunomide on progression independent of relapse activity (PIRA) in the phase 3 GEMINI relapsing MS trials.
Background:
Tolebrutinib, a brain-penetrant and bioactive Bruton’s tyrosine kinase inhibitor, reduced disability accumulation by 31% in the phase 3 non-relapsing secondary progressive MS HERCULES trial, with all disability events being independent of relapse activity.
Design/Methods:
GEMINI 1 (NCT04410978) and 2 (NCT04410991) were phase 3, double-blind, event-driven trials in participants 18–55 years old, Expanded Disability Status Scale score ≤5.5, and either ≥1 relapse in past year, ≥2 relapses in past 2 years, or ≥1 gadolinium-enhancing T1 brain lesion in past year. Participants were randomized 1:1 to receive tolebrutinib (60 mg once daily) or teriflunomide (14 mg once daily), each with matching placebo. The primary endpoint was annualized relapse rate (ARR), and the key secondary endpoint was time to onset of 6‑month confirmed disability worsening (6mCDW). PIRA was defined here as a 6mCDW event with no adjudicated relapse onset 90 days prior to or after disability onset and no adjudicated relapse onset in the 30 days prior to disability confirmation.
Results:
The trials enrolled 1873 participants (974 in GEMINI 1 and 899 in GEMINI 2), of which 67% were female and 64% were treatment naïve. Although tolebrutinib was not superior to teriflunomide in reducing ARR, the percentage of participants with 6mCDW was 8.3% with tolebrutinib and 11.3% with teriflunomide (hazard ratio, 0.71; 95% CI, 0.53–0.95). As expected, the majority (~ 80%) of 6mCDW events were PIRA. Fewer participants experienced PIRA events with tolebrutinib (6.4% of participants) compared to teriflunomide (8.5% of participants), resulting in a 27% risk reduction.
Conclusions:
Tolebrutinib-treated participants experienced fewer PIRA events in comparison to teriflunomide. These GEMINI PIRA data support the observation in HERCULES that tolebrutinib targets drivers of disability accumulation independent of effects on relapsing biology.
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