Tolebrutinib Shows Dose-Dependent MS Lesion Reduction in Phase 2b Trial
The results support continued development of tolebrutinib 60 mg in phase 3 trials for MS, based on the well-established relationship between reductions of Gadolinium-enhancing lesions and relapse rates.
Daniel Reich, MD, PhD
Treatment with tolebrutinib (Sanofi), an oral Bruton’s tyrosine kinase (BTK) inhibitor, demonstrated a dose-dependent reduction in the number of new gadolinium-enhancing (GdE) lesions and was well-tolerated among patients with relapsing-remitting multiple sclerosis (RRMS) or relapsing secondary progressive MS (SPMS) in a phase 2b study (NCT03889639).
Lead author Daniel Reich, MD, PhD, senior investigator, National Institutes of Neurological Disorders and Stroke, National Institutes of Health, and colleagues conducted a 16-week, double-blind, placebo-controlled, crossover, dose-finding trial that assigned 130 participants to tolebrutinib 5 mg (n = 33), 15 mg (n = 32), 30 mg (n = 33), and 60 mg (n = 32). Patients with RRMS and SMPS underwent MRI scans at screening and every 4 weeks over the 16-week stretch. Cohort 1 received the investigational drug for 12 weeks, then matched placebo for 4 weeks, whereas those in cohort 2 received4 weeks of placebo followed by 12 weeks of tolebrutinb.
An exponential model showed a dose-response relationship between tolebrutinib and new GdE lesions, which was used to reject the null hypothesis of a flat dose-response curve (test statistic, 2.47; P = .03). The 60-mg dose was the most efficacious, with an observed mean number of lesions of 0.13 (standard deviation [SD], 0.43) compared to 1.03 (SD, 2.50) for placebo. Furthermore, 28 of the 31 participants (90%) who received the 60-mg dose had no new GdE lesions after 12 weeks of treatment, compared with 44 of 59 participants (75%) in cohort 2 placebo period observed at week 4.
"In summary our study design with short placebo exposure established an effect of tolebrutinib on MRI measures related to new lesion formation and identified a dose to test in phase 3 trials," Reich et al concluded. "Effective treatment for acute inflammation, combined with the potential to directly modulate the immune response within the CNS—known to be a key driver of clinical progression in multiple sclerosis—provides scientific rationale to pursue phase 3 clinical trials in patients with both relapsing and progressive forms of multiple sclerosis."
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Each tolebrutinib group had similar occurrence of adverse events (AEs), none of which led to treatment or study discontinuation. Across doses, 1 serious AE was observed: a severe MS relapse in a participant who received 60-mg tolebrutinib in cohort 1. That patient did not have their study participation interrupted, and they recovered and completed the trial.
A closer analysis of weeks 1-4 showed no serious AEs. During this period, a similar number of AEs were reported across all tolebrutinib dose groups (ranging from 2 of 16 (13%) to 5 of 16 (31%) with tolebrutinib vs 23 of 66 (35%) with placebo). There were also 3 cases of elevated alanine aminotransferase concentrations over the 12-week treatment period, 2 of which had concentrations that exceeded 3 times the upper limit of normal (1 in the 30-mg group and 1 in the 60-mg group).
Analysis of new or enlarging T2 lesions, a secondary end point, was shown to have a dose-response relationship, with the linear model providing the best fit (test statistic, 4.32; P <.001). Additionally, investigators observed an 89% (95% CI, 68-96) relative reduction in the mean number of new or enlarging T2 lesions after 12 weeks of 60-mg treatment, compared with only 66% (39 of 59) of those in the placebo group.
When assessing the pharmacokinetics of tolebrutinib, the 60-mg dose had 2.5-times greater exposure over the 12 weeks of treatment compared with the 30-mg dose (mean area under curve, 19.5 ng.h/mL [coefficient of variation, 72%] vs 49.7 ng.h/mL [94%]). Meal status was well documented in 135 of 389 visits (35%), 115 of which (85%) included participants who had taken the treatment with food.
The investigational agent is currently being assessed in an ongoing long-term safety study (NCT03996291) and 4 phase 3 studies underway in relapsing MS (NCT04410978 and NCT04410991), primary progressive MS (NCT04458051), and non-relapsing SPMS (NCT04411641).
Reich presented research earlier this year at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum, February 25-27, which entailed the effects of anakinra and tolebrutinib on 7-Tesla MRI paramagnetic rim lesions in MS. Watch his commentary below, as he details the mechanisms of action and potential tolebrutinib has within the space.
