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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.

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.

Reich DS, Arnold DL, Vermersch P, et al. Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK inhibitor in relapsing multiple sclerosis: a phase 2b, randomized, double-blind, placebo-controlled trial. Lancet Neurol. Published online August 2021. doi: 10.1016/S1474-4422(21)00237-4