Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK inhibitor, in relapsing multiple sclerosis: a phase 2b, randomised, double-blind, placebo-controlled trial

Abstract

Background: Tolebrutinib is an oral, CNS-penetrant, irreversible inhibitor of Bruton's tyrosine kinase, an enzyme expressed in B lymphocytes and myeloid cells including microglia, which are major drivers of inflammation in multiple sclerosis. We aimed to determine the dose-response relationship between tolebrutinib and the reduction in new active brain MRI lesions in patients with relapsing multiple sclerosis.

Methods: We did a 16-week, phase 2b, randomised, double-blind, placebo-controlled, crossover, dose-finding trial at 40 centres (academic sites, specialty clinics, and general neurology centres) in ten countries in Europe and North America. Eligible participants were adults aged 18-55 years with diagnosed relapsing multiple sclerosis (either relapsing-remitting or relapsing secondary progressive multiple sclerosis), and one or more of the following criteria: at least one relapse within the previous year, at least two relapses within the previous 2 years, or at least one active gadolinium-enhancing brain lesion in the 6 months before screening. Exclusion criteria included a diagnosis of primary progressive multiple sclerosis or a diagnosis of secondary progressive multiple sclerosis without relapse. We used a two-step randomisation process to randomly assign eligible participants (1:1) to two cohorts, then further randomly assign participants in each cohort (1:1:1:1) to four tolebrutinib dose groups (5, 15, 30, and 60 mg administered once daily as an oral tablet). Cohort 1 received tolebrutinib for 12 weeks, then matched placebo (ie, identical looking tablets) for 4 weeks; cohort 2 received 4 weeks of placebo followed by 12 weeks of tolebrutinib. Participants and investigators were masked for dose and tolebrutinib-placebo administration sequence; investigators, study team members, and study participants did not have access to unmasked data. MRI scans were done at screening and every 4 weeks over 16 weeks. The primary efficacy endpoint was the number of new gadolinium-enhancing lesions detected on the scan done after 12 weeks of tolebrutinib treatment (assessed at week 12 for cohort 1 and week 16 for cohort 2), relative to the scan done 4 weeks previously, and compared with the lesions accumulated during 4 weeks of placebo run-in period in cohort 2. Efficacy data were analysed in a modified intention-to-treat population, using a two-step multiple comparison procedure with modelling analysis. Safety was assessed for all participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT03889639), EudraCT (2018-003927-12), and WHO (U1111-1220-0572), and has been completed.

Findings: Between May 14, 2019, and Jan 2, 2020, we enrolled and randomly assigned 130 participants to tolebrutinib: 33 to 5 mg, 32 to 15 mg, 33 to 30 mg, and 32 to 60 mg. 129 (99%) completed the treatment regimen and 126 were included in the primary analysis. At treatment week 12, there was a dose-dependent reduction in the number of new gadolinium-enhancing lesions (mean [SD] lesions per patient: placebo, 1·03 [2·50]; 5 mg, 1·39 [3·20]; 15 mg, 0·77 [1·48]; 30 mg, 0·76 [3·31]; 60 mg, 0·13 [0·43]; p=0·03). One serious adverse event was reported (one patient in the 60 mg group was admitted to hospital because of a multiple sclerosis relapse). The most common non-serious adverse event during tolebrutinib treatment was headache (in one [3%] of 33 in the 5 mg group; three [9%] of 32 in the 15 mg group; one [3%] of 33 in the 30 mg group; and four [13%] of 32 in the 60 mg group). No safety-related discontinuations or treatment-related deaths occurred.

Interpretation: 12 weeks of tolebrutinib treatment led to a dose-dependent reduction in new gadolinium-enhancing lesions, the 60 mg dose being the most efficacious, and the drug was well tolerated. Reduction of acute inflammation, combined with the potential to modulate the immune response within the CNS, provides a scientific rationale to pursue phase 3 clinical trials of tolebrutinib in patients with relapsing and progressive forms of multiple sclerosis.

Funding: Sanofi.

Figure 1:. Participant disposition and study treatment exposure

Participants were randomised in two steps: first (1:1) into two cohorts and then (1:1:1:1) into four dosage groups within each cohort. equally into one of eight treatment arms that were divided between two cohorts. Cohort 1 received tolebrutinib for 12 weeks beginning at baseline, followed by 4 weeks of placebo run-out in order to blind the treatment assignment and to provide additional safety data. Cohort 2 received placebo for 4 weeks as a run-in, followed by tolebrutinib for 12 weeks. Of the 130 participants randomised, 129 completed the treatment, and the participant with early treatment discontinuation still completed the study. For the primary analysis, an MRI assessment was excluded from analysis if the participant had received systemic corticosteroids within the 30 days prior to the MRI assessment date. Thus, MRI assessments from 126 of 130 participants were included in the primary analysis (Cohort 1: 5 mg, n=14; 15 mg, n=15; 30 mg, n=16; 60 mg, n=15. Cohort 2: 5 mg, n=17; 15 mg, n=16; 30 mg, n=17; 60 mg, n=16). R=randomisation.

Figure 2:. Primary outcome: Number of new Gd-enhancing lesions on an MRI scan after 12 weeks of tolebrutinib treatment

Panel A shows the estimated dose-response curve after applying the two-step MCP-Mod methodology; error bars represent 95% CIs. The exponential model was selected as the best fit based on the Akaike information criterion and was used to reject the null hypothesis (p=0·03). Panel B shows the mean (error bars: SD) number of new Gd-enhancing lesions per scan for pooled participants from Cohorts 1 and 2 at the end of 12 weeks of tolebrutinib treatment compared with a scan 4 weeks prior. In Cohort 2, the formation rate of new Gd-enhancing lesions over the 4-week placebo run-in period was assumed to be constant over the 16-week trial duration. Values are relative reduction in lesion count versus placebo, adjusted for presence or absence of baseline Gd-enhancing lesions, using a negative binomial model. CI=confidence interval. Gd=gadolinium. MCP-Mod=multiple comparison procedure-modelling. MRI=magnetic resonance imaging. QD=once daily. SD=standard deviation.

Figure 3:. Secondary outcome: Number of new/enlarging T2 lesions and total number of Gd-enhancing lesions on an MRI scan after 12 weeks of tolebrutinib treatment

Panel A shows the estimated dose-response curve using MCP-Mod methodology for the number of new or enlarging T2 lesions; error bars represent 95% CIs. The linear model was selected as the best fit based on the Akaike information criterion and was used to reject the null hypothesis (p<0·0001). Panel B shows the mean (SD) number of new or enlarging T2 lesions for pooled participants from Cohorts 1 and 2 at the end of 12 weeks of tolebrutinib treatment. In Cohort 2, the formation rate of new Gd-enhancing lesions over the 4-week placebo run-in period was assumed to be constant over the 16-week trial duration. Relative reductions in lesions versus placebo were analysed using a negative binomial model. Panel C shows the total number of Gd-enhancing lesions at the end of 12 weeks of tolebrutinib treatment, for which the MCP-Mod procedure did not allow for rejection of the null hypothesis. ^aRelative reduction in lesions versus placebo, with adjustment for baseline presence or absence of Gd-enhancing lesion activity using a negative binomial model. CI=confidence interval. Gd=gadolinium. MCP-Mod=multiple comparison procedure-modelling. MRI=magnetic resonance imaging. QD=once daily. SD=standard deviation.