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

Summary

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.

Introduction

Multiple sclerosis is an immune-mediated, inflammatory, demyelinating disorder leading to axon loss, neurological morbidity, and accumulating disability.¹Immuno­modu­latory treatments can result in annualised relapse rates as low as 0·10;2, 3, 4 however, these results are offset by less impressive disability outcomes. Because existing treat­ments primarily affect peripheral adaptive immunity, we aimed to test a new approach that combines peripheral and CNS immunomodulation. Our goal was to simul­taneously reduce acute and chronic neuro­inflammation. Chronic neuroinflammation is thought to contribute to tissue loss and disability accumulation, and is the most significant unmet medical need for patients with multiple sclerosis.5, 6, 7

Research in context

Evidence before this study

We searched PubMed on May 1, 2021, for clinical studies published in any language, using unrestricted dates and the terms “multiple sclerosis (MS) and Bruton’s tyrosine kinase (BTK)”, and “Bruton’s tyrosine kinase inhibitor”, “chronic lesion”, or “slowly evolving lesion”. Accumulated evidence from these studies shows that chronic neuroinflammation, driven in part by B lymphocytes and activated microglia within the CNS, is a key contributor to disability accumulation in relapsing and progressive multiple sclerosis. Bruton’s tyrosine kinase is a critical signalling element in B lymphocytes and myeloid cells. A phase 2 trial of evobrutinib, a Bruton’s tyrosine kinase inhibitor, has provided proof of concept that targeting this enzyme in patients with multiple sclerosis can lead to improved clinical and MRI outcomes. However, currently approved treatments for multiple sclerosis act primarily outside the CNS. Tolebrutinib is an investigational Bruton’s tyrosine kinase inhibitor that has been shown, in phase 1 studies, to penetrate the blood–brain barrier and reach pharmacologically relevant levels in the CNS.

Added value of this study

This phase 2b clinical trial is the first demonstration of efficacy of tolebrutinib in patients with relapsing multiple sclerosis. Using a crossover trial design that minimised exposure to placebo, we showed a dose-dependent reduction in the number of new gadolinium-enhancing brain lesions (the primary endpoint) and new or enlarging T2 lesions (a key secondary endpoint) after 12 weeks of treatment. Tolebrutinib also showed a favourable safety profile.

Implications of all the available evidence

The results of this phase 2b study support future investigation of tolebrutinib in phase 3 studies. In addition to the treatment effect shown in patients with relapsing multiple sclerosis, exploratory analysis of slowly evolving lesions raises the possibility that investigation of tolebrutinib in patients with progressive disease, in which chronic neuroinflammation is well documented, is warranted.

Bruton’s tyrosine kinase is a non-receptor tyrosine kinase that is expressed in most haematopoietic cells (excluding T cells and fully differentiated plasma cells) and connects specific cell-surface receptors to down­stream signalling pathways, linking immune stimulus to cellular activation.8, 9, 10, 11 It is a crucial signalling element in B lymphocytes and myeloid cells, including peripheral monocytes or macrophages and CNS-resident microglia.¹¹ Thus, inhibition of Bruton’s tyrosine kinase was hypo­thesised to reduce the acute inflammation associated with contrast-enhancing lesions by modulating (rather than depleting) B lymphocytes.3, 4, 12, 13, 14 Additionally, inhi­biting Bruton’s tyrosine kinase in the CNS could have beneficial effects on chronic lesions and meningeal inflammatory infiltrates.¹⁵ Both types of lesions contain microglia, perivascular or meningeal macrophages, and B-lineage cells,16, 17 and have proven to be resistant to therapeutic intervention. Thus, targeting B cells and myeloid cells both outside and inside the CNS might have a greater—and perhaps synergistic—effect on neuroinflammation and demyelination than current disease-modifying therapies.

Tolebrutinib is a small molecule that is given orally and irreversibly binds to and inhibits Bruton’s tyrosine kinase. Phase 1 studies showed pharmacologically relevant concentrations of the drug in CSF. For example, a single oral administration of 120 mg tolebrutinib in healthy volunteers resulted in a mean concentration in the CSF of 4·1 nM after 2 h, which is a therapeutically relevant exposure based on cellular assays.18, 19

In this phase 2b trial, we aimed to establish a dose-response relationship for tolebrutinib in patients with relapsing multiple sclerosis using MRI measures of disease activity, which have been validated as being predictive of reductions in clinical relapse rates.²⁰The study was further designed to determine the magnitude of effect on MRI lesions. We also pursued exploratory MRI measurements, including slowly evolving lesions⁷ and paramagnetic rim lesions.²¹ These chronic lesions, relatively resistant to approved therapies, are associated with activated microglia17, 22 and are correlated with disability accumulation in patients with multiple sclerosis.23, 24