Tolebrutinib, a Brain-penetrant Bruton s Tyrosine Kinase Inhibitor, for the Modulation of Chronically Inflamed White Matter Lesions in Multiple Sclerosis

Summary

Participation Requirements

Description

Study Description: The primary goal of this protocol is to test whether 48 weeks of treatment with tolebrutinib, an investigational, orally available, brain-penetrant, Bruton s tyrosine kinase (BTK) inhibitor, affects an imaging marker (the paramagnetic rim ) associated with chronically inflamed whi...

Study Description: The primary goal of this protocol is to test whether 48 weeks of treatment with tolebrutinib, an investigational, orally available, brain-penetrant, Bruton s tyrosine kinase (BTK) inhibitor, affects an imaging marker (the paramagnetic rim ) associated with chronically inflamed white matter lesions in multiple sclerosis (MS). In this rater-blinded but otherwise open-label study, ten adults with MS who are on stable disease-modifying treatment with intravenous anti-CD20 antibody therapy and are within 3 months of their most recent dose, have at least one paramagnetic rim lesion on 7-tesla magnetic resonance imaging (MRI), and have developed no new white matter lesions or clinical relapses for at least 6 months, will initiate treatment with tolebrutinib 60 mg/day and agree to forego further anti-CD20 or other disease-modifying therapy for the duration of the trial. Radiological, clinical, and biological outcomes are measured at 24, 48 (primary), 72, and 96 weeks, with additional interspersed visits for safety monitoring. Participants may subsequently continue on treatment until tolebrutinib is marketed or commercial development halted. A comparison group of 10 participants who meet inclusion criteria but choose to stay on anti-CD20 therapy will also be enrolled. The primary outcome measure is disappearance of one or more paramagnetic rims from white matter lesions identified at baseline. Secondary outcomes include safety and tolerability and additional radiological outcomes. Exploratory clinical, radiological, and laboratory measures will be obtained to investigate the mechanism of action of tolebrutinib and for biomarker development, and to compare the tolebrutinib and anti-CD20 cohorts. Objectives: Primary Objective: To evaluate the effects of 48 weeks of tolebrutinib treatment on the paramagnetic rim of chronically inflamed white matter lesions, as seen on 7-tesla MRI. Secondary Objectives: (1) To assess safety and tolerability of 96 weeks of treatment with tolebrutinib following intravenous anti-CD20 antibody therapy. (2) To assess the possible repair of chronically inflamed white matter lesions in which inflammation at the lesion edge has been modulated by tolebrutinib. Endpoints: Primary Endpoint: Per-patient proportion of lesions in which the paramagnetic rim has been modulated at the end of 48 weeks. Secondary Endpoints: (1) Adverse event tables. (2) Changes in T1 relaxation time within paramagnetic rim lesions at the end of 96 weeks, relative to non-rim lesions. (3) Changes in size of paramagnetic rim lesions at the end of 96 weeks, relative to non-rim lesions. Study Population: Up to 10 adults with multiple sclerosis, targeting at least 7 participants who complete 96 weeks of tolebrutinib therapy. Up to 10 adults with multiple sclerosis who meet inclusion criteria but choose to stay on anti-CD20 therapy. Phase: 2 Description of Study Intervention: Oral tolebrutinib 60 mg per day for 96 weeks, with optional long-term extension and follow-up Study Duration: 5 years Participant Duration: 96 weeks for the primary study plus optional long-term extension and follow-up

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