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

Multiple Sclerosis

MS, BTK Inhibitor

Background: Some multiple sclerosis (MS) lesions stay inflamed for very long periods of time. This type of inflammation is not affected by any MS medications. These lesions can lead to slow worsening of MS symptoms. Researchers want to see if a new drug can help. Objective: To see if tolebrutinib can help clear inflammation in MS brain lesions. Eligibility: Adults ages 18 and older with MS who are on an anti-CD20 therapy. Design: Participants will be screened under protocol #89-N-0045. Participants will have a medical history. They will have physical and neurological exams. They will have blood and urine tests. The progression of their MS will be assessed. Participants will have MRIs of the brain. The MRI scanner is shaped like a cylinder. It uses a magnetic field and radio waves to take pictures of the body. During the MRIs, participants will lie on a table that slides in and out of the scanner. Soft padding or a coil will be placed around their head. Participants may have electrocardiograms to measure the heart s electrical activity. Participants may have lumbar punctures ( spinal taps ). A small needle will be inserted into the spinal canal in the lower back. Fluid will be collected. Some participants will take tolebrutinib pills by mouth once a day for at least 96 weeks. They will stop their anti-CD20 therapy. They will have at least 10 study visits. Some participants will not take tolebrutinib. They will stay on their anti-CD20 therapy. They will have 5 study visits. Participation will last at least 96 weeks.

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, 16 adults with MS who are on stable disease-modifying treatment with anti-CD20 antibody therapy and are within 6 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 and agree to forego further anti- CD20 or other disease-modifying therapy for the duration of the trial. An initial 7 enrolled study participants started tolebrutinib at 60 mg/day (Initial Cohort). Of the Initial Cohort, participants (n=3), who had initiated tolebrutinib 60 mg will remain at 60 mg and not be escalated to 120 mg/day. The remaining participants (n=4) consented to Cohort A, who had initiated tolebrutinib 60 mg and previously escalated to 120 mg/day will remain at that dose. Radiological, clinical, and biological outcomes are measured at 24, 48, 72, 96, and 144 (Cohort A) weeks, with additional interspersed visits for safety monitoring. Participants may subsequently continue treatment until tolebrutinib is marketed or commercial development halted. A comparison group of 10 participants who meet enrollment 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 investigations are planned to study 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 60 mg/day 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 48 weeks of treatment with tolebrutinib 60 mg and 96 weeks of treatment with tolebrutinib 120 mg (Cohort A) all following 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 disappeared at the end of 48 weeks of tolebrutinib 60 mg. Secondary Endpoints: (1) Adverse event tables. (2) Changes in T1 relaxation time within paramagnetic rim lesions at the end of 96 weeks of tolebrutinib 120 mg, relative to non-rim lesions. (3) Changes in size of paramagnetic rim lesions at the end of 96 weeks of tolebrutinib 120 mg, relative to non-rim lesions. Study Population: Up to 10 adults with multiple sclerosis, targeting at least 7 participants who complete 48 weeks of therapy with tolebrutinib 60 mg in Cohort A. 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 48 weeks (Initial Cohort), and a subgroup of patients already escalated to 120 mg (Cohort A), with optional long-term extension and follow-up. Study Duration: 5 years Participant Duration: 144 weeks (Cohort A) for primary and secondary outcomes, with optional long-term extension and follow-up.

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