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

INCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

Tolebrutinib Cohorts Inclusion Criteria

Able to provide informed consent
Willingness to comply with all study procedures and availability for the duration of the study
Male or female, aged greater than or equal to 18
Diagnosed with multiple sclerosis according to the 2017 revision of the McDonald diagnostic criteria, with no new lesion formation by comparison of baseline MRI scan with a historical MRI scan at least 6 months prior
On anti-CD20 antibody treatment for at least 6 months, with the most recent dose at most 6 months prior to enrollment.
Willing to forego further anti-CD20 antibody treatment for the duration of the study

Fully vaccinated against SARS-CoV-2 by Day 0. At the time of this writing, Fully vaccinated is defined as:

Two weeks out from the second dose of a two-dose vaccine series (Moderna, Pfizer-BioNTech); or
Two weeks out from a single-dose vaccine (Johnson & Johnson/Janssen)
Note: Should guidelines change, we will amend these inclusion criteria accordingly
Has a prior 7-tesla MRI scan, no more than 1 year prior to enrollment, demonstrating at least one white matter lesion with a paramagnetic rim
For females of reproductive potential: agrees to use highly effective contraception for at least 1 month prior to dosing and to use such a method during study participation and for an additional 12 weeks after the end of tolebrutinib administration
For males of reproductive potential: agrees to use condoms or other methods to ensure effective contraception with partner; agrees not to donate sperm from the inclusion up to 12 weeks after the last dose
QuantiFERON-TB Gold negative; skin testing (e.g., tuberculin skin test) will be allowed if blood testing is not available or the blood test result is indeterminate
Agrees to adhere to Lifestyle Considerations throughout study duration
Agrees not to participate in any other interventional study while participating in this protocol

Control Cohort Inclusion Criteria:

Able to provide informed consent
Willingness to comply with all study procedures and availability for the duration of the study
Male or female, aged greater than or equal to 18
Diagnosed with multiple sclerosis according to the 2017 revision of the McDonald diagnostic criteria, with no new lesion formation by comparison of baseline MRI scan with a historical MRI scan at least 6 months prior
On anti-CD20 antibody treatment for at least 6 months, with the most recent dose at most 6 months prior to enrollment. (Participants in this cohort should remain on their baseline anti-CD20 treatment at least through week 48.)
Has a prior 7-tesla MRI scan, no more than 1 year prior to enrollment, demonstrating at least one white matter lesion with a paramagnetic rim
For females of reproductive potential: agrees to use highly effective contraception during study participation
Agrees not to participate in any other interventional study while participating in this protocol

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from participation in this study:

Tolebrutinib Cohorts Exclusion Criteria

Pregnancy or lactation
MS relapse in the 6 months prior to dosing
Febrile illness within 4 weeks prior to dosing, or persistent chronic or active infection requiring treatment with systemic antibiotics, antivirals, or antifungals.
Treatment with another investigational drug or other investigational intervention within 3 months prior to baseline
Contraindications for 7-tesla MRI

Presence of screening laboratory or ECG values outside normal limits that are considered in the PI or MAI s judgment to be clinically significant, including but not limited to:

Presence of liver injury defined as underlying hepatobiliary disease or screening alanine aminotransferase (ALT) more than 1.5 times the upper limit of normal (ULN)
At screening, positive for hepatitis B surface antigen and/or hepatitis B core antibody and/or positive for hepatitis C antibody

Any of the following:

Bleeding disorder or known platelet dysfunction at any time prior to the first screening visit
Platelet count less than 150,000/microL at the screening visit
Lymphocyte count less than 1000 cells/dL at the screening visit
Is HIV-positive
Has received any live (attenuated) vaccine (including but not limited to varicella zoster, oral polio, and nasal influenza) within 2 months before dosing

Has received any of the following medications/treatments within the specified time frame before baseline assessment:

Medication: Systemic corticosteroids, adrenocorticotropic hormone (other than used for premedication); Exclusionary if used/used within required wash-out period: 1 month prior to baseline MRI scan
Medication: Dimethyl fumarate; Exclusionary if used/used within required wash-out period: 6 months prior to dosing
Medication: Intravenous immunoglobulin, fingolimod, natalizumab; Exclusionary if used/used within required wash-out period: 6 months prior to dosing
Medication: Teriflunomide; Exclusionary if used/used within required wash-out period: 2 years prior to dosing or 1 month prior to dosing

if participant undergoes an accelerated elimination procedure and has documented teriflunomide plasma level below 0.02 mg/L

before dosing

Medication: Mildly to moderately immunosuppressive/chemotherapeutic medications such azathioprine and methotrexate; Exclusionary if used/used within required wash-out period: 6 months prior to dosing
Medication: Highly immunosuppressive/chemotherapeutic medications: mitoxantrone up to 120 mg/m2 body surface area, cyclophosphamide, cladribine; Exclusionary if used/used within required wash-out period: 2 years prior to dosing
Medication: Alemtuzumab; Exclusionary if used/used within required wash-out period: 4 years prior to dosing
Medication: Lymphoid irradiation, bone marrow transplantation, mitoxantrone (with evidence of cardiotoxicity following treatment, or cumulative lifetime dose >120 mg/m2), other strongly immunosuppressive treatments with very long-lasting effects; Exclusionary if used/used within required wash-out period: Any time
Medication: Any BTK inhibitor; Exclusionary if used/used within required wash-out period: Any time
Is receiving potent and moderate inducers and inhibitors of cytochrome P450 3A (CYP3A) or potent inhibitors of CYP2C8 hepatic enzymes.

Is receiving anticoagulant/antiplatelet therapies, including:

Acetylsalicylic acid (aspirin); half-life elimination: Parent drug: Plasma concentration: 15 to 20 minutes; Salicylates (dose dependent): 3 hours at lower doses (300 to 600 mg), 5 to 6 hours (after 1 g), 10 hours with higher doses
Antiplatelet drugs (eg, clopidogrel); half-life: 6 hours
Warfarin (vitamin K antagonist); half-life: 20-60 hours
Heparin, including low molecular weight heparin (antithrombin agents); half-life: 60-90 minutes
Dabigatran (direct thrombin inhibitor); half-life:12-17 hours
Apixaban (IV half-life: approximately 5 hours, oral half-life: approximately 12 hours), edoxaban (half-life: 10-14 hours), rivaroxaban (half-life: 5-9 or 11-13 hours in younger or elderly individuals, respectively) (direct factor Xa inhibitors)

Note: All above drugs need to be stopped at least 5 half-lives before study drug administration except for aspirin, which needs to be stopped at least 8 days before.

Has a history or presence of significant other concomitant illness that, according to the PI or MAI s judgment, would adversely affect participation in this study; examples include but are not limited to clinically significant cardiovascular, renal, hepatic, or metabolic

disease.

Acute liver disease, cirrhosis, chronic liver disease (unless considered stable for >6 months)
Has untreated hepatitis C
Has chronic hepatitis B unless stable on oral suppression and/or followed by a local hepatologist to monitor for reactivation
Has active alcohol use disorder
Has an alcohol intake greater than 2 drink per day for men, and greater than 1 drink per day for women (1 drink = approximately 14 grams of alcohol = 350 ml beer = 140 mL wine = 40 mL of spirits)
Has aspartate transaminase (AST) or alanine transaminase (ALT) levels greater than 1.5x ULN
Has a total bilirubin level greater than 1.5x ULN unless due to Gilbert s or non-liver related disorder
Has an alkaline phosphatase level greater than 2x ULN unless caused by non-liver related disorder or explained by a stable chronic liver disorder
At baseline, elevated transferrin saturation (>50% in males and >40% in females) and/or with elevated ferritin levels >500 microgram/L.
Unwilling to allow coded samples to be processed offsite
Unwilling to have coded samples and/or data saved or used in other studies.

Control Cohort Exclusion Criteria:

Pregnancy or lactation
MS relapse in the 6 months prior to baseline
Treatment with another investigational drug or other investigational intervention within 3 months prior to baseline
Contraindications for 7-tesla MRI

Has received any of the following medications/treatments within the specified time frame before baseline assessment:

Medication: Systemic corticosteroids, adrenocorticotropic hormone (other than used for premedication); Exclusionary if used/used within required wash-out period: 1 month prior to baseline MRI scan
Medication: Dimethyl fumarate; Exclusionary if used/used within required wash-out period: 6 months prior to dosing
Medication: Intravenous immunoglobulin, fingolimod, natalizumab; Exclusionary if used/used within required wash-out period: 6 months prior to dosing
Medication: Teriflunomide; Exclusionary if used/used within required wash-out period: 2 years prior to dosing or 1 month prior to dosing if participant undergoes an accelerated elimination procedure and has documented teriflunomide plasma level below 0.02 mg/L before dosing
Medication: Mildly to moderately immunosuppressive/chemotherapeutic medications such azathioprine and methotrexate; Exclusionary if used/used within required wash-out period: 6 months prior to dosing
Medication: Highly immunosuppressive/chemotherapeutic medications: mitoxantrone up to 120 mg/m2 body surface area, cyclophosphamide, cladribine; Exclusionary if used/used within required wash-out period: 2 years prior to dosing
Medication: Alemtuzumab; Exclusionary if used/used within required wash-out period: 4 years prior to dosing
Medication: Lymphoid irradiation, bone marrow transplantation, mitoxantrone (with evidence of cardiotoxicity following treatment, or cumulative lifetime dose >120 mg/m2), other strongly immunosuppressive treatments with very long-lasting effects; Exclusionary if used/used within required wash-out period: Any time
Medication: Any BTK inhibitor; Exclusionary if used/used within required wash-out period: Any time

Has a history or presence of significant other concomitant illness that, according to the PI or MAI s judgment, would adversely affect participation in this study; examples include but are not limited to clinically significant cardiovascular, renal, hepatic, or metabolic

disease.

Unwilling to allow coded samples to be processed offsite
Unwilling to have coded samples and/or data saved or used in other studies