What Is Tolebrutinib?
Tolebrutinib is an investigational drug being studied for its potential in treating various forms of multiple sclerosis. It is designed for oral administration, commonly in the form of a tablet or film-coated tablet. While specific details on its mechanism of action are not provided in the trial descriptions, its development focuses on neurological conditions. Clinical trials are exploring its efficacy and safety across different types of multiple sclerosis, including relapsing and progressive forms.
Research into Tolebrutinib involves a significant number of studies. A total of 11 clinical trials have been conducted, with 9 of these completed. These trials have collectively enrolled 6,541 participants. The earliest study began on June 24, 2019, and the most recent trial commenced on April 17, 2024. The primary sponsor for these investigations is Sanofi, with one trial also supported by the National Institute of Neurological Disorders and Stroke (NINDS).
Uses and Conditions Under Study
Tolebrutinib is primarily under investigation for the treatment of multiple sclerosis (MS) and its various subtypes. Multiple sclerosis is a chronic disease affecting the brain and spinal cord, leading to a range of symptoms such as fatigue, numbness, and problems with vision, balance, and muscle control. The drug is being studied to potentially modify the disease course in patients with MS.
Specifically, Tolebrutinib has been studied in:
- Relapsing Multiple Sclerosis: This is the most common form of MS, characterized by periods of new or worsening symptoms (relapses) followed by periods of recovery. Four trials have investigated Tolebrutinib for this condition.
- Multiple Sclerosis (general): Three trials have broadly focused on multiple sclerosis without specifying a subtype, likely encompassing various forms of the disease.
- Progressive Forms of Multiple Sclerosis: This includes Primary Progressive Multiple Sclerosis (PPMS), where symptoms gradually worsen from the outset, and Secondary Progressive Multiple Sclerosis (SPMS), which follows an initial relapsing-remitting course. Tolebrutinib has been studied in one trial for PPMS, one trial for Progressive Relapsing Multiple Sclerosis, one trial for SPMS, and one trial for Non-relapsing Secondary Progressive Multiple Sclerosis. These studies aim to determine if the drug can slow disease progression in these challenging forms of MS.
Beyond its potential therapeutic uses, Tolebrutinib has also been studied in conditions related to drug metabolism and safety. One trial investigated its effects in individuals with Renal Impairment, while another one trial examined its behavior in those with Hepatic Function Abnormal. These pharmacokinetic studies help understand how the drug is processed in the body under different physiological conditions, which is crucial for determining appropriate dosing and identifying potential safety concerns.
Dosing
Tolebrutinib is designed for oral administration and has been studied in various forms, primarily as a tablet or film-coated tablet. The specific strengths and dosing regimens have been explored across its clinical development program.
One specific strength mentioned in the trial descriptions is 60 mg orally. However, clinical trials have investigated Tolebrutinib in several different study arms and cohorts, indicating a range of dosing strategies. These include:
- Tolebrutinib (Cohort A)
- Tolebrutinib (cohort B)
- Tolebrutinib (initial cohort)
- SAR442168 (an investigational code for Tolebrutinib)
- Part 1a, Part 1b, Part 1c, Part 1d, Part 2 (referring to different phases or segments of studies)
- Cohort 1, Cohort 2
In addition to studies focusing on the drug itself, Tolebrutinib has also been investigated in comparison with other medications or in specific patient populations. These include studies involving Teriflunomide, a mild hepatic impairment group, a normal hepatic function group, a severe Renal Impairment (RI) group (Part A only), a normal Renal Function group (Part A and B), and a moderate RI group (Part B only conditional). These diverse study designs help to understand how Tolebrutinib's dosing might need to be adjusted based on individual patient characteristics or when used alongside other treatments.
Side Effects
In a clinical trial involving 872 participants taking Tolebrutinib, the most commonly reported side effect was urinary tract infection.
- 10.8% of patients taking Tolebrutinib experienced urinary tract infection, compared to 14.0% on placebo.
- 8.9% of patients taking Tolebrutinib experienced nasopharyngitis (common cold), compared to 6.2% on placebo.
- 6.7% of patients taking Tolebrutinib experienced headache, compared to 6.4% on placebo.
- 5.8% of patients taking Tolebrutinib experienced joint pain (arthralgia), compared to 4.2% on placebo.
- 5.7% of patients taking Tolebrutinib experienced back pain, compared to 5.5% on placebo.
- 5.3% of patients taking Tolebrutinib experienced influenza (flu), compared to 3.3% on placebo.
These side effects were reported in at least 5% of participants taking Tolebrutinib and more frequently than in those taking placebo, or were among the most common overall.
Clinical Trial Results
Studies have evaluated Tolebrutinib in participants with relapsing and nonrelapsing secondary progressive forms of multiple sclerosis.
Long-Term Safety and Efficacy in Relapsing Multiple Sclerosis (NCT03996291)
This long-term study assessed various doses of Tolebrutinib in participants with relapsing multiple sclerosis. The annualized relapse rate (ARR), which measures the average number of relapses per year, was lowest in the Tolebrutinib 60/60 mg group at 0.23 relapses per participant year. Other doses showed ARRs of 0.24 (15/60 mg), 0.28 (30/60 mg), and 0.26 (5/60 mg). Regarding disability progression, the Tolebrutinib 5/60 mg group showed a mean improvement of -0.10 on the Expanded Disability Status Scale (EDSS) score at Week 240, indicating reduced disability. The mean number of new Gd-enhancing T1-hyperintense lesions, which indicate active inflammation, was lowest at 0.13 lesions for the Tolebrutinib 60/60 mg group at Week 240 relative to Week 192. The mean number of new or enlarging T2 lesions per month was lowest in the Tolebrutinib 30/60 mg group at 0.15 lesions.
GEMINI 1 Study in Relapsing Forms of Multiple Sclerosis (NCT04410978)
In this study comparing Tolebrutinib 60 mg to Teriflunomide 14 mg, the annualized relapse rate was 0.130 relapses per participant year for Tolebrutinib, compared to 0.122 for Teriflunomide. Tolebrutinib led to a greater reduction in CD19+ B cells, with a median change from baseline of -60.500 cells/microliter, compared to -45.000 cells/microliter for Teriflunomide. Participants on Tolebrutinib experienced less brain volume loss, with a -0.688% change compared to -0.884% for Teriflunomide at the end of study relative to Month 6. The median time to onset of 3-month confirmed disability worsening was 14.93 months for Tolebrutinib, compared to 17.96 months for Teriflunomide.
GEMINI 2 Study in Relapsing Forms of Multiple Sclerosis (NCT04410991)
This study also compared Tolebrutinib 60 mg to Teriflunomide 14 mg. The annualized relapse rate for Tolebrutinib was 0.108 relapses per participant year, which was very similar to Teriflunomide at 0.109 relapses. Tolebrutinib showed a -0.696% change in brain volume loss, indicating less loss compared to Teriflunomide at -0.740% at the end of study relative to Month 6. The median time to onset of 3-month confirmed disability worsening was 12.11 months for both Tolebrutinib and Teriflunomide.
HERCULES Study in Nonrelapsing Secondary Progressive Multiple Sclerosis (NCT04411641)
In this study, Tolebrutinib 60 mg was compared to placebo. Tolebrutinib significantly reduced CD19+ B cells, with a median change from baseline of -63.000 cells/microliter, while placebo showed an increase of 10.000 cells/microliter. The mean number of new and/or enlarging T2-hyperintense lesions per year was lower in the Tolebrutinib group at 1.835 lesions, compared to 2.948 lesions in the placebo group. Brain volume loss was also less pronounced with Tolebrutinib, showing a -0.694% change compared to -0.776% for placebo at the end of study relative to Month 6. The median time to onset of 3-month confirmed disability progression was 12.04 months for Tolebrutinib, slightly longer than 11.96 months for placebo.
Modulation of Chronically Inflamed White Matter Lesions (NCT04742400)
This study investigated the disappearance of paramagnetic rim lesions at 48 weeks with Tolebrutinib 60 mg. Neither the Tolebrutinib cohort nor the Anti-CD20 cohort showed disappearance of these lesions (0 participants in both groups).