Tolebrutinib is an investigational oral therapy being developed to treat relapsing and progressive forms of multiple sclerosis (MS).
The therapy (formerly known as SAR442168 and PRN2246) was originally discovered by Principia Biopharma, but the company was acquired by Sanofi in 2020. Sanofi is now leading the development of tolebrutinib.
MS is an autoimmune condition in which the immune system erroneously launches an attack against healthy parts of the brain and spinal cord, leading to progressive nerve cell death and a range of neurological symptoms.
Tolebrutinib is an oral and selective small molecule inhibitor of the Bruton tyrosine kinase (BTK) enzyme, which is critical for the activity of multiple immune cell types involved in MS progression.
In particular, BTK is essential for the survival and activation of B-cells, the cells responsible for making antibodies, which are believed to be major drivers of inflammation in relapsing forms of MS. But notably, this enzyme also regulates the activation of cells of the innate immune system, including microglia, which are thought to have a more prominent role in progressive forms of MS.
These cells are not exclusive to one form of MS: B-cells also contribute to disease progression in progressive forms of MS, while innate immune cells have been found in lesions from relapsing MS patients.
By inhibiting BTK, tolebrutinib may meaningfully reduce the inflammatory activity that drives the progression of both relapsing and progressive forms of MS.
Importantly, tolebrutinib has the ability to cross the blood-brain barrier, a semi-permeable membrane that regulates which substances are able to pass from the blood into the brain and spinal cord. While multiple BTK inhibitors are in development for MS, animal studies suggest that tolebrutinib has superior brain penetration and potency compared with other therapies of the same class.
Tolebrutinib is an oral medication available in the form of film-coated tablets. In a Phase 2 clinical trial, participants were given the medication at doses ranging from 5 to 60 mg per day for about three months. A 60 mg dose, taken orally once a day, is now being tested in four Phase 3 trials.
The first-in-human clinical trial of tolebrutinib involved 94 healthy volunteers. Each received either a single tablet of treatment (ranging from 5 to 120 mg), a daily tablet for 10 days, or a placebo.
The promising safety and pharmacological findings from this study prompted Sanofi to launch additional trials.
A Phase 2b clinical trial (NCT03889639) enrolled 130 adults with relapsing forms of MS. Of them, two had active secondary progressive disease (SPMS), while the rest had relapsing-remitting MS (RRMS).
Participants were assigned to two groups. One received daily treatment with tolebrutinib at one of four doses — 5, 15, 30, or 60 mg — for 12 weeks, or about three months, followed by four weeks of a placebo. The other group was first given a placebo for four weeks followed by 12 weeks of tolebrutinib.
Results showed that the highest dose of tolebrutinib (60 mg) significantly reduced the appearance of new inflammatory brain lesions by 85%. After 12 weeks on this dose, only 10% of patients had new inflammatory lesions. Conversely, after four weeks on the placebo, 25% of patients in the second group had new brain lesions with active inflammation. The data also showed that the 60 mg dose was best at lowering the total number of new or enlarging brain lesions. It did so by 89% compared with the placebo.
The experimental medicine was overall well tolerated; the one serious side effect reported was a severe MS relapse.
Of the 129 participants who finished the original study, 125 chose to enroll in an ongoing open-label extension (NCT03996291). All of these patients continued to receive their assigned dose and were then switched to the 60 mg dose after it was selected for testing in the Phase 3 trials.
After 18 months, the number of new inflammatory brain lesions for these patients remained low, the results showed. Moreover, those who switched from the lower doses to the 60 mg experienced a reduction in active lesions to values similar to those of patients who had been on the highest dose from the start. Across groups, disability scores remained relatively stable, and relapse rates with the 60 mg dose were low — 0.17 relapses per year compared with 1.23 in the year prior to enrolling in the Phase 2b trial.
Sanofi is running four Phase 3 clinical studies — dubbed GEMINI 1, GEMINI 2, HERCULES, and PERSEUS — evaluating the efficacy and safety of tolebrutinib in relapsing and progressive forms of MS. All are presently enrolling at hundreds of locations worldwide, and Sanofi has created a website to help potential participants connect with trials for which they may be eligible.
The identically designed GEMINI 1 (NCT04410978) and GEMINI 2 (NCT04410991) trials aim to enroll a combined total of 1,800 adults with relapsing forms of MS, including RRMS and active SPMS.
Participants will be randomly assigned to treatment for three years with either a 60 mg daily dose of tolebrutinib or a standard dosage (14 mg/day) of Aubagio (teriflunomide), an approved oral MS therapy sold by Sanofi. The main goal is to assess the impact of treatment on relapse rates, but secondary measures include disability progression and improvement, as well as changes in brain lesions, brain volume, cognition, and quality of life. The studies are expected to conclude in 2023.
The other two trials are testing tolebrutinib against a placebo in people with non-relapsing forms of MS. HERCULES (NCT04411641) aims to enroll 1,290 adults, up to age 60, with non-active SPMS — meaning no relapses in the prior two years. Meanwhile, PERSEUS (NCT04458051) will involve about 990 patients, ages 18–55, with primary progressive MS (PPMS).
In both studies, participants will be treated for about four years, and the main goal is to assess the impact of treatment on disability progression, as measured with the Expanded Disability Status Scale (EDSS). Other outcome measures in both trials include changes in walking ability and hand dexterity, disability improvements, and brain volume loss. Changes in cognitive function and quality of life also will be assessed in each of the studies. Both trials are expected to end in 2024.
One Phase 2 trial (NCT04742400) now enrolling is sponsored by the National Institute of Neurological Disorders and Stroke, known as NINDS. It is seeking 30 adults with MS who are being treated with Ocrevus (ocrelizumab) or rituximab. Participants will switch to treatment with tolebrutinib, at a daily dose of 60 or 120 mg, for at least 96 weeks. The main goal is to evaluate the effect of tolebrutinib on chronically active brain lesions that are not resolved with currently approved MS therapies.
The most common side effects of tolebrutinib reported in MS clinical trials were:
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Tolebrutinib is an experimental therapy that is still being tested in multiple sclerosis patients in clinical trials. The oral medication is designed to block the activity of Bruton’s tyrosine kinase (BTK), a protein that is essential to the inflammatory activity of certain immune cells, such as B-cells and microglia. This is expected to reduce the inflammation that contributes to progressive nerve cell death in MS. One early study suggests tolebrutinib may be more potent than other therapies in its class.
Testing of tolebrutinib for multiple sclerosis is now ongoing in four Phase 3 clinical trials, which are large studies designed to assess a treatment’s efficacy. There are two studies for relapsing forms of MS, both expected to end in August 2023, and another two trials in progressive types of MS, expected to be completed in August 2024. If results from these studies are positive, they may support regulatory applications seeking the approval of tolebrutinib for MS. However, it currently is too early to know if or when the medication might be approved.
Clinical trials of tolebrutinib have not included, and are not enrolling, pregnant or breastfeeding patients. All participants who have the capacity to reproduce are required to use effective contraception methods to avoid the possibility of conceiving a child while on treatment. Consequently, it is unclear whether tolebrutinib can be safely taken during pregnancy or while nursing.
In one study, patients began seeing benefits of tolebrutinib about 90 days after starting treatment. That Phase 2 clinical trial enrolled people with relapsing forms of multiple sclerosis. A significant reduction in the number of inflammatory brain lesions became evident with tolebrutinib versus a placebo in about three months in the patients treated.
Hair loss has been reported as a side effect of tolebrutinib in a multiple sclerosis Phase 2 trial. Weight gain, however, was not among the adverse events reported in the study. Patients who experience unexpected effects of medications should consult their healthcare teams.
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