Tolebrutinib for Primary Progressive Multiple Sclerosis

(PERSEUS Trial)

Not currently recruiting at 993 trial locations

Overseen By Trial Transparency email recommended (Toll free number for US & Canada)

Age: 18 - 65

Sex: Any

Trial Phase: Phase 3

Sponsor: Sanofi

Must not be taking: Anticoagulants, Antiplatelets, CYP3A inducers

Disqualifiers: HIV, Hepatitis, Tuberculosis, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 12 to 60 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new oral medication called Tolebrutinib to determine if it can slow disability progression in people with primary progressive multiple sclerosis (PPMS). Researchers aim to compare this drug to a placebo (a pill with no active medicine) in improving symptoms, brain scans, thinking skills, physical abilities, and overall quality of life. The trial will also assess the drug's safety and tolerability for participants. Individuals diagnosed with PPMS who have previously faced difficulties or unsuccessful results with ocrelizumab treatment might be suitable candidates for this trial. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial requires that participants stop taking certain medications, such as those for multiple sclerosis within a specified time frame, and those that affect liver enzymes or blood clotting. It's best to discuss your current medications with the trial team to see if any need to be stopped.

Is there any evidence suggesting that Tolebrutinib is likely to be safe for humans?

Research has shown that tolebrutinib is generally safe, as past studies have indicated. In earlier research, patients typically tolerated tolebrutinib well, with few serious side effects. These studies examined its use in conditions similar to primary progressive multiple sclerosis (PPMS).

One study focused on the long-term safety of tolebrutinib in individuals with relapsing forms of multiple sclerosis. It found that most participants experienced only mild to moderate side effects. Common side effects included headaches and some digestive issues, but these were not severe for most people.

While these findings are promising, treatments can affect individuals differently. Ongoing research will provide more detailed information about safety in people with PPMS. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for multiple sclerosis?

Unlike the standard treatments for primary progressive multiple sclerosis, which often focus on managing symptoms and slowing progression through immunosuppressants and disease-modifying therapies, Tolebrutinib targets a specific enzyme called Bruton's tyrosine kinase (BTK). This enzyme is involved in the activation of immune cells that contribute to the disease process. By inhibiting BTK, Tolebrutinib has the potential to more directly address the underlying immune mechanisms at play. Researchers are excited because this approach could offer a more targeted treatment option, potentially improving outcomes for patients with fewer side effects compared to the broader immune suppression seen with current therapies.

What evidence suggests that Tolebrutinib might be an effective treatment for primary progressive multiple sclerosis?

Research shows that tolebrutinib, also known as SAR442168, holds promise for treating multiple sclerosis (MS). Earlier studies found tolebrutinib effective in slowing the progression of disability in various MS types, including secondary progressive MS. It blocks a protein called BTK, which plays a role in the immune system and brain inflammation, potentially reducing nerve damage caused by the immune system. Early studies in similar MS types demonstrated that tolebrutinib can decrease the number of new brain lesions on MRI scans and improve patients' physical abilities and quality of life. Although more information is needed for primary progressive MS specifically, these early results are encouraging. Participants in this trial will receive either tolebrutinib or a placebo to evaluate its effectiveness in primary progressive MS. ^{1 2 6 7 8}

Who Is on the Research Team?

Clinical Sciences & Operations

Principal Investigator

Sanofi

Are You a Good Fit for This Trial?

This trial is for adults aged 18-55 with Primary Progressive Multiple Sclerosis (PPMS) as per the McDonald criteria, an EDSS score of 2.0 to 6.5, and a disease duration less than 15 years if severely disabled or less than 10 years if not. Participants must use contraception and cannot be pregnant or breastfeeding.

Inclusion Criteria

You have been diagnosed with primary progressive multiple sclerosis using specific criteria from 2017.

My MS symptoms started less than 15 years ago if my disability is severe, or less than 10 years if it's mild.

Participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: Is not a woman of child bearing potential (WOCBP) OR Is a WOCBP and agrees to use an acceptable contraceptive method

Exclusion Criteria

You have a history of alcohol or drug abuse within the last year before the screening.

I have not been hospitalized for a psychiatric condition in the last 2 years.

You have important abnormal results from blood tests or heart tests done before the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive SAR442168 or placebo once daily to evaluate efficacy and safety in delaying disability progression in PPMS

12 to 60 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Placebo
• Tolebrutinib

Trial Overview The study tests Tolebrutinib's effectiveness against a placebo in slowing down disability progression in PPMS patients. It also examines its impact on clinical outcomes, MRI lesions, cognitive function, physical ability, quality of life, safety/tolerability and how it moves through and acts in the body.

How Is the Trial Designed?

Group I: SAR442168 Experimental Treatment 1 Intervention

Dose 1 of oral SAR442168 once daily

Group II: Placebo Placebo Group 1 Intervention

Placebo to match the SAR442168 once daily

Who Is Running the Clinical Trial?

Sanofi

Lead Sponsor

Trials

2,246

Recruited

4,085,000+

Paul Hudson

Sanofi

Chief Executive Officer since 2019

Degree in Economics from Manchester Metropolitan University

Christopher Corsico

Sanofi

Chief Medical Officer

MD from Cornell University, MPH in Chronic Disease Epidemiology from Yale University

Published Research Related to This Trial

Tolebrutinib, a drug targeting Bruton's tyrosine kinase, is rapidly absorbed and extensively metabolized in the body, with 78% of the administered dose eliminated through feces.

One of its metabolites, M2, retains significant inhibitory activity against Bruton's tyrosine kinase, similar to the parent drug, suggesting that both tolebrutinib and M2 contribute to its therapeutic effects in treating inflammation related to multiple sclerosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Absorption, Metabolism, and Excretion of [14C]-Tolebrutinib After Oral Administration in Humans, Contribution of the Metabolites to Pharmacological Activity. Nicolas, O., Moliner, P., Soubayrol, P., et al.[2023]

Remibrutinib, a selective BTK inhibitor, effectively reduced neurological symptoms in mouse models of multiple sclerosis (MS) by inhibiting B cell-driven pathology and showing strong BTK occupancy in immune organs and the brain.

The drug demonstrated a dual mechanism of action: it inhibited pathogenic B cell activity without depleting B cells or broadly inhibiting T cells, while also exerting direct anti-inflammatory effects on microglia, suggesting it could be a promising new treatment for MS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Remibrutinib (LOU064) inhibits neuroinflammation driven by B cells and myeloid cells in preclinical models of multiple sclerosis. Nuesslein-Hildesheim, B., Ferrero, E., Schmid, C., et al.[2023]

Tirabrutinib, a second-generation Bruton's tyrosine kinase inhibitor, has been shown to maintain Karnofsky Performance Status (KPS) and improve quality of life (QoL) in patients with relapsed or refractory primary central nervous system lymphoma (r/r PCNSL) over a median follow-up of 14.9 months.

Patients experienced significant improvements in global health status and emotional functioning, indicating that tirabrutinib not only helps manage the disease but also enhances the overall well-being of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Karnofsky Performance Status and quality of life in patients with relapsed or refractory primary CNS lymphoma from a phase I/II study of tirabrutinib. Arakawa, Y., Narita, Y., Nagane, M., et al.[2023]

In a 16-week study involving 130 participants with relapsing multiple sclerosis, tolebrutinib demonstrated a dose-dependent reduction in new active brain lesions, with the highest efficacy observed at the 60 mg dose.

Tolebrutinib was well tolerated, with only one serious adverse event reported and no treatment-related deaths, suggesting it is a safe option for reducing inflammation in multiple sclerosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK inhibitor, in relapsing multiple sclerosis: a phase 2b, randomised, double-blind, placebo-controlled trial. Reich, DS., Arnold, DL., Vermersch, P., et al.[2023]

Tolebrutinib, a BTK inhibitor, was found to be well-tolerated in a first-in-human study involving multiple dose levels, with all treatment-related side effects being mild, indicating a favorable safety profile.

The drug effectively crosses the blood-brain barrier and shows significant BTK occupancy in both peripheral and central nervous system cells, suggesting its potential for targeting inflammation in various conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 clinical trial evaluating safety, exposure and pharmacodynamics of BTK inhibitor tolebrutinib (PRN2246, SAR442168). Owens, TD., Smith, PF., Redfern, A., et al.[2022]

Evobrutinib, a Bruton's tyrosine kinase inhibitor, was generally well tolerated across multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus trials, with similar rates of treatment-emergent adverse events (TEAEs) compared to placebo (66.2% vs 62.4%).

The analysis included data from 1083 patients across various trials, revealing that serious infections and liver enzyme elevations were comparable between evobrutinib and placebo, indicating a favorable safety profile for this medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterisation of the safety profile of evobrutinib in over 1000 patients from phase II clinical trials in multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus: an integrated safety analysis. Montalban, X., Wallace, D., Genovese, MC., et al.[2023]

Citations

1. icer.org icer.org/wp-content/uploads/2025/07/ICER_MS_Final-Report_For-Publication_071525.pdf

Tolebrutinib for Secondary Progressive Multiple Sclerosis We reviewed the clinical effectiveness of tolebrutinib for the treatment of non-relapsing SPMS compared to best supportive care, defined as ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04458051

NCT04458051 | Primary Progressive Multiple Sclerosis ... Primary Objective: To determine the efficacy of SAR442168 compared to placebo in delaying disability progression in primary progressive multiple sclerosis ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8434816/

Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK ... Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK inhibitor, in relapsing multiple sclerosis: a phase 2b, randomised, double-blind, placebo- ...

4. sanofistudies.com sanofistudies.com/cwout/CW-V9DEXS//au/en/listing/286397/primary-progressive-multiple-sclerosis/

Primary Progressive Multiple Sclerosis (PPMS) Study of ... This study investigates the effectiveness of an investigational medication compared to a placebo in delaying the progression of disability in individuals with ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8841436/

Phase 1 clinical trial evaluating safety, exposure and ... Tolebrutinib (PRN2246, SAR442168) is a potent BTK inhibitor that covalently binds the kinase, resulting in durable inhibition with the potential ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03996291

NCT03996291 | Long Term Safety and Efficacy Study of ... Primary Objective: To determine the long-term safety and tolerability of SAR442168 in RMS participants. Secondary Objective:.

7. sciencedirect.com sciencedirect.com/science/article/pii/S3050623925000574

Safety and efficacy of Bruton's tyrosine kinase inhibitors in ... Redfern, et al. Phase 1 clinical trial evaluating safety, exposure and pharmacodynamics of BTK inhibitor tolebrutinib (PRN2246, SAR442168).

8. thelancet.com thelancet.com/journals/laneur/article/PIIS1474-4422(21)00237-4/abstract

Safety and efficacy of tolebrutinib, an oral brain-penetrant ... Exclusion criteria included a diagnosis of primary progressive multiple sclerosis or a diagnosis of secondary progressive multiple sclerosis without relapse.