Tolebrutinib for Primary Progressive Multiple Sclerosis

(PERSEUS Trial)

Recruiting at 921 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

767 Participants Needed

Trial Summary

What is the purpose of this trial?

Primary Objective: To determine the efficacy of SAR442168 compared to placebo in delaying disability progression in primary progressive multiple sclerosis (PPMS) Secondary Objectives: To evaluate efficacy of SAR442168 compared to placebo on clinical endpoints, magnetic resonance imaging (MRI) lesions, cognitive performance, physical function, and quality of life To evaluate safety and tolerability of SAR442168 To evaluate population pharmacokinetics (PK) of SAR442168 in PPMS and its relationship to efficacy and safety To evaluate pharmacodynamics of SAR442168

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.

What data supports the effectiveness of the drug tolebrutinib for primary progressive multiple sclerosis?

Research shows that tolebrutinib, a drug that blocks an enzyme involved in inflammation, has been effective in reducing new active brain lesions in patients with relapsing multiple sclerosis, suggesting potential benefits for other forms of the disease. ^{1 2 3 4 5}

Is tolebrutinib safe for humans?

Tolebrutinib has been tested in humans and was generally well-tolerated, with any side effects being mild. It was studied in a trial where participants took different doses, and it showed a good safety profile. ^{1 2 3 6 7}

What makes the drug tolebrutinib unique for treating primary progressive multiple sclerosis?

Tolebrutinib is unique because it is an oral drug that can cross the blood-brain barrier to inhibit Bruton's tyrosine kinase, an enzyme involved in inflammation, directly in the central nervous system. This ability to target inflammation in the brain and spinal cord makes it different from many other treatments for multiple sclerosis. ^{1 2 3 5 8}

Research Team

Clinical Sciences & Operations

Principal Investigator

Sanofi

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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 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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Phase 1 clinical trial evaluating safety, exposure and pharmacodynamics of BTK inhibitor tolebrutinib (PRN2246, SAR442168). [2022]

2. England 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. [2023]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Absorption, Metabolism, and Excretion of [14C]-Tolebrutinib After Oral Administration in Humans, Contribution of the Metabolites to Pharmacological Activity. [2023]

4. England 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. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Antibody response to SARS-CoV-2 vaccines in patients with relapsing multiple sclerosis treated with evobrutinib: A Bruton's tyrosine kinase inhibitor. [2023]

6. England 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. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Remibrutinib (LOU064) inhibits neuroinflammation driven by B cells and myeloid cells in preclinical models of multiple sclerosis. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Masitinib in Progressive Forms of Multiple Sclerosis: A Randomized, Phase 3, Clinical Trial. [2022]