Exploring the Potential of BTK Inhibitors in Primary Progressive MS: The PERSEUS Trial

Previous research has shown that primary progressive multiple sclerosis (PPMS) impacts about 10% to 15% of individuals with MS, where the disease can lead to a gradual increase in disability over time.¹ The clinical course of PPMS differs widely among patients, some may experience radiological activity while others do not, and progression may or may not even occur in some patients.² A prior study reported that in 2 to 5 years of onset, 21.4% and 32.8% of patients with PPMS, respectively, developed moderate disability, while 3.3% and 14.1% progressed to severe disability. Interestingly, 4.7% of patients showed no progression to moderate disability even after 20 years.³

Despite the limited current treatment landscape for PPMS, several emerging clinical trials are aiming to develop a therapy for patients affected by this autoimmune disease. The ongoing phase 3, randomized, double-blind, PERSEUS phase 3 study (NCT04458051) currently assesses Sanofi’s investigational Bruton’s tyrosine kinase (BTK) inhibitor tolebrutinib among patients with PPMS, with results anticipated in the second half of 2025. The primary objective of the study tests the efficacy of tolebrutinib in delaying disability progression relative to a placebo cohort.

For the secondary objectives of the trial, researchers will investigate the efficacy of tolebrutinib compared with placebo on clinical end points, MRI lesions, cognitive performance, physical function, and quality of life. Investigators will also evaluate the safety and tolerability as well as the population pharmacokinetics of tolebrutinib in PPMS and its relationship to efficacy and safety. Additionally, the study will assess the pharmacodynamics of tolebrutinib among participants. The duration of the trial will vary by each participant, with a treatment duration of approximately 12 to 60 months. As of currently, the study has 277 locations.

Bruce Cree, MD, PhD, MAS, FAAN

(Credit: UCSF Health)

“MS effects multiple aspects of patients’ lives beyond what is measured by the Kurtzke/Neurostatus expanded disability status scale (EDSS). Understanding the therapeutic effect of a drug on cognitive impairment, which is a major sources of disability that is not well measured by the EDSS, is equally important. Brain MRI measures of new lesion formation and volumetric changes that are a consequence of brain atrophy is also important for helping understand a treatment’s effect,” PERSEUS trial investigator Bruce Cree, MD, PhD, MAS, FAAN, clinical research director of the UCSF Multiple Sclerosis Center, told NeurologyLive^®. “Quantitative brain MRI measures complement what we learn from clinical assessments of disability and cognitive dysfunction. Some aspects of MS, such as pain and fatigue, are cannot be measured objectively and therefore patient reported outcomes that look at quality of life aid are our only way into understanding these important but uniquely subjective aspects of living with MS.”

Eligible participants are patients aged 18 to 55 with a diagnosis of PPMS according to the 2017 McDonald criteria and an EDSS score between 2.0 and 6.5. Participants must have positive cerebrospinal fluid oligoclonal bands or an elevated Immunoglobulin G (IgG) index, either during screening or in previous documentation.Participants must not be pregnant or breastfeeding and must either be a patient of childbearing potential using an approved contraceptive method or not be of childbearing potential. Additionally, participants must not have access to ocrelizumab or, if available, must either have experienced adverse effects, safety concerns, or failed to respond to ocrelizumab treatment.

Participants will be excluded if they have conditions that may affect study participation, such as short life expectancy, active infections (e.g., HIV, hepatitis, tuberculosis), chronic infections, recent malignancy, or alcohol/drug abuse. Other exclusions include significant lab or ECG abnormalities, bleeding disorders, low platelet count, or abnormal lymphocyte counts. Recent live vaccines, major surgery, or MS treatments in specified timeframes, as well as certain medications (e.g., cytochrome P450 inducers, anticoagulants), and contraindications to MRI, will also disqualify participants.

“The biggest challenge for this study was finding participants. PPMS represents only 5-10% of MS patients. In the USA and much of Western Europe, ocrelizumab is available for PPMS treatment. Therefore, finding individuals who were willing to participate in a placebo-controlled trial posed a major logistic challenge,” Cree said in a recent interview. “Study participants could be recruited from countries where ocrelizumab was not available or in countries where ocrelizumab is available for PPMS, participants who did not respond to ocrelizumab or who could not obtain ocrelizumab due to under-insurance could be recruited. Furthermore, that another BTKi (fenebrutinib) was also recruiting PPMS for a head-to-head trial versus ocrelizumab introduced competition for potential participants.”

Tolebrutinib is an oral, brain-penetrant, and bioactive BTK inhibitor that targets B cells and microglia, having the potential to modulate both peripheral and central pathologic processes in MS that lead to disability accumulation. To date, the investigational BTK inhibitor has been assessed in other clinical trials including for patients with non-relapsing secondary progressive MS (nrSPMS) and relapsing MS.

“Assuming that the PERSEUS study achieves success on the primary end point and shows that tolebrutinib is effective in preventing disability worsening in PPMS, then the additional clinical and imaging endpoints will help patients and clinicians understand the overall therapeutic effect of treatment,” Cree said. “A key unanswered question will be how does the PERSUS study of tolebrutinib compare with the ORATORIO study of ocrelizumab in PPMS? Comparing across trials is particularly challenging in MS because of high degrees in variability of the populations under study. Differences in inclusion/exclusion criteria as well as the potential for spectrum bias (an overall shift in the characteristics of the population under study due to other factors) will make the comparison of PERSEUS to ORATORIO particularly challenging.”

“Nonetheless, if tolebrutinib is approved for treatment in PPMS, I suspect that we will see a substantial group of individuals who were treated with ocrelizumab, but who have continued to progress despite treatment, be interested in switching to tolebrutinib.Unfortunately, tolebrutinib is associated with a risk of serious liver injury. In the clinical trial program, adjustments had to be made for monitoring liver functions during the first 90 days of treatment,” Cree added. “I suspect that similar intensive monitoring will be necessary in practice. Hopefully the study sponsor understands the need to help support clinicians and their patients with these vitally important safety assessments so that the medication can be transitioned smoothly from the clinical trial setting into clinical practice.”

Presented at the 2024 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress, held September 18-20, late-breaking results from the phase 3 HERCULES trial (NCT04411641) showed that tolebrutinib had a significant effect on disability accumulation compared with placebo in patients with nrSPMS.^4,5 In the trial, findings showed that tolebrutinib delayed the time to onset of 6-month confirmed disability progression (CDP), the primary end point, by 31% compared with placebo (HR, 0.69; 95% CI, 0.55-0.88; P = .0026) in this patient population. In addition, the number of patients who experienced confirmed disability improvement, another secondary end point, increased by nearly 2-fold, 10% for those treated with tolebrutinib compared with 5% those in the placebo group (HR, 1.88; 95% CI, 1.10-3.21; nominal P = .021).

HERCULES comprised of 1131 patients aged between 18 to 60 years with nrSPMS (mean age was, 48.9 years; women, 62%) and Expanded Disability Status Scale (EDSS) score of 3.0–6.5. Eligible participants also had inclusive, documented proof of disability progression in the prior 12 months and no clinical relapses in the prior 24 months before screening. In the study, investigators randomized participants 2:1 to receive 60-mg once daily oral tolebrutinib or matching placebo. The primary end point of the trial was time to onset of 6-month CDP, as measured by EDSS, and secondary end points included other measures of disability, MRI outcomes and safety.

Additional late-breaking data of tolebrutinib from the phase 3 GEMINI 1 (NCT04410978) and GEMINI 2 (NCT04410991) trials at ECTRIMS 2024 showed that the treatment failed to meet its primary end point of reducing annualized relapse rate (ARR) in comparison with teriflunomide (Aubagio; Sanofi). Although, importantly, the trials did show positive data on a key secondary end point of pooled 6-month CDW, significantly delaying the time to onset of worsening. All told, on the primary end point of ARR, the pooled data from the 2 trials indicated no significant difference between the teriflunomide group (n = 940) and the tolebrutinib-treated group (n = 933), both of which recorded rates of 0.12.^6,7

The overall ARR rate ratio was 1.03 (95% CI, 0.84-1.25; P = .80). In GEMINI 1, those respective rates for the teriflunomide group (n = 488) and the tolebrutinib group (n = 486) were 0.12 and 0.13, respectively, for an ARR rate ratio of 1.06 (95% CI, 0.81-1.39; P = 0.67). Likewise, in GEMINI 2, the rates for the teriflunomide group (n = 452) and the tolebrutinib group (n = 447) were both 0.11, respectively, for an ARR rate ratio of 1.00 (95% CI, 0.75-1.32; P = .98).

Regarding the secondary end points of time to 6-month CDW, the pooled data showed a 29% risk reduction (HR, 0.71; 95% CI, 0.53-0.95; P = .023) for the tolebrutinib group (9.9%) compared with the teriflunomide group (13.2%). When exploring time to 3-month CDW, there was a 27% risk reduction (HR, 0.73; 95% CI, 0.57-0.94; P = .018) for the tolebrutinib group (14.7%) compared with the teriflunomide group (18.5%).

REFERENCES
1. Thompson AJ, Carroll W, Ciccarelli O, et al. Charting a global research strategy for progressive MS-An international progressive MS Alliance proposal. Mult Scler. 2022;28(1):16-28. doi:10.1177/13524585211059766
2. Gurevich M, Zilkha-Falb R, Sherman J, et al. Machine learning-based prediction of disease progression in primary progressive multiple sclerosis. Brain Commun. 2025;7(1):fcae427. Published 2025 Jan 8. doi:10.1093/braincomms/fcae427
3. Achiron A, Dreyer-Alster S, Gurevich M, et al. Definitions of primary-progressive multiple sclerosis trajectories by rate of clinical disability progression. Mult Scler Relat Disord. 2021;50:102814. doi:10.1016/j.msard.2021.102814
4. Fox RJ, Bar-Or A, Traboulsee A, et al. Efficacy and Safety of Tolebrutinib Versus Placebo in Non-Relapsing Secondary Progressive Multiple Sclerosis: Results from the Phase 3 HERCULES Trial. Presented at: 2024 ECTRIMS; September 18-20; Copenhagen, Denmark. Abstract 4027.
5. Tolebrutinib demonstrated a 31% delay in time to onset of confirmed disability progression in non-relapsing secondary progressive multiple sclerosis phase 3 study. News Release. Sanofi. Published September 20, 2024. Accessed January 29, 2025. https://www.sanofi.com/en/media-room/press-releases/2024/2024-09-20-09-30-00-2949552
6. Oh J, Arnold DL, Cree BAC, et al. Efficacy and Safety of Tolebrutinib Versus Teriflunomide in Relapsing Multiple Sclerosis: Results from the Phase 3 GEMINI 1 and 2 Trials. Presented at: ECTRIMS Congress; September 18-20, 2024; Copenhagen, Denmark. Abstract 4026/O135
7. Tolebrutinib meets primary endpoint in HERCULES phase 3 study, the first and only to show reduction in disability accumulation in non-relapsing secondary progressive multiple sclerosis. News release. Sanofi. September 2, 2024. Accessed January 29, 2025. https://www.sanofi.com/en/media-room/press-releases/2024/2024-09-02-05-00-00-2938875