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Sanofi observed a dose-response relationship based on reduction of new active gadolinium-enhancing T1-hyperintense lesions after 12 weeks of treatment with SAR442168.
John Reed, MD, PhD
Sanofi has announced promising topline results from its phase 2b study of SAR442168 for the treatment of relapsing multiple sclerosis (RMS).1
The oral, brain-penetrant, selective small molecule that inhibits Bruton’s tyrosine kinase (BTK) significantly reduced MS disease activity as measured by brain lesions on MRI. Detailed results will be presented at a later medical meeting.
“This molecule may be the first B-cell-targeted MS therapy that not only inhibits the peripheral immune system, but also crosses the blood-brain barrier to suppress immune cells that have migrated into the brain, while also modulating the brain-resident microglia cells that have been implicated in MS progression,” said John Reed, MD, PhD, Sanofi’s global head of research and development, in a statement.1 “We are encouraged by these clinical results and look forward to rapidly advancing our brain-penetrant BTK inhibitor into pivotal clinical trials.”
Given the results, Sanofi plans to initiate 4 phase 3 clinical trials in patients with RMS and progressive MS, beginning later this year. The trials will explore the drug’s effect on MS relapse rates, disability progression, and central nervous system damage associated with MS.
The phase 2b study (NCT03889639) was a randomized, double-blind, placebo-controlled, cross-over, 12-week dose-ranging trial that included 120 patients, 60 of whom were initially randomly assigned to receive 1 of 4 doses of the study drug for 12 weeks before crossing over to placebo for an additional 4 weeks. The remaining 60 patients received placebo for 4 weeks and then crossed over to the study drug.
Sanofi said that they observed a dose-response relationship based on reduction of new active gadolinium-enhancing T1-hyperintense brain lesions after 12 weeks of treatment with SAR442168. The dose used in the upcoming phase 3 studies will be determined using the dose-response curve observed in this trial.1
In addition, patients who completed the week 16 visit will be eligible to enroll in a long-term safety study.
SAR442168 isn’t the only BTK inhibitor being explored in MS. Last year, Merck/EMD Serono reported promising results from their phase 2 study of evobrutinib at the AAN Annual Meeting, suggesting that the investigational therapy can significantly reduce relapse rates and brain lesions in patients with MS compared with placebo over 48 weeks.2
In that trial, 267 patients were randomly assigned to one of 5 groups: 3 groups were given evobrutinib either 25 mg once daily, 75 mg once daily, or 75 mg twice daily; the 4th group was given placebo; and the 5th group was given dimethyl fumarate.
Patients who received evobrutinib 75 mg once or twice daily saw significant and rapid reductions in the number of gadolinium-enhancing T1 lesions by week 12, with those reduction maintained through week 48. In addition, 79% of patients assigned to receive the 75 mg dose twice daily remained relapse free over 48 weeks of treatment, with an annualized relapse rate of 0.11 (0.04-0.25).2
Based on these results, 2 pivotal phase 3 trials have been launched in relapsing MS: EVOLUTION RMS1 (NCT04032158) and EVOLUTION RMS2 (NCT04032171), which are identical in design. The trials will enroll up to 950 participants each who will be randomly assigned to either 75 mg evobrutinib twice daily or interferon beta-1a (Avonex; Biogen). The primary end point will be annualized relapse rate at 96 weeks of treatment.3
1. Sanofi brain-penetrant BTK inhibitor meets primary endpoint of Phase 2 trial in relapsing multiple sclerosis [news release]. Paris, France: Sanofi. February 6, 2020. sanofi.com/en/media-room/press-releases/2020/2020-02-06-07-00-00. Accessed February 6, 2020.
2. Montalban X, Arnold DL, Weber MS, et al. Placebo-controlled trial of an oral BTK inhibitor in multiple sclerosis. N Engl J Med. Published online May 10, 2019. doi: 10.1056/NEJMoa1901981.
3. Positive Phase II Data Further Highlights Clinical Proof of Concept for Evobrutinib, First Oral Bruton´s Tyrosine Kinase (BTK) Inhibitor to Report Positive Phase II Clinical Results in MS [news release]. Darmstadt, Germany: Merkc KGaA. Published May 10, 2019. emdgroup.com/en/news/pp2-data-further-highlights-clinical-proof-of-concept-for-evobrutinib-10-05-2019.html. Accessed January 6, 2020.