FDA Places Partial Hold on Evobrutinib Initiation in Newly Enrolled Patients With MS


Evobrutinib, a highly selective BTK inhibitor, has previously demonstrated positive impacts on relapse rates and neurofilament light in patients with relapsing multiple sclerosis.

Because of safety concerns, the FDA has placed a partial clinical hold on the initiation of evobrutinib (EMD Serono), an investigational Bruton’s tyrosine kinase (BTK) inhibitor, in new patients and those with less than 70 days of exposure. EMD Serono noted that this decision does not impact the status of the ongoing phase 3 EVOLUTION trial program, which is fully enrolled, with results still expected to be read out in the fourth quarter of 2023.1

The decision to stop dosing stemmed from an assessment of 2 recently reported cases of laboratory values suggestive of drug-induced liver injury that have been identified during the phase 3 studies—EVOLUTION RMS 1 (NCT04338022) and EVOLUTION RMS 2 (NCT04338061). Both patients were asymptomatic, did not need any medical intervention or hospitalization for the condition, and liver enzymes fully normalized after discontinuation of the study medication.

Evobrutinib, a highly selective, central nervous system-penetrant agent, will continue to be closely monitored by an Independent Data Monitoring Committee in the phase 3 program. Additionally, Merck KGaA, Darmstadt, Germany, will work closely with the FDA to establish the best path forward for the future trials of evobrutinib.

This was not the first time safety concerns halted a BTK inhibitor’s clinical program. Earlier this year, Sanofi announced it was discontinuing its phase 3 URSA study (NCT05132569) assessing its BTK inhibitor tolebrutinib as a potential treatment for myasthenia gravis, citing drug-induced liver injury as the reason for it. At the time, the company announced completed enrollment for its phase 3 HERCULES study assessing the agent in nonrelapsing progressive multiple sclerosis (MS).2

Just recently, new data from a preclinical assessment of evobrutinib demonstrated superior efficacy compared with anti-CD20 treatment for targeting compartmentalized neuroinflammation in multiple sclerosis (MS).3 The findings supported the BTK inhibitor as a promising therapy for persistently targeting neuroinflammation and disease progression in MS. They were presented in a poster at the annual Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum held February 23-25, 2023, in San Diego, California, by senior author Jorge Alvarez, BSc, PhD, assistant professor, University of Pennsylvania School of Veterinary Medicine.

In that assessment, evobrutinib reduced both disease severity (65% reduction; P <.0001) and immunopathological parameters of disease (56% reduction; P <.01) in progressive-like experimental autoimmune encephalitis mice (pEAE) compared with anti-CD20 (clone: SA271G2) treatment. The favorable effects of evobrutinib paralleled with a significant gain in body weight and decrease in cumulative disease score in comparison with anti-CD20 treatment (54% disease score reduction; P <.001).3

Evobrutinib’s effect was demonstrated in a phase 2 study (NCT02975349) and its open-label extension (OLE), which were presented at the 2022 Consortium of Multiple Sclerosis Centers (CMSC) Annual Meeting. Following a double-blind 48-week treatment period, the agent showed an acceptable tolerability, as well as maintained efficacy over a 2.5-year period in patients with relapsing MS. All, told, the annualized relapse rate at the end of the OLE was 0.12 (95% CI, 0.07-0.20) for patients who received evobrutinib 75 mg twice daily.4

Later that year, at the 2022 European Committee for Treatment and Research in Multiple Sclerosis Congress, data from the trial and its OLE highlighted evobrutinib’s impact on neurofilament light (NfL), a marker of neuroaxonal damage. All told, evobrutinib decreased neurofilament (NfL) levels in a dose-dependent manner during the 12-week double-blind period, and these reduced levels were maintained up to week 144.5

For those who switched from placebo to evobrutinib 75 mg BID in the open-label extension, NfL levels overall and within the original double-blind treatment groups were reduced to similar levels. In comparison with placebo treatment with evobrutinib 75 mg BID resulted in reduced NfL z-scores in a dose-dependent manner as early as week 12, and were significantly sustained for up to week 48. Notably, when stratified by z-scores, investigators identified an association between lower NfL z-score and number of gadolinium-enhancing T1 and T2 lesions.

1. Initiation of new patients on evobrutinib paused in the US; fully enrolled phase 3 evobrutinib studies continue. News release. April 12, 2023. Accessed April 12, 2023. https://www.emdgroup.com/en/news/evobrutinib-12-04-2023.html
2. Strong sales performance and double digit EPS growth marketing the achievement of the 2022 profitability milestone. News release. Sanofi. February 3, 2023. Accessed April 12, 2023. https://ml-eu.globenewswire.com/Resource/Download/d262b473-3732-4b2e-bdd3-35c114256045
3. Kebir H, Li C, May MJ, Church ME, Boschert U, Alvarez JI. The Bruton’s Tyrosine Kinase Inhibitor Evobrutinib Demonstrates Superior Efficacy in Targeting Compartmentalized Neuroinflammation Compared to Anti-CD20 Treatment. Presented at ACTRIMS Forum 2023; February 23-25; San Diego, California. Abstract P149.
4. Kuhle J, Kappos L, Montalban X, et al.Evobrutinib significantly reduces relapses and MRI outcomes in patients with multiple sclerosis: association with baseline neurofilament light chain levels. Presented at: CMSC Annual Meeting, 2022; June 1-4; National Harbor, Maryland. Abstract DMT18
5. Kuhle J, Kappos L, Montalban X, et al. Evobrutinib, a Bruton’s tyrosine kinase inhibitor, decreases neurofilament light chain levels over 2.5 years of treatment in patients with relapsing multiple sclerosis. Presented at: ECTRIMS Congress 2022; October 26-28; Amsterdam, Netherlands. Abstract EP1021
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