Emerging Class of Medications for Multiple Sclerosis: Examining the Development of BTK Inhibitors

NeurologyLiveSpring 2024
Volume 7
Issue 1

A panel of experts MS specialists provided commentary on the clinical development of these therapies, some of the specific agents within the pipeline, and how to navigate potential safety concerns.

CURRENT THERAPIES FOR MULTIPLE SCLEROSIS (MS) are effective in reducing both relapses and relapse-associated worsening of disability, which is assumed to be mainly associated with transient infiltration of peripheral cells into the central nervous system (CNS). Despite the expansion in therapeutic options for those with relapsing MS, none of these disease-modifying treatments slow disability accumulation or neurodegeneration.1

In an effort to overcome the limitations of B-cell–depleting therapies for MS, research has shifted gears toward Bruton tyrosine kinase (BTK) inhibitors. Research has shown that BTK is an essential proximal component of several signaling pathways downstream of the B-cell receptor that controls B-cell maturation, survival, and activation, as well as production of cytokines and antigen-dependent stimulation of T cells.2

To keep the clinical community informed on the latest updates in the development of BTK inhibitors, NeurologyLive assembled a panel of experts in the field: Jiwon Oh, MD, PhD; Gavin Giovannoni, MBBCh, PhD, FCP, FRCP, FRCPath; Amit Bar-Or, MD, FRCPC, FAAN, FANA; Krzysztof Selmaj, MD, PhD; and Patrick Vermersch, MD, PhD. The group of MS specialists provided commentary on the clinical development of these therapies, some of the specific agents within the pipeline, and how to navigate potential safety concerns.

Clinical Development and Advantages of BTK Inhibitors

For some patients with MS, finding an optimal therapy for their condition is a challenge. There remains several unmet needs that BTK inhibitors look to address. “The prospect of BTK inhibition in MS [is] to impact both relapse-related biology in the periphery [and] CNS compartmentalized inflammation of both infiltrating B cells and macrophage, but also resident microglia,” said Bar-Or, chief of the Division of Multiple Sclerosis and Related Disorders at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia.

“Over the [past] 10 years, we’ve realized that suppressing focal inflammatory activity is not sufficient to control MS, so people who are free of relapses in MRI activity often get worse,” said Giovannoni, chair of neurology at the Blizard Institute at Barts and The London School of Medicine and Dentistry at Queen Mary University of London in the United Kingdom. “The process that drives what I refer to as small ring MS—often CNS related and inside the CNS compartment—is a B-cell population, and because the current monoclonal antibody or anti-CD20s don’t get in, the advantage is the BTK [inhibitors] will get in and potentially inhibit the CNS B-cell compartment.”

Pipeline Overview

Currently, the safety and efficacy of 5 BTK inhibitors are being evaluated in patients with relapsing MS or progressive MS: evobrutinib (Merck KGaA/EMD Serono), tolebrutinib (Sanofi), fenebrutinib (Roche), remibrutinib (Novartis), and orelabrutinib (InnoCare). Fenebrutinib and tolebrutinib are the only agents with trials in progressive MS.

Evobrutinib, a covalent BTK inhibitor, had its effect demonstrated in a phase 2 study (NCT02975349) and an open-label extension (OLE), where the agent showed an acceptable tolerability and maintained efficacy over a 2.5-year period in patients with relapsing MS.3 Vermersch, a neurologist and vice president of research and biology at the University of Lille, in France, said that, “considering the impact of BTK inhibition into the [CNS], it’s great to also see the impact on the cell during part of the disease, the patient related outcomes.”

Gavin Giovannoni, MBBCh, PhD, FCP, FRCP, FRCPath, discusses safety concerns in treatment while Patrick Vermersch, MD, PhD, listens

Gavin Giovannoni, MBBCh, PhD, FCP, FRCP, FRCPath, discusses safety concerns in treatment while Patrick Vermersch, MD, PhD, listens

He added, “What we have seen even early during the core period until week 48, we have quite an impact if we consider, for example, some subscales of the [36-item Short Form Survey]. For example, vitality and mental health—we have a significant impact vs placebo and the low dose of evobrutinib, which I think is interesting in a short period of time.”

Unfortunately, the therapy did not meet its primary end points in the subsequent phase 3 EVOLUTION trials of relapsing MS, which had preliminary data released in December 2023. The totality of that data is still expected to be presented at a future scientific meeting.4

In addition to evobrutinib, the panel discussed the phase 2 results of fenebrutinib and tolebrutinib. In FENopta (NCT05119569), a double-blind, placebo-controlled 12-week study, fenebrutinib met its primary and secondary end points, demonstrating a significant reduction in MRI markers of MS activity in the brain relative to placebo.5

In a long-term phase 2 extension study, tolebrutinib 60 mg/d for 2.5 years was safe for patients with relapsing MS, with no new signals.6 Led by Oh, a staff neurologist and medical director of the BARLO Multiple Sclerosis Program at St Michael’s Hospital at the University of Toronto in Ontario, Canada, the study included 125 individuals with relapsing MS who were on tolebrutinib 5, 15, 30, or 60 mg/d for the double-blind portion, and subsequently switched to 60 mg/d for the OLE.


Thought leaders Mark Freedman, MD, MSc, HBSc, CSPQ, FANA, FAAN, FRCPC; Tanuja Chitnis, MD; and Ahmed Obeidat, MD, PhD, review the latest data and trends regarding the use of neurofilament light chain and other biomarkers in MS diagnosis and treatment.

View video: neurologylive.com/cmsc-nfl-ms

“Specifically, the 60-mg dose of tolebrutinib reduced T1 gadolinium-enhancing lesions by [approximately] 85%. In addition, there were reductions, as expected, in new and enlarging T2 lesions,” Oh said. “Although similar to the evobrutinib phase 2 clinical trial, clinical end points were not the primary end point and the study was not powered to detect a difference. It was very clear that the annualized relapse rate reduced, particularly with people on the tolebrutinib at 60 mg, and Expanded Disability Status Scale scores remained stable.”

Navigating Safety Concerns

Like with any new class of therapies, safety remains the biggest priority when evaluating whether agents should continue their development. Several of these BTK inhibitors have had trials stopped or placed on hold because of cases of drug-induced liver injury.7-9 The panel provided commentary on the relatively few number of cases seen and whether it would impact the decision to use such therapy. “I don’t think this is going to change our practice, because when you think about other therapies we use—teriflunomide and the S1P [receptor modulators], even ocrelizumab—there is an incidence of transaminase elevations with all our therapies,” Giovannoni said. “We used to monitor liver function [and] abnormalities, and even with anticonvulsants, we see this problem. My gut feeling is I don’t think it’s going to be a major problem if these drugs get through the pipeline.”

Oh noted that although it may be an inconvenience, as long as frequent lab monitoring is required early on, it’s something that could be relatively easy to manage. “Elevated liver enzymes are something that we as [MS] neurologists and neurologists in general are pretty familiar with,” she said.

If these therapies were to be approved, the panel agreed that a strategy to minimize risk will need to be implemented. Vermersch noted that when the data on each of the BTK inhibitor therapies are viewed collectively, these risks could be a class effect, with almost 50% of cases including an additional risk factor. “Probably, before treating a patient with a BTK inhibitor, screening for hepatitis [might be a good strategy], for example. Also screening to test for nonalcoholic steatohepatitis and ferritin level, and discussing the alcohol consumption [with the patient], as it may be also a risk factor. Screening for other drugs with a potential interaction with BTK inhibitors for liver toxicity, as well.

1. Krämer J, Bar-Or A, Turner TJ, Wiendl H. Bruton tyrosine kinase inhibitors for multiple sclerosis. Nat Rev Neurol.2023;19(5):289-304. doi:10.1038/s41582-023-00800-7
2. Rip J, Van Der Ploeg EK, Hendriks RW,Corneth OBJ. The role of Bruton’s tyrosine kinase in immune cell signaling and systemic autoimmunity. Crit Rev Immunol. 2018;38(1):17-62. doi:10.1615/CritRevImmunol.2018025184
3. 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: 2022 Consortium of Multiple Sclerosis Centers Annual Meeting; June 1-4, 2022; National Harbor, MD. Abstract DMT18.
4. Merck KGaA, Darmstadt, Germany provides update on phase III results for evobrutinib in relapsing multiple sclerosis. News release. Merck KGaA. December 6, 2023. Accessed February 8, 2024. https://www.emdgroup.com/en/news/evobrutinib-phase-lll.html
5. Genentech’s BTK inhibitor fenebrutinib significantly reduced brain lesions in people with relapsing forms of multiple sclerosis. News release. Genentech.May 17, 2023. Accessed February 8, 2024. https://www.businesswire.com/news/home/20230516005196/en/Genentech%E2%80%99s-BTK-Inhibitor-Fenebrutinib-Significantly-Reduced-Brain-Lesions-in-People-With-Relapsing-Forms-of-Multiple-Sclerosis
6. Oh J, Syed S, Li T, Salloum N, Turner TJ, Fox RJ. Safety and clinical efficacy outcomes from the long-term extension study of tolebrutinib in participants with relapsing multiple sclerosis: 2.5-year results. Presented at: 2023 American Academy of NeurologyAnnual Meeting; April 22-27, 2023; Boston, MA. Abstract 002056.
7. Initiation of new patients on evobrutinib paused in the US; fully enrolled phase IIIevobrutinib studies continue. News release. Merck KGaA. April 12, 2023. Accessed February 8, 2024. https://www.emdgroup.com/en/news/evobrutinib-12-04-2023.html
8. Media update: patient enrollment of phase III tolebrutinib trials paused in the US. News release. Sanofi. June 30, 2022. Accessed February 8, 2024. https://www.sanofi.com/en/media-room/press-releases/2022/2022-06-30-05-30-00-2471767
9. Fenebrutinib multiple sclerosis clinical trial program update. News release. Genentech. November 30, 2023. Accessed February 8, 2024. https://www.gene.com/media/statements/ps_113023
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