Updates in Bruton Tyrosine Kinase Inhibition for Multiple Sclerosis

Despite a large increase in commercially available disease-modifying therapies (DMTs) for multiple sclerosis (MS) over the past 2 decades, many people with MS develop substantial disability because of ongoing inflammatory and degenerative processes within the central nervous system (CNS). Although true comparative effectiveness studies are lacking, clinical trials leading to new DMT approvals have shown incremental improvements in various clinical and radiologic outcome measures. New DMTs, including oral options in the early 2010s and the anti-CD20 monoclonal antibodies ocrelizumab, ofatumumab, and ublituximab since 2017, have been adopted rapidly by practitioners and patients.

Bruton tyrosine kinase inhibitors (BTKIs) offer a novel mechanism of action to target the inflammatory and degenerative processes of MS.¹ Several BTKIs are being studied in late-phase clinical trials in people with MS, with the potential to become the next wave within the DMT marketplace. Herein, we discuss the mechanism of action of BTKIs and potential advantages this may offer in treatment of MS, updates on clinical development of these medications, and other factors that may affect approval, adoption, and choice among BTKIs for MS.

Potential Advantages of BTK Inhibition in MS

Bruton tyrosine kinase (BTK) is a cytoplasmic nonreceptor tyrosine kinase that is part of the Tec family of kinases. BTK is expressed in all hematopoietic cells except for T cells, natural killer cells, and plasma cells. BTK acts as an intracellular signal transducer involved in pathways that lead to modulation of gene expression important for B-cell proliferation, maturation, and differentiation.² Autoreactive B cells implicated in autoimmune conditions are more dependent on BTK signaling than other B cells.³ Positive results from clinical trials of anti-CD20 monoclonal antibodies in people with MS support the concept of peripheral B-cell depletion in MS. However, broad B-cell depletion leaves people at increased risk of infection. BTK inhibition, by comparison, may mitigate this risk by preferentially downregulating pathogenic autoreactive B cells.⁴

The blood–brain barrier (BBB) serves to separate the CNS compartment from the periphery. By means of various immunomodulatory and immunosuppressive mechanisms, most currently available DMTs exert their influence in the periphery, leading to indirect effects within the CNS.⁵ Although the underlying pathophysiology of MS is highly complex and incompletely understood, compartmentalized inflammation behind the BBB is believed to be an important driver of pathology in MS. The presence of ectopic lymphoid follicles—aggregates of B and T lymphocytes within the meninges—supports the concept of immune dysregulation within the CNS and is associated with clinically progressive MS.⁶ Other CNS resident cells behind the BBB, including astrocytes and microglia, also appear to play an important role in neurodegeneration and clinically progressive disease.^7,8

Apart from the small molecule cladribine and lipophilic sphingosine-1-phosphate (S1P) receptor modulators, DMTs are unable to cross the BBB in substantial proportions to exert a direct effect on resident CNS cells.⁵ As small, lipophilic molecules, BTKIs act not only on the immune system in the periphery but also penetrate the CNS and may exert a direct effect on compartmentalized inflammation (Figure 1). BTK inhibition has also been shown to promote remyelination in ex vivo and in vivo models,⁹ and one study showed a significant effect of BTKIs on radiologic markers of leptomeningeal inflammation in an animal model of MS,¹⁰ further supporting the possible effect of these medications behind the BBB.

Supportive Evidence for BTK Inhibition in MS as Learned from Studies in Other Conditions

The first-generation BTKI ibrutinib was initially developed as treatment for B-cell lymphoid malignancies, but BTK inhibition in general has since been investigated in several autoimmune and allergic or inflammatory disorders that share underlying pathophysiologic mechanisms with MS. Rheumatoid arthritis (RA) pathogenesis involves dysregulated B-lymphocyte proliferation as well as aberrant myeloid cell activation, and fenebrutinib has shown efficacy in reducing RA activity in people with inadequate response to either methotrexate or tumor necrosis factor–α inhibitors.¹¹ Pemphigus is an autoantibody-mediated skin disease driven by aberrant antibody production by B cells; phase 2 studies of tirabrutinib in refractory pemphigus have shown remission without major safety concerns.¹² Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by B-cell dysfunction with autoantibody formation and immune complex deposition; mouse models have demonstrated prevention and amelioration of SLE symptoms with BTK inhibition.¹³ Studies have also shown that BTK inhibition plays a role in preventing maturation of infiltrating macrophages or neutrophils in a brain ischemia model, and use of ibrutinib strongly protected against brain injury.¹⁴ In addition to the potential for myelin repair,⁹ this broad array of pharmacologic effects also occurs in pathways shared by MS pathophysiology, thus offering a multifaceted approach to targeting MS.

BTK Inhibitors Under Investigation in MS

Compared with first-generation BTKIs, second-generation BTKIs are more specific for BTK (as compared with other tyrosine kinases), potentially limiting off-target effects such as arrhythmias and bleeding disorders.¹⁵ Although all BTKIs in development for MS are administered orally, differences in BTK selectivity, reversibility of binding, potency, and degree of CNS penetrance may lead to differences in clinical outcomes (Table 1). Evobrutinib, orelabrutinib, remibrutinib, and tolebrutinib all exert their effect by means of irreversible covalent bonding to BTK, leading to sustained inhibition, whereas fenebrutinib binds reversibly to BTK, requiring sustained BTKI exposure to maintain inhibition.¹ Differences in BTK selectivity and CNS penetrance have been shown in preclinical models (eg, remibrutinib may exhibit greater selectivity for BTK than evobrutinib, and tolebrutinib may reach the CNS in greater concentrations than evobrutinib and fenebrutinib).^16,17 However, further in-human work is needed and is underway to clarify these pharmacokinetic and pharmacodynamic differences. A detailed discussion of the 5 second-generation BTKIs that are being investigated in phase 2 and phase 3 clinical trials as potential therapies for MS follows.

Evobrutinib

Evobrutinib was studied in a 24-week, multicenter, double-blind, randomized controlled phase 2 trial of 267 people with relapsing MS. Five treatment arms were included: placebo, evobrutinib 25 mg once daily (QD), evobrutinib 75 mg QD, evobrutinib 75 mg twice daily (BID), and open-label dimethyl fumarate as an active comparator. Evobrutinib 75 mg QD led to a significant reduction in adjusted rate ratio for contrast-enhancing lesions (CELs) compared with placebo (0.30), the primary outcome measure. Secondary end points, including relapse rate and relapse-free status at 24 weeks, were not significantly different compared with placebo but trended toward significance at higher doses of evobrutinib; these clinical outcomes appeared comparable with those of dimethyl fumarate. Use of evobrutinib was associated with nasopharyngitis and elevations in liver and pancreatic function tests.¹⁸ Open-label extension (OLE) data, including 164 participants out to 2.5 years at the time of this writing, have not shown any additional treatment-related adverse events. Elevations in liver function tests were only observed in those who had received dimethyl fumarate and switched to evobrutinib 25 mg QD. Pancreatic enzyme elevation occurred in up to 11.3% of participants but was asymptomatic.¹⁹ Post hoc analysis of OLE data demonstrated a significant and sustained reduction in neurofilament light chain, a biomarker of neuroaxonal damage in MS, with evobrutinib 75 mg BID compared with placebo.²⁰ OLE data also suggest a dose–response in annualized relapse rate (ARR), with participants receiving evobrutinib 75 mg BID having the lowest ARR (0.12).¹⁹ This finding informs the twice-daily dosage being used in 2 ongoing identical phase 3, multicenter, randomized, double-blind, double-dummy, active controlled trials in people with relapsing MS comparing evobrutinib with teriflunomide (evolutionRMS 1 and evolutionRMS 2 [Study of Evobrutinib in Participants with RMS], ClinicalTrials.gov Unique Identifiers NCT04338022 and NCT04338061) (Table 2). These trials aim to determine the clinical efficacy of evobrutinib with ARR as the primary outcome. Secondary outcome measures include markers of disease activity (eg, CELs), disease progression (eg, time to Expanded Disability Status Scale [EDSS] progression), biomarkers (eg, neurofilament light chain levels), patient-reported outcomes, and safety. Each trial aims to enroll 898 participants worldwide, and both are expected to be completed in September 2023 (Figure 2).

Fenebrutinib

Though a smaller phase 2 clinical trial evaluating the effect of fenebrutinib on CELs is ongoing (FENopta [A Study to Investigate the Efficacy of Fenebrutinib in Relapsing Multiple Sclerosis], Unique Identifier NCT05119569), clinical development has been accelerated based on positive results from other phase 2 clinical trials of BTKIs in MS. Fenebrutinib is being studied head-to-head against teriflunomide in 2 identical phase 3 clinical trials in people with relapsing MS (FENhance [A Study to Evaluate the Efficacy and Safety of Fenebrutinib Compared with Teriflunomide in Relapsing Multiple Sclerosis], Unique Identifiers NCT04586010 and NCT04586023). ARR is the primary clinical outcome in both trials, with secondary outcome measures including time to confirmed disability progression (CDP), number of CELs, changes in brain volume on MRI, and additional markers of cognitive function and safety. These trials each aim to enroll 736 participants and are expected to be completed in late 2025.

Fenebrutinib is also being investigated in primary progressive MS. A phase 3, multicenter, international, randomized, double-blind, double-dummy trial comparing fenebrutinib with ocrelizumab is underway (FENtrepid [A Study to Evaluate the Efficacy and Safety of Fenebrutinib Compared with Ocrelizumab in Adult Participants with Primary Progressive Multiple Sclerosis], Unique Identifier NCT04544449). The primary outcome is time to a composite measure of CDP—which includes EDSS, walking speed, and the 9-hole peg test (itself a marker of upper extremity function)—and is met when progression is confirmed 12 weeks later. Secondary end points include composite 24-week CDP, changes in brain volume, and additional patient-reported outcomes, measures of cognition, and safety markers. This trial aims to enroll 946 participants with targeted completion in early 2026.

Orelabrutinib

Orelabrutinib is under investigation in a phase 2, randomized, double-blind, placebo-controlled clinical trial in people with relapsing MS (A Phase 2 Study of Orelabrutinib in Patients with Relapsing-Remitting Multiple Sclerosis; Unique Identifier NCT04711148). The trial is structured as a dose-ranging study with participants evenly randomized to placebo or 1 of 3 doses of orelabrutinib (50 mg QD, 80 mg QD, or 50 mg BID). As with other phase 2 BTKI studies for relapsing MS, the primary outcome measure is new CELs, with secondary outcome measures including ARR, change from baseline EDSS, and incidence of treatment-emergent adverse events. This trial aims to enroll 160 participants; an OLE phase is planned to follow, and, assuming positive results of this phase 2 study, phase 3 studies are expected.

Remibrutinib

Although no phase 1 or 2 trials of remibrutinib have been conducted in people with MS, a phase 2b dose-finding trial of remibrutinib in chronic spontaneous urticaria demonstrated a favorable side effect profile without new safety signals compared with other early-phase BTKI trials in MS.²¹ Remibrutinib is being studied alongside teriflunomide in 2 identical phase 3, randomized, double-blind, double-dummy trials of people with relapsing MS (Efficacy and Safety of Remibrutinib Compared to Teriflunomide in Participants With Relapsing Multiple Sclerosis; Unique Identifiers NCT05147220 and NCT05156281). The primary end point is ARR, with highlighted secondary end points including 3- and 6-month CDP as measured by EDSS, imaging markers including new or enlarging T2 lesions and T1 CELs, and neurofilament light chain concentration, among others. Both studies aim to enroll 800 participants and are estimated to be completed in October 2025.

Tolebrutinib

Tolebrutinib was studied in an international, multicenter, double-blind, placebo-controlled, crossover phase 2b study of 130 people with relapsing MS. Participants were first randomized to 1 of 2 cohorts: within 1 cohort, participants were randomized to 1 of 4 doses of tolebrutinib (5 mg QD, 15 mg QD, 30 mg QD, or 60 mg QD) for 12 weeks, followed by 4 weeks of placebo; the second cohort received 4 weeks of placebo followed by 12 weeks of 1 of the 4 tolebrutinib doses. The primary end point was number of CELs, and a dose-dependent decrease was observed, with a relative reduction of 85% in the tolebrutinib 60 mg QD dosing groups compared with the placebo period. The most common adverse event was headache; no safety-related discontinuations occurred. Although 1 MS relapse requiring hospitalization occurred in the 60 mg QD dosing group, ARR was not assessed because of the short duration of the trial.²² However, OLE data, encompassing 124 of the original trial participants out to 18 months, showed an ARR of 0.17 (all treated with tolebrutinib 60 mg QD) and low numbers of new or enlarging T2 lesions and CELs.²³

Tolebrutinib is being investigated in multiple phase 3 clinical trials in all MS subtypes. Two identical international, multicenter, randomized, double-blind phase 3 clinical trials in people with relapsing MS comparing tolebrutinib 60 mg QD with teriflunomide are in progress (GEMINI 1 and GEMINI 2 [Relapsing Forms of Multiple Sclerosis Study of Bruton’s Tyrosine Kinase Inhibitor Tolebrutinib (SAR442168)], Unique Identifiers NCT04410978 and NCT04410991). The primary outcome measure for these trials is ARR, with highlighted secondary end points related to confirmed disability worsening, new or enlarging T2 lesions, CELs, brain atrophy on MRI, and other safety markers and patient-reported outcomes. Two other randomized, double-blind, placebo-controlled phase 3 clinical trials are evaluating tolebrutinib in people with progressive forms of MS: nonrelapsing secondary progressive MS (HERCULES [Nonrelapsing Secondary Progressive Multiple Sclerosis Study of Bruton’s Tyrosine Kinase Inhibitor Tolebrutinib (SAR442168)], Unique Identifier NCT04411641) and primary progressive MS (PERSEUS [Primary Progressive Multiple Sclerosis Study of Bruton’s Tyrosine Kinase Inhibitor Tolebrutinib (SAR442168)], Unique Identifier NCT04458051). The primary outcome measure of these trials is 6-month CDP, with additional secondary clinical, radiologic, patient-reported, and safety outcomes.

Concerns Regarding Potential Hepatotoxicity

The Food and Drug Administration (FDA) placed phase 3 studies of tolebrutinib on a partial clinical hold in mid-2022 after cases of drug-induced hepatotoxicity were identified, leading to a pause in US recruitment for these trials. Hepatotoxicity has rarely been seen with use of BTKIs in other conditions.²⁴ The independent data monitoring committee overseeing all tolebrutinib trials subsequently recommended pausing recruitment globally while these cases were investigated further. Both tolebrutinib trials for relapsing MS have fully enrolled 900 participants each, and currently enrolled participants are continuing treatment per the FDA and independent data monitoring committee recommendations; completion is targeted for late summer 2023.²⁵ However, recruitment for studies of nonrelapsing secondary progressive MS and primary progressive MS remained paused as of December 2022; it is unclear how this will affect the targeted primary study completion date of August 2024. Similarly, the FDA placed the phase 2 study of orelabrutinib on a partial clinical hold in the US in December 2022 after cases of hepatotoxicity were identified, raising suspicion for a possible BTKI class effect. The pharmaceutical company has paused recruitment for the study outside of the US as well, likely delaying the planned July 2023 completion date.²⁶

Additional Practical Considerations in BTKI Clinical Development

Differences in safety and efficacy from ongoing phase 3 trials should ultimately determine the preferred BTKI for treatment of MS. However, other practical considerations such as expected patient compliance (given the QD and BID dosing options under investigation); insurer coverage, patient support, and affordability; and timing of commercial approval can all be expected to influence treatment decisions. Recent history has suggested a first-to-market advantage for various DMT classes, including S1P receptor modulators (Gilenya), fumarates (Tecfidera), and B-cell–depleting monoclonal antibodies (Ocrevus). This first-move advantage allowed these medications to establish brand recognition among patients, prescribers, and insurers. Assuming comparable clinical data among the BTKI trials, it remains to be seen whether such an advantage will be conferred among these medications upon their expected regulatory approval; this may be particularly relevant as the soonest completion dates of phase 3 trials in relapsing MS are near each other. It is also important to consider that those first to market will also generally become first to patent expiry, and with that comes weakening of patient support programs and the possibility of major insurer coverage changes, which may contribute to the ultimate landscape of clinical use of BTKIs in MS.

Summary

BTKIs offer a novel mechanism for the treatment of autoimmune and inflammatory conditions, and may present advantages over existing DMTs for people with MS. Early-phase data of BTKIs in people with MS show promise, and several BTKIs are currently in large-scale phase 3 trials for all forms of MS. Completion of these large-scale trials will elucidate safety of these medications, especially regarding hepatotoxicity. The MS community eagerly awaits these results, but whether and to what extent these therapies are eventually incorporated into the MS treatment paradigm remains to be seen.