MS Minute: Update on BTK Inhibitors for Multiple Sclerosis—A New Treatment That Brings New Hope

Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system (CNS) classically characterized by the formation of inflammatory demyelinating lesions within the brain, spinal cord, and optic nerves. Although it most commonly presents clinically as an intermittent, relapsing disease (relapsing-remitting MS [RRMS]), a small proportion of individuals experience a slowly progressive course from onset (primary progressive MS). Over time, at least half of individuals who started with RRMS will experience a gradual accumulation of neurologic disability independent of clinical relapses, which is called secondary progressive MS (SPMS).¹

Despite substantial progress made over the past several decades in developing a variety of effective therapies for RRMS, treatment options for progressive MS (which comprises both primary progressive MS and SPMS) remain limited, highlighting the need for better understanding of the mechanisms and pathophysiologic processes underlying progressive MS. Although additional research is needed to delineate the mechanisms involved, what is clear is that peripherally driven inflammation (the predominant driver of clinical relapses and new lesions on MRI) as well as compartmentalized inflammation within the CNS and neurodegeneration (the likely drivers of progressive MS) play a role in determining the clinical course of MS.² In recent years, several hallmarks of progressive MS have emerged, including the presence of smoldering compartmentalized inflammation within the CNS, chronic microglia activation, oxidative stress, mitochondrial dysfunction, incomplete remyelination, and dysregulation of iron homeostasis.² Of the currently approved disease-modifying therapies (DMTs) for MS, few cross the blood–brain barrier (BBB), and all appear to primarily target the peripheral immune system. This may be why most trials of approved DMTs failed to show benefit in progressive MS.

Bruton Tyrosine Kinase Inhibitors

Among the therapies currently being investigated for use in progressive MS are Bruton tyrosine kinase (BTK) inhibitors. BTK is a Tec family tyrosine kinase that is expressed by many hematopoietic cells, with T lymphocytes and plasma cells being notable exceptions. BTK is involved in the development and activity of B cells, and pharmacologic inhibition of BTK prevents activation of downstream signaling pathways such as PLCγ2, thus preventing antigen-driven activation and proliferation as well as B-cell–dependent T-cell activation (Figure). Thus, a BTK inhibitor is expected to downregulate B-cell function without reducing the total number of B cells in contrast to B-cell–depleting monoclonal antibodies, which destroy B cells.^2,3

Figure. Depiction of Bruton tyrosine kinase (BTK) in intracellular cascade within B cells and microglia and the potential location where BTK inhibitors may act. 

The original BTK inhibitor, ibrutinib (Imbruvica; Pharmacyclics, Sunnyvale, CA), was approved for the treatment of leukemia and lymphoma in 2013, but other, more selective BTK inhibitors have since been developed. The newer generation of BTK inhibitors has less off-target kinase inhibition, which is thought to decrease side effects and increase safety. Several of these newer BTK inhibitors are being investigated for use in autoimmune conditions, including MS.^3-5 Table 1 provides a list of BTK inhibitors in clinical development for use in MS along with their chemical characteristics.

This class of medications has garnered particular interest as a potential treatment for progressive MS due to the ability of some of them to cross the BBB and possibly downregulate activation and polarization of microglia within the CNS.⁶ Thus, BTK inhibitors have the potential to alter dysregulated B lymphocytes in both the peripheral nervous system and CNS as well as microglia within the CNS. Through these effects, they may be capable of targeting the chronic compartmentalized CNS inflammation seen in progressive MS, which has evaded treatment to date. There is also some preliminary evidence that BTK inhibitors may alleviate oxidative stress and promote remyelination, possibly through their impact on microglia.²

Recent Evidence

Several BTK inhibitors have been studied in phase 2 trials for the treatment of RRMS. As is typical of those trials, the primary outcome measure was new lesion activity as seen on brain MRI. Treatment with evobrutinib 75 mg daily was found to decrease the total number of gadolinium-enhancing lesions on weekly MRI scans from week 12 to week 24 by 56% compared with placebo.²⁰ Treatment with tolebrutinib 60 mg daily was found to decrease new gadolinium-enhancing lesions by 87% after 12 weeks of treatment.²¹ These encouraging phase 2 trial results prompted phase 3 trials in both relapsing MS and progressive MS.

Evobrutinib was tested in 2 phase 3 trials for RRMS—EvolutionRMS 1 and 2 (NCT04338022; NCT04338061)—which included 2290 participants randomized to treatment with either evobrutinib or teriflunomide. Neither trial showed a difference in relapse rate between groups (adjusted rate ratio, 1.02 [0.75–1.39]; P=.55 for EvolutionRMS1 and 1.00 [.74–1.35]; P=.51 for EvolutionRMS2). In the secondary analyses, evobrutinib did not decrease the risk of disability progression compared with teriflunomide. Serum neurofilament light chain concentrations at week 12 showed no difference between evobrutinib and teriflunomide in EvolutionRMS1 and a nominal difference in EvolutionRMS2. There was no difference in new or enlarging T2 lesions or individual-reported outcomes. The rate of gadolinium-enhancing lesions was slightly higher in the evobrutinib-treated group.²²

Tolebrutinib, another BTK inhibitor, was also tested in people with RRMS through 2 phase 3 trials—GEMINI 1 and 2 (NCT04338061; NCT04410991)—which included 1873 participants randomized to treatment with either tolebrutinib or teriflunomide. In both trials, tolebrutinib failed to meet its primary end point of a reduction in relapse rate compared with teriflunomide (adjusted rate ratio, 1.06 [0.81 to 1.39]; P=.67 in GEMINI 1 and 1.00 [0.75 to 1.32]; P=.98 in GEMINI 2). Tolebrutinib also did not reduce the number of new or worsening T2 lesions on MRI scans and was, in fact, inferior to teriflunomide in terms of the rate of gadolinium-enhancing lesions, similar to what was seen in the EvolutionRMS studies. Whereas a slower rate of brain atrophy was seen in the tolebrutinib-treated group relative to the teriflunomide-treated group in GEMINI 1, no such difference was seen in GEMINI 2. However, when 6-month sustained disability worsening was evaluated in the predefined aggregate analysis across the 2 trials, treatment with tolebrutinib was associated with a 29% reduction compared with teriflunomide, although no formal statistical testing was conducted because the primary outcome was not met.²³

Tolebrutinib was also recently evaluated in nonrelapsing SPMS through a third phase 3 trial—HERCULES (NCT04411641)—in which 1131 participants were randomized 2:1 to treatment with either tolebrutinib or placebo. To be eligible for the study, individuals had to not have experienced any clinical relapses in the previous 2 years despite exhibiting evidence of disability progression within the past year. The primary outcome of HERCULES was met, whereby individuals treated with tolebrutinib demonstrated a 31% relative risk reduction in 6-month confirmed disability worsening compared with placebo. Among the study’s secondary outcomes, individuals in the tolebrutinib group had a lower rate of new or enlarging lesions. Those in the tolebrutinib group also had a slightly lower risk of slowed walking as measured by the timed 25-foot walk test and higher chance of disability improvement, although these were not tested statistically because a hierarchical testing method was stopped when there was no effect of tolebrutinib on hand function as measured by the 9-hole peg test. Brain atrophy progression was similar between the 2 groups.²⁴

At first, it may seem surprising that drugs that decreased new MRI lesions by 56% to 87% compared with placebo in phase 2 trials did not reduce annualized relapse rates compared with teriflunomide, which is a frequent comparator used in phase 3 RRMS trials. However, the teriflunomide phase 2 trial showed a 66% reduction in gadolinium-enhancing lesions in the 14-mg treatment arm over 36 weeks of treatment.²⁵ In addition, initial reports from the long-term extension studies of evobrutinib and tolebrutinib suggested decreased efficacy on MRI lesion activity with long-term treatment.^26,27 This apparent tolerance after long-term treatment with evobrutinib and tolebrutinib is an unexpected finding and has never been seen with an MS DMT. It remains unclear whether decreased efficacy on MS disease activity with long-term treatment will be seen with all BTK inhibitors, but the observation with evobrutinib and tolebrutinib emphasizes the importance of long-term open-label extension studies, even for phase 2 trials.

The GEMINI studies observed a slowing of disability progression with tolebrutinib treatment that was not seen in the EvolutionRMS studies with evobrutinib treatment, even though the same dose of teriflunomide was used as the comparator in both studies. One possible explanation is that tolebrutinib readily crosses the BBB at biologically relevant concentrations, whereas evobrutinib does not appear to do so.¹⁸ Gradual progression of disability (also called progression independent of relapses) is thought to be driven by pathologic processes located within the CNS, in which case a drug accessing the CNS is likely required for a biologic effect on gradual progression of disability.²⁸ Studies of BBB penetration by another BTK inhibitor, fenebrutinib, have yielded conflicting results.^18,29 In addition to fenebrutinib, several other BTK inhibitors are at various stages of clinical trial studies in MS, including remibrutinib, orelabrutinib,³⁰ and BIIB091 (Table 2). Whether any of these can overcome the tolerance findings with respect to peripheral inflammation seen with evobrutinib and tolebrutinib remains to be seen. Table 2 summarizes the available phase 2 and phase 3 results for BTK inhibitors in the clinical stages of development.

Side Effects and Tolerability

BTK inhibitors are generally well-tolerated, with a slightly increased rate of infections (mostly respiratory infections) and rare liver function test elevations being the main reported safety events. In individuals with relapsing MS, increased rates of minor bleeding events (petechia and heavy menses) were observed with tolebrutinib treatment. Liver enzyme elevations higher than 3 times the upper limit of normal have occurred in between 4% and 11% of individuals. Severe elevations with liver enzymes >20 times the upper limit of normal can be seen, occurring in ~0.5% of tolebrutinib-treated individuals. To date, these severe, 20-times upper limit of normal cases have been seen only in the first 3 months of treatment, which provides a target window for intensive monitoring.^22-24 Most individuals have normalization of their liver enzymes with treatment discontinuation, although 1 participant in the HERCULES trial died from complications related to liver failure, which emphasizes the severity of this complication and the importance of monitoring.²⁴

Discussion

BTK inhibitors are a new class of therapy being studied in MS. Based on the results of the first 2 BTK inhibitors to make it through phase 3 trials, their efficacy against relapsing pathology (clinical relapses and new lesions on MRI) appears modest, but the BBB-penetrant tolebrutinib appears to slow progression independent of relapses in both relapsing MS and nonrelapsing SPMS. Whereas the results of the GEMINI trials (ie, no effect on relapse rate but slowing of disability progression) may at first seem like a surprising paradox, they lend support to previous observations that much, if not most, disability accumulation in MS occurs independent of relapses.³¹ They also suggest that we may finally have a therapy that specifically targets the distinct underlying pathology of progressive MS. The observation that tolebrutinib produced a similar reduction in disability in the relapsing MS trials (GEMINI 1 and 2) as was seen in the nonrelapsing SPMS trial (HERCULES) provides independent confirmation of the disability results reported from the HERCULES trial and suggests that these benefits are unlikely a spurious finding. However, the benefit of tolebrutinib reported for progressive MS and only modest benefit reported for relapsing MS pathology complicates the placement of tolebrutinib in MS treatment algorithms, which recently have favored early initiation of highly effective anti-inflammatory therapies. Although there is emerging evidence that discontinuing DMTs for relapsing MS is a reasonable consideration in older individuals, stopping relapsing MS therapy in younger individuals is often associated with a return of relapsing disease activity.^32,33 This makes the use of tolebrutinib in younger individuals somewhat challenging. In these younger individuals, combining a CNS-penetrant BTK inhibitor with a therapy that has more robust activity against relapsing MS pathology might be considered but needs careful study of efficacy, safety, and tolerability.

As other neuroprotective agents are developed, it will be important to know how those agents might be combined with BTK inhibitors. These and many other clinically relevant questions remain unanswered. Nevertheless, BTK inhibitors are the first class of medications to slow disability progression in SPMS without clinical relapses, although safety concerns need to be recognized and monitored.