Bruton Tyrosine Kinase Inhibitors: A New Hope for the Management of Progression in MS?

DESPITE RECENT EXPANSION of the therapeutic armamentarium of disease-modifying treatments for patients with multiple sclerosis (MS), a large proportion of patients receiving highly effective therapies continues to experience signs of clinical worsening. The mechanisms involved in progression in MS are complex, but recent data suggest that microglia activation within the central nervous system (CNS) plays a critical role in amplifying chronic “smoldering” inflammation, resulting in progression independent of relapse activity (PIRA). Given their effect on microglia activation, Bruton tyrosine kinase (BTK) inhibitors have received much attention as promising therapeutic strategies for managing progression in MS.

Smoldering MS: An Unmet Need

The term PIRA, or smoldering MS, was coined to distinguish clinical worsening that occurs despite a lack of acute inflammatory disease activity.¹ Several mechanisms have been proposed to explain the underpinning processes involved in MS pathogenesis.² In a practical sense, the pathophysiology of MS could be viewed as a chronic smoldering inflammatory process accompanied by a series of acute inflammatory events, often represented clinically by acute relapses and/or focal MRI activity.

It is clear that adaptive immunity plays a fundamental role in driving acute inflammatory responses in MS: specifically, peripheral activation of autoreactive T cells leading to B-cell differentiation into antibody-secreting plasma cells.³ Subsequent migration of activated T and B lymphocytes through the blood-brain barrier (BBB) into the CNS results in focal demyelination and axonal transection, resulting in further recruitment of monocytes and macrophages from the periphery. Aside from the downstream consequences of acute focal damage that occurs over days to weeks and causes relapse-associated worsening, there are delayed, postinflammatory neurodegenerative processes that account for accumulation of clinical disability. PIRA is assumed to be caused by an interplay between CNS-resident cells and migrated hematopoietic cells. Perhaps the most relevant mechanism within the brain is microglia activation, an essential mechanism in smoldering inflammation.⁴

Microglia function is highly variable. Depending on the inflammatory milieu, microglia can differentiate into diverse phenotypes resulting in neurotoxic pathways leading to neurodegeneration, or alternatively exert important roles in promoting neuroprotection, downregulation of inflammation, and stimulation of repair.⁵ In MS, chronically activated microglia have been associated with focal smoldering pathology known as slowly expanding lesions (SELs) by the release of proinflammatory cytokines and inflammatory mediators.⁶ In contrast to active demyelinating lesions, the pathology of SELs is characterized by a low degree of inflammation and with T and B cells at the lesion core surrounded by a dense network of activated iron-laden microglia and macrophages. SELs with paramagnetic rims of activated microglia at their edges contribute to the failure of remyelination, resulting in further destruction of the surrounding parenchyma, often correlating with a more severe clinical outcome.⁷ To date, disease-modifying therapies have little if any effect on microglia activation within the CNS. In this regard, one promising strategy may be the inhibition of BTK, an enzyme involved in the activation of microglial cells.⁸

BTK: Cell Expression and Signaling Pathways

BTK is a cytoplasmic enzyme, part of the Tec (tyrosine kinase expressed in hepatocellular carcinoma) family of kinases. BTK plays a critical role in activation of B cells, macrophages, and microglial cells, but not T or natual killer (NK) cells.⁹ Many cell types within the hematopoietic lineage express BTK, including B cells, dendritic cells, mast cells, neutrophils, macrophages, platelets, erythrocytes, and hematopoietic stem cells.¹⁰ Within the CNS, BTK is mainly expressed in microglia and to a lower extent in astrocytes.¹⁰

BTK plays a role in the signaling cascades of a variety of immunologically relevant receptors, including the B-cell receptor (BCR), toll-like receptors, Fc receptors, and chemokine receptors. Perhaps the most relevant role of BTK in MS is through the BCR signaling cascade. BCR is activated upon binding of an antigen, which initiates a cascade of intracellular signaling events in which BTK is involved. BTK regulates incoming, extracellular signals into cellular responses; inhibition of BTK signaling can result in decreased B-cell proliferation, immunoglobulin class switching, cytokine production and release, and myelin repair.¹¹

BTK Inhibitors: Pharmacology

BTK inhibitors are lipophilic small molecules that can be orally administered. According to their mode of action and based on their mode of binding to BTK, the inhibitors are classified into 2 types: irreversible inhibitors (evobrutinib, tolebrutinib, remibrutinib, orelabrutinib), which form a covalent bond with the amino acid residue Cys481 in the ATP-binding site of BTK; and reversible inhibitors (fenebrutinib and BIIB091), which bind to specific pockets in the Src homology 3 domain by weak, reversible forces (hydrogen bonds or hydrophobic interactions), inducing an inactive conformation of the kinase (TABLE 1).

Covalent kinase inhibitors have a significant advantage in that high selectivity is possible through a combination of noncovalent and covalent interactions. A drawback of irreversible inhibitors is that drug resistance can develop when BTK variations at the catalytic site are not able to bind efficiently to irreversible inhibitors in treated patients. Noncovalent BTK inhibitors are designed to inhibit specific BTK mutations, and these agents have demonstrated clinical activity in patients who have previously failed on covalent BTK inhibitors. This has been seen in the context of malignancies, and is poorly understood in MS.¹²

Currently Approved BTK Inhibitors: Indications and Safety Concerns

Several BTK inhibitors have been developed, and 3 compounds— ibrutinib, acalabrutinib, and zanubrutinib—are already approved as drugs by the FDA and the European Medicines Agency for the management of hematological and neoplastic disorders (TABLE 2).

Ibrutinib, an irreversible binder that forms a covalent bond to a cysteine in the kinase’s catalytic region, was the first in its class; acalabrutinib and zanubrutinib followed as the next-generation inhibitors, though only in the United States and European Union, with zanubrutinib also earning approval in China. In most cases, these compounds have been used for the management of B-lymphocyte tumors. However, an increasing number of trials are testing these molecules in rheumatoid arthritis, pemphigus, and systemic lupus erythematosus.

The adverse effects (AEs) vary among BTK inhibitors. Atrial fibrillation, ventricular arrhythmias, conduction disorders, and hypertension have been observed in patients receiving ibrutinib.^13,14 Although this needs further investigation, there is evidence that the risk of cardiovascular AEs increases over time.¹⁵ Hemorrhages, skin manifestations, diarrhea, and cardiovascular diseases have been reported for certain covalently binding inhibitors. The molecular mechanisms causing these AEs are not clear. However, it has been speculated that covalent inhibitor AEs are caused by off-target binding to other kinases with cysteine in their binding site. The use of fenebrutinib in a series of autoimmune indications such as rheumatoid arthritis, systemic lupus erythematosus, and chronic spontaneous urticaria, suggested a low incidence of adverse reactions. Of those, 5% of fenebrutinib-treated patients in randomized controlled trials (n = 299) reported nasopharyngitis (6%), nausea (5.7%), and headache (5.4%).¹⁶ No patients experienced atrial or ventricular tachyarrhythmias. Bleeding or bruising was reported in 23 patients (7.7%) receiving fenebrutinib vs 3.2% receiving placebo, with no cases of major hemorrhage reported.¹⁶

BTK Inhibitors: Clinical Studies in MS

Targeting microglial activity in MS progression by inhibiting BTK activation represents a promising therapeutic strategy. So far, 5 BTK inhibitors—evobrutinib, tolebrutinib, fenebrutinib, remibrutinib, and orelabrutinib—have been tested for the treatment of patients with MS (TABLE 3). Although all these inhibitors are small molecules, they differ in their distinct characteristics.¹⁷ Evobrutinib, a selective BTK inhibitor, has already met its primary end point in a phase 2 clinical trial (NCT02975349) for the treatment of patients with relapsing-remitting MS, defined as total number of T1 gadolinium-enhancing lesions. However, evobrutinib showed no effect on progression of disability.¹⁸

At the time of the development of this publication, the FDA has decided to place on partial clinical hold tolebrutinib and orelabrutinib clinical studies due to safety concerns, particularly related to elevation of liver function abnormalities.

Discussion

BTK inhibitors represent a potential new class of medications for patients with MS. They are small molecules that can more easily cross the BBB. Other treatments for patients with MS, namely monoclonal antibodies, do not cross the BBB and do not exert their effect directly in the CNS. BTK inhibitors also affect a wide variety of immune cells, including B cells, NK cells, and microglia, which all play major roles in MS inflammation. Targeting B cells is a proven strategy for managing relapsing MS with multiple approved medications with this mechanism of action. These medications include ocrelizumab (Ocrevus; Genentech) and ofatumumab (Kesimpta; Novartis) whereas alemtuzumab and oral cladribine (Mavenclad; EMD Serono) deplete both B and T cells.

BTK inhibitors’ effect on microglia is particularly promising for managing PIRA and progressive MS. Evidence suggests that progressive MS is driven by cells from within the CNS such as microglia and astrocytes rather than peripheral immune cells.¹⁹ Currently, there is 1 FDA-approved medication for primary progressive MS, ocrelizumab, and none for secondary progressive MS. Ocrelizumab was shown to reduce 12-week confirmed disability worsening by 24%. However, there is no direct evidence that ocrelizumab crosses the BBB, and microglia do not express CD20.²⁰ Fenebrutinib is being studied in primary progressive MS, whereas tolebrutinib is being studied in both primary and secondary progressive MS. The development of new therapies that directly affect CNS immune cells could prove a significant breakthrough for patients with progressive MS.

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