BTK inhibitors: From the treatment of cancer to multiple sclerosis
The role of BTK inhibitors (BTKis) in cancer treatment has been well-established, but what prospects do they have in treating MS? Essential results from clinical trials are looming on the horizon.
Bruton’s tyrosine kinase inhibitors (BTKis) are molecules that inhibit Bruton’s tyrosine kinase: a soluble tyrosine kinase that is involved in the development, maturation, and signaling of B-cells. BTK functions downstream of the B-cell receptor, hence the main mechanism of action of BTKis is to disrupt this signaling pathway in both normal and malignant B-cells.1
Since BTK regulates the cell proliferation, survival, and migration of malignant B-cells, they are vital targets for anti-cancer therapies. Several BTKis have already been approved by the Food and Drug Administration (FDA) for the treatment of B-cell malignancies.2,3 The abundant expression and constitutive activity of BTK in the pathogenesis of B-cell hematological malignancies make BTKis an attractive treatment option in this setting, but repurposing these agents is also offering new hope for patients with solid tumors, exemplified by ongoing investigations in breast cancer and prostate cancer.
With a growing understanding of BTKis for hematological malignancies where B-cells replicate uncontrollably, it has also become questioned whether these BTKis could be used in other diseases where the immune system is dysregulated. One of these diseases is multiple sclerosis (MS), where autoreactive B-cells play a central role in the pathogenesis, not only via antibody production but also through pro-inflammatory cytokine production, antigen presentation, and T-cell activation.4
The rationale for using BTKis in MS treatment was further based on the success of anti-CD20 antibodies, such as rituximab and ocrelizumab, in treating rheumatoid arthritis, MS, and other autoreactive B-cell disorders.5 However, these directed antibodies unselectively target B-cells regardless of their pathogenic or protective status and consequently carry a high risk of a range of adverse events (AEs). Importantly, BTKis, especially second-generation BTKis, are thought to deplete disease-causing B-cells more selectively, keeping the healthy B-cell repertoire somewhat intact and avoiding detrimental AEs such as increased vulnerability to opportunistic infections.5
The improvements in BTKis have made them candidates for treating MS in humans. In fact, second-generation agents target immune cells more selectively, can cross the blood-brain barrier, and may have alternative roles in other immune cells, such as microglia. Preclinical studies agree on the fact that BTKis influence meningeal inflammation and cortical demyelination in animal models of MS, suggesting their activity within the central nervous system has the potential to tackle compartmentalized inflammation and neurodegeneration.4
Sharing her work presented at the ACTRIMS Forum 2022, Rochelle Benoit of Memorial University of Newfoundland, St. John’s, Newfoundland, Canada, states that human-derived macrophages treated with evobrutinib and tolebrutinib had a significant decrease in pro-inflammatory cytokine release, which is an additional benefit that BTKis might offer in treating MS.
Dr Ahmed Obeidat, MD, PhD, Medical College of Wisconsin, Milwaukee, WI, says that second-generation BTKis have both; 1) improved desired, on-target effects, like the modulation of B-cell activity, and 2) fewer off-target effects, such as bleeding.
BTKis are regularly compared to more traditional disease modifying therapies that work in the periphery to reduce the inflammatory disease activity of MS and associated relapses. The hope is that BTKis will mitigate relapses like these other therapies, in addition to tackling disease progression since they are able to have direct effects on brain resident B-cells through their penetrant nature.4
Phase II and III trials are ongoing to address whether BTKis will become prominent in the treatment of MS. Currently, there are four BTKis being investigated: tolebrutinib, evobrutinib, orelabrutinib, and fenebrutinib.5 Successful Phase II trials have shown a significant reduction in relapse rates and new MRI lesions in relapsing MS with the use of these agents.
With a variety of BTK inhibitors available (e.g., covalent, reversible), Phase III trials will hopefully dissect which ones are more favorable for MS treatment. The GEMINI 1 and 2 (NCT04410978; NCT04410991) and EVOLUTION RMS1 and RMS2 (NCT04338022; NCT04338061) trials are looking at tolebrutinib and evobrutinib, respectively, in relapsing forms of MS, while PERSEUS (NCT04458051) and HERCULES (NCT04411641) address the use of tolebrutinib in primary and secondary progressive MS, respectively. Fenebrutinib is also in Phase III for relapsing-remitting MS, active secondary progressive MS, and primary progressive disease.
For progressive MS, the clinical trials aim to observe a reduction or halt of disability worsening.6 Celia Oreja-Guevara, MD, PhD, University Hospital San Carlos, Madrid, Spain, believes this is the most important question at the moment, as BTKis are anti-inflammatory but also hopefully neuroprotective, which would decrease disease progression and promote “better evolution of the disease”.
Although this is promising, Nikolaos Grigoriadis, MD, PhD, Aristotle University of Thessaloniki, Thessaloniki, Greece, reminds us that “we need to be very patient because MS is a very peculiar disease in the end.”Therefore, remaining aware and cautionary of AEs is very important.
As we await the results of these trials, investigations should continue into the role of BTKis on microglia and other cell types in the CNS. The earliest Phase III trial results are expected in August 2023 for relapsing MS and August 2024 for progressive MS.6 Therefore, the jury remains out until then, with clinical trials likely providing answers that will alter the therapeutic landscape of MS.