The emergence of BTK inhibitors in multiple sclerosis treatment: Companies close in on approval

Bruton tyrosine kinase (BTK) inhibitors are typically used to treat B-cell malignancies, but they have also recently attracted interest for their potential in treating the autoimmune disorder multiple sclerosis, in which the body’s immune system mistakenly attacks myelin, a coating around the nerves to protect them from damage. This causes a disruption in communication between the brain and the body that results in a range of debilitating symptoms like muscle weakness, problems with balance and coordination, numbness, and blurry vision. 

In this article, we explore how BTK inhibitors could help to treat multiple sclerosis and which candidates currently show promise in the clinic. 

How can BTK inhibitors treat multiple sclerosis? 

The relatively recent success of selective B-cell depletion therapies, like FDA-approved Ocrelizumab (Ocrevus) and Ofatumumab (Kesimpta), in patients with multiple sclerosis has led to a shift in the understanding of the pathogenesis of the disease, in which B cells are now considered to play a significant role in both the inflammatory and neurodegenerative components of the disease process.

This is why BTK inhibitors are currently being explored as a potential treatment for multiple sclerosis; they target BTK, an enzyme that is expressed in B cells (as well as in myeloid cells, which also play a role in multiple sclerosis pathology). Therefore, by inhibiting the BTK enzyme, B cell activation can be blocked, which drug developers hope will then stop the proinflammatory cascade that usually follows. 

Additionally, one of the main benefits of using BTK inhibitors for the treatment of multiple sclerosis is that they have a proven ability to cross the blood-brain barrier, which can often be an obstacle in the treatment of central nervous system (CNS) disorders. 

Big pharma leading the way in the development of BTK inhibitors for multiple sclerosis

It is fair to say that big pharma has led the way in heavily backing the potential of BTK inhibitors in the treatment of multiple sclerosis. Currently, three companies are leading the race after taking their candidates into late-stage trials: Sanofi, Roche, and Novartis. 

Sanofi’s tolebrutinib leads the race for FDA approval 

The BTK inhibitor for multiple sclerosis that is currently furthest ahead in the development pipeline is Sanofi’s tolebrutinib, an oral brain-penetrant drug designed to target smoldering neuroinflammation, a key driver of disability progression in multiple sclerosis. 

Unlike currently approved multiple sclerosis therapies, which primarily address peripheral inflammation, tolebrutinib is able to cross the blood-brain barrier to achieve therapeutic cerebrospinal fluid concentrations, allowing it to modulate B-lymphocytes and disease-associated microglia within the CNS. This mechanism is believed to address the underlying pathology of progressive multiple sclerosis by targeting the inflammatory processes that contribute to neurodegeneration and disability accumulation.

Despite the U.S. Food and Drug Administration (FDA) placing a partial clinical hold on the candidate in 2022 due to a limited number of cases of drug-induced liver injury – something that has affected multiple companies during the development of their BTK inhibitors – the drug has since soared ahead and has recently achieved positive phase 3 results that are likely to lead to its approval as the first BTK inhibitor for multiple sclerosis. More specifically, it would be the first and only brain-penetrant BTK inhibitor to both treat non-relapsing secondary progressive multiple sclerosis and slow disability accumulation independent of relapse activity. 

In September 2024, Sanofi presented positive results from its phase 3 HERCULES study of tolebrutinib at the 40th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). In the trial, the BTK inhibitor demonstrated a 31% delay in the time to onset of confirmed disability progression in non-relapsing secondary progressive multiple sclerosis compared to placebo. Furthermore, twice as many patients who received tolebrutinib experienced confirmed disability improvement compared to those receiving placebo (10% compared to 5%).

Last month, the pharma giant announced that the FDA is evaluating the regulatory submission of tolebrutinib under priority review to treat non-relapsing secondary progressive multiple sclerosis and to slow disability accumulation independent of relapse activity in adult patients. The target action date for the FDA decision is September 28, 2025. Meanwhile, a regulatory submission is also under review in the European Union (EU). 

According to Clinical Trials Arena, experts previously interviewed by leading data and analytics company GlobalData stated that, if tolebrutinib does receive approval, it is likely to be accompanied by a boxed warning, as well as risk evaluation and mitigation strategies, due to the prior concerns regarding its liver-associated side effects. 

Fenebrutinib, Roche’s BTK inhibitor, demonstrates efficacy in phase 2 multiple sclerosis trial

Despite also suffering a setback in November 2023 when the FDA placed its BTK inhibitor fenebrutinib on a partial clinical hold due to cases of liver injury, Roche has recently seen success for its multiple sclerosis candidate in phase 2 trials. 

Indeed, in September 2024, Roche announced extremely encouraging results for fenebrutinib; the drug demonstrated near-complete suppression of disease activity and disability progression for up to 48 weeks in patients with relapsing multiple sclerosis. During the open-label extension period of the phase 2 trial, 96% of patients were free of relapses at one year and had no disability progression over 48 weeks. Additionally, an analysis of MRI scans revealed that 99% of patients were free of T1 gadolinium-enhancing lesions (areas of active inflammation used to track disease progression). 

It is worth noting that fenebrutinib stands out from some of the other candidates because it is a reversible, non-covalent Bruton’s tyrosine kinase (BTK) inhibitor. This means that it may potentially contribute to better long-term safety and could address drug resistance seen in covalent BTK inhibitors, which form permanent bonds. 

Roche is currently conducting three phase 3 trials for fenebrutinib, including the FENhance 1 and 2 trials in relapsing multiple sclerosis, and the FENtrepid trial in primary progressive multiple sclerosis. Data from these studies, which will characterise the effects of fenebrutinib on disease progression across the multiple sclerosis spectrum, are expected at the end of 2025.

Novartis tests BTK inhibitor remibrutinib in phase 3 trials for relapsing multiple sclerosis

Swiss giant Novartis is also testing its BTK inhibitor in phase 3 trials in patients with relapsing multiple sclerosis. The studies are called REMODEL I and II and are recruiting around 800 participants. 

The trials include an initial double-blind part lasting up to 30 months, which will then be followed by an open-label extension study lasting up to five years. During the initial phase, researchers will be testing remibrutinib against Aubagio, an approved disease-modifying drug for multiple sclerosis. All participants in the extension phase will then just receive remibrutinib.

Although Novartis’ drug has not been tested in early-stage trials specifically for multiple sclerosis, it has been studied as a treatment for other autoimmune-related conditions, including chronic spontaneous urticaria – a skin condition characterized by itchy, red, raised patches or bumps – and was found to be efficacious and well-tolerated with no serious side effects.

Preliminary study results for the multiple sclerosis trials are expected in April 2026.

Biogen pushes on with in-house BTK inhibitor despite dropping licensed BTK asset belonging to InnoCare

Another giant of the biopharma industry, Biogen, is also developing a BTK inhibitor for multiple sclerosis. 

Similar to Roche’s fenebrutinib, Biogen’s candidate, called BIIB091, is a reversible, non-covalent BTK inhibitor that could address the drug resistance seen in covalent BTK inhibitors. It is currently being tested in a phase 2 trial as a monotherapy, as well as in combination with diroximel fumarate, Biogen’s already-approved disease-modifying drug for the treatment of relapsing forms of multiple sclerosis that is sold under the brand name Vumerity.

The study, which will enroll 275 participants in total, will be split into two parts, with safety as the primary end point for part one and reductions in T1 gadolinium-enhancing lesions for part two. 

The completion date for the trial is listed as November 2026, so we can potentially expect to hear an update on the candidate’s progress later this year or early next year. 

Although Biogen is choosing to progress with BIIB091, it decided to ditch Chinese biotech InnoCare Pharma’s BTK inhibitor orelabrutinib in February 2023, just 19 months after it had paid $125 million for exclusive rights to the candidate in the field of multiple sclerosis worldwide and certain other autoimmune diseases outside of China. Biogen did not specify why it had dropped the candidate at the time, but the decision came a couple of months after the FDA placed a partial clinical hold on the BTK inhibitor due to drug-related cases of liver injury. 

Nevertheless, InnoCare remained confident in orelabrutinib and rightly so, as it has since achieved positive phase 2 results demonstrating that it was highly effective in reducing new/enlarging gadolinium-enhancing lesions in patients with relapsing-remitting multiple sclerosis over a 24-week period. Additionally, in terms of safety, there were no serious treatment-emergent adverse events recorded in the 80mg once daily dosage group, which was considered the most efficacious. Notably, this group had the lowest liver-related adverse events compared with placebo.

At the conclusion of InnoCare’s end of phase 2 meeting with the FDA in September last year, an agreement was reached on the initiation of a phase 3 trial in patients with primary progressive multiple sclerosis. InnoCare was also encouraged to conduct a second phase 3 trial of orelabrutinib in patients with progressive multiple sclerosis and secondary progressive multiple sclerosis. 

BTK inhibitors for multiple sclerosis: Can efficacy overcome safety concerns? 

Although BTK inhibitors clearly hold potential for treating multiple sclerosis, mitigating side effects has proven to be difficult, leading to limited success in the space and a limited pipeline of candidates. As can be seen from the many clinical holds placed on companies developing BTK inhibitors, safety issues are a genuine concern, with liver injuries being the main one. 

However, the good news is that these clinical holds have been lifted in many cases, and companies like Sanofi and Roche have managed to continue the development of their BTK inhibitors into late-stage trials. 

With the efficacy of these candidates being so high and side effects limited, it is likely that the FDA will approve these BTK inhibitors – but they may come with a boxed warning. Then it is up to doctors and patients to decide whether they believe the benefits outweigh the potential safety concerns. 

Ultimately, whether BTK inhibitors will become a breakthrough in multiple sclerosis treatment, we will just have to wait and see.