BTK Inhibitors for MS Have Had Bumpy Ride

The race is on as several drugmakers get closer to the finish line in developing the first Bruton tyrosine kinase (BTK) inhibitor to treat multiple sclerosis (MS). BTK is a nonreceptor enzyme expressed in B cells and myeloid cells, both of which play a significant role in MS pathology. B cells in particular are found in demyelinated areas, chronic plaques and the cerebral spinal fluid of people with MS. These cells release proinflammatory cytokines that contribute to MS symptoms and disease progression. Inhibiting the BTK enzyme can block B cell activation and, drug developers hope, keep the proinflammatory cascade that follows from getting started.

Drug development for MS occurs in the context of a typology that groups the disease into categories based on the trajectory of the disease and the symptoms. The most common is relapsing-remitting MS (RRMS), in which a person has new or worsening symptoms (relapse) followed by periods of recovery (remittance). Most patients with RRMS eventually develop secondary progressive MS (SPMS), in which symptoms worsen with or without a halting
course of relapses.

Primary progressive MS (PPMS) is characterized by gradual worsening from the beginning of the disease without relapsing-remitting cycles.

Most disease-modifying therapies available today for MS target RRMS. Only Ocrevus (ocrelizumab), made by Genentech, is approved for PPMS. The BTK inhibitors could disrupt MS treatment in a good way.

But the BTK inhibitors have been on a bumpy ride. After several pharmaceutical companies dealt with FDA-imposed partial clinical holds of BTK inhibitor trials due to liver toxicity issues, Merck KGaA took its BTK inhibitor, evobrutinib, out of
the running. That left three other companies with BTK inhibitor candidates still moving ahead into
late-stage trials.

Tolebrutinib

Furthest along in the pipeline is tolebrutinib, developed by Paris-based Sanofi to potentially treat SPMS, PPMS and relapsing forms of MS. The investigational agent is an oral central nervous system penetrant that infiltrates the cerebrospinal fluid to modulate B cells and microglial cells in the central nervous system.

The company presented results from several phase 3 studies of tolebrutinib at a major MS meeting in Copenhagen, Denmark, in September 2024. In the HERCULES study, tolebrutinib delayed the time to onset of confirmed disability progression by 31% compared with placebo in participants with nonrelapsing secondary progressive SPMS. Additionally, twice as many patients who received tolebrutinib experienced confirmed disability improvement compared with those receiving placebo.

In terms of safety, 4.1% of participants receiving tolebrutinib experienced elevated liver enzymes compared with 1.6% of those receiving placebo, and 0.5% of patients in the tolebrutinib group had an enzyme increase more than 20 times the upper limit of normal. Apart from one patient, all liver issues were resolved without medical intervention. One patient required a liver transplant because of liver toxicity and died due to transplant complications.

All liver toxicity issues occurred within the first 90 days of receiving the study drug, and no serious liver issues have happened since the company increased the frequency of liver monitoring about halfway
through the trial.

The GEMINI 1 and 2 studies were phase 3 trials comparing tolebrutinib with the standard treatment Aubagio (teriflunomide) in patients with relapsing forms of MS. These studies did not meet their primary end points, and some of the news coverage emphasized that tolebrutinib had come up short.

However, pooled data of the secondary end points showed that tolebrutinib delayed the onset of disability worsening by 29%. That favorableresult aligns with the 31% delay in disability worsening seen in the
HERCULES trial.

Based on these and other results, Sanofi plans to file for approval with the FDA and drug regulators in other countries starting in late 2025.

Fenebrutinib

Next in line is Roche and Genentech’s fenebrutinib. The oral BTK candidate performed well in an open-
label extension of the phase 2 FENopta study of patients with relapsing forms of MS. The vast majority (96%) of participants who received fenebrutinib experienced no relapses after one year and no disability progression over 48 weeks. Roche presented these results at the same MS meeting in Copenhagen where Sanofi presented the tolebrutinib findings.

In addition, an analysis of MRI scans revealed no new T1 lesions, an indication of no active inflammation. In patients who received fenebrutinib during the open-label period, T2 lesions, markers of chronic disease burden, were three times lower than they had been at the end of the blinded study period.

Only one patient (1%) experienced liver enzyme elevation, which resolved after treatment discontinuation. Fenebrutinib is a noncovalent (reversible) oral agent with 130 times more affinity for BTK than for other kinases, according to preclinical study results. These are attributes that Roche claims may help minimize side effects and ultimately improve the agent’s long-term safety profile.

Fenebrutinib is currently in two phase 3 trials comparing it with Aubagio in patients with relapsing forms of MS. Another phase 3 trial, FENtrepid, is comparing fenebrutinib with Ocrevus in adults with PPMS.

Remibrutinib

Swiss drugmaker Novartis is developing remibrutinib, an oral, highly selective, covalent BTK inhibitor currently in phase 3 studies for the potential treatment of relapsing MS. The REMODEL I and II trials are recruiting about 800 participants aged 18 to 55 years with relapsing forms of MS.

The studies include an initial double-blind section lasting up to 30 months, followed by an open-label extension study lasting up to five years. During the initial phase, researchers will randomly assign patients to receive remibrutinib or Aubagio. All participants in the extension phase will receive the study drug.The primary end point is the annualized relapse rate. Secondary end points include annual new or enlarging T2 lesions, confirmed disability progression at three and six months, the number of T1 lesions, and the percentage of patients without evidence of disease activity. Preliminary study results are expected in April 2026.