September and October 2025 have proven busy for multiple sclerosis (MS) professionals, as many gathered at three major conferences to discuss trials in the indication that could alter the current treatment paradigm.

At the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), the International Symposium on MS & NMOSD, and the World Congress of Neurology, which opened their doors to attendees across the two months, experts across the globe convened to consider the best up-and-coming therapies for MS – a disease that is estimated to impact 2.9 million people worldwide.

At the forefront of these conversations were disease-modifying therapies (DMTs), which are used to reduce the prevalence and severity of relapses, while slowing the formation of new lesions in the brain and spinal cord.

While a range of DMTs are already approved for MS, three drugs are currently making their way through Phase III trials, including a Bruton’s tyrosine kinase (BTK) inhibitor, a CD20 cell killer and a dihydroorotate dehydrogenase (DHODH) inhibitor.

Novartis seeks MS scope expansion for remibrutinib

Following the recent approval of its oral Bruton’s tyrosine kinase (BTK) inhibitor Rhapsido (remibrutinib) in chronic spontaneous urticaria, Swiss pharma giant Novartis is looking to expand the drug’s label to include relapsing MS (rMS). To achieve this, the company is conducting the Phase III REMODEL-2 study (NCT05156281), where Rhapsido will go up against Sanofi’s DMT, Aubagio (teriflunomide).

The global trial, which spans 246 locations across 25 countries, is set for primary completion by 30 April 2026 – enrolling an estimated 800 patients with rMS.

Maya Zeineddine, clinical associate professor at Lebanese American University, has high hopes for the drug: “As a BTK inhibitor, Rhapsido has a novel mechanism of action for MS, meaning it can modulate B-cell signalling in a different way to all other available therapies.”

Zeineddine is also intrigued by Rhapsido’s capacity to trigger both myeloid and microbial activation within the central nervous system (CNS), which allows it to target both peripheral and central inflammation.

“BTK inhibitors such as Rhapsido and Sanofi’s tolebrutinib hold great potential in MS – especially in primary and secondary progressive subsets,” she adds.

Claire Winchester, head of research and information at UK-based patient advocacy charity MS Trust, echoes this sentiment, noting: “BTK inhibitors have some efficacy in progressive MS, which is one of the real unmet needs in the indication. If Rhapsido can demonstrate its effectiveness in late-stage trials, then it could have a place in the treatment paradigm.”

However, both Winchester and Zeineddine caveat that patients given Rhapsido will need to be carefully monitored for liver toxicity – an adverse event (AE) associated with BTK inhibitors. While Zeineddine believes that the drug’s safety profile is “manageable and minimally burdensome to the patient monitoring process”, Winchester sees Rhapsido’s hepatotoxicity as a more notable issue.

She warns: “Constant patient monitoring takes up clinic space.

“As there are other drugs which are as good at dealing with relapses without the requirement for monitoring, Rhapsido may not become a front-runner in the MS treatment paradigm.”

Christie Wong, managing neurology analyst at GlobalData, seconds this, stating: “Rhapsido could be positioned to be prescribed in rMS patients who have low inflammatory activity following treatment with anti-CD20 mAbs.”

Rituximab makes MS clinical trial comeback

Researchers at the Haukeland University Hospital (HUH) are putting CD20 killer rituximab to the test in a late-stage trial. Once touted as promising, Roche discontinued the drug’s development in MS in favour of a next-generation alternative, anti-CD20 monoclonal antibody (mAb) Ocrevus (ocrelizumab), which gained FDA approval in its new subcutaneous form in 2024.

Rituximab has been approved in oncology indications, including lymphoma and chronic lymphocytic leukaemia (CLL).

Despite Roche’s call to terminate rituximab’s development programme in MS, the drug is commonly prescribed as a cost-effective off-label treatment across Europe and the Middle East.

In the investigator-led OVERLORD-MS trial (NCT04578639) trial, rituximab is being pitted against Ocrevus. The study’s estimated completion date is 14 September 2025, and 214 patients across 12 Scandinavian locations are enrolled.

Wong notes that rituximab’s once-yearly dosing schedule could “offer more convenience” to patients compared with Ocrevus, which requires an intravenous infusion every six months.

Winchester is also surprised to see rituximab back in trials, as she thought the drug had “missed its moment”.

She says: “Rituximab is cheap, relative to other branded alternatives, so it can be attractive to have in the mix. However, I do not think it will replace Ocrevus or Kesimpta (ofatumumab) in the general MS population.”

Zeineddine has a rosier outlook on rituximab, as the efficacy of anti-CD20 drugs “have been proven by extensive, global real-world studies”. She also believes that it is the most cost-effective therapy for MS, meaning more patients will be able to access treatment.

Immunic bets on vidofludimus calcium

Another company seeking a stake in the MS market is Immunic, which is currently evaluating its dihydroorotate dehydrogenase (DHODH) inhibitor, vidofludimus calcium, in the Phase III ENSURE-1 trial (NCT05134441). This global study hopes to enrol around 1,050 patients across 86 sites in 16 countries. A topline readout for this trial is expected in 2026.

Despite Immunic’s high hopes, Zeineddine is less confident about the drug’s potential, noting its status as a “low efficacy therapy”.

She also notes that vidofludimus would have to outperform Aubagio (teriflunomide) in terms of efficacy to make it to market. If it were to achieve this, Zeineddine believes that its role would “likely be confined to patients uncomfortable with high-efficacy therapies due to their associated AEs”.

She cautions: “While it seems to be more tolerable than Aubagio from Phase II findings, its low efficacy may be a hurdle for physicians who are considering prescribing it.”

Though Winchester was once intrigued by vidofludimus, its failure to offer a statistically significant improvement to brain atrophy in the Phase II CALLIPER study (NCT05054140)  dampened her excitement for the drug.

“Neuroprotection is something most MS patients are seeking, as they want to preserve the function they still possess, rather than just thinking about relapse control,” she says.

“If Immunic can prove that the drug reduces brain atrophy and enhances neuroprotection, it may hold more potential in the MS market,” Winchester adds.

Despite muted interest from Zeineddine and Winchester, Wong notes that vidofludimus has shown some promise as an oral therapy for patients with rMS, as it “suppressed disease activity and delayed disability progression in the Phase II EMPhaSIS trial (NCT03846219)”.

Wong elaborates: “Key opinion leaders interviewed by GlobalData had mixed opinions on vidofludimus, with some envisioning it playing a ‘me-too’ role similar to Aubagio in MS”. However, she adds that the drug’s dual mode of action and suggested additional neuroprotective properties could offer it a leg up on the market.

Wong concludes: “To compete against Aubagio and generic formulations of teriflunomide, vidofludimus calcium must demonstrate positive findings in large Phase III trials in relapsing and progressive populations while Immunic would need to employ strong marketing.”