Tolebrutinib

Novartis appears to have broken the curse of the BTK inhibitor class. The Swiss pharma announced Tuesday that two phase 3 trials for Rhapsido in relapsing multiple sclerosis hit their goals without any liver safety flags. The phase 3 Remodel-1 and -2 trials showed that Rhapsido (remibrutinib) beat Sanofi’s older drug Aubagio (teriflunomide) at reducing annualized relapse rate in relapsing MS, the studies’ primary endpoint, according to Novartis. The Novartis BTK drug also improved inflammatory brain lesions and demonstrated “clinically meaningful” reductions in secondary endpoints related to disability progression. A positive trend was observed in three-month confirmed disability progression, with nominal significance at the six-month mark in a preplanned combined analysis of the two identical trials. During an investor call in July, Novartis CEO Vas Narasimhan defined an improvement in disability progression in the “mid-teens” as clinically meaningful. But perhaps more importantly, Novartis said Rhapsido was well tolerated as the trials found “no liver safety signal, including no cases meeting Hy’s Law criteria,” which are used by doctors to identify patients at high risk of a fatal drug-induced liver injury. Nearly 2,000 patients participated in the two studies, in which patients were randomized 1:1 to receive either Rhapsido or Aubagio. Novartis plans to seek regulatory approval for Rhapsido in relapsing MS globally. Data from the two Remodel trials will be presented at MSToronto2026 in October. For years, the promise of the BTK inhibitor class in multiple sclerosis was undercut by recurring liver toxicity signals, which previously triggered FDA clinical holds on competing drugs from Sanofi and Roche. The concerns culminated in an FDA rejection for Sanofi’s tolebrutinib in non-relapsing secondary progressive MS, a form of the neurological disorder that involves a steady, continuous worsening of disability over time. In a complete response letter, the FDA specifically raised the risk of severe drug-induced liver injury recorded in tolebrutinib’s trials, including six cases that met Hy’s Law. As for Roche’s fenebrutinib, which was the subject of an FDA partial clinical hold in 2023 following two cases of elevated liver enzymes, the Swiss drugmaker recently reported one Hy’s Law case for its BTK drug and one for Aubagio in the phase 3 FENhance1 study in relapsing MS. “It’s also really important to note that since we put liver monitoring in place in the clinical trials, we have not seen any more cases,” Roche’s pharma chief, Teresa Graham, said during an investor call in January. “So I think we feel very good about the overall benefit-risk profile that we have with fenebrutinib, particularly when you consider the other half of that coin, which is the benefit.” In both FENhance1 and FENhance2, investigators saw eight deaths in the fenebrutinib arm, including two that were tied to the Roche BTK drug. There was one death (0.1%) among patients who took Aubagio. A Novartis spokesperson confirmed to Fierce that no treatment-related deaths were reported in the Remodel trials for Rhapsido. Rhapsido got its initial FDA approval in September 2025 as a treatment for chronic spontaneous urticaria (CSU), also known as chronic hives. In MS, Roche’s infused CD20 antibody Ocrevus has been the top-selling therapy, as Novartis’ self-injected CD20 drug Kesimpta plays catch up with fast sales growth. Now, with Rhapsido, Novartis aims to introduce a new oral option, potentially given ahead of biologics. “Despite advances in treatment, an unmet need remains for oral therapies that can deliver robust relapse prevention, slow disability progression, while maintaining a favorable safety profile,” Novartis’ chief medical officer, Shreeram Aradhye, said in a Sept. 1 statement. “The positive Remodel results underscore the potential of remibrutinib as a high-efficacy oral therapy for people living with RMS with a differentiated benefit-risk profile.” Besides annualized relapse rate and MRI performance, disability progression data will be important to determine where Rhapsido could be placed relative to the B-cell antibodies, Narasimhan said during the July investor call. Novartis is also testing its BTK drug in other forms of MS and other immune-related conditions. Besides MS and CSU, the company recently reported a positive pivotal readout for Rhapsido in chronic inducible urticaria and has launched a phase 3 in food allergy following promising mid-stage data, with a separate phase 3 ongoing in hidradenitis suppurativa. Tuesday’s announcement comes on the heels of the revelation of three deaths from Novartis’ investigational autoimmune CAR-T program, rapcabtagene autoleucel, in which patients died from complications caused by serious immune adverse reactions. As a result, Novartis has paused development of the CD19 candidate across multiple clinical studies, including a phase 1/2 involving relapsing MS patients.

Novartis' oral BTK inhibitor Rhapsido (remibrutinib) met the primary endpoint in two Phase III trials in relapsing multiple sclerosis (RMS), significantly reducing annualised relapse rates (ARRs) versus Sanofi's Aubagio (teriflunomide), the company said Tuesday.The Swiss pharma announced the results Tuesday, and with the data in hand, it's now gearing up to file for regulatory approvals worldwide, which could broaden Rhapsido's reach beyond its current indication of chronic spontaneous urticaria, where it is already cleared in the US and EU (see – Spotlight On: Novartis looks to play long game with Rhapsido/remibrutinib).Novartis said that aside from the main ARR goal, Rhapsido also demonstrated superiority on all key secondary measures in both the REMODEL-1 and REMODEL-2 studies, including reduction of MRI lesions.The trials generated signals suggesting a potential benefit on disability progression as well. In a preplanned combined analysis of the two studies, Rhapsido showed a "positive trend" on three-month confirmed disability progression and a nominally significant reduction in six-month confirmed disability progression. Detailed results are due to be presented at MSToronto2026 next month.BTK safety in the spotlightSafety is likely to be a key focus of the forthcoming data, particularly given concerns surrounding liver toxicity with BTK inhibitors (see – Spotlight On: Can positive Phase III data set Novartis' remibrutinib up as the BTKi to beat in multiple sclerosis?).Novartis said Rhapsido was well tolerated in REMODEL-1 and REMODEL-2 and that its safety profile was consistent with the broader development programme involving more than 4500 participants across multiple indications. Of note, the company reported no liver safety signal either, including no cases meeting Hy's Law criteria."The positive REMODEL results underscore the potential of remibrutinib as a high-efficacy oral therapy for people living with RMS with a differentiated benefit-risk profile," said Shreeram Aradhye, the company's chief medical officer.With Tuesday's topline readouts, Rhapsido becomes the second BTK inhibitor to post a Phase III win in RMS, following Roche's fenebrutinib. That drug reduced ARRs by 51% and 59% versus Aubagio over a period of at least 96 weeks in the FENhance 1 and FENhance 2 trials, respectively. However, its development has been marred by deaths and liver-related findings.Specifically, across 1497 patients in the FENhance studies, there were eight deaths among those on fenebrutinib and one in the Aubagio arm. Roche stated earlier this year that the fatalities were due to "various causes and at different points in treatment," and that analyses were ongoing.Liver transaminase elevations were comparable with Aubagio across the FENhance studies. In FENhance 1, there was one Hy's Law case in the fenebrutinib arm and another with Aubagio; both were asymptomatic and resolved after study drug discontinuation.In an interview with FirstWord earlier this year, Staley Brod — professor of neurology and director of the Multiple Sclerosis/Neuro-immunology division at Medical College of Wisconsin – suggested the lingering BTK class safety concerns related to liver toxicity signals and an imbalance in deaths in the fenebrutinib trials may make some prescribers cautious (see – KOL Views Q&A: Roche needs to lean on fenebrutinib's efficacy, oral dosing to overcome safety questions, monitoring demands in MS).