Evaluating Oral BTK Inhibitor Remibrutinib in Phase 3 Study for Generalized Myasthenia Gravis: The RELIEVE Trial

Welcome to NeurologyLive's Clinical Trial in Focus. Every month, an ongoing clinical trial in the landscape of neurology is featured, highlighting the design of the study, the targeted patient population, the enrollment criteria, the primary and secondary end points, and its potential implications for clinical care. This month’s spotlight is the phase 3 RELIEVE trial (NCT06744920) assessing remibrutinib (Rhapsido; Novartis), a selective oral Bruton's tyrosine kinase (BTK) inhibitor currently approved for chronic spontaneous urticaria (CSU), in adults with generalized myasthenia gravis (gMG).^1,2

Study Design

Presented at the 2025 American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) meeting, held October 29 to November 1, in San Francisco, by lead author Heinz Wiendl, MD, director of the Department of Neurology and Neuroscience at the University of Freiburg Medical Center, RELIEVE is a randomized, double-blind, placebo-controlled, multicenter phase 3 study that will enroll approximately 180 adults with gMG.¹ In the trial, participants will be assigned 1:1 to remibrutinib or matching placebo added to stable standard-of-care (SOC) therapy.

The study includes a 6-month double-blind core phase followed by an open-label extension (OLE) of up to 60 months. The primary end point is the change from baseline to month 6 in the Myasthenia Gravis Activities of Daily Living (MG-ADL) total score, with secondary end points including changes in Quantitative Myasthenia Gravis (QMG) and Myasthenia Gravis Composite (MGC) scores, as well as the incidence of adverse events (AEs).

Inclusion and Exclusion Criteria

Eligible participants are adults aged 18 to 75 years with a confirmed gMG diagnosis, reflecting moderate to severe generalized disease, and a baseline MG-ADL score of 6 or greater, with at least half of that score attributable to nonocular symptoms. In addition, patients who are acetylcholine receptor positive (AChR+), muscle-specific tyrosine kinase positive (MuSK+), or double-seronegative (AChR-/MuSK-), and seronegative are all eligible, a design choice that intentionally includes a population historically underrepresented in pivotal trials.

Exclusion criteria reflect washout requirements for agents that could confound outcome interpretation. These disqualifying treatments include IVIg or plasmapheresis in the prior month, rituximab in 6 months, eculizumab (Soliris; Alexion) in 2 months, ravulizumab Ultomiris; Alexion) or other complement inhibitors in 3 months, and anti-FcRn therapies such as efgartigimod (Vyvgart; argenx) in 3 months. Recent or planned thymectomy also disqualifies enrollment.

Remibrutinib in Multiple Sclerosis

The BTK Inhibitor remibrutinib being studied in the ongoing global phase 3b RESHAPE trial (NCT06846281) in patients with relapsing multiple sclerosis (RMS) who transition from ocrelizumab versus those who continue treatment with ocrelizumab (Ocrevus; Genentech). Presented at 2026 Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum, held February 5-7, in San Diego, California, RESHAPE will be enrolling approximately 360 participants to be randomized 1:1 to either switch to remibrutinib or continue ocrelizumab, with about 180 individuals assigned to each treatment arm.³

Eligible participants are adults aged 40 to 70 years with RMS who are receiving ocrelizumab at standard doses in routine clinical practice, are neurologically stable in 30 days prior to randomization, and are considered suitable for switching to remibrutinib. In the RESHAPE study, the primary efficacy end point will be annualized rate of new or enlarging T2 lesions at 24 months compared with baseline. Other key secondary endpoint include the proportion of participants achieving no evidence of disease activity-3 from baseline to 24 months, with additional secondary efficacy and safety outcomes also evaluated.

Remibrutinib in Various Autoimmune Disorders

In a prior analysis of remibrutinib, presented at the 9th Congress of the European Academy of Neurology, held July 1-4, in Budapest, Hungary, the agent demonstrated a positive safety profile and was well tolerated at all doses for up to 100 mg twice a day among patients with various autoimmune disorders.⁴ Data was collected from 267 patients with CSU 49 patients with Sjögren syndrome, and 47 patients with asthma, as well as an interim analysis of a 52-week open label extension (OLE) study in CSU.

Across the selected trials, 363 patients received remibrutinib at doses ranging from 10 mg to 100 mg once or twice daily for 12 to 52 weeks. Safety was assessed based on reports of AEs, including serious AEs and AEs of special interest (AESIs), as well as vital signs, electrocardiograms (ECGs), and laboratory parameters. AEs occurring in more than 10% of patients treated with remibrutinib included infections and infestations, and skin, subcutaneous, gastrointestinal, and nervous system disorders.

Original Approval

In September 2025, the FDA approved remibrutinib as the first and only oral BTK inhibitor BTKi for adults with CSU who remain symptomatic despite antihistamine therapy.² The twice-daily pill does not require injections or lab monitoring and offers a targeted approach to controlling the itching and hives of CSU by blocking BTK activity, an immune pathway that drives histamine and inflammatory mediator release.

The agency’s decision on the approval was based on results from the phase 3 REMIX-1 (NCT05030311) and REMIX-2 (NCT05032157) studies in patients who remained symptomatic on second-generation H1 antihistamines. The majority of patients treated remibrutinib with versus placebo achieved well-controlled disease as early as 2 weeks and at 12 weeks, and about 33% of patients achieved complete absence of itch and hives at 12 weeks. The most common AEs were nasal congestion, sore throat, and runny nose (nasopharyngitis), bleeding, headache, nausea, and abdominal pain.

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REFERENCES
1. Willi R, Bril V, Howard J, et al. Relive: A Phase 3 Study Evaluating the Efficacy and Saftey of Remibrutinb in Generalized Myasthenia Gravis. Presented at 2025 American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) Annual Meeting, held October 29-November 1, in San Francisco, California.
2. Novartis receives FDA approval for Rhapsido® (remibrutinib), the only oral, targeted BTKi treatment for chronic spontaneous urticaria (CSU). News release. Novartis. September 30, 2025. Accessed June 25, 2026. https://www.novartis.com/news/media-releases/novartis-receives-fda-approval-rhapsido-remibrutinib-only-oral-targeted-btki-treatment-chronic-spontaneous-urticaria-csu.
3. Hersh CM, Oreja-Guevara C, de Seze J, et al. Efficacy and Safety of Remibrutinib After Switching From Ocrelizumab in Participants With Relapsing Multiple Sclerosis: RESHAPE Study Design. Presented at ACTRIMS Forum 2026; February 5-7; San Diego, California. P113.
4. Airas L, Williams M, Chitnis T, et al. Remibrutinib: A Novel BTKi in Development for MS With a Favorable Safety Profile in Various Autoimmune Disorders. Presented at the 2023 European Academy of Neurology; July 1-4; Budapest, Hungary EPO-146.