Highlights
- Fenebrutinib reduced new T1 gadolinium-enhancing brain lesions by 69% compared to placebo over 12 weeks in patients with relapsing multiple sclerosis (RMS).
- During the 48-week open-label extension, 96% of participants remained relapse-free, with a low annualized relapse rate of 0.04.
- Fenebrutinib was well tolerated, with no serious adverse events or deaths; mild hepatic enzyme elevations and headaches were more common compared to placebo.
- Further studies are warranted to confirm efficacy in progressive MS and long-term safety.
Clinical Background and Disease Burden
Multiple sclerosis (MS) is a chronic, immune-mediated disorder characterized by demyelination and neurodegeneration in the central nervous system. Relapsing multiple sclerosis (RMS) encompasses the majority of new MS diagnoses and is marked by episodes of neurological worsening (relapses) and the development of new brain lesions detectable by MRI. Despite numerous disease-modifying therapies (DMTs), many patients continue to experience relapses, MRI activity, or treatment-limiting adverse effects. Bruton’s tyrosine kinase (BTK) inhibitors have emerged as a novel class targeting both adaptive and innate immune responses—key drivers of MS pathogenesis. However, recent trials have raised questions about the magnitude and durability of BTK inhibition benefits in MS, necessitating rigorous evaluation of new agents such as fenebrutinib.
Research Methodology
The FENopta study (NCT05119569) is a multicentre, double-blind, randomized, placebo-controlled, phase 2 trial conducted at 18 centers across Europe and North America. Eligible participants were 18–55 years old with RMS, an Expanded Disability Status Scale (EDSS) score between 0.0–5.5, and recent documented disease activity. Patients were randomized in a 2:1 ratio to receive oral fenebrutinib (200 mg twice daily) or placebo for 12 weeks. Stratification was performed based on the presence or absence of T1 gadolinium-enhancing (Gd+) lesions on screening brain MRI. Both patients and investigators were blinded to treatment allocation.
After the double-blind phase, participants could enter an optional open-label extension (OLE) to receive fenebrutinib for up to 192 weeks, with continued MRI and clinical assessments.
The primary efficacy endpoint was the combined number of new T1 Gd+ lesions at weeks 4, 8, and 12. Secondary endpoints included annualized relapse rate (ARR) during the OLE and safety/tolerability. Efficacy analyses included randomized patients with evaluable post-baseline MRIs; safety analyses were conducted in all treated patients.
Key Findings
Between March 2022 and March 2023, 109 RMS patients were randomized: 73 received fenebrutinib and 36 received placebo. Efficacy analysis included 70 fenebrutinib-treated and 36 placebo-treated patients, each with valid post-baseline MRIs.
The primary endpoint—mean combined number of new T1 Gd+ lesions at weeks 4, 8, and 12—was 0.077 (95% CI 0.043–0.135) in the fenebrutinib group and 0.245 (0.144–0.418) in the placebo group, representing a 69% relative reduction (95% CI 34–85, p=0.0022) with active treatment. This reduction demonstrates robust and early suppression of new focal inflammatory activity in the CNS.
During the open-label extension (up to 48 weeks), the unadjusted annualized relapse rate was 0.04, with 96% (95 of 99) of patients remaining relapse-free. This suggests that fenebrutinib’s clinical benefits may be durable, at least in the short to intermediate term.
Regarding safety, adverse events more common in the fenebrutinib group included hepatic enzyme elevations (6% vs 0%), headache (4% vs 3%), and nasopharyngitis (3% vs 0%). Importantly, there were no serious adverse events or deaths reported during the randomized phase.
Mechanistic Insights and Biological Plausibility
Fenebrutinib is a highly selective, noncovalent, reversible BTK inhibitor. BTK plays a critical role in B-cell receptor signaling and in modulating innate immune activity, particularly in microglia. Preclinical studies support fenebrutinib’s ability to modulate both B-cell and myeloid cell activation, reducing pro-inflammatory signaling within the CNS (Langlois J et al., J Neuroinflammation 2024). This dual action is hypothesized to underlie its efficacy in suppressing new MRI lesion formation and, potentially, long-term neuroprotection.
Controversies and Limitations
While the FENopta trial demonstrates a significant reduction in new MRI lesions and a highly favorable short-term relapse profile, several limitations merit discussion:
– The study was relatively short (12 weeks double-blind, 48 weeks OLE), limiting assessment of long-term efficacy and safety.
– The sample size was modest (109 randomized), and the trial was not powered for definitive clinical endpoints such as confirmed disability progression.
– The population included only RMS patients; efficacy in progressive MS remains unknown.
– As with all industry-sponsored trials, there is potential for sponsorship bias, although rigorous blinding and methodology were employed.
Additionally, the broader class of BTK inhibitors has yielded mixed results in MS, with questions about the sustainability of MRI and clinical benefits beyond the first year. Larger, longer-term phase 3 studies are essential to clarify fenebrutinib’s risk-benefit profile and its place among existing DMTs.
Conclusion
Fenebrutinib demonstrated robust suppression of new inflammatory brain lesions and a low relapse rate in RMS patients over 12–48 weeks, with an acceptable safety profile. These data position fenebrutinib as a promising BTK inhibitor for RMS. Further research is required to determine its long-term safety, durability of efficacy, and impact on progressive MS subtypes. Clinicians and researchers should continue to monitor emerging data as phase 3 trials unfold.
References
Bar-Or A, Dufek M, Budincevic H, Drulovic J, Habek M, Hua LH, Weber MS, Thomas P, Napieralski J, Mitzner MC, Ratchford JN, Clayton D, Harp CT, Kuruvilla D, Qi Q, Chen YF, Xu Y, Goodyear A, Oh J; FENopta Study Group. Safety and efficacy of fenebrutinib in relapsing multiple sclerosis (FENopta): a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial and open-label extension study. Lancet Neurol. 2025 Aug;24(8):656-666. doi: 10.1016/S1474-4422(25)00174-7.
Langlois J, Lange S, Ebeling M, Macnair W, Schmucki R, Li C, DeGeer J, Sudharshan TJJ, Yong VW, Shen YA, Harp C, Collin L, Keaney J. Fenebrutinib, a Bruton’s tyrosine kinase inhibitor, blocks distinct human microglial signaling pathways. J Neuroinflammation. 2024 Oct 27;21(1):276. doi: 10.1186/s12974-024-03267-5.