Phase 2 Trial Evaluates Fenebrutinib Dosing in Children With Relapsing MS

Fenebrutinib, an investigational oral Bruton tyrosine kinase (BTK) inhibitor developed by Roche, is being evaluated in children and adolescents with relapsing multiple sclerosis (RMS) in the phase 2 FENerations1 trial (NCT07161258). The study design is being presented at the 10th Joint ACTRIMS-ECTRIMS Meeting (MSToronto), held October 21 to 23 in Toronto, Canada.¹

The open-label, single-arm study is enrolling approximately 8 to 12 participants aged 10 to younger than 18 years with RMS and recent inflammatory activity. Participants receive fenebrutinib during a dose-exploration period expected to last 12 weeks, followed by an optional extension of up to 96 weeks and a 4-week safety follow-up after treatment discontinuation. No pediatric pharmacokinetic (PK), pharmacodynamic (PD), efficacy, or safety findings are reported in the abstract.¹

Led by Henry Koiti Sato, MD, MSc, coordinator of the neurology service and neuroimmunology department at the Neurological Institute of Curitiba in Brazil, and investigators stated that the findings will help establish an appropriate dosing regimen for further clinical investigation of fenebrutinib in pediatric-onset RMS.¹

Coprimary End Points Assess Drug Exposure and MRI Activity

FENerations1 has 2 coprimary end points: plasma fenebrutinib concentration, used to estimate systemic exposure parameters, and the total number of new T1 gadolinium-enhancing (Gd+) lesions on MRI, which investigators describe as an indirect measure of the drug's PD effects. Safety assessments include treatment-emergent adverse events, vital signs, electrocardiograms, laboratory parameters, and monitoring for suicidal ideation.¹

According to Roche, the study is recruiting participants aged 10 to 17 years.² The trial aims to characterize how fenebrutinib is processed in the body, assess its effects on MRI measures of disease activity, and evaluate safety at different doses. Specific dose levels are not detailed in the abstract.¹

Study Results Awaited

The study status, participating countries, active sites, enrollment, and baseline characteristics will be presented at a future date. It does not report pediatric PK parameters, MRI lesion counts, efficacy outcomes, or adverse event rates. The study is intended to inform dose selection for subsequent clinical investigation. It is not designed to establish definitive efficacy in pediatric RMS.¹

Rationale for a Pediatric Program

The investigators noted that pediatric-onset MS is characterized by high disease activity and frequent relapses, although relatively few disease-modifying therapies (DMTs) are approved and available for this population. They also cited evidence associating early use of high-efficacy DMTs with better disease activity control than moderate- or low-efficacy treatments.¹

Fenebrutinib is an oral, central nervous system-penetrant, noncovalent, reversible, highly selective BTK inhibitor. The FENerations1 investigators noted that additional evidence is needed to characterize its PK profile and assess the potential role of BTK inhibition in children and adolescents with RMS.¹

Additional Context

In adults with RMS, fenebrutinib reduced annualized relapse rates compared with teriflunomide in the phase 3 FENhance 1 (NCT04586010) and 2 (NCT04586023) trials, which enrolled a combined 1497 participants. The relative reductions were 51.1% in FENhance 1 (P < .001) and 58.5% in FENhance 2 (P < .0001). Fenebrutinib also reduced new T1 Gd+ lesions by 70.7% and 77.6%, respectively (both P < .0001).³

Presented by Jacqueline Nicholas, MD, MPH, neuroimmunologist and director at OhioHealth MS Center, the data also suggested potential benefits on disability progression while reinforcing the therapy's manageable safety profile, including findings related to liver enzyme monitoring. NeurologyLive sat down with Nicholas to gain further insight into the clinical implications of these findings.

However, differences in 12-week composite confirmed disability progression were not statistically significant in either trial (FENhance 1: hazard ratio [HR], 0.80; 95% CI, 0.63-1.02; FENhance 2: HR, 0.87; 95% CI, 0.69-1.11). Across both trials, 7 deaths occurred in the fenebrutinib groups (0.9%) compared with 1 (0.1%) in the teriflunomide groups during the reporting period.³

In the phase 3 FENtrepid trial in primary progressive MS, fenebrutinib met the primary end point of noninferiority to ocrelizumab for reducing disability progression (HR, 0.88; 95% CI, 0.75-1.03).⁴

On September 30, 2026, the US Food and Drug Administration accepted a new drug application for fenebrutinib under priority review for RMS and primary progressive MS. Fenebrutinib remains investigational and is not approved for these indications.⁵

REFERENCES
1. Sato HK, Kotulska K, Powell G, et al. A phase II, open-label, single-arm trial to evaluate pharmacokinetics, pharmacodynamics, safety and tolerability of fenebrutinib in children and adolescents with relapsing multiple sclerosis (FENerations1): study design and baseline characteristics. Abstract 1041. Presented at: MSToronto2026, 10th Joint ACTRIMS-ECTRIMS Meeting; October 21-23, 2026; Toronto, Canada.
2. A study to see how fenebrutinib is processed in the body, how well it works to prevent signs of relapsing multiple sclerosis and how safe it is in children and teenagers with relapsing multiple sclerosis. Roche ForPatients. https://forpatients.roche.com/en/trials/autoimmune-disorder/multiple-sclerosis/a-pharmacokinetics--pk---pharmacodynamics--pd---safety--83549.html
3. Genentech's fenebrutinib significantly reduced relapses versus standard of care to approximately one every 17 years in RMS. Genentech. News Release. Published April 21, 2026. Accessed October 21, 2026. https://www.gene.com/media/press-releases/15109/2026-04-21/genentechs-fenebrutinib-significantly-re
4. Genentech's fenebrutinib is the first investigational medicine in over a decade that reduces disability progression in primary progressive multiple sclerosis (PPMS). Genentech. News Release. February 7, 2026. Accessed October 21, 2026. https://www.gene.com/media/press-releases/15098/2026-02-07/genentechs-fenebrutinib-is-the-first-inv
5. Genentech’s fenebrutinib is the first BTK inhibitor to receive U.S. FDA filing acceptance in both relapsing and primary progressive multiple sclerosis. News release. Genentech. September 29, 2026. Accessed September 30, 2026. https://www.gene.com/media/press-releases/15130/2026-09-29/genentechs-fenebrutinib-is-the-first-btk