fenebrutinib (RG7845) / Roche - LARVOL DELTA

Evidence-Based Information on Newer Drugs for Chronic Spontaneous Urticaria (AAD 2026) - " Bruton Tyrosine Kinase inhibitors, remibrutinib and fenebrutinib, are fast-acting, oral medications with a favorable safety and efficacy in CSU and greater potency in type IIb autoimmune urticaria...Quilizumab, canakinumab, Tezepelumab, and benralizumab are not beneficial in CSU. BTK inhibitors are efficacious in CSU and may be superior to omalizumab for type IIb autoimmune urticaria, where disease control is often delayed and limited with anti-IgE agents. Ligelizumab and dupilumab are safe and effective alternatives to omalizumab for anti-histamine-resistant CSU."

Chronic Spontaneous Urticaria • Dermatology • Immunology • Urticaria • IL4 • IL4R

A Phase I Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Fenebrutinib and Effect on the QT/QTc Interval in Healthy Participants. (PubMed, Clin Transl Sci) - "Part B was a randomized, double-blind, single-dose, four-way crossover study that included both therapeutic and supratherapeutic fenebrutinib doses, a positive control (moxifloxacin 400 mg), and placebo. In the regression analysis, UBs of one-sided 95% CIs for ΔΔQTcF at the maximum concentration of fenebrutinib were < 10 ms: 4.4 and 7.8 ms with the therapeutic and supratherapeutic doses, respectively. Overall, both doses of fenebrutinib had no clinically meaningful impact on QT interval and were well tolerated, supporting fenebrutinib's favorable safety profile and continued clinical development."

Clinical • Journal • P1 data • PK/PD data • CNS Disorders • Multiple Sclerosis

Efficacy and Safety of Fenebrutinib vs Ocrelizumab in Primary Progressive Multiple Sclerosis: Primary Results of the Phase III FENtrepid Study (AAN 2026) - P2, P3 | "FENtrepid will provide the first evidence on the effect of fenebrutinib treatment on disability progression in PPMS, relative to an active comparator of ocrelizumab."

Clinical • P3 data • CNS Disorders • Inflammation • Multiple Sclerosis

Efficacy and Safety of Fenebrutinib vs Teriflunomide in Relapsing Multiple Sclerosis: Results of the FENhance 1 and 2 Studies (AAN 2026) - No abstract available

Clinical • Late-breaking abstract • CNS Disorders • Multiple Sclerosis

Genentech's Fenebrutinib Confirms Its Potential as First and Only BTK Inhibitor for Relapsing and Primary Progressive MS in Third Positive Phase III Study (FENhance 1) (Genentech Press Release) - "FENhance 1 met its primary endpoint, showing investigational fenebrutinib significantly reduced relapses by 51% compared to teriflunomide in relapsing multiple sclerosis (RMS), consistent with FENhance 2 results showing 59% reduction...Secondary endpoints in both RMS studies show statistically significant and clinically meaningful reductions in brain lesions. Additionally, all progression endpoints show favorable trends for fenebrutinib...Full data from the FENhance 1 and 2 studies will be shared at the American Academy of Neurology (AAN) Annual Meeting 2026 and submitted to regulatory authorities together with data from the FENtrepid study."

Filing • P3 data • Multiple Sclerosis

Involvement of Btk in Cardiovascular Disease and Its Therapeutic Targeting. (PubMed, Circulation) - "First-generation BTKi such as ibrutinib demonstrate antithrombotic efficacy but are limited by off-target effects, including bleeding and atrial fibrillation. Second- and third-generation inhibitors (eg, acalabrutinib, zanubrutinib, and pirtobrutinib) show enhanced selectivity, reducing cardiovascular toxicity in patients with B-cell malignancies. Highly selective BTKi (fenebrutinib and remibrutinib) do not show bleeding in clinical trials of various autoimmune disorders, and covalent selective BTKi applied at low dosage are expected to selectively inhibit Btk in platelets without bleeding side effects. Preclinical data and early observations from compassionate use in patients with atypical autoimmune thrombosis highlight the potential of BTKi as selective antithrombotic agents beyond traditional therapies. This review conceptualizes and underscores Btk's pivotal role at immune-thrombosis interfaces in atherothrombosis, advocating for precision medicine approaches..."

Journal • Review • Atherosclerosis • Atrial Fibrillation • Cardiovascular • Hematological Disorders • Hematological Malignancies • Immunology • Inflammation • Oncology • Primary Immunodeficiency • Thrombosis • NLRP3

Efficacy and Safety of Fenebrutinib vs Ocrelizumab in Primary Progressive Multiple Sclerosis: Primary Results of the Phase III FENtrepid Study (ACTRIMS Forum 2026) - P2, P3 | "FENtrepid will provide the first evidence on the effect of fenebrutinib treatment on disability progression in PPMS, relative to an active comparator of ocrelizumab."

Clinical • Late-breaking abstract • P3 data • CNS Disorders • Inflammation • Multiple Sclerosis

Systemic Treatments for Chronic Spontaneous Urticaria: Anti-IgE and Beyond. (PubMed, J Allergy Clin Immunol Pract) - "Current standard of care includes nonsedating H1-antihistamines and omalizumab, which targets peripheral blood IgE and downregulates mast cell and basophil IgE receptors...Dupilumab received FDA approval for H1-antihistamine-refractory CSU, supporting targeting type 2 cytokines, IL-4 and IL-13. Most recently, a Bruton's tyrosine kinase inhibitor (BTKi), remibrutinib, demonstrated significant reductions in Urticaria Activity Score over 7 days in phase 3 trials, leading to FDA approval. Newer c-Kit (cKit or KIT) inhibitors have also shown efficacy in CSU and CIndU, with barzolvolimab showing sustained efficacy post-treatment...Some drugs have been halted in development because of safety concerns, such as fenebrutinib (BTKi), THB001 (Larvol; c-Kit inhibitor), and EP262 (MRGPRX2 antagonist), whereas others, targeting the alarmin thymic stromal lymphopoietin (tezepelumab), the Th2 cytokine IL-5 (mepolizumab) and its receptor IL-5R (benralizumab), as well as lirentelimab..."

Journal • Review • Cardiovascular • Chronic Spontaneous Urticaria • Dermatology • Immunology • Urticaria • IL13 • IL4 • IL5 • SIGLEC8 • TSLP • TYK2

Late-breaking Phase III FENtrepid results presented at ACTRIMS show investigational fenebrutinib met its primary endpoint of non-inferiority compared to the current standard of care, OCREVUS, in reducing disability progression in PPMS (GlobeNewswire) - "Fenebrutinib numerically reduced the risk of disability progression by 12% compared to OCREVUS as early as 24 weeks; additional analysis showed potential benefit in upper limb function....The cCDP12 primary endpoint included the confirmed disability progression (CDP) based on the Expanded Disability Status Scale (EDSS) for functional disability, the timed 25-foot walk (T25FW) for walking speed and the nine-hole peg test (9HPT) for upper limb function. The strongest treatment effect was observed on the risk of worsening on the 9HPT by 26% (HR 0.74; 95% CI: 0.56, 0.98) compared to OCREVUS....Regulatory submission for fenebrutinib in both PPMS and RMS is planned following the Phase III FENhance 1 readout, expected mid first half of 2026."

Filing • Late-breaking abstract • P3 data • Multiple Sclerosis

Invitation to Roche’s Virtual Neurology/ACTRIMS Investor Event (Roche Press Release) - "We are pleased to invite investors and analysts to participate in our virtual event on Monday, 9 February 2026, to highlight Roche’s neurology pipeline and new data from the Phase III FENtrepid study evaluating fenebrutinib vs. Ocrevus (ocrelizumab) in PPMS, which will be presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum from 5-7 February 2026."

P3 data • Multiple Sclerosis

Emerging IgE and non-IgE targeted therapies for chronic urticaria. (PubMed, Ann Allergy Asthma Immunol) - "Dupilumab received FDA approval for antihistamine refractory chronic spontaneous urticaria (CSU) supporting the targeting of type-2 cytokines, IL-4 and IL-13, in this disease. Bruton's tyrosine kinase (BTK) inhibitors show promise, with remibrutinib receiving FDA approval and demonstrating significant reductions in UAS7 in Phase 3 trials. c-Kit (c-Kit or KIT) inhibition with barzolvolimab shows robust efficacy with sustained effects post-treatment...Although some programs have been discontinued due to safety concerns or lack of efficacy such as fenebrutinib (BTK inhibitor), THB001 (c-Kit inhibitor), EP262 (MRGPRX2 antagonist), tezepelumab (anti- TSLP), as well as lirentelimab and AK006 (Siglec-targeting agents), these studies have informed many of the other positive studies. In summary, over the last year, we have seen the CU pipeline mature with multiple Phase 3 programs and new approvals representing diverse mechanisms of action. Nevertheless, significant..."

Journal • Review • Chronic Spontaneous Urticaria • Dermatology • Immunology • Urticaria • IL13 • IL4 • TSLP

Liver signals again trigger partial FDA hold on Roche's fenebrutinib MS studies (Firstwordpharma Press Release) - "...the FDA is once again intervening in the late-stage development of fenebrutinib for multiple sclerosis (MS), placing a partial clinical hold on the US arm of the programme following new reports of liver enzyme abnormalities in ongoing Phase III trials....As a result, new patient enrollment in the US for the FENhance I relapsing MS (RMS) study has been paused as regulators investigate the cases and whether they perhaps point to a broader liver-safety signal for the BTK inhibitor class. Enrollment outside the US continues uninterrupted....Both patients were asymptomatic, and lab values normalised after treatment was discontinued, according to Roche."

Trial suspension • Multiple Sclerosis

Platelets of Patients Who Lack Bruton Tyrosine Kinase (BTK) Do Not Aggregate in Response to Fcγriia Activation: Implications for Developing Safe Treatments for Patients with Thrombotic Disorders Related to Fcγriia Activation (ASH 2024) - "Washed platelets (WP) and platelet-rich plasma (PRP) were prepared and treated with vehicle control (DMSO 0.02%), ibrutinib, or fenebrutinib (DMSO 0.02%) for 20 min at room temperature. Blood Adv 2019; 3 : 4021). Collectively, these data suggest that it may be possible to target just BTK itself for pathological conditions dependent on FcγRIIa-mediated activation, including heparin-induced thrombocytopenia and thrombosis and related thrombotic disorders, without compromising hemostasis."

Clinical • Cardiovascular • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Oncology • Orthopedics • Primary Immunodeficiency • Thrombocytopenia • Thrombosis • BTK • FCGR2A • FCGR2B

Roche…announced today that the first Phase III (FENhance 2) of two pivotal, similarly-designed Phase III studies (FENhance 1 and 2) in patients with relapsing multiple sclerosis (RMS) met its primary endpoint. (Roche Press Release) - "Fenebrutinib, an investigational Bruton’s tyrosine kinase (BTK) inhibitor, significantly reduced the annualised relapse rate (ARR) compared to teriflunomide over a period of at least 96 weeks of treatment....Full data from both studies will be shared at upcoming medical meetings; once the second RMS study (FENhance 1) has read out, which is expected in the first half of 2026, all data together will be considered for submission to regulatory authorities."

P3 data • Multiple Sclerosis

Addressing the Unmet Need in Chronic Spontaneous Urticaria: A Network Meta-Analysis of Novel and Established Therapies (EADV 2025) - "Interventions: Oral agents: Cyclosporine, fenebrutinib, hydroxychloroquine, methotrexate, remibrutinib. Subcutaneous agents: Barzolvolimab, benralizumab, dupilumab, ligelizumab, omalizumab, quilizumab, tezepelumab...Efficacy: i. All treatments except benralizumab, methotrexate, and quilizumab significantly improved UAS7, ISS7, HSS7, and DLQI vs. placebo... 1. Barzolvolimab is the most effective therapy for symptom control (UAS7/HSS7/ISS7). 2."

Retrospective data • Chronic Spontaneous Urticaria • Dermatology • Immunology • Urticaria

Safety and efficacy of bruton's tyrosine kinase inhibitors for the treatment of chronic spontaneous urticaria: a systematic review and meta-analysis of randomized controlled trials (EADV 2025) - "Materials & We performed a systematic review and meta-analysis of five randomized controlled trials (RCTs), following PRISMA guidelines, to compare BTK inhibitors, including remibrutinib, rilzabrutinib and fenebrutinib, to placebo at 4, 8, and 12 weeks in patients with CSU. BTK inhibitors offer a valuable, safe, and effective treatment option for CSU, particularly in cases that are refractory to second-generation H1-antihistamines."

Retrospective data • Review • Cardiovascular • Chronic Spontaneous Urticaria • Dermatology • Immunology • Urticaria

Fenebrutinib maintains early and sustained low disease activity in patients with relapsing multiple sclerosis: 2-year results from the FENopta open-label extension (ECTRIMS 2025) - P2 | "PwRMS treated with FEN for 2 y had near complete suppression of acute inflammatory disease activity, and a high percentage met NEDA-3. Reductions in B-cell, Ig and NfL levels were observed. These results are consistent with the proposed dual mechanism of action, acting on the underlying pathophysiology of both relapses and nonrelapsing progression."

Clinical • CNS Disorders • Infectious Disease • Inflammation • Multiple Sclerosis • Nephrology • Novel Coronavirus Disease • Respiratory Diseases • NEFL

Fenebrutinib two-year Phase II FENopta OLE results (Genentech Press Release) - "Patients enrolled in the OLE had a low annualized relapse rate (ARR) of 0.06, and during this time, there was no disability progression, as measured by the EDSS. At two years, MRI scans detected zero new T1 gadolinium-enhancing (T1-Gd+) lesions, which are markers of active inflammation."

P2 data • Multiple Sclerosis

FENerations1: A Pharmacokinetics (PK), Pharmacodynamics (PD), Safety and Tolerability Study of Fenebrutinib in Children and Adolescents With Relapsing Multiple Sclerosis (RMS) (clinicaltrials.gov) - P2 | N=12 | Recruiting | Sponsor: Hoffmann-La Roche

New P2 trial • CNS Disorders • Multiple Sclerosis

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. (PubMed, Lancet Neurol) - P2 | "Fenebrutinib was well tolerated and exerted an early, robust, and sustained effect of limiting new focal brain lesions. Further studies are needed to better characterise the safety and efficacy of fenebrutinib on both relapsing multiple sclerosis and non-relapsing progressive multiple sclerosis."

Clinical • Journal • P2 data • CNS Disorders • Infectious Disease • Multiple Sclerosis • Pain

Assessing the role of TR in PROTAC development for BTK (ACS-Fall 2025) - "This project explores how changes in residence time (tR) translate when inhibitors are converted into PROTACs and how this influences the ternary complex formation and initial degradation velocity, focusing on Fenebrutinib and GDC-0834. To isolate warhead effects, we will retain PTD-10's linker and E3 ligase ligand. We hypothesize that the tR ratio will be conserved, enhancing our understanding of tR's role in PROTAC function for selective protein degradation."

Targeted Protein Degradation

Platelet Aggregation Initiated by Fc gamma RIIa Engagement Requires Bruton’s Tyrosine Kinase (BTK) (ISTH 2025) - "Adding ibrutinib or fenebrutinib to WP abrogated the response to high dose CRP. Table or Figure Upload"

Cardiovascular • Hematological Disorders • Immunology • Primary Immunodeficiency • Thrombocytopenia • Thrombosis • BTK • FCGR2A

Bruton's Tyrosine Kinase Inhibitor Attenuates Mast Cell Activation via Both FceRI- and MRGPRX2-Mediated Pathways (EAACI 2025) - "Method Remibrutinib and fenebrutinib were used to inhibit BTK signaling. Conclusion BTK inhibitors attenuate both FceRI- and MRGPRX2-mediated mast cell activation. These findings highlight the protective role of BTK inhibitors in the treatment of CSU, not only by suppressing immunoglobulin synthesis but also by directly inhibiting mast cell activation."

Immunology

FENhance 2: Study to Evaluate the Efficacy and Safety of Fenebrutinib Compared With Teriflunomide in Relapsing Multiple Sclerosis (RMS) (clinicaltrials.gov) - P3 | N=751 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Nov 2025 ➔ Jul 2027

Trial completion date • CNS Disorders • Multiple Sclerosis

FENhance: A Study to Evaluate the Efficacy and Safety of Fenebrutinib Compared With Teriflunomide in Relapsing Multiple Sclerosis (RMS) (clinicaltrials.gov) - P3 | N=746 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Nov 2025 ➔ Nov 2027 | Trial primary completion date: Oct 2025 ➔ Jan 2026

Trial completion date • Trial primary completion date • CNS Disorders • Multiple Sclerosis