fenebrutinib (RG7845) / Roche - LARVOL DELTA

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

FENtrepid: A Study to Evaluate the Efficacy and Safety of Fenebrutinib Compared With Ocrelizumab in Adult Participants With Primary Progressive Multiple Sclerosis (clinicaltrials.gov) - P3 | N=985 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Dec 2026 ➔ Jul 2027 | Trial primary completion date: Jan 2026 ➔ Sep 2025

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

Bruton Tyrosine Kinase in Lesions of Multiple Sclerosis and 3 of Its Models. (PubMed, Neurol Neuroimmunol Neuroinflamm) - "Our results demonstrate that BTK immunoreactivity is normally undetectable in uninjured areas or normal-appearing white matter of human and murine CNS, but that expression becomes prominent in lesions with hypercellular aggregates of microglia and macrophages. Staining for pBTK reveals that its upregulation declines in the later stage of lysolecithin and chronic stage of EAE injury while BTK upregulation is maintained. Our collective results support the rationale of using brain-penetrant BTK inhibitors to modulate the elevation of this enzyme in microglia/macrophages within inflamed plaques of MS."

Journal • CNS Disorders • Immunology • Multiple Sclerosis • BTK

Genentech’s Fenebrutinib Maintains Near-Complete Suppression of Disease Activity and Disability Progression for up to Two Years in People With Relapsing Multiple Sclerosis (Businesswire) - P2 | N=109 | FENopta (NCT05119569) | Sponsor: Hoffmann-La Roche | "Genentech...announced today new, 96-week data for fenebrutinib demonstrating that patients with relapsing multiple sclerosis (RMS) maintained no disability progression and low levels of disease activity for up to two years...Ninety-nine patients entered the OLE and 93 remained in the OLE after 96 weeks. During the OLE period, patients treated with fenebrutinib for up to 96 weeks had a low annualized relapse rate (ARR) of 0.06, and during this time there was no disability progression, as measured by the Expanded Disability Status Scale (EDSS)...Three Phase III clinical trials are ongoing, including the FENhance 1 and 2 trials in RMS and the FENtrepid trial in primary progressive multiple sclerosis (PPMS). The first data from these studies, which will characterize the effects of fenebrutinib on disease progression across the multiple sclerosis spectrum, are expected at the end of 2025."

P2 data • P3 data • Multiple Sclerosis

Next generation Bruton's tyrosine kinase inhibitors - characterization of in vitro potency and selectivity. (PubMed, Eur J Pharmacol) - "BTKi ranked in their selectivity as follows (most selective to least): remibrutinib, fenebrutinib, evobrutinib, orelabrutinib, rilzabrutinib and tolebrutinib. These data suggest that next generation BTKi show important differences in their in vitro target binding and selectivity when compared under the same conditions."

Journal • Preclinical • Allergy • Immunology

Biological and target synthetic treatments for chronic spontaneous urticaria: A systematic review and network meta-analysis. (PubMed, Clin Transl Allergy) - "The findings of this study indicate that the biological agent omalizumab 300 mg and the oral small molecule remibrutinib at doses of 35 mg, 25 mg, or 10 mg are recommended for patients with antihistamine-refractory CSU."

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

Fenebrutinib Maintains Low Disease Activity in Relapsing Multiple Sclerosis: Results from the FENopta Trial Open-label Extension (AAN 2025) - P2 | "Participants with RMS receiving fenebrutinib for 1 year had low ARR, stable EDSS and low MRI disease activity. Fenebrutinib maintained a favorable safety profile with high retention in the OLE. Three Phase III clinical trials are underway."

Clinical • CNS Disorders • Infectious Disease • Multiple Sclerosis • Nephrology • Novel Coronavirus Disease

How Does Fenebrutinib Work? Exploring Kinetic and Mechanistic Features That Influence BTK Potency, Selectivity and Pharmacology (ACTRIMS Forum 2025) - P2, P3 | "Fenebrutinib (FEN) is being developed because it is a potent and highly selective noncovalent reversible BTKi that has shown efficacy in several diseases, including a Ph 2 RMS study (NCT05119569) and is currently in Ph 3 trials in RMS (NCT04586010, NCT04586023) and PPMS (NCT04544449).Objectives: Define the BTK binding mechanisms and selectivities of FEN and irreversible covalent inhibitors remibrutinib (REMI), tolebrutinib (TOL) and evobrutinib (EVO); compare their projected relative rates of BTK inhibition at clinical-dose concentrations reported in human CSF. Using biochemical kinetic competition binding assays, we defined binding mechanisms to BTK and to an off-target BMX, a related cytoplasmic protein tyrosine kinase. Fenebrutinib’s slowly reversible binding mechanism allows for potent, selective BTK inhibition and illustrates how kinetic and mechanistic features of drug-target interactions impact pharmacology. Fenebrutinib’s properties and observed..."

CNS Disorders • Hematological Disorders • Immunology • Multiple Sclerosis

Fenebrutinib Maintains Low Disease Activity in Relapsing Multiple Sclerosis: Clinical, Safety and Biomarker Results From the FENopta Open-Label Extension (ACTRIMS Forum 2025) - P2 | "PwRMS treated with FEN for 1 year had near complete suppression of acute inflammatory disease activity. FEN maintained a favorable safety profile, with high patient retention in the OLE. Reductions in Ig and B-cell levels were observed, consistent with FEN’s mechanism of action."

Biomarker • Clinical • CNS Disorders • Infectious Disease • Inflammation • Multiple Sclerosis • Nephrology • Novel Coronavirus Disease • Renal Calculi

Fenebrutinib, a Bruton's tyrosine kinase inhibitor, blocks distinct human microglial signaling pathways. (PubMed, J Neuroinflammation) - "Our study enhances the understanding of BTK functions in human microglial signaling that are relevant to MS pathogenesis and suggests that fenebrutinib could attenuate detrimental microglial activity associated with FcγR activation in people with MS."

IO biomarker • Journal • CNS Disorders • Immunology • Inflammation • Multiple Sclerosis • NLRP3 • TLR4

IMG-004, a selective noncovalent reversible Bruton's tyrosine kinase inhibitor, demonstrated potent pharmacodynamic effects (EADV 2024) - "IMG-004 bound to BTK with a prolonged residence time of 34.75 h, compared with 11.01 h shown by an in-house made fenebrutinib analog. IMG-004, a unique noncovalent reversible BTK inihibitor, demonstrated potent BTK inhibition in vitro and protective efficacy in a cGvHD model in vivo. IMG-004 is a promising potential therapeutic agent for chronic autoimmune diseases. Table 1."

IO biomarker • PK/PD data • Chronic Graft versus Host Disease • Chronic Spontaneous Urticaria • Dermatology • Graft versus Host Disease • Hidradenitis Suppurativa • Immunology • Inflammation • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • Urticaria • CD63 • CD69