fenebrutinib (RG7845) / Roche - LARVOL DELTA

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

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

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

Fenebrutinib maintains low disease activity in relapsing multiple sclerosis: results from the FENopta trial open-label extension (ECTRIMS 2024) - P2 | "Participants with RMS treated with FEN for 1 year had a low ARR, stable EDSS and low MRI disease activity. FEN maintained a favourable safety profile with high retention in the OLE. Three Phase III clinical trials are underway to better char-acterise the effects of FEN on disease progression across the MS spectrum."

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

Exposure-response analysis of fenebrutinib in patients with relapsing multiple sclerosis (ECTRIMS 2024) - P2 | "No exposure-safety correlations were observed with liver enzyme elevations or renal function in pwRMS. PwRMS with higher FEN exposure had numerically lower cumulative T1 Gd+ and T2 lesion counts at Week 12 compared with pwRMS with lower exposure; however, sample size was limited for the exposure-efficacy analysis."

Clinical • CNS Disorders • Inflammation • Inflammatory Arthritis • Multiple Sclerosis • Rheumatoid Arthritis • Rheumatology

Elucidating the potential of fenebrutinib, a noncovalent and reversible Bruton's tyrosine kinase inhibitor, to modulate microglial inflammation in human brain cell systems (ECTRIMS 2024) - "Overall this work increases our understanding of potential BTK functions in human microglial signaling and neuroinflammation relevant to MS pathogenesis. In addition to its effects on B-cell functions, these human cell data suggest that BTK inhibition via FEN could act on microglia to attenuate pathogenic neuroinflammation associated with FcγR activation, while preserving other basic microglial functions. Further bio-marker and efficacy assessments in clinical trials may help to confirm the clinical relevance of this effect on microglia."

CNS Disorders • Inflammation • Multiple Sclerosis • NEFL • NLRP3 • TLR4

Roche’s fenebrutinib demonstrated near-complete suppression of disease activity and disability progression for up to 48 weeks in patients with relapsing multiple sclerosis (Roche Press Release) - P2 | N=109 | FENopta (NCT05119569) | Sponsor: Hoffmann-La Roche | "During the OLE period, 96% of patients treated with fenebrutinib were free of relapses at one year, with an annualised relapse rate (ARR) of 0.04, and no change in disability over 48 weeks as measured by the Expanded Disability Status Scale (EDSS)...At 48 weeks, 99% of patients were free of T1 gadolinium-enhancing (T1-Gd+) lesions, markers of active inflammation. Over the 48 weeks of OLE with continued fenebrutinib treatment, there was three times more reduction in the volume of T2 lesions...The safety profile of fenebrutinib in the OLE was consistent with previously reported data...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). Data from these studies...are expected at the end of 2025."

P2 data • P3 data • CNS Disorders • Immunology • Multiple Sclerosis

Effect on neutrophil migration and antimicrobial functions by the Bruton's tyrosine kinase inhibitors tolebrutinib, evobrutinib and fenebrutinib. (PubMed, J Leukoc Biol) - "Also, in vivo CXCL1-induced migration was unaffected by BTK inhibitors. Collectively, this study provides novel insights into the impact of BTK inhibitors on neutrophil functions, thereby holding important implications for autoimmune or hematological diseases where BTK is crucial."

Journal • CNS Disorders • Hematological Disorders • Immunology • Inflammation • Multiple Sclerosis • CXCL1 • CXCL8 • IL1B

Comparative CNS Pharmacology of the Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib Versus Other BTK Inhibitor Candidates for Treating Multiple Sclerosis. (PubMed, Drugs R D) - "Tolebrutinib was the only candidate of the three that attained relevant CSF exposure in non-human primates."

Journal • CNS Disorders • Multiple Sclerosis

Molecular docking based comparative study of antiviral compounds on SARS-CoV-2 spike protein. (PubMed, Nat Prod Res) - "Using molecular docking and the Lipinski five rule, this study illustrates possible compounds with strong binding affinities, their molecular interactions, for both naturally occurring and man-made drugs. Computational approach is applied, and it is concluded that, drugs like Withanolide, Dihydroergocristine, Fenebrutinib, and Ergotamine shows binding energies between -8.3 and -9.1 kcal/mol, and are possible candidate for anti covid drug."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

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 | Recruiting ➔ Active, not recruiting

Enrollment closed • CNS Disorders • Multiple Sclerosis

Impact of Fenebrutinib Treatment on MRI Outcomes and Cerebrospinal Fluid Penetrance in Multiple Sclerosis: Results from the Phase II FENopta Study (AAN 2024) - P2 | "These data from FENopta highlight the potential of fenebrutinib for treating RMS by reducing MRI lesions with a favorable safety profile. Early findings show CSF penetration and indicate that fenebrutinib was detected in CSF at clinically relevant concentrations to impact mechanisms underlying chronic progressive disease biology in MS."

P2 data • CNS Disorders • Inflammation • Multiple Sclerosis • CD63 • CD69

A Two-part, Phase I Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Fenebrutinib (Part A) and the Effect of Fenebrutinib on the QT/QTc Interval in Healthy Participants (Part B) (AAN 2024) - "Single therapeutic and supratherapeutic doses of fenebrutinib were well tolerated. Fenebrutinib had no clinically meaningful impact on QT/QTc interval."

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