fenebrutinib (RG7845) / Roche - LARVOL DELTA

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: Feb 2027 ➔ Jul 2027

Trial completion date • CNS Disorders • Multiple Sclerosis

Emerging pharmacotherapies for chronic spontaneous urticaria: spotlight on BTK inhibitors. (PubMed, Expert Opin Pharmacother) - "BTK inhibitors act on intracellular pathways involved in mast-cell activation, basophil signaling, and B-cell mediated immune responses. Studies have shown reductions in disease activity across multiple BTK inhibitors, with benefit observed early after treatment initiation in several studies. Remibrutinib is the first BTK inhibitor approved for CSU and has the most extensive phase 3 evidence. Oral administration may provide a treatment option for patients. Defining the place of BTK inhibitors within treatment algorithms and identifying patients most likely to benefit from this approach remain areas for future research."

Journal • Review • Chronic Spontaneous Urticaria • Dermatology • Immunology • Urticaria

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: Jul 2027 ➔ Feb 2027

Trial completion date • CNS Disorders • Multiple Sclerosis

Absolute binding free energy calculations reveal how Bruton's tyrosine kinase (BTK) mutations disrupt inhibitor binding at the molecular level | Poster Board #1112 (ACS-Fall 2026) - "The non-covalent inhibitors analyzed include Pirtobrutinib (PDB ID: 8FLL), Fenebrutinib (PDB ID: 5VFI), YDA (PDB ID: 7LTZ), 73T (PDB ID: 5T18), and L0Z (PDB ID: 6S90). Graphical representation illustrates BTK catalytic site. The two-dimensional structures show all the five inhibitors mentioned in the abstract."

Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Targeted Protein Degradation

Improving oral bioavailability of PTD-10, a fenebrutinib-based BTK PROTAC | Poster Board #1118 (ACS-Fall 2026) - "Future work will mainly focus on biological evaluation, such as DC50 and Dmax calculations, permeability assays (PAMPA and Caco-2), in vitro PK/PD studies, etc. Additionally, we are also exploring alternate E3 ligases like DCAF1 to see how that affects degradation efficiency and cellular uptake. These studies aim to develop BTK PROTACs with improved potency, increased bioavailability, and enhanced therapeutic potential."

Targeted Protein Degradation

Efficacy and Safety of Fenebrutinib vs Ocrelizumab in Primary Progressive Multiple Sclerosis: Primary Results of the Phase III FENtrepid Study (EAN 2026) - P2, P3 | "FENtrepid will provide evidence on the benefits and risks of fenebrutinib vs ocrelizumab on disability progression in PPMS."

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 (EAN 2026) - P3 | "While other BTKis have not shown superiority to teriflunomide in suppressing disease activity, the FENhance trials will determine whether fenebrutinib's unique molecular design, optimized CNS exposure and promising Phase II results translate into significant benefits in RMS."

Clinical • CNS Disorders • Multiple Sclerosis

Time to Meaningful Clinical Response Across Approved and Emerging Therapies for Antihistamine-Refractory Chronic Spontaneous Urticaria: A Network Meta-Analysis. (PubMed, J Clin Med) - " All drugs except rilzabrutinib 400 mg daily demonstrated faster mean time to MCID than placebo. Fenebrutinib had the fastest mean time to MCID (0.67-0.76 weeks), and tezepelumab the slowest (5.41-5.65 weeks)...Omalizumab, dupilumab, and ligelizumab demonstrated statistically significant reductions in time to MCID compared with placebo. Head-to-head trials with standardized outcome reporting would enable more definitive comparative conclusions."

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

Emerging Role of BTK Inhibitors in Multiple Sclerosis: From Immunobiology to Clinical Translation. (PubMed, Brain Sci) - "BTK inhibitors reduce inflammatory disease activity in relapsing MS and have emerging efficacy in progressive MS phenotypes; however, continued monitoring for hepatotoxicity is warranted. Optimization of CNS penetrance and pharmacologic selectivity may influence long-term clinical positioning."

Journal • Review • CNS Disorders • Immunology • Inflammation • Multiple Sclerosis

Mechanistic Insights into the Role of Artificial Intelligence and Machine Learning in the Diagnosis and Management of Multiple Sclerosis. (PubMed, Pathophysiology) - "Notable recent contributions include the SuStaIn-based identification of two biologically distinct MS trajectories distinguished by early versus late serum neurofilament light chain elevation, the MindGlide deep learning platform enabling longitudinal analysis of archived routine clinical MRI data, the T-cell morphological classifier predicting natalizumab treatment response before drug initiation, and the fenebrutinib Phase III program that produced the first Bruton's tyrosine kinase inhibitor results meeting primary endpoints in both relapsing and primary progressive MS. A proposed AI-Enhanced Management Protocol (AMP-26) reflecting 2026 clinical standards is included as an appendix. Throughout, emphasis is placed on mechanistic interpretability: the distinction between models that correlate features with outcomes and models whose decision logic reflects established MS pathobiology is considered a prerequisite for clinical credibility and regulatory readiness."

Journal • Review • CNS Disorders • Multiple Sclerosis • NEFL

Efficacy and Safety of Fenebrutinib vs Ocrelizumab in Primary Progressive Multiple Sclerosis: Primary Results of the Phase III FENtrepid Study (CMSC 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. Funding: Sponsored by F. Hoffmann-La Roche Ltd; writing and editorial assistance were provided by Nucleus Global and funded by F. Hoffmann-La Roche Ltd."

Clinical • P3 data • CNS Disorders • Multiple Sclerosis

Efficacy and Safety of Fenebrutinib Vs Teriflunomide In Relapsing Multiple Sclerosis: Results of the Fenhance 1 and 2 Studies (CMSC 2026) - P2, P3 | "Fenebrutinib (FEN) is a uniquely designed, noncovalent, highly selective, CNS-penetrant BTKi that has shown reductions in MRI disease activity in the Phase II relapsing MS FENopta trial (NCT05119569) and time to disability progression parity with ocrelizumab in the Phase III primary progressive MS (PPMS) FENtrepid trial (NCT04544449). FEN achieved superiority in ARR and significant reductions in MRI disease activity vs TER. With positive results in both PPMS and RMS, FEN is the first oral BTKi to demonstrate efficacy on both relapsing and progressive biologies. Funding: Sponsored by F. Hoffmann-La Roche Ltd; writing and editorial assistance were provided by Nucleus Global and funded by F. Hoffmann-La Roche Ltd."

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

Fenebrutinib Demonstrates Superior Efficacy in Reducing Relapses and Brain Lesions in Pivotal Phase 3 MS Trials (Pharmacy Times) - "New data from 2 large-scale phase 3 clinical trials, FENhance 1 and FENhance 2...Fenebrutinib achieved superiority in the annualized relapse rate (ARR) across both studies. In FENhance 1, fenebrutinib reduced the ARR to 0.061, compared to 0.125 for teriflunomide. In FENhance 2, the efficacy was even more pronounced, with an ARR of 0.054 for fenebrutinib versus 0.130 for the control group. These results were statistically significant, with P-values of less than 0.001 in both instances...For T1 gadolinium-enhancing (T1 Gd+) lesions, which indicate active inflammation, fenebrutinib showed a reduction of 70.7% in FENhance 1 and 77.6% in FENhance 2....Safety data showed that the proportion of patients experiencing adverse events (AEs) was generally similar between the treatment arms."

P3 data • Immunology • Multiple Sclerosis

Bruton's Tyrosine Kinase Inhibitors in Multiple Sclerosis: Mechanistic Considerations Across Relapsing and Progressive Disease. (PubMed, Molecules) - "Second-generation BTK inhibitors, including evobrutinib, tolebrutinib, fenebrutinib, remibrutinib, and orelabrutinib, have advanced through Phase II-III development in MS. This review integrates molecular pharmacology and the most recent clinical evidence available through 2026 to examine how pharmacologic properties translate into stage-dependent therapeutic positioning. We also consider safety constraints within a disease-stage-specific benefit-risk framework, aiming to clarify the evolving role of BTK inhibition in MS."

Journal • Review • CNS Disorders • Inflammation • Multiple Sclerosis

Bruton's Tyrosine Kinase Inhibitors in Multiple Sclerosis. (PubMed, Drugs) - "In particular, tolebrutinib has demonstrated efficacy against disability progression in non-relapsing secondary progressive MS, while fenebrutinib has recently shown promise in both relapsing and primary progressive MS. However, adverse events include elevated liver enzymes, which can reach life-threatening levels. This review highlights the role of BTK in immune signaling and the rationale for BTK inhibition in MS, discusses the evolution of BTK inhibitors for MS and other indications, summarizes findings from Phase 2 and Phase 3 trials in RMS and PMS, and explores practical questions around the potential use of BTK inhibitors in real-world practice."

Journal • Review • CNS Disorders • Inflammation • Multiple Sclerosis

Bruton's Tyrosine Kinase Inhibitors for Chronic Spontaneous Urticaria: A Systematic Review and Meta-Analysis. (PubMed, J Cutan Med Surg) - "Neither the incidence of adverse events (AEs; RR 1.06; 95% CI 0.84-1.33; P = .47), nor serious AEs (RR 1.17; 95% CI 0.34-4.02; P = .71) was significantly different between groups. BTK inhibitors offer a valuable, safe, and effective treatment option for CSU, particularly in cases that are refractory to second-generation H1 antihistamines."

Journal • Retrospective data • Review • Chronic Spontaneous Urticaria • Dermatology • Immunology • Pruritus • Urticaria

Efficacy and Safety of Fenebrutinib vs Ocrelizumab in Primary Progressive Multiple Sclerosis: Primary Results of the Phase III FENtrepid Study (AAN 2026) - P2, P3 | "Primary efficacy and safety results will be presented. Conclusions 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) - P2, P3 | "Conclusions The FENhance studies will provide evidence on the efficacy and safety of fenebrutinib vs teriflunomide in adult patients with RMS. While other BTKis have not shown superiority to teriflunomide in suppressing disease activity in RMS, the FENhance trials will determine whether fenebrutinib’s unique molecular design, optimized CNS exposure and promising Phase II results translate into significant benefits addressing both relapsing and progressive disease biologies in patients with RMS relative to teriflunomide."

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

Roche…announced today new data from the positive Phase III FENhance 1 and 2 studies, which met their primary endpoint (GlobeNewswire) - "The studies showed that fenebrutinib, an investigational non-covalent Bruton’s tyrosine kinase (BTK) inhibitor, reduced the annualised relapse rate (ARR) by 51.1% (p<0.001) in FENhance 1 and 58.5% (p<0.0001) in FENhance 2 compared with teriflunomide in patients with relapsing multiple sclerosis (RMS) over 96 weeks....The results were shared today as a late-breaking presentation at the 2026 American Academy of Neurology (AAN) Annual Meeting....Secondary endpoints showed that fenebrutinib significantly reduced disease activity in the brain, as evidenced by MRI scans. Fenebrutinib reduced markers of active inflammation by 70.7% (p<0.0001) in FENhance 1 and 77.6% (p<0.0001) in FENhance 2 compared with teriflunomide, as measured by new T1 gadolinium-enhancing (T1-Gd+) lesions....The totality of data from all three Phase III fenebrutinib studies will be submitted to regulatory authorities."

Late-breaking abstract • P3 data • Multiple Sclerosis

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

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