AC676 / Accutar Biotech - LARVOL DELTA

New Targets and Drugs on the Horizon in Chronic Lymphocytic Leukemia (SOHO 2025) - P1, P1/2 | "12 Treatment planning for patients with " double refractory " CLL — CLL that is resistant to a covalent BTKi and venetoclax — is a relatively novel but emerging scenario in the clinic...Noncovalent (Reversible) BTK Inhibitors In the BRUIN-321 phase 3 randomized trial of pirtobrutinib monotherapy versus the control arm of the investigator's choice between idealisib plus rituximab or bendamustine plus rituximab, pirtobrutinib had improved PFS (14 vs 8.7 months, Hazard ratio [HR] 0.54, P = 0.0002) and a superior time to next treatment or death compared to the control arm (24 vs 10.9 months, HR 0.37, P < 0.0001)...Nemtabrutinib is another noncovalent BTKi under clinical investigation, demonstrating an overall response rate (ORR) of 36.4% in CLL patients in the phase 1 study (n = 22 patients)...23,24 Thus far, data for three orally administered BTK degraders — NX-2127, NX-5948 and BGB-16673 23–25— have been presented, and there are ongoing clinical..."

IO biomarker • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Leukemia • Lymphoma • Oncology • CD20 • PRKCB • PRKCH • ROR1

Bruton Tyrosine Kinase Degraders: Current Concepts. (PubMed, Am J Clin Oncol) - "While BTK inhibitors (BTKi), such as ibrutinib, have been effective, resistance-both intrinsic and acquired-poses a significant challenge, often associated with BTK mutations like C481S...Agents such as NRX-0492, BGB-16673, NX-5948, NX-2127, HZ-Q1060, ABBV-101, and AC676 have shown significant BTK degradation in preclinical and early clinical trials...These BTK degraders have demonstrated favorable safety profiles, with manageable adverse events, and offer a novel therapeutic avenue for patients with BTKi-resistant malignancies. As clinical trials progress, these degraders hold the potential to significantly enhance treatment outcomes, offering a new frontier in personalized cancer therapy."

Journal • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Targeted Protein Degradation • BTK

BTK Is the Target That Keeps on Giving: A Review of BTK-Degrader Drug Development, Clinical Data, and Future Directions in CLL. (PubMed, Cancers (Basel)) - "We focus on four agents which are under investigation in B-cell malignancies in early clinical trials: BGB-16673, NX-2127, NX-5948, and AC676. Further trials investigating these agents in combination with other targeted CLL agents may help to further understand their applicability. An effective, tolerable oral class of drugs would be invaluable in the treatment of patients with multiply relapsed CLL/SLL."

Clinical data • Journal • Review • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • Targeted Protein Degradation • BCL2

BTK Is the Target That Keeps on Giving: A Review of BTK-Degrader Drug Development, Clinical Data, and Future Directions in CLL (Multidisciplinary Digital Publishing Institute) - "Encouraging pre-clinical data show that this MOA allows BTK protein degraders to overcome common BTK mutations. We focus on four agents which are under investigation in B-cell malignancies in early clinical trials: BGB-16673, NX-2127, NX-5948, and AC676. Preliminary data suggest a comparable safety and toxicity profile between agents across this drug class with many patients on phase 1 trials deriving durable clinical benefit. Optimal sequencing of BTK degraders in the therapeutic landscape of CLL/SLL treatment is yet to be established."

Review • Chronic Lymphocytic Leukemia • Small Lymphocytic Lymphoma

A Phase 1 Study of AC676, a Novel BTK Chimeric Degrader, in Patients with B-Cell Malignancies (ASH 2024) - P1 | "However, current therapeutic options using covalent BTK inhibitors like ibrutinib and non-covalent inhibitors like pirtobrutinib face challenges due to intolerance and the emergence of mutations in BTK, including residues C481 and L528, leading to resistance. Liquid biopsy next generation sequencing will be performed and will include assessment of mutations within BTK. Study enrollment began in April 2023, with 6 sites currently open in the United States (NCT05780034)."

Clinical • P1 data • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • Targeted Protein Degradation • Waldenstrom Macroglobulinemia • CRBN • PLCG2

AC676, an Orally Bioavailable BTK Chimeric Degrader in Patients With B-cell Malignancies (SOHO 2024) - P1 | "However, available therapeutic options using BTK inhibitors, such as ibrutinib and pirtobrutinib, can result in resistance, primarily due to the development of signaling or structural mutations. Secondary objectives include the evaluation of anti-tumor activity and the pharmacokinetic profile. Study enrollment began in April 2023, and 5 sites are currently open in the United States (NCT05780034)."

Clinical • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • Waldenstrom Macroglobulinemia • CRBN • PLCG2

A Phase I study evaluating AC676, an innovative BTK chimeric degrader, in patients with relapsed and refractory B-cell malignancies (AACR 2024) - P1 | "However, therapy using covalent BTK inhibitors such as ibrutinib, and non-covalent inhibitors such as pirtobrutinib, can still result in resistance, primarily due to the development of mutations in BTK including residues C481 and L528. Secondary objectives include the evaluation of anti-tumor activity and the pharmacokinetic profile following single and multiple doses. Study enrollment began in April 2023 with three sites currently open in the United States (NCT05780034)."

Clinical • P1 data • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • Waldenstrom Macroglobulinemia • CRBN • PLCG2

A Study of AC676 for the Treatment of Relapsed/Refractory B-Cell Malignancies (clinicaltrials.gov) - P1 | N=60 | Recruiting | Sponsor: Accutar Biotechnology Inc | Not yet recruiting ➔ Recruiting

Enrollment open • Hematological Malignancies • Mantle Cell Lymphoma • Oncology

Accutar Biotechnology Announces First Patient Dosed with AC0676 in Phase 1 Study in Patients with Relapsed/Refractory B-cell Malignancies (Businesswire) - "Accutar Biotechnology...announced the dosing of the first patient in a Phase 1 study of AC0676, an orally bioavailable, chimeric degrader molecule designed to target and degrade Bruton's Tyrosine Kinase (BTK) with high potency, selectivity, and broad mutant coverage."

Trial status • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Non-Hodgkin’s Lymphoma • Oncology

Accutar Biotechnology Announces FDA Clearance of IND Application for Phase 1 Trial of AC0676 in B-cell Malignancies (Businesswire) - "Accutar Biotechnology...announced that the U.S. Food and Drug Administration (FDA) has cleared the company’s investigational new drug application (IND) for AC0676 for the treatment of patients with relapsed/refractory B-cell malignancies. AC0676 is an orally bioavailable, chimeric degrader molecule designed to target and degrade Bruton's Tyrosine Kinase (BTK) with high potency, selectivity, and broad mutant coverage....Accutar expects to begin enrollment of a Phase 1 clinical trial for AC0676 in the beginning of the second quarter of 2023....The Phase 1 study will assess the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of AC0676 treatment in patients with relapsed/refractory B-cell malignancies."

IND • New P1 trial