A Phase 1 Study of AC676, a Novel BTK Chimeric Degrader, in Patients with B-Cell Malignancies

Abstract

Study Background Bruton tyrosine kinase (BTK) is an intracellular signaling molecule crucial to the B cell receptor pathway. The development of drugs that inhibit BTK has transformed the management of patients with B-cell malignancies. 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. AC676 is designed as a chimeric degrader to specifically target and degrade BTK using a proprietary Protein-Protein Interaction Targeting Chimeras (PPI-TAC) platform by Accutar Biotech. By linking a BTK ligand to the cereblon E3-ligase recruiting ligand, AC676 brings BTK in proximity to cereblon, which induces subsequent ubiquitination and degradation of BTK. AC676 effectively degrades BTK proteins regardless of identified resistance mutations, including C481, kinase dead L528 and others; and thus, may be effective for the treatment of patients who progress on both covalent and non-covalent BTK inhibitors. Notably, it is also effective in cell lines expressing gain of function PLCG2 mutants, suggesting that it disrupts BTK's scaffolding function. Additionally, AC676 does not degrade cereblon neo-substrates, so neutropenia is not expected to be an on-target effect. This abstract describes an ongoing first in human Phase 1 trial of AC676. Study Description AC676-001 is a Phase 1 dose-escalation study of AC676 administered orally once daily as monotherapy in patients with relapsed and refractory B-cell malignancies. Approximately 60 patients may be enrolled. Eligible patients must be ≥ 18 years, and have one of the following histologically confirmed relapsed or refractory disease types: Chronic lymphocytic leukemia and small lymphocytic lymphoma, non-germinal center type, Diffuse large B cell lymphoma, Follicular lymphoma, Mantle cell lymphoma, Marginal zone lymphoma, and Lymphoplasmacytic lymphoma including Waldenstrom macroglobulinemia Patients must have received at least two prior systemic therapies or lack other standard of care therapies that would provide significant clinical benefit. They must have measurable disease per disease-specific response criteria and an Eastern Cooperative Oncology Group performance status of ≤ 1. The Dose-escalation phase will start with an accelerated titration phase, followed by a standard 3+3 phase. AC676 is administered orally once daily on a 28-day cycle, with doses ranging from 50mg to 600mg. In the absence of discontinuation due to excess toxicity, treatment is continued until disease progression or lack of clinical benefit. The primary objective of the study is to evaluate the safety and tolerability of AC676. Secondary objectives include assessing anti-tumor activity and the pharmacokinetic profile following single and multiple doses. Pharmacodynamic response will be assessed by measurement of BTK blood levels. 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).

Topics & Concepts