Abstract 7185: Long acting injectable FHD-609 micro-suspension: A potent BRD9 degrader with comparable efficacy, reduced frequency of dosing in preclinical models
Authors: Meiyun Lin, Ammar Adam, Abira Pyne Ramakrishnan, Hafiz Ahmad, Xiaohuan Wu, Brandon Antonakos, Chong-Hui Gu, Ashish Ramani, Victoria Amaral, Claudia Dominici, Qianhe Zhou, Mike Collins, Jessica Piel, Sal Topal, Brian Ethell, Kelly McKiernan, Scott Innis
Journal: Cancer Research (2024)

Abstract Bromodomain-containing protein 9 (BRD9) is a unique component of the non-canonical Brahma-associated factor (ncBAF) complex, essential for cancer cells relying on this complex for survival. This makes it an attractive target for cancer treatment. In synovial sarcoma (SS), SS18-SSX fusion protein drives disease progression and integrates into BAF complexes, promoting tumor growth. Targeting BRD9 degradation is a potential therapeutic approach for SS tumors, as it depletes the essential SS18-SSX fusion protein upon which cancer cells depend for survival within the BAF complex. FHD-609, a potent heterobifunctional degrader of BRD9, has been administered intravenously (IV) in medical facilities twice weekly during clinical trials. In order to facilitate less frequent and more convenient patient-centric dosing, a long acting injectable formulation was developed that allows subcutaneous (SC) or intramuscular (IM) dosing every 4 weeks in preclinical studies. The formulation is an aqueous microsuspension containing the drug along with a polymer and surfactant which provides sustained release of FHD-609 upon injection. We compared the long acting injectable formulation dosed once every 4 weeks to the IV formulation dosed twice a week for the pharmacokinetic and pharmacodynamic properties, as well as the efficacy of the long in xenograft models of different sensitivities, including cell line-derived xenografts (CDX) and patient-derived xenografts (PDX). Our results showed that a single dose of the injectable suspension formulation was well-tolerated in mice and exhibited a significantly flatter PK profile than IV injection with a lower peak to trough ratio and detectable compound concentrations 4 weeks post dose. Moreover, it demonstrated comparable in vivo efficacy and BRD9 protein degradation to the standard intravenous (IV) administration. The long acting FHD-609 injectable formulation has the potential to offer better patient compliance and acceptance in clinical settings than IV dosing. The long acting injectable formulation provides a promising and effective drug delivery option for various protein degraders that are not orally bioavailable. Citation Format: Meiyun Lin, Ammar Adam, Abira Pyne Ramakrishnan, Hafiz Ahmad, Xiaohuan Wu, Brandon Antonakos, Chong-Hui Gu, Ashish Ramani, Victoria Amaral, Claudia Dominici, Qianhe Zhou, Mike Collins, Jessica Piel, Sal Topal, Brian Ethell, Kelly McKiernan, Scott Innis. Long acting injectable FHD-609 micro-suspension: A potent BRD9 degrader with comparable efficacy, reduced frequency of dosing in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7185.