Preclinical development of ONCT-505, an Androgen Receptor Antagonist and Degrader, as New Potential Therapeutic for Kennedy's Disease

Project Summary: Kennedy’s disease, also known as spinobulbar muscular atrophy (SBMA), is a progressive neurodegenerative disease caused by genetic polyglutamine copies in the N-terminal domain (NTD) of the androgen receptor (AR). Recent research has shown that the mutant AR protein misfolds, aggregates, and abnormally interacts with other proteins, leading to androgen dependent lower motor neuron degeneration and skeletal muscle atrophy. Currently, there are no treatments available to slow, stop or even reverse the progression of SBMA; therefore, the unmet medical need is high to discover novel therapeutic agents against the disease. Experimental studies for the treatment of SBMA have focused on interaction of the AR with testosterone. Removing testosterone via castration in animal models appears to be protective and restores some lost function. AR knockout in SBMA patient-derived stem cells differentiated into neurons reverses the neurotoxic effects of the mutant AR. These findings have led to the use of anti-androgenic therapies for SBMA treatment. Our awarded Phase 1 SBIR grant to evaluate our NTD-binding selective AR antagonists and degraders (DAARIs) in preclinical models of SBMA and our Phase 2 SBIR grant have generated strong in vitro and in vivo data, and preclinical manufacturing development to progress the development of ONCT-505 as a potential SBMA therapy. Our objective is to generate specific data for ONCT-505, described below, that will ultimately support the submission of an investigational new drug (IND)-application. ONCT-505 has been studied in various preclinical models of AR-dependent diseases, including SBMA and advanced prostate cancer. Importantly, ONCT-505, unlike any other molecule targeting the AR, binds to the AR activation function-1 (AF-1) domain in the NTD and leads to signaling antagonism and ultimately AR protein degradation via ubiquitin/proteasome pathway. ONCT-505 is orally bioavailable with pharmacokinetic (PK) and drug-like properties suitable for drug development and demonstrated efficacy in SBMA preclinical models better than surgical castration. The molecule did not show overt toxicity up to 200 times the ED50 (effective dose of 50% observed efficacy) in pilot toxicology studies and also lacks cross reactivity with other proteins. These properties make ONCT-505 an ideal candidate for further evaluation as potential small molecule therapeutic for patients suffering from SBMA. Successful completion of the outlined studies will result in a clinical drug candidate with demonstrated preclinical efficacy, well-documented safety profile, and scalable GMP-compatible manufacturing process.