Kennedy's disease, also known as spinobulbar muscular atrophy (SBMA), is a progressive neurodegenerative disease caused by genetic polyglutamine expansion 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. The AR pathway is a very important area being studied in SBMA. 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. This 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 has provided strong in vivo data that support the submission of this Phase 2 application to continue the preclinical development of ONCT-505 a potential SBMA therapy. Our objective is to generate certain data for ONCT-505 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.
Public Health Relevance Statement: PROJECT NARRATIVE Kennedy's disease is a progressive genetic neurodegenerative disease caused by an abnormal androgen receptor (AR) protein. There is currently no effective treatment available to slow, stop, or reverse the disease. Based on promising preclinical results obtained under a funded Phase 1 STTR grant, this Phase 2 SBIR grant application proposes to perform preclinical development studies with our androgen receptor antagonist and degrader ONCT-505 to destroy the AR protein as a potential therapeutic for Kennedy's disease.
Project Terms: Award; Biological Assay; Assay; Bioassay; Biologic Assays; Biological Availability; Bioavailability; Physiologic Availability; Castration; Surgical Castration; Chemistry; Pharmaceutical Chemistry; Medicinal Chemistry; Pharmaceutic Chemistry; Disease; Disorder; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Engineering; Follow-Up Studies; Followup Studies; Grant; Hormone Receptor; In Vitro; Industry; Manuals; Transgenic Mice; Mitochondria; mitochondrial; Mutagenicity Tests; Genetic Toxicity Tests; Genotoxicity Tests; Mutagen Screening; mutagen testing; Neurons; Nerve Cells; Nerve Unit; Neural Cell; Neurocyte; neuronal; Patients; Permeability; Drug Kinetics; Pharmacokinetics; Phenotype; Plasma Proteins; Productivity; Proteins; Receptor Aggregation; Receptor Capping; Androgen Receptor; Records; Research; Rodent; Rodentia; Rodents Mammals; Safety; Signal Transduction; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Testosterone; Therapeutic Testosterone; Trans-Testosterone; Toxicology; Ubiquitin; APF-1; ATP-Dependent Proteolysis Factor 1; HMG-20; High Mobility Protein 20; United States Food and Drug Administration; Food and Drug Administration; USFDA; Investigational New Drug Application; Area; Clinical; Phase; Medical; Series; 20S Catalytic Proteasome; 20S Core Proteasome; 20S Proteasome; 20S Proteosome; Macropain; Macroxyproteinase; Multicatalytic Proteinase; Prosome; Proteasome; Proteasome Endopeptidase Complex; Proteosome; multicatalytic endopeptidase complex; Evaluation; Ligand Binding Protein; Ligand Binding Protein Gene; Protein Binding; bound protein; Binding Proteins; Development Plans; Funding; Toxicokinetics; CaCo2; Caco-2 Cells; Therapeutic; Therapeutic Agents; Metabolic; Genetic; polyglutamine; Poly Q; polyQ; Kennedy Syndrome; Bulbospinal Neuronopathy; Kennedy's Disease; X-Linked Bulbo-Spinal Atrophy; Oral; Musculoskeletal; Neurodegenerative Disorders; Degenerative Neurologic Diseases; Degenerative Neurologic Disorders; Nervous System Degenerative Diseases; Neural Degenerative Diseases; Neural degenerative Disorders; Neurodegenerative Diseases; Neurologic Degenerative Conditions; degenerative diseases of motor and sensory neurons; degenerative neurological diseases; neurodegenerative illness; experience; mutant; protein degradation; Metabolic Protein Degradation; Protein Turnover; Regulatory Protein Degradation; receptor; Receptor Protein; Animal Model; Animal Models and Related Studies; model of animal; Toxic effect; Toxicities; Spinobulbar Muscular Atrophy; Spinobulbar Atrophy; Property; cross reactivity; drug development; Molecular Interaction; Binding; Dose; Data; Applications Grants; Grant Proposals; Pre-Clinical Model; Preclinical Models; Receptor Activation; Regulatory Affairs; in vivo; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Small Business Technology Transfer Research; STTR; Transgenic Model; transgenic trait; Pathologic; Knock-out; Knockout; Process; Development; developmental; safety study; Pathway interactions; pathway; pre-clinical; preclinical; stem cell differentiation; motor neuron degeneration; determine efficacy; efficacy analysis; efficacy assessment; efficacy determination; efficacy examination; evaluate efficacy; examine efficacy; efficacy evaluation; manufacturing process; scale up; NH2-terminal; N-terminal; neurotoxic; new drug treatments; new drugs; new pharmacological therapeutic; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel pharmaco-therapeutic; novel pharmacological therapeutic; novel therapy; novel therapeutics; effective treatment; effective therapy; pre-clinical efficacy; preclinical efficacy; process optimization; drug candidate; skeletal muscle atrophy; skeletal muscle breakdown; skeletal muscle loss; skeletal muscle protein loss; skeletal muscle wasting; phase 1 trial; phase I trial; Formulation; small molecule therapeutics; androgenic; experiment; experimental research; experiments; experimental study; efficacy study; pre-clinical development; preclinical development; androgen dependent; androgen responsive; androgen sensitive; drug safety; pharmaceutical safety; medication safety; advanced prostate cancer; antagonist; antagonism; pharmacologic; pre-Investigational New Drug meeting; Pre IND FDA meeting; Pre-IND mtg; pre-IND consultation; pre-IND discussion; pre-IND meeting; manufacture
