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news.DiscoveryBioMed learned in recent months that it was awarded a new Phase 1 SBIR grant from the National Institutes of Health (NIH) to perform high-throughput screening (HTS)-based drug discovery and validation to discover novel small molecules that attack the secondary phase of autosomal dominant polycystic kidney disease (ADPKD).
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Concomitant with this news, DBM, Inc. was also approved to proceed with the Phase 2 portion of a Fast Track SBIR-funded program funded by the NIH to develop a new chemical series into a new chemical entity (NCE) and future drug to fight the initial phases of ADPKD.
New future drugs from these dual programs may also have utility in attenuating secretory diarrhea and renal, urologic and other forms of cancer and fibrosis, respectively.
The Phase 2 portion of the Fast Track SBIR award also continues to fund a collaboration with the Baltimore PKD Center who is conducting and will continue to conduct proof-of-concept studies in vivo in multiple and different genetic mouse models of ADPKD. Dr. Terry Watnick, M.D. is a Professor of Medicine and the Director of the Baltimore PKD Center based at the University of Maryland School of Medicine in Baltimore, MD.
She is a dual PI on the SBIR award and is directing these studies along with Dr. David Huso, DVM, Ph.D. at Johns Hopkins who is Director of Mouse Models and Biobank Core C of the Baltimore PKD Center.
Both SBIR awards were granted by the NIH’s National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK). "DBM is very grateful for the continued support from the NIDDK. Without their grant support and without a vigorous commitment to funding applied and translational research, our efforts would stall and not have acceleration. We are truly humbled by the NIDDK’s funding and guidance," Dr. Schwiebert pointed out.
The new Phase 1 SBIR award also has Dr. Deborah Mai as a dual PI leading the biological assay efforts and Dr. John Streiff continuing to collaborate with chemistry expertise.
While the new Phase 1-driven work is in its early stages, DBM’s lead anti-proliferative drug class being developed and advanced in Fast Track SBIR-funded efforts is selectively anti-proliferative against human hyperproliferative cells in vitro.
Not only is the drug cytostatic at nanomolar concentrations and cytotoxic at micromolar concentrations to hyperproliferative ADPKD cystic epithelial cells and supporting fibroblasts, but this drug class also has the same therapeutic effects on all 60 human cancer cell lines tested in the NCI-60 panel (work performed by the NCI DTP).
The drug is also potent and effective in multiple human cancer cell lines derived from different tissues resistant to first-line existing chemotherapeutic drugs. Importantly, the lead drug class is without effect on normal cells derived from a variety of human tissues or on diseased cells that are not hyperproliferative. Most critically, Phase 1 work initiated in vivo proof-of-concept studies in a rapid-onset mouse model of ADPKD with our collaborators in Baltimore.
"The lead drug is safe and well-tolerated in wild-type, heterozygous and homozygous mice at the maximum tolerated dose. Proof of concept efficacy studies are in progress with lead analogs within this chemical class," per data reported by the Baltimore PKD Center.
"Continued studies with this dose and additional doses of the drug are in progress." An additional slower-onset PKD mouse model is being chosen for follow-on studies. "Not only is this initial in vivo work very encouraging, but we also have defined closely a specific mechanism of action assessment that we are solidifying further," explained DBM principals.
Future steps in the program include understanding if the drugs can prolong survival of ADPKD mice, medicinal chemistry optimization for the best in vivo route of administration of the drug, re-testing analogs for potency and efficacy in vitro on human hyperproliferative primary cultures, and deeper in vivo proof-of-concept and preclinical testing of the lead drug. This work scripts full IND-enabling studies that would lead to GMP and GLP production and testing and, ultimately, clinical studies.