ST. LOUIS--(BUSINESS WIRE)--DiscoveryBioMed, Inc. (DBM, Inc.) 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). 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.
“ADPKD is a debilitating disease that causes cysts in both kidneys and cysts or dilations of other tissues such as liver, pancreas and vasculature. Although a slowly progressing disorder over decades, it is dominantly inherited in families or kindreds. Family members at risk are screened via ultrasound and/or MRI after their teenage years for signs of kidney enlargement or renal cyst formation,” explained Dr. Erik Schwiebert, the Founder of DiscoveryBioMed, Inc. and a principal investigator on the SBIR awards. “Although symptoms arise variably in the affected population, the enlarged cystic kidneys often become inflamed or infected and, once too large for the abdomen, cause intense flank pain. ADPKD is the leading genetic disease that triggers the need for kidney removal and dialysis and/or transplantation. And, often, the kidneys are removed due to that unbearable pain before kidney function is lost fully.” There are no ADPKD-specific drugs as yet available for patients in the US; only re-purposed drugs are being developed and are not yet approved in Europe or the US. There remains an unmet need to discover multiple types of drugs that will fight the multiple stages of ADPKD: the initial stages of kidney tissue remodeling and ADPKD cystic kidney cell hyperproliferation and the secondary stages of cyst formation and enlargement that also include hyperproliferation of the cells that line and support the cysts and fluid accumulation inside of fully formed cysts. “Ultimately, the ADPKD research community envisions a battery of multiple and different drugs to treat ADPKD preventatively and/or while the disease is progressing. If one can discover a drug that halts ADPKD cystic cell and supportive cell hyperproliferation to attempt to prevent cyst formation and another that attempts to block fluid accumulation into already formed cysts, one is attacking both phases of the disease and should attenuate disease progression. We are seeking to attain this goal with our dual programs. Other research groups and companies are also working on these angles and we wish them well,” Dr. Schwiebert stressed.
About DiscoveryBioMed, Inc.
This program is another example of DBM’s novel approach to drug discovery, namely Humanized Drug Discovery. This program used multiple human hyperproliferative cell cultures with which to discover and validate this novel anti-proliferative drug class. DBM is utilizing human epithelial cell platforms for its new Phase 1 SBIR-driven study. DBM is focused on this program and another R&D program in Lead Optimization for cystic fibrosis (CF) and other chronic lung and vascular diseases. DBM also has a novel program in Metabolic Disease where it is currently profiling multiple hit-to-lead chemical classes in primary human fat cells. DBM is continuing its CRO services business; however, it is now confined to the Renal/Urologic/Oncologic, Respiratory, and Metabolic areas. See the DBM website, www.discoverybiomed.com, for more information about the company, its new foci, and its scientific strategies and methods.
About the Baltimore PKD Center
The Baltimore PKD Center is a full-service P30-funded Center supported by the NIDDK and directed by Dr. Terry J. Watnick, M.D. It has an Administrative Core, an Antibody and Expression Vector Production Core, a PKD Mouse Models and BioBank Core, a Cell Culture and Engineering Core, and a Clinical Studies Core. For more information, visit the Center website at www.baltimorepkdcenter.org.