The word “undruggable” has hampered pursuit of the most compelling biological targets, drawing from established opinion that pharmacological modulation was not possible. Scientists at Dogma Therapeutics(“Dogma”) were determined to challenge this assumption. Dogma has discovered an orally-bioavailable small molecule PCSK9 inhibitor. By strategically focusing on small molecule inhibitors, Dogma can readily combine their compounds with current standard of care and dramatically disrupt the health economics of PCSK9-based therapies.
Several antibody-based inhibitors emerged following the rapid accreditation of the PCSK9 target through human genetics. However, despite large outcome trials showing a 15-20% reduction in cardiac events, the cost-effectiveness and wide use of antibody-based PCSK9 injectables has been questioned. Alternate approaches to PCSK9 inhibition have been stymied by the expansive binding surface targeted by the antibodies, and to date, only indirect approaches to PCSK9 inhibition by small molecules have been reported.
Dogma has discovered small molecule inhibitors that directly bind to a novel, cryptic binding pocket in PCSK9. Guided by dozens of high-resolution x-ray structures of inhibitors bound to the PCSK9 protein, these molecules have been optimized to picomolar affinity. When orally administered to dyslipidemic non-human primates, multiple Dogma inhibitors elicit significant and robust lowering of LDL-C following multiple weeks of administration.
“We are excited to progress our first-generation oral PCSK9 inhibitor into the clinic to understand the potential for LDL lowering with our approach,” noted co-founder Brian Hubbard, Ph.D. “Human data with our oral PCSK9 inhibitor will provide valuable feedback for ongoing research and catalyze our ability to deliver this important modality to more patients. I would like to thank our scientific partners to date – Charles River and Viva Biotech – for their commitment to this project and their world-class problem solving.”
Since inception, Dogma has developed a highly collaborative research model that leverages scientific expertise across the globe. This collaborative model was created by Charles River, a leading, full-service drug discovery and early-stage development company, who, with its global, integrated drug discovery and safety assessment platform, has worked on 85% of drugs approved by the FDA in 2018. In this project, Charles River scientists and project leads contributed medicinal chemistry, structural biology and biophysics, cell biology and PK/PD expertise. “Charles River has played an integral role in the launch and progression of Dogma with their broad drug discovery expertise and knowledge,” noted Hubbard.
“Our team is extremely proud to have worked closely with Dogma throughout the development of its oral PCSK9 inhibitor,” said Birgit Girshick, Corporate Executive Vice President of Global Discovery and Safety Assessment at Charles River. “This ground-breaking project could prove transformational in the management of hypercholesterolemia and cardiovascular disease.”
The second key partner, Viva Biotech, is a leading structure-based, integrated drug discovery platform company. Viva has a full spectrum of early-stage drug discovery technologies from hit identification to clinical candidate nomination, combined with a unique equity-for-service model. Viva has incubated more than 30 startup biotech companies similar to Dogma and plans to work with 100 more in the next 2 years.
“It was an exceptionally rewarding experience for our team to have a close partnership with Dogma and Charles River as we rapidly advanced the program towards clinical study,” said Zhixiong Ye, Chief Scientific Officer at Viva Biotech. “An orally-bioavailable small molecule PCSK9 inhibitor will greatly impact the unmet medical needs of cardiovascular patients.”
More information on the teams can be found here: