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Collaborative Science Drives a Breakthrough for Cardiovascular Patients

Scientists at Dogma Therapeutics have discovered orally bioavailable small molecule PSCK9 inhibitors which, when administered to dyslipidemic large animals, are found to elicit significant and robust lowering of LDL cholesterol following multiple weeks of oral dosing. The breakthrough holds great promise for patients suffering from hypercholesterolemia and cardiovascular disease.

Following accreditation through human genetics, PCSK9 has long been an attractive target; 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.

Coming at a time when such biological targets were previously thought to be “undruggable,” the discovery is the result of close collaboration between Dogma, Charles River’s drug discovery team, and Viva Biotech, proving that partnerships are key to moving drugs forward. Working together, the team overcame the challenges of PCSK9’s expansive binding surface by finding small molecule inhibitors that directly bind to a novel, cryptic binding pocket in PSCK9. Guided by dozens of high-resolution x-ray structures of inhibitors bound to the PCSK9 protein, these molecules have been optimized to picomolar affinity, thus making oral administration possible. Charles River contributed extensive expertise in medicinal chemistry, structural biology and biophysics, cell biology, pharmacokinetics and pharmacodynamics to the project, supporting Dogma from the earliest stages of discovery through delivery of the clinical candidate.

“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.”