Challenges of creating first‑in‑class medicines

Synopsis: This episode is proudly sponsored by Quartzy. In this far-reaching conversation, Rahul Chaturvedi speaks with John Lepore, CEO & President of ProFound Therapeutics and CEO-Partner at Flagship Pioneering, tracing a career shaped by a deep commitment to understanding the causal machinery of human disease. John shares how a Harvard-trained physician-scientist evolved into a biotech leader building one of the industry’s most ambitious platform companies. Reflecting on 17 years at GSK — from academic cardiologist to running global research — John describes the moment he realized traditional target discovery had reached its limits. That insight propelled him into Flagship’s venture-creation ecosystem and ultimately into leading ProFound Therapeutics, where the team is uncovering tens of thousands of previously unknown human proteins that could fundamentally reshape drug discovery and unlock true first-in-class opportunities. John also offers a candid look at today’s biotech leadership realities: navigating capital-tight markets, fostering high-trust pharma partnerships, making disciplined early kill decisions, and using AI to extract causal insights from vast proteomic datasets. Together, he and Rahul explore why the expanded human proteome may be medicine’s next great frontier — and what it takes, scientifically and psychologically, to lead a company bold enough to pursue it. Biography: John Lepore, M.D., is CEO and President of ProFound Therapeutics and CEO-Partner at Flagship Pioneering, where he is leading a new era of drug discovery by harnessing the expanded proteome to build a pipeline of first-in-class medicines. A physician-scientist and accomplished pharma executive, he joined ProFound following a 17-year career at GSK, where he was most recently SVP, Head of Research, leading a 2,500+ person global team and driving a renewed focus on immunology and human genetics across target discovery and validation, modality platforms, drug discovery, and clinical translation. He also chaired GSK’s Research Review and Investment Board, guiding capital allocation and R&D strategy. Under his leadership, GSK advanced 15 Phase 1 programs with first- or best-in-class potential and executed $1B+ in strategic R&D deals. Before joining the biopharma industry, Dr. Lepore was a faculty cardiologist and research investigator at the University of Pennsylvania, where his lab investigated the transcription regulation of cardiovascular development. He currently serves on the boards of ProFound, KSQ Therapeutics, and the Innovation Growth Board of Mass General Brigham. Dr. Lepore received his B.S. in Biology from the University of Scranton and his M.D. from Harvard Medical School, after which he completed his residency and post-doctoral training at Massachusetts General Hospital and the Harvard School of Public Health.