409 ‒ Inside modern drug development: the science, economics, and regulatory hurdles

Lloyd B. Klickstein is a physician-scientist who has spent more than 20 years at the intersection of drug discovery, healthy aging, and preventive medicine. Drawing on his experience in academic medicine, translational research, and biotechnology, Lloyd walks through the full arc of modern drug development. He explains how scientists identify an unmet medical need and decide which diseases and therapeutic targets are worth pursuing. From there, he takes us through the process of engineering a drug, testing it in animals, and navigating clinical trials and regulatory approval. Using bimagrumab as a case study, Lloyd explains the rationale for targeting myostatin and activin signaling to increase muscle mass and strength and describes how the antibody was engineered and screened. He then walks through what was learned from early clinical trials. Unexpected effects on fat mass and type 2 diabetes helped reshape bimagrumab’s development as a potential treatment for obesity, including its use in combination with semaglutide. Along the way, Peter and Lloyd explore the differences among drug modalities, including biologics and small-molecule therapeutics. They discuss the roles of patents and capital allocation in drug development, along with the requirements for IND submission and GMP manufacturing. They also examine why developing a new drug takes so long and costs so much, and why identifying failures early is critical.

0:00:00 – Intro
0:00:11 – Lloyd’s path from academic medicine to translational drug development
0:09:21 – Drug modalities, patents, and the economics of innovation
0:22:08 – Choosing sarcopenia as a target for drug development, and confronting the problem of measuring falls
0:36:54 – The rationale for bimagrumab: improving muscle mass and strength by targeting myostatin and activin signaling (and why follistatin failed)
0:44:47 – Engineering and screening the bimagrumab antibody, and the cost of developing a new drug
0:56:07 – From candidate antibodies to animal proof of concept (impressive muscle hypertrophy)
1:05:16 – Toxicology, capital allocation, and the path to an IND
1:18:04 – IND requirements, GMP manufacturing, and gray market peptides
1:24:54 – First in-human study design, patient selection, and protection of healthy volunteers
1:39:00 – Phase 1 dosing, pharmacodynamics, and global trial strategy
1:50:05 – Phase 2 lessons on muscle mass, function, and nutrition
1:57:40 – Bimagrumab’s effects on fat mass and type 2 diabetes
2:07:30 – The BELIEVE trial of bimagrumab plus semaglutide
2:20:40 – Selective mTORC1 inhibition and the challenge of testing geroprotection
2:25:13 – A new pharmacologic approach to cancer prevention

View show notes here: https://peterattiamd.com/lloydklickstein2/
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About:

The Peter Attia Drive is a deep-dive podcast focusing on maximizing longevity, and all that goes into that from physical to cognitive to emotional health. With over 90 million episodes downloaded, it features topics including exercise, nutritional biochemistry, cardiovascular disease, Alzheimer’s disease, cancer, mental health, and much more.

Peter Attia is the founder of Early Medical, a medical practice that applies the principles of Medicine 3.0 to patients with the goal of lengthening their lifespan and simultaneously improving their healthspan.

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