Ep169: Kevin Fitzgerald on the Past & Future of RNAi Medicines

Episode Summary

Executive Summary: Kevin Fitzgerald traces his path from a modest upstate New York upbringing to becoming CSO at Alnylam, emphasizing how RNAi evolved from a risky delivery problem into a validated drug platform. He argues that genetically validated targets, biomarkers, and iterative engineering made RNA medicines highly successful, and that the field’s next phase is expanding beyond the liver into new tissues and combination therapies.

Main Topics: Personal path into science and biotech (Priority: 4/5): Fitzgerald describes growing up with limited resources, discovering science through hands-on lab work, and moving from academia to industry after training at Cornell and Princeton. Early scientific training and fascination with genetics (Priority: 4/5): His graduate and postdoctoral work centered on C. elegans, transgenic mice, and cancer biology, including notable work on Notch signaling that shaped his later interests. Transition from academia to Bristol-Myers Squibb (Priority: 4/5): He explains his initial reluctance to leave academia, the mentorship that encouraged him to try industry, and how genomics and compound-troubleshooting work in pharma broadened his perspective. Joining Alnylam and the delivery challenge in RNAi (Priority: 5/5): Fitzgerald recounts arriving at Alnylam early in its history and seeing delivery as the central engineering problem for RNAi medicines, especially for getting siRNA into cells and the correct intracellular compartment. PCSK9 and the power of genetically validated targets (Priority: 5/5): He uses PCSK9 as a canonical example of choosing targets with strong human genetics, measurable biomarkers, and a liver-centric biology that made it ideal for RNAi drug development. Platform evolution: from liver to other tissues (Priority: 5/5): The discussion covers the shift from lipid nanoparticles and liver-targeted conjugates to delivery in tissues like the brain, muscle, and adipose, enabling broader therapeutic possibilities. Why RNAi remains competitive versus gene editing/gene therapy (Priority: 4/5): Fitzgerald argues RNAi offers controllable, reversible pharmacology, unlike one-time editing, and can be tailored for safety, dose adjustment, and antidote-like reversal. Future of RNA medicine: combinations and common disease (Priority: 5/5): He predicts RNAi will move beyond rare monogenic disorders into multi-target combination strategies for prevalent diseases such as hypertension, Alzheimer’s, and other complex conditions.

Key Arguments: RNAi became viable because Alnylam solved delivery through iterative engineering; the biology was broadly conserved, but the chemistry and targeting were the hard part. Choosing targets with strong human genetic validation materially improves the probability of success because it reduces biological uncertainty and supports dose selection. Biomarkers make early clinical readouts more informative, allowing faster go/no-go decisions and increasing development efficiency. RNAi is especially attractive for chronic, silent diseases because infrequent dosing can improve adherence compared with daily pills. The platform’s historical approval rate appears well above industry average, supporting the idea that target selection and modality matter. Expansion beyond the liver unlocks many more diseases because RNAi works in many cell types once delivery is solved. Compared with gene editing, RNAi’s reversibility and controllable duration are major advantages when long-term safety is uncertain. Combination RNAi therapies may ultimately address complex diseases better than single-target drugs by hitting multiple pathogenic drivers at once.

Data Points: Years at Alnylam: nearly 20 years - Fitzgerald notes he is approaching his 20th year at the company next year. Start year at Alnylam: 2005 - He joined Alnylam in 2005. Company size when he joined: about 90-110 employees - He estimates Alnylam had roughly this many employees when he arrived. Bristol-Myers Squibb tenure: about 2.5 years - He spent roughly two and a half years at BMS before moving on. Postdoc length: about 2.5 years - He says his Harvard Medical School postdoc lasted around two and a half years. High-risk industry benchmark: about 1 in 10 - He cites the standard rule of thumb that only one of ten programs entering clinic may reach FDA approval. Alnylam batting average: about 5-6 out of 10 - He estimates Alnylam’s historical clinical success rate is substantially higher than the industry norm. PCSK9 knockdown in early human study: 80% - He cites one early patient in a TTR trial who showed an 80% knockdown, proving human RNAi activity. APP lowering in people: up to 90% - He says Alnylam has shown APP can be lowered up to 90% with a single intrathecal injection. ASGPR receptor abundance: about 1 million copies per cell - He uses this to explain liver-targeted GalNAc conjugate delivery. Genetic protection from cardiovascular disease: 88% - He references a study showing people with partial PCSK9 loss of function were 88% protected from cardiovascular disease and heart attacks. Phase 1 selection window: early look-see cohorts - He describes taking small disease cohorts into phase 1 to quickly assess target engagement and efficacy.

Pivotal Quotes: "it's just the first inning for RNAi" — Kevin Fitzgerald: He uses baseball language to describe how early the field still is, despite major clinical progress. "It's only a failure if you didn't learn." — Kevin Fitzgerald: He explains his view of program setbacks and why incomplete or negative data can still be valuable. "As your mentor, it's my job to see that you get to do what you want to do." — Phil Leder (quoted by Kevin Fitzgerald): His postdoc mentor’s advice helped him take the leap from academia to industry.

Implications: The episode frames RNAi as a maturing, highly engineerable drug class with expanding reach beyond rare liver diseases. For biotech, the lesson is that smart target selection, strong biomarkers, and reversible design can de-risk development and open large new markets.