Ep191: Emily Conley on Small Molecules to Correct a Rare Kidney Disease

What It Covers

Emily Conley, CEO of Renaissance Bio, explains how the company is developing oral small molecule correctors and potentiators to treat autosomal dominant polycystic kidney disease (ADPKD), a genetic condition affecting 300,000 patients in the US and Europe, by targeting the polycystin protein complex using a framework borrowed from cystic fibrosis drug development.

Key Questions Answered

• •CF Corrector Playbook: The corrector-potentiator drug class pioneered by Vertex for cystic fibrosis provides a direct template for ADPKD. Vertex's tezacaftor and elexacaftor combination corrects 129 CF mutations by targeting one inherently unstable protein region rather than individual mutations. Renaissance applies this same logic to polycystin proteins, seeking a pan-mutant corrector that addresses broad ADPKD patient populations rather than single mutations.
• •Genetic Heterogeneity as the Core Drug Development Problem: No single ADPKD mutation appears in more than 2% of patients, compared to delta-F508 in CF, which covers 90% of patients. This heterogeneity historically deterred drug developers. Renaissance's response is to screen compounds across a large panel of patient mutations simultaneously, only advancing chemical matter that demonstrates correction across multiple mutations, not just one.
• •Biomarker Strategy Shortens Clinical Timelines: The FDA has aligned with Regulus Therapeutics that halting total kidney volume growth — measurable via MRI over 12 months — qualifies for accelerated approval in ADPKD. A urinary biomarker measuring polycystin protein excreted in urine provides earlier proof of target engagement. This regulatory framework reduces the need for multi-year outcome trials, lowering development cost and timeline substantially.
• •Risk Layering Framework for Startup Selection: After shutting down Federation Bio, where manufacturing risk, target risk, and indication risk compounded simultaneously, Conley applied a deliberate risk-stacking filter when evaluating Renaissance. She prioritized genetically validated targets, an established modality with clinical precedent, existing biomarkers, and a proven patient population — reducing the number of simultaneous unknowns compared to her prior venture.
• •Polycystin Rescue Reverses Disease in Mouse Models: A landmark study by Renaissance SAB member Steve Somlo demonstrated that genetically restoring PKD1 expression in mice after disease onset did not merely halt progression — it reversed established kidney disease. This finding shifted the field's understanding of ADPKD from irreversible to potentially correctable, providing the foundational scientific rationale for targeting polycystin proteins therapeutically rather than managing downstream symptoms.
• •Early Intervention as a Future Commercial Opportunity: ADPKD progresses silently from birth through the twenties and thirties, with patients typically reaching end-stage renal disease in their forties through sixties. If correctors prove efficacious in advanced patients, the same mechanism could theoretically prevent cyst formation in younger at-risk individuals — those with an affected parent who carry the dominant mutation — representing a substantially larger addressable population than late-stage trials alone.