Regulus Therapeutics (RGLS) Status Update summary

Regulatory and clinical alignment

• Achieved alignment with FDA on a single pivotal Phase III trial design, endpoints, and accelerated approval pathway using total kidney volume (TKV/htTKV) at one year and eGFR at two years as primary endpoints.

• FDA confirmed non-clinical, CMC, and clinical pharmacology plans are acceptable, with no adverse findings in chronic toxicity studies in mice and NHPs, supporting a large safety margin.

• Phase III will enroll approximately 336 patients, randomized 2:1 to 300 mg farabursen or placebo, focusing on moderate to severe ADPKD (Mayo Class 1C–1E), with protocol finalization and regulatory interactions ongoing.

• Sample size and powering assumptions are based on achieving at least a 50% reduction in TKV growth rate, similar to tolvaptan, with two sample size re-estimation procedures to ensure adequate power for both endpoints.

• Phase III initiation is targeted for Q3 2025, with CRO/vendor selection underway.

Interim clinical data and safety

• All 26 patients in cohort four completed dosing; interim efficacy data available for 14, with full results expected March–April 2025.

• Safety and tolerability profile at 300 mg is favorable, with no serious adverse events, dose-limiting toxicities, or discontinuations; injection site reactions are mild and transient.

• Mechanistic activity (polycystin-1 and -2 biomarkers) at 300 mg matches the plateau seen at 3 mg/kg, confirming optimal target engagement and dose-dependent increases.

• No acute changes in kidney function markers (BUN, KIM-1, eGFR) observed, supporting a reassuring safety profile.

• The enrolled population had significant disease burden, mirroring the target Phase III population.

Efficacy and biomarker insights

• Notable reductions in TKV/htTKV growth rate observed at 2 mg/kg, 3 mg/kg, and 300 mg fixed dose, with combined cohorts showing a high probability of achieving ≥50% reduction at one year.

• Conditional probability analyses suggest a strong likelihood of success for the TKV/htTKV endpoint in Phase III.

• No clear correlation between body weight and TKV effect; TKV is height-adjusted.

• Early evidence suggests some patients experience actual kidney size reduction, with about half in cohort four showing shrinkage.

• Exploratory results indicated efficacy was consistent across Mayo Imaging Class and PKD1 mutation types.