Regulus Therapeutics Completes Phase 1b Trial of Farabursen for ADPKD

Regulus Therapeutics Inc., a biopharmaceutical company dedicated to developing innovative microRNA-targeting medicines, has announced promising results from its fourth cohort in a Phase 1b MAD study of farabursen aimed at treating autosomal dominant polycystic kidney disease (ADPKD). This study is a significant step forward for the potential treatment of this common and severe genetic kidney disorder.

The Phase 1b MAD study is a double-blind, placebo-controlled trial that investigates the safety, tolerability, pharmacokinetics, and pharmacodynamics of farabursen in adults with ADPKD. Conducted over three months of treatment with an additional month for follow-up, the trial included three weight-based dose levels and a fixed dose level of 300 mg. The primary focus was on changes in urinary polycystin (PC1 and PC2) levels, with exploratory analysis on the rate of height-adjusted total kidney volume (htTKV) growth—a crucial indicator of disease progression.

In the fourth cohort of this study, 26 patients were administered a fixed 300 mg dose of farabursen bi-weekly for three months. Consistent with previous interim analyses, this cohort showed a similar mechanistic response. Urinary PC1 and PC2 levels, which inversely correlate with disease severity, demonstrated significant increases compared to placebo (PC1 p=0.026, PC2 p=0.014). Additionally, the mean htTKV growth rate was effectively halted, averaging 0.05% over four months compared to a 2.58% increase in the placebo group.

An exploratory analysis highlighted that patients treated with either 3 mg/kg or the 300 mg fixed dose of farabursen showed a statistically significant reduction in htTKV growth. The comparison involved 35 farabursen-treated patients against a large historical control group of 550 placebo-treated patients from prior ADPKD trials. Results indicated a mean reduction in htTKV growth rate of -0.14% in the farabursen group, contrasting with a 1.87% increase in the placebo group, achieving statistical significance (p=0.0056). Such findings suggest that farabursen directly impacts disease progression by limiting abnormal cyst growth in the kidneys.

Moreover, the safety and tolerability profile of the 300 mg dose was favorable and consistent with earlier trial data, reinforcing its potential as the optimal dose for further trials. Dr. Preston Klassen, President and Head of Research & Development at Regulus Therapeutics, expressed confidence in these results, emphasizing the potential of 300 mg of farabursen to provide optimal target exposure for future research phases. The repeated demonstration across multiple cohorts that kidney growth can be halted in ADPKD patients within a short treatment period is promising for the upcoming Phase 3 trial.

With the complete data from the fourth cohort now available, Jay Hagan, CEO of Regulus Therapeutics, highlighted the positive outcome's alignment with prior expectations. Farabursen presents a promising addition to the limited therapeutic options for ADPKD patients. The company is preparing to initiate a pivotal Phase 3 trial later this year, following alignment with the FDA on crucial elements of the trial design, including a 12-month htTKV endpoint for Accelerated Approval and a 24-month endpoint for Full Approval.

ADPKD is a common genetic disorder characterized by the development of multiple fluid-filled cysts in the kidneys, often leading to end-stage renal disease. Affecting approximately 160,000 individuals in the United States and millions worldwide, this disease currently has limited treatment options. Farabursen, a novel oligonucleotide designed to target the kidney and inhibit miR-17, has shown promising results in preclinical models and early-phase clinical trials, positioning it as a potential breakthrough in ADPKD treatment.