Regulus Therapeutics Reports Positive Phase 1b Data for RGLS8429 in ADPKD Trial

Regulus Therapeutics Inc., a biopharmaceutical company that specializes in developing innovative medicines targeting microRNAs, has announced promising topline results from the third cohort of its Phase 1b MAD study of RGLS8429. This study focuses on the treatment of autosomal dominant polycystic kidney disease (ADPKD). The Phase 1b MAD study is a double-blind, placebo-controlled trial that evaluates the safety, tolerability, pharmacokinetics, and pharmacodynamics of RGLS8429 in adults with ADPKD. The trial investigates RGLS8429 across three weight-based dose levels and one fixed dose level, measuring changes in urinary polycystins 1 and 2 (PC1 and PC2), height-adjusted total kidney volume (htTKV), cyst architecture, and general kidney function.

PC1 and PC2 are protein products of the PKD1 and PKD2 genes, inversely correlating with the severity of the disease. The trial's fourth cohort, which aims to include up to 30 patients, has commenced enrollment. These patients will receive an open-label fixed dose of 300 mg of RGLS8429 every other week for three months. Besides PC1 and PC2, the trial will also evaluate safety and imaging biomarkers.

In the third cohort, 16 participants were randomly assigned in a 3:1 ratio to receive either 3 mg/kg of RGLS8429 or a placebo every other week for three months. The results indicated that RGLS8429 was well tolerated, showing no safety concerns. Evidence of a mechanistic dose response was observed, with notable increases in PC1 and PC2 at the 3 mg/kg dose level compared to earlier cohorts. Across all doses tested, the percent change from baseline in PC1 and PC2 demonstrated a dose response, with statistical significance at 3 mg/kg compared to the placebo.

Exploratory MRI imaging analysis suggested that RGLS8429 reduced htTKV at the 3 mg/kg dose level after three months of treatment. Furthermore, 70% of subjects showed reductions in htTKV after completing the 3 mg/kg dose level. Dr. Preston Klassen, President and Head of Research & Development at Regulus Therapeutics, expressed satisfaction with the consistent mechanistic response and reduction in htTKV at the 3 mg/kg dose level. He noted that the safety and tolerability profile was appropriate, supporting the ongoing and final 300 mg fixed dose cohort in this Phase 1b trial. Dr. Klassen believes these data could potentially lay the groundwork for a pivotal Phase 2/3 study of RGLS8429 under an Accelerated Approval regulatory pathway, pending discussions with the FDA.

Regulus Therapeutics CEO Jay Hagan emphasized that the positive results from the third cohort build on the success of the first two cohorts. He highlighted the reduction in htTKV seen in most patients as further evidence of RGLS8429's potential to address the underlying genetic cause of ADPKD.

The company plans to request an End-of-Phase 1 meeting with the FDA in the fourth quarter of this year, with the intention of providing a data update from the open-label fourth and final cohort of the Phase 1b MAD study by the end of the year.

ADPKD is one of the most common human monogenic disorders caused by mutations in the PKD1 or PKD2 genes. It leads to the development of multiple fluid-filled cysts in the kidneys, often progressing to end-stage renal disease in about half of the patients by age 60. In the United States, approximately 160,000 people are diagnosed with ADPKD, with a global prevalence estimated between 4 to 7 million.

RGLS8429 is a next-generation oligonucleotide designed for the treatment of ADPKD. It inhibits miR-17 and preferentially targets the kidney. Preclinical models have shown improvements in kidney function, size, and other measures of disease severity. The Phase 1 SAD study completed in September 2022 demonstrated a favorable safety and pharmacokinetic profile for RGLS8429. Subsequent Phase 1b MAD study data from the first three cohorts have continued to reflect positive outcomes, with the fourth cohort currently underway.