Regulus Therapeutics Inc. announced positive topline results from the second cohort of patients in its Phase 1b MAD study of RGLS8429 for the treatment of ADPKD. The Phase 1b MAD study is a double-blind, placebo-controlled trial evaluating the safety, tolerability, pharmacokinetics and pharmacodynamics (PK/PD) of RGLS8429 in adult patients with ADPKD. The study is evaluating RGLS8429 treatment across three different weight-based dose levels, including measuring changes in urinary polycystins 1 and 2 (PC1 and PC2), height-adjusted total kidney volume (htTKV), cyst architecture, and overall kidney function.

PC1 and PC2 are the protein products of the PKD1 and PKD2 genes and have been shown to inversely correlate with disease severity. The third cohort is being dosed at 3mg/kg of RGLS8429 or placebo every other week for three months. The Company recently added a fourth cohort for an open label fixed dose of 300mg of RGLS8429 dosed every other week for three months.

Based on the results from this second cohort, the Company plans to amend the protocol to increase the sample size to up to 30 patients. In addition to PC1 and PC2 and safety, imaging biomarkers will also be evaluated. In the second cohort, 14 patients were randomized 3:1 to receive either 2 mg/kg of RGLS8429 or placebo every other week for three months.

RGLS8429 was well tolerated with no safety findings of concern. Clear evidence of a mechanistic dose response at a 2mg/kg dose level based on urinary PC1 and PC2 polycystin levels was observed. Urinary measurements of PC1 and PC2 demonstrated greater biological activity of RGLS8429 at 2mg/kg compared to 1mg/kg and placebo, which was most evident after 3 months of dosing.

Exploratory results of imaging-based biomarkers were encouraging with 3 patients with the highest increases in PC1 and PC2 having reductions in htTKV >4%, with corresponding reductions in total kidney cyst volume (TKCV). These data suggest potential impact on htTKV and TKCV, which the Company will further explore at higher doses in cohorts 3 and 4. The ongoing Phase 1b study is evaluating RGLS8429 dosing at 3 mg/kg in cohort 3 and will explore a 300 mg fixed dose in cohort 4 that will provide higher exposure in a larger number of patients based on anticipated body weight. In addition, the Company recently held a Type D meeting with FDA to discuss the accelerated approval pathway.

The meeting was constructive and confirms the potential for an accelerated approval pathway based on a single Phase 2 study of RGLS8429 for the treatment of ADPKD.