Abstract: TH-PO1200
RGLS8429 Increases Urinary PC1 and PC2 and May Reduce Height-Adjusted Total Kidney Volume (htTKV) in Patients with ADPKD
Session Information
- Late-Breaking Science Posters
October 24, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Cystic
Authors
- Yu, Alan S.L., The University of Kansas Medical Center, Kansas City, Kansas, United States
- Garg, Rekha, Regulus Therapeutics Inc, San Diego, California, United States
- Bellovich, Keith A., St. Clair Nephrology Research, Detroit, Michigan, United States
- Silva, Arnold L., Boise Kidney and Hypertension Institute, Boise, Idaho, United States
- Padgett, Claire S., Regulus Therapeutics Inc, San Diego, California, United States
- Lee, Edmund Chun Yu, Regulus Therapeutics Inc, San Diego, California, United States
- Valencia, Tania M., Regulus Therapeutics Inc, San Diego, California, United States
- Kline, Timothy L., Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Gregory, Adriana, Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Carroll, Kevin, KJC Statistics Limited, Cheadle, United Kingdom
- Patel, Vishal, The University of Texas Southwestern Medical Center, Dallas, Texas, United States
Background
ADPKD is caused by mutations in either PKD1 or PKD2, leading to reduced expression or function of PKD-encoded proteins PC1 and PC2. This results in widespread dysregulated gene expression, hyperproliferation of renal tubular epithelia, formation of multiple cysts, progressive enlargement of the kidneys, and declining renal function. The microRNA miR-17 inhibits PKD1 and PKD2 and is implicated in the dysregulated gene expression observed in ADPKD. RGLS8429 is an anti-miR-17 oligonucleotide that derepresses miR-17 mRNA targets, including PKD1 and PKD2, leading to increased PC1 and PC2 and amelioration of PKD in multiple mouse models.
Methods
We conducted a randomized, double-blind, placebo-controlled, Phase 2a MAD study in patients with ADPKD evaluating RGLS8429 in 3 weight-based cohorts (1, 2, 3 mg/kg). The key inclusion criteria were Mayo Class 1C, 1D, or 1E, and an eGFR between 30-90 mL/min/1.73 m2. The treatment duration was 12 weeks with RGLS8429 or placebo subcutaneous injection Q2W x 7 doses, with an end of study visit 4 weeks after the last dose. We measured urinary PC1 and PC2 levels before and at multiple points after randomization. An exploratory analysis of the change in htTKV from the baseline compared to the end of study was conducted.
Results
We enrolled 42 subjects (32 RGLS8429, 10 placebo) with balanced baseline characteristics between RGLS8429 group and placebo. RGLS8429 was well tolerated. RGLS8429 treatment raised urinary PC1 and PC2 levels in a dose-dependent manner. The change from baseline to end of study in PC1 and PC2 levels was statistically significant in the 3 mg/kg cohort (n=11) compared to the placebo cohort (n=9). Geometric least squares mean percent change in htTKV over 16 weeks was 2.5, 1.4, -0.6, and -0.6 for placebo, 1, 2, and 3 mg/kg groups, respectively. 70% of subjects receiving 3 mg/kg had a reduction in htTKV.
Conclusion
Results provide clinical proof of dose-responsive RGLS8429 mechanistic activity on PC1 and PC2. Exploratory analysis suggests a reduction of htTKV at 2 and 3 mg/kg doses over a relatively short treatment period. Findings validate miR-17 as a potential therapeutic target for ADPKD. A Phase 2/3 registrational trial is being planned.
Funding
- Commercial Support – Regulus Therapeutics