Kidney Week

Abstract: PO1244

RGLS4326 Increases Urinary PC1 and PC2 Levels in Individuals with Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Session Information

• Cystic Kidney Disease - I
  November 04, 2021 | Location: On-Demand, Virtual Only
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1001 Genetic Diseases of the Kidneys: Cystic

Authors

• Lee, Edmund, Regulus Therapeutics Inc, San Diego, California, United States

Edmund Lee, PhD

• Valencia, Tania M., Regulus Therapeutics Inc, San Diego, California, United States

Tania M. Valencia,

• Owen, Tate, Regulus Therapeutics Inc, San Diego, California, United States

Tate Owen,

• Neben, Steven, Regulus Therapeutics Inc, San Diego, California, United States

Steven Neben,

• Cremer, Karl F., Regulus Therapeutics Inc, San Diego, California, United States

Karl F. Cremer,

• Garg, Rekha, PharmaDRS Consulting LLC, San Diego, California, United States

Rekha Garg,

• Drygin, Denis, Regulus Therapeutics Inc, San Diego, California, United States

Denis Drygin,

• Ward, Christopher J., University of Kansas Medical Center, Kansas City, Kansas, United States

Christopher J. Ward,

• Yu, Alan S.L., University of Kansas Medical Center, Kansas City, Kansas, United States

Alan S.L. Yu,

• Patel, Vishal, The University of Texas Southwestern Medical Center Department of Internal Medicine, Dallas, Texas, United States

Vishal Patel,

Background

ADPKD is caused by mutations of either PKD1 or PKD2 genes, leading to reduced function of their respective protein products PC1 and PC2. Both proteins are secreted in exosomes, and their urinary levels inversely correlate with ADPKD severity. RGLS4326, a novel oligonucleotide inhibitor of miR-17, preferentially delivers to kidney tubules and cysts, derepresses miR-17 targets Pkd1 and Pkd2, increases PC1 and PC2, and attenuates cyst growth in multiple PKD mouse models. Whether RGLS4326 treatment would increase PC1 and PC2 in individuals with ADPKD was unknown.

Methods

An open-label, adaptive design, dose-ranging, Phase 1b clinical study is ongoing to evaluate RGLS4326 safety, pharmacodynamics and pharmacokinetics in individuals with ADPKD. The study will enroll ~27 patients (9 per cohort) treated subcutaneously with one of three RGLS4326 doses (1, 0.3, and 0.1 or 0.5 mg/kg Q2W x 4 doses) and will be followed for 28 days after the last dose (Day 71). The major inclusion criteria are Mayo Imaging Classification of 1C, 1D, or 1E, and GFR between 30-90 mL/min/1.73 m². The urinary biomarkers include PC1 and PC2 on exosomes, kidney injury marker 1 (KIM1), and neutrophil gelatinase-associated lipocalin (NGAL).

Results

Nine patients (mean GFR 49 mL/min/1.73m², mean age 50 yr) were enrolled in the first cohort; each patient received four doses of 1mg/kg of RGLS4326 Q2W. RGLS4326 was well tolerated with no serious adverse events. PK profiles were similar to healthy volunteers, with a plasma half-life of 9 hours and plasma AUC levels after the first and fourth dose ~2x higher in patients. Changes in both PC1 and PC2 at the end of study from baseline were statistically significant (p=0.0004 and p=0.026, respectively), with mean % increase in PC1 and PC2 of 58% and 38%, respectively.

Conclusion

These data provide clinical proof that RGLS4326 delivers to cystic kidneys of individuals with ADPKD, where it inhibits miR-17 and thereby derepresses PC1 and PC2. The results also imply ongoing miR-17-mediated repression of Pkd1 and Pkd2 in humans, further validating miR-17 as a therapeutic target for ADPKD treatment.

Funding

• Commercial Support – Regulus Therapeutics