Regulus Therapeutics Inc. announced top-line results from the first cohort of patients with ADPKD in its ongoing Phase 1b clinical trial of RGLS4326. The study is evaluating the safety, pharmacokinetics, and effects on pharmacodynamic biomarkers of multiple doses of RGLS4326 in patients with ADPKD. In the first cohort, nine patients were enrolled and received 1 mg/kg of RGLS4326 subcutaneously every other week for four doses. Safety, pharmacokinetics, and certain disease related biomarkers were evaluated through the course of the study. The biomarkers included: Polycystin 1 (PC1) and Polycystin 2 (PC2) which are the protein products of the PKD1 and PKD2 genes respectively, kidney injury marker 1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), as well as urea and creatinine and were chosen to evaluate changes in disease related measures. RGLS4326 was well tolerated by all nine patients with no serious adverse events reported. All reported adverse events were mild and generally transient in nature. Overall, the pharmacokinetic profile of RGLS4326 in patients with ADPKD was similar to the pharmacokinetic profile observed in a prior healthy volunteer study with the following observations: The half-life of RGLS4326 in plasma was slightly longer in patients with impaired renal function and did not exhibit any signs of accumulation in plasma. RGLS4326 plasma concentrations in patients were elevated relative to healthy volunteers with mean plasma AUC levels after the first and fourth dose approximately two-fold higher in patients. Higher plasma exposure is anticipated to lead to higher kidney exposure allowing for potential dose reductions needed to achieve desired kidney exposure. A statistically significant increase in the PC1 biomarker was observed in the first cohort of this study. The mean increase at Day 71 (n=8) compared to baseline was greater than 50% and all patients had double digit increases in PC1 levels with an overall trend showing increasing levels of both PC1 and PC2 over time. Mean PC2 levels increased compared to baseline levels (>20%) however the results did not reach statistical significance. Importantly, at the time of the analysis, mutational status was not known and may further contribute to understanding differences in response rates. Approximately 85% of patients with ADPKD are reported to have a mutation in the PKD1 gene, while the remaining 15% have a mutation in the PKD2 gene. Measured levels of these biomarkers (PC1 and PC2) inversely correlate with disease severity and are believed to be directly linked to the underlying genetic drivers of the disease. Regulus believes these initial data demonstrate that RGLS4326 engages the target miR-17 leading to de-repression of the PKD1 and PKD2 genes and the resultant increases in measured polycystin levels. In addition to polycystin changes, one other notable improvement was observed in NGAL levels for one patient in the first cohort. As anticipated, NGAL levels for nearly all patients in this study were within the normal range. However, one patient had levels that were approximately twice the normal range at baseline and that individual saw NGAL levels drop to within the normal range by the end of study. Further analyses of the data are ongoing to better understand drivers of response and correlations with baseline characteristics and other parameters. Data from this first cohort is planned to be submitted for presentation at Kidney Week, the American Society of Nephrology annual meeting being held in November 2021.