Pharmacokinetics, Safety, and Tolerability of Anti-miR-17 Oligonucleotide RGLS4326 in Healthy Adult Subjects

Autosomal dominant polycystic kidney disease (ADPKD) is the most common form of polycystic kidney disease in adults and is characterized by progressive renal cyst formation and enlargement of the kidneys. The expression of microRNA-17 (miR-17) family is increased in kidney samples from ADPKD patients. RGLS4326 is a short oligonucleotide inhibitor of miR-17 that preferentially distributes to the kidney and displaces miR-17 from translationally active polysomes. Here, we present pharmacokinetics (PK), safety, and tolerability of RGLS4326 from phase 1 single-ascending dose (SAD) and multiple-ascending-dose (MAD) studies in healthy subjects. Healthy adult subjects received a placebo or a single-ascending subcutaneous dose of 0.05, 0.2, 0.6, 2, and 6 mg/kg or a multiple-ascending dose of 0.1, 0.3, and 1 mg/kg (four doses, once every 2 weeks). In the SAD study, plasma exposures increased in a dose-proportional manner across the dose range. Geometric mean t_1/2 values ranged from ≈3 to 8 h after subcutaneous injection to the abdomen, with longer t_1/2 values of ≈11 to 20 h and lower plasma exposures after subcutaneous injection to the upper arm or thigh. Urinary excretion increased with dose and ranged from 37% to 63%. In the MAD study, the mean elimination t_1/2 ranged from ≈5 to 7 h and plasma exposures increased in proportion to the dose range. The mean dose excreted in the urine for the 0.1 and 0.3 mg/kg doses was 35.2% to 39.3% compared to 46.5% to 48.1% for the 1.0 mg/kg dose. RGLS4326 was generally well tolerated, and no dose limiting treatment emergent adverse events were observed.