859-P: ALN-KHK, an Investigational RNA Interference Therapeutic, Successfully Targets Hepatic Ketohexokinase in a Single Ascending Dose Study of Overweight to Obese Adults

Introduction & Objective: Rising obesity rates are attributed in part to high dietary sugar consumption, including fructose, which is linked to development of hepatosteatosis and type 2 diabetes. ALN-KHK is an investigational RNA interference therapeutic designed to decrease hepatic ketohexokinase (KHK) expression, thus reducing fructose metabolism by targeting its initial step and potentially decreasing hepatic lipogenesis. The objectives of this Phase 1/2 Part A single ascending dose study (NCT05761301) were to evaluate safety, tolerability, and pharmacology of ALN-KHK in overweight to obese adults. Methods: Healthy adults with a BMI of 27-34.9 kg/m2 were randomized 3:1 to receive a single subcutaneous dose of ALN-KHK or placebo. Five dose cohorts (25, 75, 150, 300, and 600 mg) were evaluated over a 3-month period with follow up for up to 9 months. The primary endpoint assessed safety and tolerability. Secondary endpoints characterized pharmacokinetics and pharmacodynamics of ALN-KHK after a fructose tolerance test (FTT) prior to dosing and on Days 29, 57, 85, and 169. Results: Forty participants enrolled (N=30, ALN-KHK; N=10, placebo; mean (SD) age, 45.4 (11.5) years; mean (SD) BMI, 29.7 (1.7) kg/m2; 67.5% male). By data cutoff, all adverse events were mild, non-serious, and resolved. Increasing doses of ALN-KHK were generally associated with dose- and time-dependent increases in serum fructose area under the curve (AUC) and urinary fructose fraction excreted after FTT. Preliminary data showed a mean (SD) increase from baseline of 178.0% (84.4%) in serum fructose AUC with 300 mg at Day 85. Reduction of fibroblast growth factor 21 after FTT was also observed. Conclusion: Interim results of this first clinical study of ALN-KHK demonstrate an encouraging safety and tolerability profile with target engagement in overweight to obese adults, supporting its further evaluation in patients with type 2 diabetes. Disclosure E. Maratos-Flier: Employee; Alnylam Pharmaceuticals. T. Nandi: None. K. Boyle: Employee; Alnylam Pharmaceuticals, Inc. X. Li: None. Y. Wu: Employee; Alnylam Pharmaceuticals, Inc. L. Noetzli: Employee; Alnylam Pharmaceuticals, Inc. Stock/Shareholder; Alnylam Pharmaceuticals, Inc. F. Kajbaf: Employee; Alnylam Pharmaceuticals, Inc. G. Morelli: None. Funding Alnylam Pharmaceuticals, Inc.