PHILADELPHIA – A novel treatment strategy tackling hypertriglyceridemia via long-acting agents targeting two specific culprit genes caused a stir based on the highly encouraging early results of two small proof-of-concept studies presented at the American Heart Association scientific sessions.
ARO-APOC3 is a small interfering ribonucleic acid molecule (siRNA) targeting the apolipoprotein C-III gene (APOC3) specifically within hepatocytes, while ARO-ANG3 is an siRNA targeting hepatic angiotensinlike protein 3 (ANG3). ARO-APOC3 is being developed as a potential treatment for familial chylomicronemia syndrome, a rare disorder associated with triglyceride levels in excess of 800 mg/dL, as well as for patients with severe hypertriglyceridemia and associated pancreatitis – a far more common condition – and ultimately, perhaps, for patients with hypertriglyceridemia and heart disease. ARO-ANG3, which lowers very-low-density lipoprotein (VLDL) as well as LDL cholesterol while increasing HDL cholesterol levels, is under development as a treatment for high triglycerides, homozygous familial hypercholesterolemia, nonalcoholic fatty liver disease, and metabolic diseases.
Christie M. Ballantyne, MD, presented the results of the phase 1/2a study of ARO-APOC3, which included 40 healthy subjects who received a single subcutaneous injection of the RNA inhibitor at 10, 25, 50, or 100 mg and were followed for 16 weeks. At the highest dose, it reduced serum APOC3 levels by 94%, triglyceride levels by 64%, LDL cholesterol levels by up to 25%, and VLDL by a maximum of 68%, while boosting HDL cholesterol levels by up to 69%. These substantial changes in lipids remained stable through week 16.
The observed prolonged duration of effect provides a potential opportunity for dosing quarterly or perhaps even twice a year. This would be ideal for patients who have problems with adherence to daily therapy with statins and other oral agents, observed Dr. Ballantyne, professor of medicine and professor of molecular and human genetics at Baylor College of Medicine, Houston.
Gerald F. Watts, MBBS, DM, DSc, PhD, presented a separate phase 1/2a, 16-week study of a single dose of ARO-ANG3 at 35, 100, 200, or 300 mg in 40 dyslipidemic subjects who were not on background lipid-lowering therapy. The impact on lipids was similar to that achieved by silencing apolipoprotein C-III, except that the reduction in LDL cholesterol was larger and ARO-ANG3 reduced HDL cholesterol in dose-dependent fashion by up to 26%. As in the ARO-APOC3 study, the safety profile of the ANG3 RNA inhibitor raised no concerns, with no study dropouts and no serious adverse events, added Dr. Watts, professor of medicine at the University of Western Australia, Perth.