First-in-human trial of PCSK9 gene editing therapy for lowering cholesterol: a new frontier in cardiovascular pharmacotherapy? News from AHA

Abstract

Gene editing for treating hypercholesterolaemia ( the heart-1 study) featured in a late-breaking science session at the recent American Heart Association ( AHA) meeting in Philadelphia and may auger the onset of a new era in cardiovascular medical therapy.Cholesterol-lowering is proven and effectiv e f or reducing the risk of clinical outcome events and for reducing mortality in patients with atherosclerotic cardiovascular disease ( A SC VD) . 1 -4 However, despite the extensive therapeutic armamentarium currently available, many patients do not reach their recommended cholesterol goal.Gene editing therapy is an exciting new approach that aims to provide a long-term therapeutic solution for hypercholesterolaemia by inactivating the gene for PCSK9, a key molecule regarding cellular low density cholesterol ( LDL) receptor regulation and hence circulating cholesterol levels.Gene therapy could provide a one-shot, single-course, long-term, possibly life-term, approach for lowering LDL cholesterol, an attractive treatment option, especially in patients with familial hypercholesterolaemia, who need life-long treatment commencing at an early age.Heart-1 is an ongoing, open-label, ascending dose, phase 1b study designed to assess the safety and tolerability of VERVE-101, an in vivo adenine base-editing therapy, in patients with familial hypercholesterolaemia.The interim analysis reported 10 patients, all of whom had established A SC VD and were at high risk for cardiovascular events.Despite oral lipid-lowering therapy, LDL cholesterol levels were high ( mean entry LDL cholesterol 193 mg/dL) .After pre-medication with dexamethasone and antihist amines , a single dose of VERVE-101 was administered via peripheral intravenous infusion across 4 escalating-dose cohorts ( 0.1, 0.3, 0.45, and 0.6 mg/kg) .The results were encouraging.At 28 days, the blood PCSK9 level was reduced by 59 and 84% in patients treated with the 0.45 mg/kg dose, and by 47% in the patient receiving the 0.6 mg/kg dose.LDL-cholesterol decreased by 39 and 48% with the 0.45 mg/kg dose, and by 55% with the 0.6 mg/kg dose.The 55% reduction of LDL persisted for 6 months.In a preclinical study with monkeys, LDL-cholesterol reduction lasted 2.5 years after a single dose of the medication.The treatment did have side effects.Participants experienced brief flu-like symptoms, including fever, headaches, and body aches, as well

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