Gene silencers cut ATTR-CM death and heart events 20 per cent, except with tafamidis
A meta-analysis of two phase 3 outcome trials of transthyretin gene silencing covered 2,086 people with transthyretin amyloid cardiomyopathy. Against placebo the drugs cut all-cause death and recurrent cardiovascular events by 20 per cent. Six-minute walk distance improved by 22.2 metres. In people already taking a transthyretin stabiliser the rate ratio sat at 0.97. Plozasiran, given as 25 mg every three months, cut triglycerides 79 per cent and 81 per cent in two trials, against about 27 per cent on placebo.
Science··Morning
Pooled silencers cut death and recurrent heart events 20 per cent
The meta-analysis pooled HELIOS-B, with 654 people on vutrisiran, and CARDIO-TTRansform, with 1,432 on eplontersen, covering 2,086 people with transthyretin amyloid cardiomyopathy. Against placebo the drugs cut all-cause death and recurrent cardiovascular events by 20 per cent (rate ratio 0.80, 95 per cent confidence interval 0.69-0.94; P = 0.006). All-cause death was lower as well (hazard ratio 0.74, 95 per cent confidence interval 0.61-0.91), and six-minute walk distance improved by 22.2 metres. The two phase 3 outcome trials of transthyretin gene silencing now sit in one pooled estimate rather than in separate readouts.[1]
The rate ratio was 0.97 alongside a transthyretin stabiliser
The benefit was not uniform. In people not already taking a transthyretin stabiliser the rate ratio was 0.69 (95 per cent confidence interval 0.57-0.85); in those on one it was 0.97 (95 per cent confidence interval 0.77-1.23), with a heterogeneity P of 0.03. Only tafamidis was used as the stabiliser. The authors list five limitations: the pooling uses trial-level summaries rather than individual patient data, it is underpowered for the combination question, eligibility and follow-up differed between the trials, and background heart-failure treatment differed as well.[1]
Plozasiran cut triglycerides 79 per cent and 81 per cent at one year
SHASTA-3 and SHASTA-4, run in 24 countries and funded by Arrowhead Pharmaceuticals, assigned people with triglycerides at or above 500 mg/dL to plozasiran or placebo. Patients received 25 mg by subcutaneous injection every three months for a year. At the 12th month triglycerides had fallen 79 per cent in SHASTA-3 and 81 per cent in SHASTA-4, against about 27 per cent on placebo. Acute pancreatitis events fell 78 per cent against placebo, and the announcement reports a 100 per cent reduction in the higher-risk subgroup with triglycerides above 880 mg/dL and a previous episode. Treatment was stopped for adverse events in 1.4 per cent of patients on plozasiran and 0.8 per cent on placebo. Gerald Watts of the University of Western Australia presented the results at the ESC Congress; the trials have not yet appeared in a journal.[2]
