Weekly journal scan: a new small-interfering RNA to fight a genetic cardiovascular risk factor

Key points• In this multicentre, placebo-controlled, double-blind, randomized, company-funded, Phase 1 study, the authors sought to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single-ascending subcutaneous doses of LY3819469 (lepodisiran), a short-interfering RNA targeting lipoprotein(A) [Lp(a)] in subjects with elevated Lp(a) levels. 1 • The trial was conducted at five clinical sites in the USA and Singapore.Inclusion criteria were age between 18 and 65 years in the USA and between 21 and 65 years in Singapore, without any known cardiovascular disease (CVD) except dyslipidaemia or well-controlled hypertension, a body mass index between 18.5 and 40 kg/m 2 , and Lp(a) serum levels of 75 nmol/L or more (or 30 mg/dL or more).• The primary outcome was the safety and tolerability of single ascending doses of lepodisiran.Secondary outcomes included plasma levels of lepodisiran for 168 days after dose administration and changes in fasting Lp(a) serum concentrations through a maximum follow-up of 48 weeks.The trial sponsor collected the data, and the statistical analyses were performed by a contract research organization.The trial was not powered for statistical hypothesis testing.• A total of 48 adult subjects were enrolled in the trial.Participants were randomized to receive placebo or a single subcutaneous dose of lepodisiran (4, 12, 32, 96, 304, or 608 mg).The mean age was 47 years, with 35% women, 48% Asian, 15% Black or African American, and 33% White.The median baseline Lp(a) concentration for the entire population enrolled was 113 nmol/L (Interquartile range [IQR], 82-151 nmol/L), varying from 78 nmol/L (IQR, 50-152 nmol/L) for the 4 mg of lepodisiran group to 167 nmol/L (IQR, 124-189 nmol/L) for the 96 mg dose group.The mean low-density lipoprotein (LDL) cholesterol level was 132 mg/dL.• Plasma concentrations of lepodisiran reached peak levels within 10.5 h and were undetectable by 48 h.From baseline to 48 weeks, the maximal median change in Lp(a) concentration ranged from -3 mmol/L (IQR, -18 to -12 nmol/L) in the placebo group to -127 nmol/L (IQR, -147 to -84 nmol/L) in the 608 mg dose group.The maximal median percentage change in Lp(a) concentration was -5% (IQR, -16% to 11%) in the placebo group, -41% (IQR, -47% to -20%) in the 4 mg of lepodisiran group, -59% (IQR, -66% to -53%) in the 12 mg dose group, -76% (IQR, -76% to -75%) in the 32 mg dose group, -90% (IQR, -94% to -85%) in the 96 mg dose group, -96% (IQR, -98% to -95%) in the 304 mg dose group, and -97% (IQR, -98% to -96%) in the 608 mg dose group.The percentage change in Lp(a) level lasted longer with the highest doses of lepodisiran, with a median Lp(a) concentration below the lower limit of detection for the majority of the study period.For the 608 mg dose of lepodisiran, the median change in Lp(a) concentration was -94% (95% confidence interval [CI], -94% to -85%) at Day 337.• There were no serious drug-related adverse effects (a facial injury after a fall 141 days after injection was classified as a serious adverse event), and overall, treatment was well tolerated, with the most common adverse events reported being headache and rhinorrhoea.