Encouraging data for lepodisiran as Lp(a) lowering therapy 

A substantial reduction in lipoprotein(a) was achieved with a single subcutaneous injection of lepodisiran, a siRNA-targeting mRNA for the LPA gene. Together with the favourable safety profile of this agent, the results support the further development of lepodisiran. 

“Lepodisiran is a siRNA designed to degrade the mRNA coding for apolipoprotein(a), thereby reducing translation of the LPA gene,” explained Dr Steven Nissen (Cleveland Clinic, OH, USA) [1]. The current phase 1 trial (NCT04914546) evaluated the safety and efficacy of lepodisiran in 48 participants with Lp(a) serum concentrations of ≥75 nmol/L who did not have known cardiovascular disease at enrolment. “Participants were randomised to 1 of 6 single-dose levels of lepodisiran, ranging from 4 mg to 608 mg, or to a placebo, all subcutaneously administered,” outlined Dr Nissen. The primary outcome measures were safety and Lp(a) serum concentrations through 48 weeks.

At 48 weeks, the mean reduction in Lp(a) was 94% in the highest dose group, showing a long duration of effect on Lp(a) levels (see Figure). The rate of adverse events (AEs) was overall low, and no dose-related trend could be observed in the occurrence of AEs. Headache, COVID-19, rhinorrhoea, and ECG patch erythema were the most common AEs. Injection-site reactions were reported as well but not more frequently in the active arms than in the placebo arm.

Figure: Median percentage reduction in lipoprotein(a) over time [1]



Lepodisiran was cleared from the plasma rapidly. “Even in the highest dose level, the drug was essentially gone from the plasma at 48 hours, reducing systemic exposure,” mentioned Dr Nissen. “This is a major advantage of this approach.”

Thus, lepodisiran delivered promising results as an Lp(a)-lowering agent in the current phase 1 study, supporting further development of the drug. “Nucleic acid therapeutics offer a highly promising approach to treat this previously untreatable disorder,” concluded Dr Nissen. “Cardiovascular outcomes trials will determine whether these therapies can reduce the incidence of major adverse cardiovascular events.”

1. 
   
   1. Nissen SE, et al. Lepodisiran: an extended-duration siRNA targeting lipoprotein(a). LB06, AHA Scientific Sessions 2023, 11–13 November, Philadelphia, USA.

Copyright ©2024 Medicom Medical Publishers



Posted on 29 January 202423 April 2024