Preclinical development and phase 1 trial of a novel siRNA targeting lipoprotein(a)

Novel insights into lipoprotein(a): News from Atherosclerosis

“…In a recent phase I dose escalation study [25], olpasiran, a first-in-class N-acetylgalactosamine-conjugated siRNA, substantially reduced Lp(a) concentration with effects persisting for several months. Although at an early stage of development, these findings support for continued investigation with this agent.…”

Cascade testing for elevated lipoprotein(a) in relatives of probands with high lipoprotein(a)

“…However, a clinical trial is underway to test this hypothesis in high-risk individuals utilizing an anti-sense oligonucleotide targeted at the mRNA transcript of the apo(a) gene that decreases the hepatic production of Lp(a) particles (NCT04023552) [29] . A potent and more durable form of RNA therapeutics, utilizing the principle of small interfering RNA, has also recently been described [30] . At present, the value of screening for elevated Lp(a), including the cascade testing approach described in the present study, is to mitigate cardiovascular risk by addressing modifiable behavioural and clinical risk factors with established interventions, including use of statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors [ 6 , 27 ].…”

RNA-based therapy in the management of lipid disorders: a review

“…A dose-ranging phase 2 trial was conducted in patients with established CVD and Lp(a) > 60 mg/dL. Patients were randomly assigned to treatment with varying doses of pelacarsen (20 mg QW or Q2W or Q4W, 40 mg Q4W, 60 mg Q4W) over a six-month period [ 63 ]. Reduction in Lp(a) levels of 72% was observed in patients receiving 60 mg Q4W while patients treated with 20 mg QW showed an 80% reduction in Lp(a) (Table 3 ).…”

“…Olpasiran is an siRNA which selectively inhibits the transcription of LPA mRNA restricting production of Lp(a) [ 17 , 63 ].…”