siRNA targeting LPA mRNA lowers Lp(a) levels

ACC 2022 A phase 1 single ascending dose study showed that subcutaneous injection of SLN360, an siRNA targeting mRNA for the LPA gene, lowered Lp(a) up to 98% in adults with elevated Lp(a) levels.

Presented at ACC.22 by Steven Nissen, MD (Cleveland, OH, USA)

Introduction and methods

Lipoprotein(a) (Lp[a]) is an important biomarker to help identify patients at high residual CV risk. Unfortunately, there are to date no therapies available to lower Lp(a).

SLN360 is a siRNA targeting LPA mRNA. SLN360 can thereby suppresses the translation of LPA mRNA in the liver which prevents the production of apolipoprotein(a), a key component of Lp(a). The current placebo-controlled and double-blind single ascending dose study investigated the effects of SLN360 on Lp(a)-levels in adults with elevated Lp(a).

A total of 32 men and women, aged 18-70 years without ASCVD or aortic stenosis and with Lp(a) ≥150 nmol/L (~60 mg/dL) were included in the APOLLO trial. Participants were divided into 4 cohorts (8 participants per cohort). 2 participants per cohort (8 in total) received placebo, the other 6 participants per cohort received one of four doses (30, 100, 300 or 600 mg) of SLN360 via a single subcutaneous injection. Participants were closely monitored for 24 hours after dosing and assessed periodically for a follow-up period of 150 days.

Main results

• Participants receiving 300 mg and 600 mg of SLN360 achieved a maximum Lp(a) reduction of 96% and 98%, respectively. Lp(a) reduction at 150 days was 71% in the 300 mg dose cohort and 81% in the 600 mg dose cohort, compared to baseline.
• The highest two doses also reduced LDL-c levels by 21% and 26% (mean percent reduction).
• There were no serious adverse events related to SLN360.

Conclusion

This phase 1 single ascending dose study showed that subcutaneous injection of SLN360, an siRNA targeting mRNA for the LPA gene, lowered Lp(a) up to 98%. At 150 days after injection, reductions of 71% and 81% were observed after the 300 mg and 600 mg doses. SLN360 was well tolerated.

Nissen said that these findings support further development of this therapy. Further studies are needed to investigate whether reductions in Lp(a) can have an impact on incidence of ASCVD or prevent progression of aortic stenosis.

-Our coverage of ACC.22 is based on the information provided during the congress–

This study was simultaneously published in JAMA. Watch the video about this trial