siRNA therapy reduces Lp(a) in patients with established ASCVD

Reduction of Lipoprotein(a) With Small Interfering RNA: The Results of the Ocean(a)-DOSE Trial

Presented at the AHA Scientific Sessions 2022 by: Michelle L. O’Donoghue, MD - Boston, MA, USA

Introduction and methods

There is a large body of evidence to show that Lp(a) is associated with CV events independent of traditional risk factors. In addition, mendelian randomization data show a causal relationship between Lp(a) and CHD risk. Olpasiran is a siRNA that is directed to the liver via a GalNAc moiety. Inside the hepatocyte, the antisense strand is loaded into an RNA-induced silencing complex (RISC). Transcription of the LPA gene results in apo(a) mRNA. RISC binds to the apo(a) mRNA leading to degradation of the mRNA, thereby preventing translation and assembly of Lp(a).

The OCEAN(a)-DOSE study was a double-blind, multinational phase 2 dose-ranging study that enrolled patients aged 18-80 years with ASCVD and Lp(a)>150 nmol/L. A total of 281 patients were randomized 1:1:1:1:1 to receive olpasiran 10 mg Q12W, olpasiran 75 mg Q12W, olpasiran 225 mg Q12W, olpasiran 225 mg Q24W, or placebo for 36 weeks. The primary endpoint was percent change in Lp(a) from baseline to week 36.

Main results

Efficacy

• The placebo-adjusted percent change in Lp(a) from baseline to week 36 was -70.5% in the olpasiran 10 mg Q12W group, -97.4% in the olpasiran 75 mg Q12W group, -101.1% in the olpasiran 225 mg Q12W group, and -100.5% in the olpasiran 225 mg Q24W group.
• The proportion of patients achieving an Lp(a) concentration <125 nmol/L at week 36 was 0% in the placebo group, 66.7% in the olpasiran 10 mg Q12W group, 100% in the olpasiran 75 mg Q12W group, 100% in the olpasiran 225 mg Q12W group, and 98.1% in the olpasiran 225 mg Q24W group.
• In doses of 75 mg or higher, there was very limited interpatient variability in percent change in Lp(a) from baseline to week 36.
• There was no effidence of effect modification across any of the prespecified subgroups (age, sex, race, region, baseline Lp(a), baseline LDL-c, high-potency lipid-lowering therapy).
• Olpasiran also lowered LDL-c and ApoB consistently across the olpasiran groups. Percent change in LDL-c and ApoB was -23.7% and -18.9% ,respectively, in the olpasiran 75 mg Q12W group, and -23.1% and -17.6%, respectively, in the olpasiran 225 mg Q12W group.

Safety

• Olpasiran appeared to be safe, which few adverse events leading to drug discontinuation.
• There was no increase in incidence of myalgia, liver-related adverse events, hyperglycemia, and new-onset or worsening diabetes mellitus with olpasiran.
• Olpasiran did increase injection site reactions and related hypersensitivity reactions. Overall, these appeared to be mild and tended to be self-limiting and resolved within 48 hours without treatment.

Conclusion

The phase 2 OCEAN(a)-DOSE study showed that olpasiran dosed 75 mg or higher every 12 weeks reduces Lp(a) by >95% from baseline to 36 weeks in patients with elevated Lp(a) and established ASCVD. Olpasiran appeared to be safe. There was an increase in injection site reactions and related hypersensitivity reactions, which were overall mild in severity and resolved without treatment.

-Our reporting is based on the information provided at the AHA Scientific Sessions-