Olpasiran leads to dramatic reductions in Lp(a) concentrations

Olpasiran, a small interfering RNA, successfully reduced lipoprotein(a) (LP[a]) levels by >90% in patients with atherosclerotic cardiovascular disease (ASCVD) in the phase 2 OCEAN(a)-DOSE trial. The agent was well tolerated with only modest increases in mild injection site reactions.

According to a previously published register study in a predominantly European population, concentrations of Lp(a) are associated with ASCVD [1]. About 20% of patients with pre-existing ASCVD had a high Lp(a) concentration (≥150 nmol/L) and this was an independent risk factor for cardiovascular events.

Olpasiran is a small interfering RNA designed to lower the body's production of apolipoprotein(a), a key component of Lp(a). Associate Prof. Michelle O´Donoghue (Brigham and Women's Hospital, MA, USA) presented the results of the double-blind, placebo-controlled treatment period of the phase 2 OCEAN(a)-DOSE trial (NCT04270760), evaluating olpasiran in 281 adult participants with Lp(a) levels >150 nmol/L and evidence of ASCVD [2]. Participants were randomly allocated to olpasiran in one of the 4 different doses for 12 or 24 weeks (10 mg q12 weeks, 75 mg q12 weeks, 225 mg q12 weeks or 225 mg q24 weeks). The primary endpoint was the percentage change in Lp(a) from baseline to week 36 compared with placebo. The study included 34 sites in 7 countries all over the world.

The median baseline Lp(a) concentration of participants was approximately 260 nmol/L. At week 36, olpasiran treatment led to impressive reductions in Lp(a) levels. This reduction was >95% in the highest 2 dose groups. The primary endpoint was met, with a -70.5% change in the 10 mg dose group, and >90% in all other dose groups (see Figure). Moreover, almost all participants achieved an Lp(a) value below the established risk threshold of 125 nmol/l on doses >75 mg (66.7% at 10 mg dose and >98% at higher doses). The treatment effect was independent of age, sex, race, region, baseline Lp(a), baseline low-density lipoprotein-cholesterol (LDL-C), and given high-potency lipid-lowering therapy. “You can appreciate there was no evidence of effect modification across any of these prespecified subgroups,” Dr O´Donoghue said. Therapy with olpasiran also lowered LDL-C. Overall, the agent was well tolerated with an increased occurrence of injection site reactions and related hypersensitivity reactions. However, these were described as mild in severity and resolved without treatment.

Figure: Percentage change in Lp(a) concentrations adjusted for placebo at 36 weeks of treatment with increasing doses of olpasiran [2]



Prof. Stephen Nicholls (Victorian Heart Hospital at Monash University Clayton, Australia), the discussant of this trial, emphasised the existence of “known unknowns” of Lp(a), such as whether lowering Lp(a) will reduce cardiovascular risk and how much Lp(a) lowering will be required to achieve this.

1. 
   
   1. Patel AP, et al. Arterioscler Thromb Vasc Biol. 2021;41(1):465–74
   2. O´Donoghue ML. Reduction of lipoprotein(a) with small interfering RNA: The results of the Ocean(a)-DOSE trial. LBS.05, AHA Scientific Sessions 2022, 05–07 November, Chicago, USA.

 

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Posted on 11 January 202313 June 2024