Infrequent inclisiran dosing effective for lipid-lowering in the primary prevention setting

Twice-yearly maintenance dosing of inclisiran reduces atherogenic lipoproteins for primary prevention of patients with elevated LDL-C* despite statin use, according to the analysis of the primary prevention cohort from the ORION-11 trial.

“[We initially administered] inclisiran 284 mg or placebo … on days 1 and 90,” said the researchers. Following which, these were given every 6 months thereafter up to 540 days (end of study [EOS]).

At day 510, mean percentage change in LDL-C from baseline with inclisiran was −42 percent whereas with placebo, it was +1.8 percent (–44-percent difference; p<0.0001). A similar trend was seen in terms of mean time-adjusted percentage change in LDL-C from baseline after day 90 and up to EOS (−40 percent vs +0.6 percent for placebo; –41-percent difference; p<0.0001). [Eur Heart J 2022;43:5047-5057]

Absolute change in LDL-C was greater with inclisiran vs placebo from baseline to day 510 (−1.6 vs −0.06 mmol/L), as was time-adjusted absolute change in LDL-C from baseline after day 90 and up to EOS (−1.4 vs −0.1 mmol/L; p<0.0001 for both).

Of note, two-thirds of inclisiran recipients achieved at least a 50-percent reduction in baseline LDL-C levels at any time during the study. With placebo, only 9 percent were able to achieve this outcome.

Mean placebo-corrected percentage changes in non-HDL-C* and apolipoprotein B (apoB) from baseline to day 510 were −40 percent and −36 percent, respectively. The corresponding placebo-corrected time-adjusted percentage changes after day 90 and up to EOS were −35.3 percent and −34.8 percent (p<0.0001 for all).

Placebo-corrected absolute change in non-HDL-C from baseline to day 510 was −1.7 mmol/L, while time-adjusted absolute change from baseline after day 90 and up to EOS was −1.5 mmol/L. With apoB, the corresponding values were −40.4 and −39.3 mg/dL (p<0.0001 for all).

PCSK9** levels dropped by 65 percent with inclisiran and rose by 16 percent with placebo at day 510 (p<0.0001).

“[These data imply that patients] derived significant reductions in atherogenic lipoprotein levels even with twice-yearly maintenance dosing,” they said.

Safety

Inclisiran use was tied to more adverse events (AEs) than placebo (93 percent vs 84 percent), but most were mild to moderate, with the most common AEs occurring at a similar rate between arms, they noted.

The higher rates of AEs, serious AEs, and treatment-emergent AEs at injection site (mainly mild; none were persistent or severe) observed with inclisiran may be due to the small number of primary prevention patients. “[A]s such, the clinical relevance is uncertain,” they said.

Substantial, sustained response

A total of 203 high-risk primary prevention patients (those with clinical ASCVD*** or ASCVD risk equivalent; mean age 63 years, 53 percent female) from ORION-11 were randomized 1:1 to receive inclisiran or placebo. They had elevated LDL-C levels (mean 3.6 mmol/L) despite use of maximally tolerated doses^# of statins with or without additional lipid-lowering therapy.

CVD remains the leading cause of disability and death globally, with >50 percent of deaths occurring among those without prior CVD history. [www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds); accessed February 12 2023; J Am Coll Cardiol 2016;68:1690-1697] “[H]ence, population health strategies that improve approaches to primary prevention at a global level are important,” said the researchers.

In this study, inclisiran – an siRNA^## therapy targeting hepatic PCSK9 production – administered subcutaneously twice-yearly (following the initial and 3-month doses) effectively reduced multiple atherogenic lipoproteins across a broad range of high-risk primary prevention patients with elevated LDL-C despite maximally tolerated statins. It was also generally well-tolerated.

The time-adjusted percentage reductions corresponded to time-adjusted mean absolute reductions in LDL-C, non-HDL-C, and apoB levels with over a year of treatment, reflecting the efficiency and feasibility of this siRNA-based regimen as adjunctive lipid-lowering treatment in the primary prevention setting, they said.

“Perhaps more importantly, the infrequent dosing regimen … did not result in attenuation of efficacy, providing clinically significant time-adjusted reductions in [LDL-C, non-HDL-C, and apoB levels], indicating a substantial and sustained lipid-lowering response among those treated with inclisiran,” the researchers said.