Pooled ORION analysis boosts lipid-lowering potential of inclisiran

After the initial and 3-month doses, twice-yearly dosing of inclisiran led to effective and sustained LDL-C* reduction in patients with and without polyvascular disease (PVD**), according to a pooled analysis of the ORION-9, ORION-10, and ORION-11 phase III trials.

“Persistently elevated LDL-C causes atherosclerotic cardiovascular disease (ASCVD) and is strongly associated with an increased risk of CVD,” said Professor Wolfgang Koenig from the German Heart Centre Munich, Germany, during his presentation at ESC 2021. “[A]bout 25 percent of patients with ASCVD do have PVD, [which is an] independent predictor of poor CV outcomes.”

Patients eligible for these trials are those with HeFH***, established ASCVD, or with ASCVD risk equivalent (n=3,454 [470 with PVD]; mean age 65 years, 68 percent male, mean LDL-C 2.78 mmol/L). Participants were randomized 1:1 to receive either inclisiran sodium 300 mg or placebo (days 1, 90, 270, and 450) and followed until day 540. [ESC 2021, Evolving Frontiers for CAD]

At day 510, mean percentage change in LDL-C from baseline was significantly greater with inclisiran vs placebo, be it among those with (–40.9 percent vs 8.0 percent) or without PVD (–45.8 percent vs 5.7 percent). A similar trend was seen in terms of absolute change in LDL-C from baseline (–1.3 vs 0.2 mmol/L [PVD] and –1.4 vs 0.1 mmol/L [no PVD]; p<0.0001 for all).

Similarly, mean time-adjusted change (percentage and absolute) in LDL-C from baseline to after days 90 and 540 was greater with inclisiran vs placebo (p<0.0001 for all).

Day 510 also saw marked reductions in other atherogenic lipids with inclisiran vs placebo in the PVD arm (mean percentage change, –28.8 percent vs 3.8 percent [total cholesterol], –42.3 percent vs 5.6 percent [non-HDL-C^#], –39.7 percent vs 3.0 percent [apolipoprotein B], and –14.9 percent vs 11.7 percent [lipoprotein(a)]). A similar trend was seen in the no-PVD arm (mean percentage change, –29.8 percent vs 2.9 percent, –43.1 percent vs 3.5 percent, –40.5 percent vs 1.7 percent, and –13.8 percent vs 9.7 percent; p<0.0001 for all).

There were similar proportions of patients with treatment-emergent adverse events (TEAEs) between the inclisiran and placebo arms within the PVD (81 percent vs 84 percent) and no-PVD arms (76 percent for both). Those with PVD though had numerically more TEAEs than those without. “[This] is not much of a surprise, as these are more severely diseased patients,” explained Koenig.

The only significant TEAE reported with inclisiran was bronchitis (PVD arm; risk ratio, 3.16) which, according to Koenig, was most likely due to a chance finding. There were no signs of hepatic toxicity and muscular or renal side effects. Platelet counts between arms were no different either.

Except for a modest excess of mostly mild and transient clinically relevant TEAEs at the injection site with inclisiran vs placebo, both in the PVD (3.1 percent vs 0 percent) and no-PVD arms (5.3 percent vs 0.8 percent), inclisiran was generally well-tolerated.

“Since patients with PVD have a very high risk of CV events, intensive lipid-lowering may be beneficial to reduce such risk in this population,” said Koenig.

Clearly effective, but…

However, the benefits of inclisiran are countered by its limited availability and fairly high cost. “That is why we have to give it to high-risk patients … Inclisiran has been only approved in a few countries, and the pricing hurdle [is something] we still have to overcome,” said Koenig.

“[Nonetheless,] this new drug is very effective in lowering LDL-C, and the advantage of [twice-yearly] administration is quite unique,” said Professor Antonio Colombo from the EMO Centro Cuore Columbus, Milan, Italy, who moderated the session.

Koenig concurred, as the twice-yearly dosing “will certainly improve adherence – which is still a big issue to deal with, not only for lipid-lowering but also in hypertension and other diseases. The more we get our patients [to be] adherent, the longer they will have lower LDL-C. This will certainly translate into a reduced event rate.”