The ORION-1 experiment showed that inclisiran, an RNAi treatment that prevents PCSK9 production in the liver, may be dosed to significantly decrease LDL-C. Evolocumab inhibits PCSK9 in the bloodstream, lowering LDL-C irrespective of pre-treatment plasma PCSK9 levels. For a study, researchers investigated the possibility that the LDL-C lowering effects of inclisiran in the ORION-1 trial were correlated with pre-treatment PCSK9 levels.

Inclisiran was the subject of ORION-1, a phase 2 double-blind, placebo-controlled study (n=501) in patients with increased LDL-C despite well-tolerated statins and high CVD risk. One dosage of inclisiran (200, 300, or 500 mg) was given to the subjects on Day 1, or two doses were given on Days 1 and 90. (100, 200, or 300 mg). For the pooled 300 mg groups, LDL-C reductions at day 60 were evaluated between quartiles of baseline PCSK9. To evaluate the connection between LDL-C and PCSK9, Spearman’s correlation coefficients were computed.

In the combined 300 mg groups, there were 123 people (mean age 64; 71% male; mean BMI 28.6; 74% ASCVD; 74% statin treatment [36% high-intensity]; 7.3% ezetimibe monotherapy). Statin usage was more prevalent in those with higher pre-treatment PCSK9 levels (73% in Q1 vs. 97% in Q4). Pre-treatment PCSK9 and LDL-C did not correlate (R2 statin users=0.04; R2 non-users=0.03). At Day 60 with inclisiran, median LDL-C reductions varied from 52.2% to 55.0% across baseline PCSK9 quartiles (Table; P for heterogeneity=0.91), while median PCSK9 reductions ranged from 70.4% to 73.3% (P for heterogeneity=0.53). PCSK9 levels and LDL-C levels were inversely associated (R2=0.14).

Regardless of the amount of circulating PCSK9 before therapy, inclisiran 300 mg lowered LDL-C by 52.2% to 55.0%. Pre-treatment PCSK9 levels didn’t seem to be a very important factor in determining how well inclisiran works. Phase 3 studies are now looking at the 300 mg dosage.