Inclisiran administration potently and durably lowers LDL-C over an extended-term follow-up: the ORION-8 trial

Abstract

Aims: Data describing the long-term efficacy and tolerability of inclisiran are limited. This was explored in ORION-8, an open-label extension of preceding Phase 2 and Phase 3 placebo-controlled and open-label extension trials.

Methods and results: Following completion of the parent trial, adult patients with atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalent, or heterozygous familial hypercholesterolaemia received open-label inclisiran twice yearly (after initial and 3-month doses) until Day 990, followed by an end-of-study visit at Day 1080 or ≥ 90 days after the last dose. The study endpoints included the proportion of patients achieving pre-specified low-density lipoprotein cholesterol (LDL-C) goals [ASCVD: < 1.8 mmol/L (< 70 mg/dL); ASCVD risk equivalent: < 2.6 mmol/L (< 100 mg/dL)], percentage and absolute changes in LDL-C at end-of-study, and safety of inclisiran. Of 3274 patients, 2446 (74.7%) were followed until end-of-study. Mean age was 64.9 ± 9.9 years, 82.7% (n = 2709) had ASCVD, and mean baseline LDL-C was 2.9 ± 1.2 mmol/L. Mean cumulative exposure to inclisiran (including parent trials) was 3.7 years; maximum exposure was 6.8 years. With inclisiran, 78.4% [95% confidence interval (CI): 76.8, 80.0] of patients achieved pre-specified LDL-C goals and mean percentage change in LDL-C was -49.4% (95% CI: -50.4, -48.3). No attenuation of LDL-C lowering over time was observed. Treatment-emergent adverse events at injection site (all mild/moderate) occurred in 5.9% of the patients. Inclisiran-associated anti-drug antibodies were infrequent (5.5%) and had no impact on the efficacy or safety of inclisiran. No new safety signals were identified.

Conclusion: In the largest and longest follow-up to date with >12 000 patient-years exposure, inclisiran demonstrated consistent and effective LDL-C lowering with a favourable long-term safety and tolerability profile.

Trial registration number: ClinicalTrials.gov identifier: NCT03814187.

Keywords: Atherosclerotic cardiovascular disease; Inclisiran; Long-term exposure; Low-density lipoprotein cholesterol; Proprotein convertase subtilisin/kexin type 9.

Graphical Abstract

Long-term efficacy and safety of inclisiran. ADA, anti-drug antibody; ASCVD, atherosclerotic cardiovascular disease; EOS, end-of-study; LDL-C, low-density lipoprotein cholesterol; PY, patient-years; TEAE, treatment-emergent adverse event.

Figure 1

Study design. ^aPatients from ORION-3 did not receive any drug administration on Day 1. Only patients on placebo in ORION-9, ORION-10, and ORION-11 received an active inclisiran injection at Day 1, while patients who received inclisiran in those trials received blinded placebo at this visit; ^bEOS is either day 1080 or ≥ 90 days following the last dose of inclisiran. D, Day; EOS, end-of-study.

Figure 2

Patient disposition in the ORION-8 trial ^aOne patient from the inclisiran arm of pivotal trials ORION-9, ORION-10, and ORION-11 did not receive any injection in ORION-8. ^bThe primary reasons for discontinuation were ORION-3 rollover patients not offered to complete the full study period (8.3%), death (5.0%), withdrawal of consent (4.8%), lost to follow-up, mostly during the COVID-19 pandemic period (3.1%), other (2.3%), and adverse events (1.4%).

Figure 3

LDL-C goal attainment at EOS. The proportion of patients achieving pre-specified lipid goals at EOS in (A) the overall population and (B) patients with ASCVD and ASCVD risk equivalent. ASCVD, atherosclerotic cardiovascular disease; BL, baseline; D, Day; EOS, end-of-study; LDL-C, low-density lipoprotein cholesterol; n, number of patients at the visit.

Figure 4

LDL-C percentage change at EOS. The LDL-C percentage change at EOS in (A) the overall population and (B) patients with ASCVD and ASCVD risk equivalent. Baseline value of LDL-C was taken from the baseline of the parent trials. Δ, mean percentage change; ASCVD, atherosclerotic cardiovascular disease; BL, baseline; CI, confidence interval; D, Day; EOS, end-of-study; LDL-C, low-density lipoprotein cholesterol; n, number of patients at the visit.

Figure 5

Exploratory analysis of change in LDL-C and MACE-related safety events. The change in (A) LDL-C and (B) MACE-related safety events. Baseline value of LDL-C was taken from the baseline of the parent trials. To distinguish from visits in ORION-8, the suffix ‘F’ was added to visits in the parent (feeder) trials ORION-9, ORION-10, and ORION-11. The numbers of patients at risk are displayed at the bottom of the Kaplan–Meier plot. The dashed line denotes the transition from the parent trial to ORION-8. BL, baseline; CI, confidence interval; D, Day; LDL-C, low-density lipoprotein cholesterol.

Figure 6

Efficacy and safety by ADA Status. (A) Mean percentage change in LDL-C from baseline to EOS, and (B) Exposure-adjusted incidence rate (per 100 patient-years) for TEAE and TESAE. The ADA response was determined from the pooled analysis of ORION-3, ORION-9, ORION-10, ORION-11, and ORION-8 ADA data. ORION-1 inclisiran arm patients were excluded from the analysis because the laboratory protocol used in the ORION-1 ADA assessment was different from other studies. The exposure-adjusted incidence rates of TEAEs were calculated since the first inclisiran injection across the parent and extension studies. Δ, mean percentage change; ADA, antidrug antibody; EOS, end of study; LDL-C, low-density lipoprotein cholesterol; TEAE, treatment-emergent adverse event; TESAE, treatment-emergent serious adverse event.