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(Phase 2 ) Inclisiran in Patients at High Cardiovascular
Risk with Elevated LDL Cholesterol (single dosing)
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NEJM April 2017
Here, we present the results of the phase 2 ORION-1 trial, a dose-finding trial evaluating the efficacy of different inclisiran dosing regimens among patients who have elevated LDL cholesterol levels despite receiving the maximum possible dose of a statin and who are considered to be at high risk for atherosclerotic cardiovascular disease. Within the limits of the trial, we also evaluated the safety and efficacy of inclisiran in lowering LDL cholesterol levels.
Patients
Detailed inclusion and exclusion criteria are described in the Supplementary Appendix, available at NEJM.org. Men and women 18 years of age or older were eligible for participation in the trial if the LDL cholesterol level at screening was higher than 70 mg per deciliter (1.8 mmol per liter) (for patients with a history of atherosclerotic cardiovascular disease) or higher than 100 mg per deciliter (2.6 mmol per liter) (for patients without a history of atherosclerotic cardiovascular disease). Patients were required to have been receiving the maximum possible dose of a statin with or without additional lipid-lowering therapy at stable doses for at least 30 days before screening and were required to have no planned changes in background therapy during the course of the trial. Any use at any time of a monoclonal antibody drug targeting PCSK9 was an exclusion criterion and was prohibited during the trial. Written informed consent was obtained from all the patients before participation in the trial.
Abstract
Background
In a previous study, a single injection of inclisiran, a chemically synthesized small interfering RNA designed to target PCSK9 messenger RNA, was found to produce sustained reductions in low-density lipoprotein (LDL) cholesterol levels over the course of 84 days in healthy volunteers.
Methods
We conducted a phase 2, multicenter, double-blind, placebo-controlled, multiple-ascending-dose trial of inclisiran administered as a subcutaneous injection in patients at high risk for cardiovascular disease who had elevated LDL cholesterol levels. Patients were randomly assigned to receive a single dose of placebo or 200, 300, or 500 mg of inclisiran or two doses (at days 1 and 90) of placebo or 100, 200, or 300 mg of inclisiran. The primary end point was the change from baseline in LDL cholesterol level at 180 days. Safety data were available through day 210, and data on LDL cholesterol and proprotein convertase subtilisin–kexin type 9 (PCSK9) levels were available through day 240.
Results
A total of 501 patients underwent randomization. Patients who received inclisiran had dose-dependent reductions in PCSK9 and LDL cholesterol levels.
At day 180, the least-squares mean reductions in LDL cholesterol levels were 27.9 to 41.9% after a single dose of inclisiran and 35.5 to 52.6% after two doses (P<0.001 for all comparisons vs. placebo). The two-dose 300-mg inclisiran regimen produced the greatest reduction in LDL cholesterol levels: 48% of the patients who received the regimen had an LDL cholesterol level below 50 mg per deciliter (1.3 mmol per liter) at day 180. At day 240, PCSK9 and LDL cholesterol levels remained significantly lower than at baseline in association with all inclisiran regimens. Serious adverse events occurred in 11% of the patients who received inclisiran and in 8% of the patients who received placebo. Injection-site reactions occurred in 5% of the patients who received injections of inclisiran.
Two patients had increased levels of hepatic aspartate aminotransferase (>3 times the upper limit of the normal range), one in the single-dose placebo group and one in the single-dose 300-mg inclisiran group; the patient in the 300-mg inclisiran group also had elevations in hepatic alanine aminotransferase levels. Two additional patients (one in the two-dose 100-mg inclisiran group and one in the two-dose 300-mg inclisiran group) also had elevations in alanine aminotransferase levels. All aminotransferase elevations were transient. There were no increases in bilirubin levels that occurred in association with inclisiran or placebo among patients who had normal levels of bilirubin at baseline, and no case met the definition of Hy’s law, which states that a patient is at high risk for a fatal drug-induced liver injury if given a medication that causes hepatocellular injury (not cholestatic injury) with jaundice. One patient was positive for antidrug antibodies before the first injection; no other cases of antidrug antibody were reported.
Conclusions
In our trial, inclisiran was found to lower PCSK9 and LDL cholesterol levels among patients at high cardiovascular risk who had elevated LDL cholesterol levels. (Funded by the Medicines Company; ORION-1 ClinicalTrials.gov number, NCT02597127. opens in new tab.)
Injection-site reactions were uncommon and occurred in 4% of the patients who received one dose of inclisiran and 7% of the patients who received two doses of inclisiran; these rates are similar to the rates observed with monoclonal antibodies to PCSK917,18 and are in contrast to the rates of 76 to 84% reported with first-generation antisense oligonucleotides for LDL cholesterol reduction.19,20 Symptoms of immune activation, which is often a concern with therapies targeting RNA, were rare in association with inclisiran; there were few instances of flulike symptoms and no observed elevations in C-reactive protein. We observed no effects on platelet levels among patients receiving inclisiran, in contrast to recent reports from studies of antisense oligonucleotides and other siRNA molecules.21 We observed transient elevations in hepatic enzyme levels in three patients receiving inclisiran.
LDL Cholesterol Levels and Other Laboratory Measures
LDL cholesterol levels were already declining from baseline levels at 14 days after the first injection of inclisiran, and by day 30, the mean reductions in LDL cholesterol level ranged between 44.5 and 50.5% below baseline across all inclisiran doses tested (Figure 1B and 1D), with a nadir at approximately day 60 for the single-dose regimens and at day 150 for the two-dose regimens. The primary end point was the percentage reduction from baseline in LDL cholesterol level at day 180: the least-squares mean reductions were significantly greater after a single dose of inclisiran (27.9 to 41.9% reduction) than in association with placebo (2.1% increase) (P<0.001 for all inclisiran doses with regard to the primary efficacy end point) (Table 2). At day 240, the mean reductions in LDL cholesterol level from baseline ranged between 28.2 and 36.6% (Figure 1B).
After the second dose of inclisiran, LDL cholesterol levels were decreased (with respect to levels at baseline) by 34.2 to 44.1% at day 90 and by 41.1 to 54.6% at day 120. The differences between the two-dose regimens and placebo with regard to the primary end point were significant: at day 180, the least-squares mean reductions in LDL cholesterol levels from baseline among patients who received a two-dose inclisiran regimen ranged from 35.5 to 52.6%, whereas the placebo group had an increase from baseline of 1.8% (P<0.001 for all comparisons vs. placebo) (Table 2). Similar results were obtained with the use of imputation and an intention-to-treat analysis (Table S3 in the Supplementary Appendix). At day 240, the mean reductions in LDL cholesterol levels from baseline ranged between 26.7 and 47.2% (Figure 1D).
Among patients who received placebo against a background of the maximum possible dose of a statin, there was considerable variation at day 180 in the changes in LDL cholesterol levels from baseline (mean [±SD] absolute difference, -0.7±25.6 mg per deciliter [-0.02±0.66 mmol per liter]) (Figure 2A). In contrast, all patients who received two 300-mg doses of inclisiran had a decline in LDL cholesterol level at day 180 (mean absolute change in LDL cholesterol level, -64.2±20.7 mg per deciliter [-1.66±0.54 mmol per liter]) (Figure 2B), and 54% of the patients had a reduction of 50% or more (see the Supplementary Appendix). In this inclisiran dose group, 5%, 48%, and 66% of the patients had LDL cholesterol levels at day 180 of less than 25 mg per deciliter (0.65 mmol per liter), less than 50 mg per deciliter (1.3 mmol per liter), and less than 70 mg per deciliter (1.8 mmol per liter), respectively. At day 240, the individual cholesterol levels remained lower than at baseline in the same patient group (Figure 2C).
We found significant reductions in levels of non-HDL cholesterol and apolipoprotein B and no significant change in levels of high-sensitivity C-reactive protein among patients randomly assigned to receive inclisiran. The percentage changes from baseline for additional lipid measures are shown in Table 2.
Safety
Adverse events were reported in 76% of the patients who received inclisiran and in 76% of the patients who received placebo (Table 3). Most of these events (95%) were mild or moderate in severity (grade 1 or 2). The incidence of serious adverse events was 11% among patients who received inclisiran and 8% among patients who received placebo. Two patients discontinued participation in the trial because of adverse events: one because of a herpes zoster infection (placebo group) and the other because of influenza or nasopharyngitis (two-dose 100-mg inclisiran group). The most common adverse events (occurring in >2% of patients) were myalgia, headache, fatigue, nasopharyngitis, back pain, hypertension, diarrhea, and dizziness, and the incidences of these events did not differ significantly between groups receiving inclisiran and those receiving placebo. Injection-site reactions occurred in 4% of the patients who received a single dose and in 7% of the patients who received two doses (after one or both doses) of inclisiran (combined rate, 5%); injection-site reactions occurred in no patients assigned to placebo (Table 3).
Two patients had increased levels of hepatic aspartate aminotransferase (>3 times the upper limit of the normal range), one in the single-dose placebo group and one in the single-dose 300-mg inclisiran group; the patient in the 300-mg inclisiran group also had elevations in hepatic alanine aminotransferase levels. Two additional patients (one in the two-dose 100-mg inclisiran group and one in the two-dose 300-mg inclisiran group) also had elevations in alanine aminotransferase levels. All aminotransferase elevations were transient. There were no increases in bilirubin levels that occurred in association with inclisiran or placebo among patients who had normal levels of bilirubin at baseline, and no case met the definition of Hy’s law, which states that a patient is at high risk for a fatal drug-induced liver injury if given a medication that causes hepatocellular injury (not cholestatic injury) with jaundice. One patient was positive for antidrug antibodies before the first injection; no other cases of antidrug antibody were reported.
Two deaths occurred late in the trial. The first occurred in a patient who had been randomly assigned to the single-dose 500-mg inclisiran group and who had long-standing vasculopathy and frequent angina. He had a witnessed cardiac arrest and died at 104 days. The second death occurred in a man in the two-dose 200-mg inclisiran group who had a thoracic aortic aneurysm repaired percutaneously after study entry and in whom a fistula and sepsis subsequently developed; he died 198 days into the trial.
Table 2. Changes from Baseline in Efficacy Measures at Day 180.
Figure 1. Effect of Inclisiran on PCSK9 and Low-Density Lipoprotein (LDL) Cholesterol Levels.
The data points are means, and the I bars indicate 95% confidence intervals. The dashed vertical line in each panel indicates day 180, the day on which these end points were assessed.
Results
Patients
A total of 646 patients were screened, and 501 patients were randomly assigned to one of the two placebo groups or one of the six inclisiran groups (Figs. S1 and S2 in the Supplementary Appendix). Of these patients, 497 received inclisiran or placebo (1 patient each in the single-dose 300 mg, single-dose 500 mg, double-dose 100 mg, and double-dose 200 mg inclisiran groups did not receive an injection of inclisiran) and comprise the efficacy and safety populations. The baseline characteristics of the patients in each study group are provided in Table 1 and in Table S2 in the Supplementary Appendix. At study entry, 73% of the patients were receiving statin therapy, and 31% of the patients were receiving ezetimibe.
PCSK9 Levels
Fourteen days after a single injection of inclisiran, PCSK9 levels were reduced from baseline levels by a mean of 59.6 to 68.7% across the range of inclisiran doses from 100 mg to 500 mg, whereas mean PCSK9 levels increased by 3.8% with placebo (Figure 1A and 1C). At day 30, PCSK9 levels were reduced further, to between 66.2 and 74.0% below baseline levels, with similar reductions observed at day 60 and day 90. Among the patients who received a single-dose regimen, the mean reductions in PCSK9 levels at day 180 (a secondary end point) ranged between 47.9 and 59.3% (P<0.001 for each dose vs. placebo) (Table 2). In comparison, among the patients who received a two-dose regimen, further reductions in PCSK9 levels were observed after the second dose. At day 90, these patients had reductions of 47.0 to 62.8%, and at day 120, they had reductions of 60.4 to 74.5%. At day 180, the mean reductions from baseline in PCSK9 levels among patients who received a two-dose regimen ranged between 53.2 and 69.1% (P<0.001 for each dose vs. placebo) (Table 2). In association with both the single-dose and two-dose inclisiran regimens, the reductions in PCSK9 levels at day 240 were greater than 40% (Figure 1A and 1C).
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