Reimbursement Review

Inclisiran (Leqvio)

Sponsor: Novartis Pharmaceuticals Canada Inc.

Therapeutic area: Primary hypercholesterolemia

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Abbreviations

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Background Information of Application Submitted for Review

ASCVD = atherosclerotic cardiovascular disease; HeFH = heterozygous familial hypercholesterolemia; LDL-C = low-density-lipoprotein cholesterol; nFH = nonfamilial hypercholesterolemia; NOC = Notice of Compliance; SC = subcutaneous.

Introduction

In Canada, cardiovascular disease (CVD) is the second leading cause of death and accounted for almost 20% of all deaths in 2020.¹ Despite its pathophysiological complexity, the 1 prerequisite for atherosclerotic plaque development is the presence of low-density-lipoprotein cholesterol (LDL-C).² Hypercholesterolemia can be grouped into 2 forms: nonfamilial hypercholesterolemia (nFH), and familial hypercholesterolemia (FH, also referred to as acquired or genetic hypercholesterolemia). nFH is characterized by elevated LDL-C levels. Its etiology is likely a complex interplay between several genetic, environmental risk factors that increase the risk of nFH and include diet, smoking, physical inactivity, and other factors known to be associated with an increased risk of CVD (e.g., diabetes, chronic kidney disease, and hypertension).^3-6 In Canada, the 1 year incidence rate for atherosclerotic cardiovascular disease (ASCVD) ranges between 7.2 and 8.8 per 1,000 person years, and the 5-year prevalence of ASCVD ranges between 6.91% and 8.55% in adults.^7-9

Elevated LDL-C is directly associated with the development of atherosclerosis and ASCVD.¹⁰ The 3 main subcategories of ASCVD are coronary artery disease (CAD), cerebrovascular disease, and peripheral arterial disease (PAD). Individuals with hypercholesterolemia and a history of an atherosclerotic event are categorized as having established clinical ASCVD (i.e., they are secondary-prevention patients), whereas individuals with hypercholesterolemia at risk of developing ASCVD are considered to be primary-prevention patients. A subset of primary-prevention patients at greater risk of ASCVD is referred to an ASCVD risk-equivalent (ASCVD-RE) subset. Patient with ASCVD-RE are defined as those with type 2 diabetes mellitus, FH, or a 10-year risk of a cardiovascular (CV) event of at least 20% as assessed by the Framingham Risk Score (FRS) for CVD or equivalent.¹¹ The proportion of the overall ASCVD population considered to be at high risk is estimated to be approximately 25%.⁹ In accordance with Canadian guidelines, published literature, and validation from clinicians in Canada, patients with high-risk nFH ASCVD are defined as having any of the following criteria in the past 12 months: diabetes, recurrent vascular events, PAD, or acute coronary syndrome (ACS); and LDL-C levels greater than 1.8 mmol/L despite maximally tolerated dose (MTD) statins with or without other lipid-lowering therapies (LLTs).^9,12-17 Throughout this resubmission, patients with any of these criteria will be considered part of the high-risk ASCVD subgroup.

FH is 1 of the most common genetic disorders and is caused by mutations in the genes encoding the LDL receptor (LDLR), apolipoprotein B (ApoB), or proprotein convertase subtilisin/kexin type 9 (PCSK9), leading to high plasma levels of LDL-C.¹⁰ Depending on the number of mutant alleles, patients can be categorized as having homozygous FH (HoFH) or heterozygous FH (HeFH).¹⁸ HeFH has an estimated prevalence of approximately 1 in 250¹⁹ to 1 in 311 individuals.^20,21 The clinical presentation of FH is variable, and is affected by the number and type of mutations together with other genetic factors. Individuals with FH have elevated LDL-C levels from a young age, and the ongoing exposure to elevated LDL-C results in a higher cumulative risk of developing ASCVD.²² Patients with FH may present with physical findings such as tendon xanthomata or xanthelasma.²³ FH is associated with a higher risk of CV events than in the general population.^24-26

Inclisiran (Leqvio) was previously reviewed by CADTH in February 2022 for the same indication, and the recommendation was to not reimburse.²⁷ Key reasons for this recommendation included the fact that there was insufficient evidence that inclisiran reduces CV morbidity and mortality, or all-cause mortality, as the pivotal trials — ORION-9, ORION-10, and ORION-11 — were not designed to assess these outcomes.²⁷ Additionally, the CDA-AMC Canadian Drug Expert Committee (CDEC) noted that the long-term efficacy and safety of inclisiran has not been determined, and that there were 2 ongoing studies — ORION-4 and ORION-8 — that are expected to provide evidence to better characterize the pertinent clinical outcomes, as well as provide long-term efficacy and safety data. CDEC also noted that there was no direct comparison of inclisiran with evolocumab or alirocumab, or other add-on drugs, and that there were limitations with the submitted indirect treatment comparison (ITC), including the relatively short follow-up (24 weeks) of patients with a chronic condition.

The sponsor outlined the basis for its resubmission. To address the lack of evidence for reductions in CV morbidity and/or mortality and all-cause mortality, the sponsor included a posthoc pooled analysis of major adverse cardiovascular events (MACE) in the pivotal ORION studies and, to address concerns about long-term efficacy and harms, the findings of the long-term extension studies (ORION-3 and ORION-8). To address the lack of long-term safety data, in addition to the ORION-3 and ORION-8 studies, the sponsor submitted a pooled analysis of 7 ORION trials. Finally, the sponsor submitted a revised budget impact model to address CDA-AMC’s concerns from the first recommendation.

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of inclisiran in adults with primary hypercholesterolemia (HeFH or nFH).

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient and clinician groups that responded to CDA-AMC’s call for input and from clinical experts consulted by CDA-AMC for the purpose of this review.

Patient Input

• Two patient groups — the Canadian Heart Patient Alliance (CHPA) and the HeartLife Foundation — provided input based on survey and interview responses (CHPA) and from executives of the HeartLife Foundation.

• Patients describe a condition that is very difficult to manage, impacts their physical and mental well-being, has a significant financial burden on families, and impacts their quality of life.

• Adherence and access to newer treatments, such as the PCSK9 inhibitors, were identified by patients as key challenges in managing their condition. Patients emphasized the importance of having a safe, tolerable, and effective treatment to maintain their LDL-C below recommended thresholds. Patients also noted the importance of having a less frequent dosing regimen to manage their condition.

Clinician Input

Input From Clinical Experts Consulted by CDA-AMC

• Nonadherence, intolerance to high-intensity statins, inability to reach recommended lipid targets despite MTD statins and ezetimibe, and lack of access to PCSK9 inhibitors are the major unmet needs identified by the clinical experts in treatment of patients with HeFH and with nFH with ASCVD. Accordingly, the clinical experts believed that in addition to being another PCSK9-targeting drug, inclisiran may help with nonadherence due to the less frequent dosing schedule.

• The clinical experts believed that for patients with HeFH, in addition to those unable to reach their LDL-C target despite MTD statins, with or without ezetimibe, patients especially well suited to inclisiran would include those with other risk factors, such as smoking, diabetes, hypertension, and elevated lipoprotein (a) (Lp[a]). For patients with nFH with ASCVD, the clinical experts believed that well-suited patients would include those unable to tolerate high-intensity statins, those with early disease onset or recurrent disease, those whose LDL-C is far from the threshold, and those with the risk factors identified for patients with HeFH. The clinical experts also referenced the 2021 Canadian Cardiovascular Society (CCS) guidelines, which identified which secondary-prevention patients are likely derive the most benefit from the intensification of statin therapy with the additional use of a PCSK9 inhibitor. These included patients with recent ACS (in the past 52 weeks), diabetes mellitus or metabolic syndrome, polyvascular disease, symptomatic PAD, recurrent myocardial infarction (MI), MI in the past 2 years, previous coronary artery bypass graft (CABG) surgery, LDL-C of 2.6 mmol/L or greater or HeFH, or Lp(a) of 120 nmol/L or greater.

• The clinical experts noted that genetic testing should not be required to confirm a diagnosis of HeFH due to the lack of availability of testing, and they also noted that HeFH is underdiagnosed in Canada. Various lipid parameters would be used to assess response to treatment in addition to LDL-C, including non–high-density-lipoprotein cholesterol (HDL-C) and ApoB. Although there is no recent guidance on how frequently to assess response, after the initial titration, response is typically assessed every 6 to 12 months.

Clinician Group Input

• Fourteen clinician groups provided input: Alberta Cardiovascular Disease Prevention Collaborative (8 clinicians contributed to the input); BC Lipid Specialists (11 clinicians contributed to the input); le Centre hospitalier universitaire Dr.-Georges-L.-Dumont (CHUDGLD) (6 clinicians contributed to the input); Cambridge Cardiac Rehab Program (6 clinicians contributed to the input); CCS Dyslipidemia Guideline Committee (14 clinicians contributed to the input); Cardiology Association of Niagara (3 clinicians contributed to the input); Egyptian Cardiologists of Niagara (3 clinicians contributed to the input); Kawartha Cardiology Clinic (7 clinicians contributed to the input); Lipid Clinic of McMaster University and Hamilton Health Sciences (1 clinician contributed to the input); Mazankowski Alberta Heart Institute (3 clinicians contributed to the input); Oakville Cardiologists (9 clinicians contributed to the input); service of cardiology, Internal Medicine Department and Heart Failure Group at St. Thomas Elgin General Hospital (5 clinicians contributed to the input); Western University, Division of Cardiology, Cardiac Rehabilitation and Secondary Prevention Program (3 clinicians contributed to the input); and University of Toronto faculty and clinicians at St. Michael’s Hospital who are actively involved in the treatment of patients with ASCVD and/or lipid disorders (10 clinicians contributed to the input).

• The clinician groups agreed that the major issues with managing hypercholesterolemia, whether it be HeFH or nFH with ASCVD, are adherence (as well as intolerance) and lack of accessibility to drug therapies, and that the main outcome of interest is a reduction in lipid parameters (LDL-C, non-HDL-C, and ApoB) at 6 months, initially, and assessed annually thereafter.

• The clinician groups believed that inclisiran would be best suited for patients at risk of ASCVD or patients with FH who require additional LLT, who become refractory to statins and ezetimibe, along with those who struggle with adherence or tolerability.

Drug Program Input

Input was obtained from the drug programs that participate in the CDA-AMC reimbursement review process. The following were identified as key factors that could potentially impact the implementation of a CDA-AMC recommendation for inclisiran:

• relevant comparators

• considerations for the initiation of therapy

• considerations for continuation or renewal of therapy

• considerations for discontinuation of therapy.

The clinical expert consulted by CDA-AMC provided advice on the potential implementation issues raised by the drug program. Refer Table 4 for more details.

Clinical Evidence

Systematic Review

Description of Studies

The major focus of this resubmission was a posthoc pooled analysis of MACE from the ORION-9, ORION-10, and ORION-11 trials. These trials, all included in the original submission, were phase III, double-blind, randomized controlled trials (RCTs) comparing inclisiran to placebo in adult patients with HeFH (ORION-9) or ASCVD (ORION-10 and ORION-11) and ASCVD-RE (ORION-11) (i.e., those with diabetes, FH, or a 10-year risk of a CV event of at least 20% as assessed by the FRS for CVD or equivalent) who were receiving MTD statins or who were statin intolerant. Patients in the ORION-9 trial had a history of HeFH, with a diagnosis of HeFH confirmed by genetic testing or phenotypic Simon Broome criteria, and/or a documented history of untreated LDL-C of greater than 190 mg/dL and a family history of FH; elevated cholesterol or early heart disease may indicate FH. In all 3 ORION studies, patients were randomized (1:1) to either inclisiran sodium 300 mg or placebo in addition to MTD statins. The ORION-9, ORION-10, and ORION-11 trials enrolled 482, 1,561, and 1,617 patients, respectively. The studies were all 18 months in duration, with patients receiving 4 300 mg doses of inclisiran sodium (on day 1, day 90, day 270, and day 450). The primary outcome of the ORION-9, ORION-10, and ORION-11 trials was the percent change in LDL-C from baseline to day 510. In all trials, the coprimary end point was the average percentage change in LDL-C from baseline to the period from after day 90 and up to day 540, reflecting the start of the biannual dosing regimen. Incidences of CV death, resuscitated cardiac arrest, nonfatal MI, and nonfatal stroke (ischemic and hemorrhagic) were exploratory outcomes in the ORION trials within the composite outcome of MACE, and total deaths was a secondary outcome reported as adverse events (AEs) in the ORION studies.

Baseline characteristics of the ORION trials were balanced between groups, and generally applicable to the population in Canada. The ORION-9 trial enrolled patients with a median age of 56 years — the ratio of men to women was relatively even (47.1% men, 52.9% women) — with either ASCVD (27.4%) or ASCVD-RE (72.6%), of whom 93.2% had HeFH. A total of 73.9% of patients were on high-intensity statins at baseline, with 25.3% either partially or completely intolerant to statins, and 52.3% were treated with ezetimibe. The ORION-10 trial enrolled mostly men (69.4%), with a median age of 67 years, all with ASCVD (91.1% with coronary heart disease [CHD]). Approximately two-thirds (69.4%) of patients were on a high-intensity statin at baseline, with 22.0% partially or completely intolerant. A total of 9.9% of patients were treated with ezetimibe. The ORION-11 trial enrolled patients with ASCVD (87.4%) and ASCVD-RE (12.6%). Patients were mostly men (71.7%), with a median age of 65 years. A total of 78.0% of patients were receiving high-intensity statins, 11.4% were considered partially or completely intolerant to statins, and 7.1% of patients were treated with ezetimibe.

Efficacy Results

Major Adverse Cardiac Events

In the ORION-9, ORION-10, and ORION-11 trials, the exploratory end point of MACE was defined as the composite of CV death, resuscitated cardiac arrest, nonfatal MI, and nonfatal stroke (hemorrhagic or nonhemorrhagic), using predefined Medical Dictionary for Regulatory Activities (MedDRA) search.

As part of their resubmission, the sponsor conducted a pooled analysis of clinical outcomes from the ORION-9, ORION-10, and ORION-11 trials and provided what it referred to as a sensitivity analysis that pooled data from the ORION-10 and ORION-11 studies. The pooled analysis of all 3 trials is not relevant for this review, as it combines the HeFH and the nFH with ASCVD populations; these 2 populations are viewed separately for this review, consistent with the indication. The sensitivity analysis that was conducted to assess the effects of inclisiran (n = 1,494) compared to placebo (n = 1,477) on MACE in the ASCVD and ASCVD-RE populations is relevant.

HeFH Population: The incidence of MACE in the inclisiran and placebo arms of the ORION-9 trial were 10 (4.1%) and 10 (4.2%), respectively; the absolute number of MACE in the inclisiran and placebo arms were 10 and 11 events, respectively; the corresponding relative risk (RR) was ███ ████ ███ ████ ████.

The exploratory end point of nonfatal MI occurred in 9 (3.7%) patients experiencing | events in the inclisiran arm compared to 10 (4.2%) patients experiencing ██ events in the placebo arm, and for the exploratory end point of nonfatal stroke, no patients in either the inclisiran or placebo treatment arms experienced an event.

nFH with ASCVD: Results from the posthoc pooled analysis of the ORION-10 and ORION-11 trials showed ███ ██████ patients in the inclisiran arm experienced ███ ██████, while ███ ███████ patients in the placebo arm experienced ███ ██████. The reported hazard ratio (HR) of ████ ████ ███ █████ █████ for MACE favoured inclisiran over placebo in the pooled ORION-10 and ORION-11 patient population.

The incidence of MACE in the inclisiran and placebo arms of the ORION-10 trial was 58 (7.4%) and 79 (10.2%), respectively; the absolute number of MACE in the inclisiran and placebo arms was 66 and 90 events, respectively; the corresponding RR was ███ ████ ███ ████ ████. The incidence of MACE in the inclisiran and placebo arms of the ORION-11 trial was 63 (7.8%) and 83 (10.3%), respectively; the absolute number of MACE in the inclisiran and placebo arms was 65 and 100 events, respectively; the corresponding RR was ███ ████ ███ ████ ████.

From the same posthoc pooled analysis of ORION-10 and ORION-11, the effects of inclisiran (n = 1,494) compared to placebo (n = 1,477) on fatal or nonfatal MI outcome in the ASCVD and ASCVD-RE population showed that ██ ██████ patients in the inclisiran arm experienced ██ ██████, while ██ ██████ patients in the placebo arm experienced ██ ██████. The reported HR was ████ ████ ███ █████ █████ for fatal or nonfatal MI. The fatal or nonfatal stroke outcome in the ASCVD and ASCVD-RE population showed that ██ ██████ patients in the inclisiran arm experienced ██ ██████, while ██ ██████ patients in the placebo arm experienced ██ ██████. The HR was ████ ████ ███ █████ █████ for fatal or nonfatal stroke in the pooled ORION-10 and ORION-11 patient population.

Low-Density-Lipoprotein Cholesterol

The coprimary end points of percent change in LDL-C from baseline to day 510 and time-average percent change in LDL-C from baseline to the period from after day 90 and up to day 540 was the same for the ORION-9, ORION-10, and ORION-11 trials.

Heterozygous Familial Hypercholesterolemia: The between-group difference for inclisiran and placebo in the percent reduction in LDL-C in the ORION-9 trial was –47.9% (95% confidence interval [CI], –53.5 to –42.3; P < 0.0001). For the time-average percent change in LDL-C from baseline to the period from after day 90 and up to day 540, the least squares mean (LSM) difference from placebo favoured inclisiran in the ORION-9 trial, at −44.30% (95% CI, −48.48 to −40.12; P < 0.0001). The results of the sensitivity analyses for both outcomes were consistent with the overall population.

nFH with ASCVD: The between-group difference for inclisiran and placebo in percent reduction in LDL-C in the ORION-10 trial was – 52.2% (95% CI, –55.7 to –48.8; P < 0.0001), and in the ORION-11 trial was –49.9% (95% CI, –53.1 to –46.6; P < 0.0001). For the time-average percent change in LDL-C from baseline to the period from after day 90 and up to day 540, the LSM difference from placebo favoured inclisiran in the ORION-10 trial, at −53.78% (95% CI, −56.23 to −51.33; P < 0.0001), and in the ORION-11 trial, at −49.17% (95% CI, −51.57 to −46.77; P < 0.0001). The results of the sensitivity analyses for both outcomes were consistent with the overall population.

Harms Results

Heterozygous Familial Hypercholesterolemia

In the ORION-9 trial, the most common AEs in the inclisiran and placebo groups were nasopharyngitis (11.6% versus 8.3%), influenza (5.4% versus 8.8%), upper respiratory tract infection (6.6% versus 6.7%), and back pain (7.1% versus 4.2%). There were 18 (7.5%) patients in the inclisiran arm and 33 (13.8%) patients in the placebo arm who experienced at least 1 serious adverse event (SAE). The most common SAEs were unstable angina, myocardial ischemia, acute MI, aortic valve stenosis, and back pain. Three (1.2%) patients in the inclisiran group withdrew due to an AE, whereas no patients in the placebo group did. ███████ ███████ ██ ██████████ ████ █████ ████ ████ ████████ ███████ █████████ ████ █████████ ███ ███ ████████ ███ ██████ ████ ██ ███ ████████ █████ ███ ███ █████████ ████ ████████ ██████ ████ ██████████ ███████████ ███████ ██ ██████████

nFH with ASCVD

The frequency of AEs was consistent in the inclisiran and placebo groups, as well as across trials, with 73.5% versus 74.8% of patients, respectively, experiencing at least 1 AE in the ORION-10 trial, and 82.7% versus 81.5% experiencing at least 1 AE in the ORION-11 trial. In the ORION-10 and ORION-11 trials, SAEs occurred in 22.4% and 22.3% of patients, respectively, treated with inclisiran compared to 26.3% and 22.5% of patients, respectively, treated with placebo. Withdrawal due to adverse events (WDAEs) was similar in the ORION-10 and ORION-11 trials, at 2.4% and 2.8% of patients, respectively, treated with inclisiran and 2.2% and 2.2% of patients, respectively, treated with placebo.

██ ██████████ ██ ██████████ ██████ ███ ██████████████ █████████ ███ ████████ ████ ██████████ ███ ███████ ██ ███ █████ ███████ ████████ ███ █████████ ███ ██████ ██ ███ ███████ ███████ In all trials, fewer patients treated with placebo than with inclisiran reported AEs at the injection site. Injection-site reactions were mild to moderate, and no severe reactions were seen across trials. █████ ████ ██ █████ ███ ██████████ ███████████ ███████ ██████████ ███ ███████ ███ █████ ███████ █████ ██ ████████████████ ██████████ █████ ███████ ██ ███████ ███████

Critical Appraisal

• There are a number of issues associated with the posthoc pooled analysis provided by the sponsor for this resubmission. First of all, it is a posthoc analysis, which increases the potential for bias. The primary analysis includes all 3 pivotal trials (ORION-9, ORION-10, and ORION-11); however, this combines 2 separate populations of patients — those with HeFH and those with nFH with ASCVD — and these patients are being considered separately for this review. Importantly, the ORION-9, ORION-10, and ORION-11 trials were not powered to assess MACE, so the events were captured in the safety population, the definitions used may not be inclusive or specific enough, and there was no blinded, centralized assessment of events. Otherwise, the ORION-9, ORION-10, and ORION-11 trials appear to have been reasonably well conducted, with adequate measures to maintain blinding, a multiple testing procedure to reduce the risk of type I error, and low dropout rates.

• With respect to external validity, key issues are that clinical outcomes such as CV mortality and morbidity were not assessed in the pivotal ORION trials, and there was no active comparator, such as a PCSK9 inhibitor. Additionally, health-related quality of life (HRQoL) was not assessed in any of the included trials.

GRADE Summary of Findings and Certainty of the Evidence

Grading of Recommendations Assessment, Development and Evaluation (GRADE) was not performed for this review because it is a resubmission.

Table 2: Summary of Efficacy and Harms Data for the HeFH and nFH With ASCVD Populations

AE = adverse events; ASCVD = atherosclerotic cardiovascular disease; CI = confidence interval; HeFH = heterozygous familial hypercholesterolemia; HR = hazard ratio; LDL-C = low-density-lipoprotein cholesterol; L = litre; LSM = least squares mean; MACE = major adverse cardiovascular events; MI = myocardial infarction; nFH = nonfamilial hypercholesterolemia; NR = not reported; SAE = serious adverse event; SD = standard deviation; WDAE withdrawal due to adverse event.

^aObserved MACE counts include treatment-emergent and non–treatment-emergent adverse events.

^bA control-based pattern-mixture model (PMM) was used for missing data imputation, with 100 total imputed datasets. A mixed model for repeated measures (MMRM) on each of the 100 datasets was performed by including fixed effects for treatment, visit, interaction between treatment and visit, and baseline LDL-C as a covariates.

^c██████ ██████ █████████ ████ ███ ████████████ ██████ ██████ ████ █████████ ███ █████ ██ ████████ ███████ ██████ ████ ███████ █████ ████ ████ ████████ ████ ███ █████████████ █████████ ████████ ████ ████████ ████ ██ █████ █████ ███ ██ ██████████████████████ ███████ ██████ ████ ███ ██ ███████ ███ ████████

Sources: ORION-9 Clinical Study Report;²⁸ ORION-10 Clinical Study Report;²⁹ ORION-11 Clinical Study Report.³⁰

Long-Term Extension Studies

ORION-3^31,32 and ORION-8³³ Trials

Description of Studies

The ORION-3 trial^31,32 was a 4-year, open-label extension study of the phase II ORION-1 trial. The primary objective of this study was to assess the effect of long-term treatment with twice-yearly small interfering (si)RNA therapeutic inclisiran dosing on LDL-C reductions at day 210 compared to baseline in the ORION-1 trial. The secondary and exploratory objectives were to assess the effects of inclisiran on cholesterol and other lipids levels and PCSK9 levels for up to 4 years in each arm, as well as the long-term safety and tolerability of inclisiran. Another exploratory objective was to evaluate the effects of transitioning from evolocumab to inclisiran. A total of 382 participants were enrolled from 52 centres across 5 countries; 56 of those patients were enrolled from Canadian centres.

The ORION-8 trial is a global, open-label, long-term extension study of patients with ASCVD, ASCVD-RE, or HeFH and elevated LDL-C despite a MTD of LDL-C-lowering therapies who completed the phase II ORION-3 study, or any of the phase III ORION-9, ORION-10, or ORION-11 studies. The primary objectives of the study are to evaluate the effect of inclisiran treatment on the proportion of patients achieving prespecified LDL-C targets, and the safety and tolerability of long-term use of inclisiran. The secondary objectives are to evaluate the effect of inclisiran on LDL-C levels and other lipids and lipoproteins. The study has enrolled 3,275 participants from 268 centres in 13 countries, including Canada (3 centres).

Efficacy Results

Of the original ORION-1 cohort of 497 patients, 290 of 370 patients allocated to the drug continued into the inclisiran-only arm and 92 of 127 patients allocated to placebo entered the switching arm in the ORION-3 extension study conducted between March 24, 2017, and December 17, 2021. Overall, efficacy results were consistent and sustained up to the end of the study. In the inclisiran-only arm, LDL-C was reduced by 47.5% (95% CI, 50.7% to 44.3%) at day 210 and was sustained at that level over 1,440 days. During the 4 years of the open-label extension, the mean percentage change and mean absolute change in LDL-C concentrations in the inclisiran-only arm ranged between –34.3% and –53.8% and between –1.13 mmol/L and –1.76 mmol/L, respectively, with the upper limit of the 95% CI at all time points being lower than –30% and excluding zero. The mean percentage change and mean absolute change in LDL-C in the switching arm ranged between –38.2% and –65.7% and between –1.20 mmol/L and –2.00 mmol/L, respectively.

In the inclisiran-only arm, the mean percentage change in total cholesterol ranged from –21.1% to –30.2%, remaining relatively consistent throughout the follow-up period. Non-HDL-C, ApoB, and triglycerides also remained consistently decreased throughout the follow-up period. Lp(a) concentration decreased by 16.3% at day 30 with no meaningful changes thereafter.

In the ORION-8 trial, the proportion of patients who attained global lipid targets at day 1,080 was similar in the inclisiran-only group (78%), the switching group (79%), and the group of patients who rolled over from the ORION-3 trial (77%). Similarly, the percent of patients with ASCVD who attained global lipid targets (< 70 mg/dL) at day 1,080 was similar in the inclisiran-only group (79%), the switching group (80%), and the group of patients who were rolled over from the ORION-3 trial (77%). The percent of patients with ASCVD-RE who attained global lipid targets (< 100 mg/dL) was 73% in the inclisiran-only group, 75% in the switching group, and 77% in the group of patients who were rolled over from the ORION-3 trial.

The mean percentage change from baseline to day 1,080 in LDL-C was –49.0% (95% CI, –50.5% to –47.4%) in the inclisiran-only group, –49.7% (95% CI, –51.3% to –48.0%) in the switching group, and –50.0% (95% CI, –52.6% to –47.3%) in the group rolled over from the ORION-3 trial.

Harms Results

The most common AEs in the ORION-3 trial were infection, hypertension, arthralgia, and fatigue. In the inclisiran-only arm, 275 (96.8%) patients experienced at least 1 AE. A total of 104 (36.6%) patients experienced at least 1 SAE. Nineteen (6.7%) patients and 12 (4.2%) patients discontinued the study treatment due to AEs and SAEs, respectively.

Overall, of the 87 patients in the switching arm, 80 (92%) patients experienced at least 1 AE. Thirty (34.5%) patients experienced at least 1 SAE. Five (5.7%) patients and 3 (3.4%) patients discontinued the study treatment due to AEs and SAEs, respectively.

Over the 4-year study duration, 7 deaths (2.5%) were reported in the inclisiran group and 1 death was reported in the switching arm, and none of the deaths was assessed as drug-related.

In the ORION-8 trial, 79% of patients in each of the inclisiran-only and switching groups reported an AE, as did 64% of patients who rolled over from the ORION-3 trial. The number of patients who discontinued treatment due to an AE (██ ██ ████ █████) was similar in the inclisiran-only group and the switching group, versus ████ of patients who rolled over from the ORION-3 trial.

With respect to SAEs, 31% of patients in the inclisiran-only group, 33% of patients in the switching group, and 15% of patients who rolled over from the ORION-3 trial experienced an SAE.

With respect to AEs of special interest, the following occurred in the inclisiran-only group, the switching group, and the group of patients who rolled over from the ORION-3 trial: █████████ ████ ██████ ███ ██████ ██ ██████ ████ ███████ ██████ ███ ██████ ██ ██████ ████ ███ ███████████████ ████████ ████ ██████ ███ ██████ ████ █████ ██████ ███ ██████ ██ ██████ ███ ███ ████████████████ ███ ██ ████ ███████

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Critical Appraisal

The open-label design of the ORION-3 and ORION-8 trials is considered a limitation that could bias the results parameters. Furthermore, only those who completed the parent trials were eligible for participation in these extensions, which might have potentially led to a selection bias. The lack of a control and/or comparator arm is considered a key constraint that limits the interpretation of study outcomes.

Because the ORION-3 and ORION-8 studies consisted of patients who took part in the pivotal studies, it is reasonable to expect that the same strengths and limitations related to generalizability apply to the extension studies, with the additional caveat of potential selection bias due to the enrolment criteria.

Indirect Comparisons

Description of Studies

The sponsor submitted an ITC that compared the efficacy of inclisiran to relevant drug comparators in patients with HeFH or ASCVD (or ASCVD-RE). The objective of the sponsor-submitted report was to conduct a feasibility assessment via systematic review of the literature and, if possible, to conduct an indirect comparison evaluating the relative efficacy and safety of inclisiran versus relevant drug comparators, including ezetimibe, and other PCSK9 inhibitors in patients with HeFH or ASCVD (or ASCVD-RE).³⁴

The sponsor-submitted ITC was informed by a systematic review of RCTs conducted in April 2020. Thirty-nine studies met the inclusion criteria for the review and feasibility assessment, and 24 studies were subselected for inclusion in the ITC based on network connectivity and the homogeneity of study characteristics, patient characteristics, or outcomes that were likely modifiers of the relative treatment effects.³⁴

The analyses were conducted using a network meta-analysis (NMA). Selection of both fixed and random effects were conducted for outcomes of interest. Random-effects analyses were selected as the base case, given the number of studies per node and the observed heterogeneity in patient and trial characteristics. Three network scenarios were conducted: patients with HeFH on MTD statins, patients with ASCVD and ASCVD-RE on MTD statins, and patients with ASCVD and ASCVD-RE who are intolerant to statins. Efficacy outcomes included percent, absolute, and time-adjusted change from baseline in LDL-C, percent change from baseline in HDL-C, and safety outcomes (including total discontinuations and discontinuations due to AEs).³⁴

Efficacy Results

A total of 7 trials were included in the network for the HeFH population on MTD statins, 13 studies were included in the base-case network for the ASCVD and ASCVD-RE populations on MTD statins, where 1 closed loop was formed, and 7 trials were included in the network for ASCVD and ASCVD-RE populations intolerant to statins. In the HeFH population on MTD statins network, there was no difference between inclisiran and alirocumab or evolocumab for any efficacy or safety outcomes. In the ASCVD and ASCVD-RE population on MTD statins network, inclisiran was favoured over ezetimibe for efficacy outcomes related to LDL-C, but there was no difference between inclisiran and alirocumab or evolocumab for any efficacy or safety outcomes. In the ASCVD and ASCVD-RE population intolerant to statins network, inclisiran was favoured over ezetimibe for efficacy outcomes related to LDL-C but not safety outcomes. There was no difference between inclisiran and alirocumab or evolocumab in any efficacy or safety outcomes.

Critical Appraisal

There were several limitations to the key assumptions made in the NMA approach about the background statin use and the time of assessment of outcomes, impacting clinical and methodological heterogeneity, which resulted in limited interpretability and generalizability of the results. Although not reported or accounted for, these assumptions likely impacted treatment effects and the results of each NMA and were a significant source of heterogeneity in the studies. It was assumed in the NMA that individual statins had similar efficacy as background therapy, regardless of dose, and would not bias the results of the NMA; however, based on discussions with the clinical expert consulted by CDA-AMC, this is not considered a reasonable assumption. It was also assumed that differences in CV risk and severity would not impact the relative effects on LDL-C, and therefore no attempt was made to adjust for differences in baseline characteristics due to the number of studies and inconsistent reporting of characteristics. The NMA used 24 weeks as the time of assessment, which is considered acceptable for lipid and lipoprotein outcomes. End-of-study (EOS) values for safety were used and considered comparable if the duration of follow-up was 24 weeks or longer. Variations in trial length are bound to influence the number of patients withdrawing for various reasons and given the 24-week time of assessment, may undermine the true treatment effects. Additionally, given the biannual dosing regimen of inclisiran, a 24-week time of assessment may be insufficient to assess safety outcomes compared to the 2-week dosing regimen of alirocumab and evolocumab.

Overall, the studies included in the NMA were believed to be statistically heterogeneous based on the considerable I²; however, it is unclear what the source of heterogeneity was. The observed heterogeneity was likely due to observed and unobserved differences in patient populations across the included studies, data imputation analysis methods, and the specific background treatments allowed and/or delivered. Unidentified or unknown clinical heterogeneity (particularly treatment-effect modifiers) and methodological heterogeneity need to be explored, as it is unclear if the transitivity assumption was appropriately met.

In general, all treatments were favoured over placebo for all outcomes in each network scenario; however, the results typically displayed exceedingly wide credible intervals (CrIs), challenging the precision of the results.

Studies Addressing Gaps in the Evidence From the Systematic Review

Pooled Safety Analysis of 7 ORION Trials³⁵

Description of Studies

A posthoc analysis³⁵ comprised patients treated with 300 mg inclisiran sodium or placebo in the completed (i.e., ORION-1, ORION-3, ORION-5, ORION-9, ORION-10 and ORION-11) and ongoing (ORION-8) trials was conducted. The objective was to obtain data regarding the long-term safety and tolerability of inclisiran for up to 6 years in a large, pooled dataset from 7 completed and ongoing trials and a diverse sample of patients at risk for CV events. Exposure-adjusted incidence rates (EAIRs) and Kaplan-Meier estimates of the cumulative incidence of reported treatment-emergent adverse events (TEAEs), abnormal laboratory measurements, and the incidence of antidrug antibodies (ADAs) were analyzed.

This analysis included 3,576 patients treated with inclisiran for up to 6 years and 1,968 patients treated with placebo for up to 1.5 years, with 9,982.1 and 2,647.7 patient-years (PYs) of exposure, respectively.

Harms Results

At least 1 SAE was reported in 32.2% and 22.1% of patients in the inclisiran and placebo groups, respectively. The most common SAEs were cardiac, reported in 11.6% and 9.0% of patients, respectively. At least 1 AE led to study drug discontinuation in 3.2% and 1.7% of patients in the inclisiran and placebo groups, respectively.

AEs at the injection site were more frequent with inclisiran (9.3%) than with placebo (1.8%). AEs at the injection site leading to study drug discontinuation were higher with inclisiran (0.1 per 100 PYs) than with placebo (0.0 per 100 PYs).

Kaplan-Meier analyses showed that AEs that were serious or that led to discontinuation; hepatic, muscle, and kidney events; incident diabetes; and elevations of creatine kinase or creatinine accrued at a comparable rate between groups for up to 1.5 years, with similar trends continuing for inclisiran beyond this period. Fewer major CV events reported as AEs occurred with inclisiran during this period. Treatment-induced ADAs were uncommon with inclisiran (4.6%), and few of these were persistent (1.4%).

Critical Appraisal

Internal Validity: The findings are derived from pooled data from 7 clinical trials with specific inclusion criteria; thus, patient populations enrolled at different times may have had different clinical characteristics not reflected in the tables of baseline characteristics and may not be fully reflective of a general population. Although EAIRs were calculated, no direct comparison of events between inclisiran and placebo is possible beyond the first 1.5 years, and only a few patients were exposed to inclisiran for more than 4 years, which limits the ability to draw meaningful conclusions.

External Validity: The pooled-data analysis consisted of patients who took part in the pivotal studies, so it is reasonable to expect that the same strengths and limitations related to generalizability apply to this study.

Conclusions

The major areas of focus for this resubmission were to address the lack of formal assessment of clinical outcomes data from the ORION-9, ORION-10, and ORION-11 trials, and the lack of longer-term safety and efficacy data for inclisiran. Given the indication, the 2 populations — patients with HeFH (ORION-9) and patients with nFH with ASCVD (ORION-10 and ORION-11) — should be viewed separately. There was no evidence that inclisiran reduced the risk of MACE in the HeFH population in ORION-9; however, according to the clinical experts, this type of data has not been available from clinical trials of other drugs, given that these events would be less frequent in this population over the typical follow-up period of a clinical trial, and that HeFH is less common than nFH. There was evidence of a reduced risk of MACE with inclisiran treatment in the nFH with ASCVD population when the results of ORION-10 and ORION-11 were pooled; however, this was a posthoc analysis and it is important to note that these trials were not designed to compare these outcomes between treatment groups. The conclusions about inclisiran regarding lipid parameters remain the same: inclisiran elicits a statistically and clinically significant reduction in LDL-C and a similar improvement in other lipid parameters, and this improvement in LDL-C appeared to be maintained throughout the 3 years of additional treatment with inclisiran during the open-label ORION-8 trial. There was no indication of any new safety or tolerability concerns with inclisiran during the long-term extensions, or when the results of various ORION trials were pooled. The ITC submitted by the sponsor did not provide conclusive evidence on the relative efficacy and safety of inclisiran compared to other PCSK9 inhibitors or ezetimibe in the context of HeFH or ASCVD. The ITC is of minimal value when comparing the efficacy of inclisiran with other PCSK9 inhibitors or ezetimibe, because it did not include an evaluation of clinical outcomes.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of inclisiran in the treatment of primary hypercholesterolemia in patients with HeFH or nFH with ASCVD.

Disease Background

The contents of this section have been informed by materials submitted by the sponsor and clinical expert input. The following information has been summarized and validated by the CDA-AMC review team.

In Canada, CVD is the second leading cause of death and accounted for almost 20% of all deaths in 2020.¹ CVD encompasses multiple diseases and can be subdivided in different ways, including its atherosclerotic origin. Atherosclerosis is the build-up of cholesterol and fatty deposits (plaque) inside arteries, which can eventually narrow the vessel lumen.^36,37 Despite its pathophysiological complexity, the 1 prerequisite for atherosclerotic plaque development is the presence of LDL-C.² A clinical condition in which an individual has elevated levels of cholesterol, including LDL-C, is referred to as hypercholesterolemia. Hypercholesterolemia can be grouped into 2 forms: nFH and FH (also referred to as acquired or genetic hypercholesterolemia). nFH is characterized by elevated LDL-C levels. Its etiology is likely a complex interplay between several genetic and environmental risk factors, rather than a simple monoallelic disruption of the LDLR gene. Environmental risk factors that increase the risk of nFH include diet, smoking, physical inactivity, and other factors known to be associated with an increased risk of CVD (e.g., diabetes, chronic kidney disease, and hypertension).^3-6 In Canada, the 1-year incidence rate for ASCVD ranges between 7.2 and 8.8 per 1,000 person years, and the 5 year prevalence of ASCVD ranges between 6.91% and 8.55% in adults.^7-9

Elevated LDL-C is directly associated with the development of atherosclerosis and ASCVD.¹⁰ The 3 main subcategories of ASCVD are CAD, cerebrovascular disease, and PAD. To best manage their patients, clinicians stratify individuals based on their risk of a first (primary prevention) or a recurrent (secondary prevention) clinical event using their demographic and clinical pedigrees. Individuals with hypercholesterolemia and a history of an atherosclerotic event are categorized as having established clinical ASCVD (i.e., they are secondary-prevention patients), whereas individuals with hypercholesterolemia at risk of developing ASCVD are primary-prevention patients. A subset of primary-prevention patients at greater risk of ASCVD are referred to as having an ASCVD-RE. Patient with ASCVD-RE are defined as those with type 2 diabetes mellitus, FH, or a 10-year risk of a CV event of at least 20% as assessed by the FRS for CVD or equivalent.¹¹ The proportion of the overall ASCVD population considered to be at high risk is estimated to be approximately 25%.⁹ In accordance with Canadian guidelines and published literature and validation from Canadian clinicians, patients at high-risk for nFH with ASCVD are defined as patients who meet any of the following criteria: diabetes, recurrent vascular events, PAD, or ACS in the past 12 months; and LDL-C levels greater than 1.8 mmol/L despite MTD statins with or without other LLTs.^9,12-17 Throughout this resubmission, the high-risk ASCVD subgroup will refer to patients with any of these criteria.

FH is 1 of the most common genetic disorders and is caused by mutations in the genes encoding LDLR, ApoB, or PCSK9, leading to high plasma levels of LDL-C.¹⁰ Depending on the number of mutant alleles, patients can be categorized as having HoFH or HeFH.¹⁸ HeFH has an estimated prevalence of approximately 1 in 250 individuals;¹⁹ but a more recent worldwide meta-analysis suggests a prevalence of approximately 1 in 311.^20,21 The clinical presentation of FH is variable, affected by the number and type of mutations together with other genetic factors. Individuals with 2 mutated LDLR alleles (HoFH or compound heterozygotes) have higher LDL-C levels than those with 1 mutant allele (HeFH).¹⁸ Individuals with FH have elevated LDL-C levels from a young age, and the ongoing exposure to elevated LDL-C results in a higher cumulative risk of developing ASCVD.²² Patients with FH may present with physical findings such as tendon xanthomata or xanthelasma.²³ Multiple diagnostic criteria for FH exist, but the CCS recommends the proposed criteria developed by FH Canada. A diagnosis of FH should be considered in patients with a baseline LDL-C of at least 5 mmol/L for patients who are at least 40 years of age (or LDL-C ≥ 4.0 mmol/L for patients aged < 18 years; LDL-C ≥ 4.5 mmol/L for patients aged ≥ 18 years and < 40 years). The presence of 1 or more major criteria (DNA mutation, tendon xanthomas, LDL-C ≥ 8.5 mmol/L) establishes a diagnosis of definite FH.³⁸ FH is associated with an increased risk of CV events compared with the general population.^24-26 For example, a Canadian prospective observational study of 339 patients with definite or probable HeFH with a mean follow-up of 10.9 years documented a baseline ASCVD history of 12.1% and mean LDL-C level of 5.9 mmol/L.³⁹ The incidence of adverse vascular outcomes were as follows: any CV event was 33.5 per 1,000 PYs; and MI, CABG, percutaneous coronary intervention, angina, and transient ischemic attack and/or ischemic stroke (IS) was 6.5, 6.5, 11.9, 7.6, and 1.1 per 1,000 PYs, respectively.³⁹ Importantly, the probability of having a second CV event 1 year after the first CV event was 52%, increasing to 59% in the 5 years after the first event, indicating that most recurrent events occur within the first year in this population.³⁹ Compared with the general population, all-cause mortality is reported to be 1.4-fold to 1.9-fold higher in patients with FH.⁴⁰ Last, the impact on HRQoL is generally prolonged and follows the course of recovery. Some patients do not fully recover, so the event may have a prolonged impact on HRQoL, especially if subsequent complications develop; recurrent events have a particularly substantial humanistic burden because they can have a cumulative impact on a patient’s HRQoL, with studies demonstrating worse HRQoL in patients with recurrent events.^41-43 Figure 1 is a proposed Canadian definition for HeFH that is being adopted by many cardiologists across Canada, according to the clinical experts consulted by CDA-AMC on this review.

Figure 1: Proposed Canadian Definition of FH

ASCVD = atherosclerotic cardiovascular disease; FH = familial hypercholesterolemia; LDL-C = low-density-lipoprotein cholesterol; yr = year.

*Secondary causes of high LDL-C should be ruled out (severe or untreated hypothyroidism, nephrotic syndrome, hepatic disease [biliary cirrhosis], medication especially antiretroviral drugs).

**Causal DNA mutation refers to the presence of a known FH-causing variant in the LDLR, APOB, or PCSK9 gene, based on the presence of the variant in the ClinVar, HGMD, or WDLV databases, in the proband or a first-degree relative.

Source: Ruel et al. Simplified Canadian definition for familial hypercholesterolemia, Can J Cardiol. 2018 Sep;34(9):1210 to 1214. Copyright 2018 by the authors. Available from: https://onlinecjc.ca/article/S0828-282X(18)30383-0/fulltext. Reprinted in accordance with Creative Commons Attribution 4.0 International Licence (CC BY 4.0): https://creativecommons.org/licenses/by/4.0/50.⁴⁴

The impact of ASCVD on mortality must also be considered. For example, all-cause mortality was 5.5% in the year after a CV event in an Italian study,⁴⁵ whereas 11.5% and 13.9% of patients died in the 6 months after a first and second CV event, respectively, in a UK-based study.⁴⁶ CV-specific in-patient mortality was also high, and in-patient mortality was shown to be 11.4 per 1,000 PYs in a US-based study.⁴⁷ CV mortality was shown to increase after a subsequent CV event (1 prior CV event: 4.7 per 100 PYs; ≥ 2 prior CV events: 6.7 per 100 PYs) in a Swedish study.⁴⁸ Furthermore, rates of subsequent CV events are higher in patients with ASCVD. In the US, patients with ASCVD had a 7-fold higher rate of CV events over the 12 months after diagnosis than patients without ASCVD,⁴⁹ and approximately a third of patients experienced a CV event over 5 years of follow-up after a first event.⁵⁰ A Swedish population-based study assessed the risk of MACE, including MI, IS, and CV death in individuals with prior ASCVD (defined as having MI, IS, or PAD), identified in national population-based registers.⁴⁸ Over a mean follow-up of 7.3 years, 44% of patients experienced a CV event. The MACE composite rate (defined as MI, IS, or CV death) was 6.3 per 100 PYs, while the ASCVD composite end point (defined as including MI, IS, unstable angina, coronary revascularization, or CV death) was 7.0 per 100 PYs.⁴⁸

Standards of Therapy

The contents of this section have been informed by materials submitted by the sponsor and clinical expert input. The following information has been summarized and validated by the CDA-AMC review team.

The LDL-C goal for patients with FH without ASCVD (primary prevention) is a 50% reduction from baseline (i.e., untreated LDL-C) and attainment of an LDL-C of less than 2.5 mmol/L.^12,23 For patients with FH and established ASCVD (secondary prevention), the approach recommended is the same as for patients with ASCVD; namely, the attainment of LDL-C levels consistently below 1.8 mmol/L.¹²

The 2021 CCS Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in Adults recommend that CV risk assessment be conducted every 5 years for men and women aged 40 to 75 years, using the modified FRS or the Cardiovascular Life Expectancy Model to guide therapy and reduce major CV events.¹² The CCS guidelines also provide specific guidance to mitigate CVD risk.¹² The previous CCS guidelines, published in 2016, recommended maintenance of an LDL-C level of less than 2.0 mmol/L in patients with ASCVD (i.e., secondary prevention),⁵¹ but this was revised to a lower threshold of less than 1.8 mmol/L in the updated 2021 guidelines.¹² Patients with ASCVD-RE (i.e., those with diabetes mellitus > 40 years) should be treated to maintain an LDL-C of less than 2.0 mmol/L.¹²

Nonpharmacological interventions for hypercholesterolemia promote a healthy diet and lifestyle, which can have beneficial lipid-lowering effects and CV outcomes.^12,52 Guidelines highlight modifiable risk factors of weight control, dietary patterns, physical inactivity, smoking, alcohol consumption, and psychosocial factors (i.e., sleep patterns, mental health) that can be targeted for the primary prevention of CVD, with observed beneficial responses in LDL-C, HDL-C, and triglyceride levels, and reductions in CV events and mortality.^12,39,51 Furthermore, for the secondary prevention of CV events, it is recommended that sedentary behaviour be limited, physical activity be encouraged, and previously identified modifiable lifestyle factors be addressed so that they have an additive effect on a reduction of ASCVD events.¹²

Per CCS guidelines, statins are first-line therapy for individuals with hypercholesterolemia.¹² Statins are classified as low-to-moderate intensity (i.e., lowering LDL-C by 30% to < 50%) or high intensity (i.e., lowering LDL-C by > 50%; examples, according to the clinical experts, would include atorvastatin 40 mg to 80 mg daily, or rosuvastatin 20 mg to 40 mg daily).⁶ They are generally well tolerated, but may be uncommonly associated with myalgia and myopathy that may rarely progress to rhabdomyolysis, abnormalities in liver enzymes, and an increased risk of new-onset diabetes.⁵³ Statin intolerance has been reported to occur in 10% to 20% of patients. Adherence to statin therapy ranges from 25% to 61% over 3 to 5 years in patients with ASCVD.^54-59

Ezetimibe is a second-line therapy and is usually combined with statins in patients who do not achieve LDL-C goals with statins alone or administered as monotherapy in patients who are intolerant to statins.¹² Ezetimibe is generally well tolerated but may be associated with gastrointestinal disorders, headache, fatigue, and myalgia.⁶⁰ Importantly, LDL-C levels are only reduced by 10% to 20% from baseline with concomitant statin therapy, which may prove to be insufficient to optimally lower LDL-C in patients with HeFH or ASCVD, especially in patients with ASCVD whose LDL-C remains above 1.8 mmol/L despite MTD statin therapy.^12,60,61

Bile acid sequestrants are also a second-line therapy (alternative to ezetimibe) and can be used alone or combined with statins and/or ezetimibe.^12,51 Their use is currently limited by a high burden of AEs (particularly gastrointestinal side effects), limited efficacy, and drug-drug interactions.^51,62 As such, they have only a very minor role in contemporary lipid management, according to the clinical experts consulted by CDA-AMC on this review.

PCSK9 inhibitors are recommended as an add-on therapy to lower LDL-C in patients whose LDL-C remains above target despite MTD statin therapy.¹² Evolocumab and alirocumab have recently been introduced into clinical practice and can lower LDL-C levels by approximately 45% to 60% in patients taking MTD statins with or without ezetimibe.⁶³ In large phase III clinical trials, PCSK9 inhibitors were shown to significantly reduce the risk of CV events when added to recommended LLT (MTD statins with or without ezetimibe).^64,65 Safety data from clinical trials of evolocumab and alirocumab suggest that both therapies are well tolerated.^64-66 Evolocumab and alirocumab are administered by subcutaneous (SC) self-injection every 2 weeks or monthly by the patient or their caregiver, following appropriate guidance provided by a health care professional on the proper SC injection technique.^67,68 Evolocumab and alirocumab (referred to as PCSK9 inhibitor monoclonal antibodies in this resubmission) were recommended for public reimbursement by CDA-AMC as adjunct therapies to diet and MTD statins for the treatment of patients with HeFH or patients with clinical ASCVD who need additional LDL-C reduction.^69,70 However, evolocumab and alirocumab are currently only reimbursed for patients with HeFH in most provinces, including Ontario,^71,72 and are not reimbursed under typical circumstances for the treatment of ASCVD in any province, due to unsuccessful negotiations with the pan-Canadian Pharmaceutical Alliance.^73,74

Despite the availability of statins and other LLTs, most patients with FH, as well as most patients with nFH with ASCVD, fail to achieve guideline-recommended LDL-C levels, thus remaining at high risk for preventable morbidity and mortality attributable to future CV events. Key reasons for failure to sufficiently lower LDL-C include tolerability issues, challenges with medication adherence, and, for ASCVD patients, lack of access to additional LLTs with sufficient LDL-C-lowering efficacy.

The 2021 CCS dyslipidemia guidelines highlight that within the ASCVD population with nFH, there exist subgroups of patients who are deemed to be at high risk for future events (more so than a general group of patients with ASCVD; e.g., patients with stable angina) and who derive the largest absolute benefit from intensification of LLTs with PSCK9 inhibitors.¹² These subgroups include recent (defined as patients hospitalized for an index ACS event to 52 weeks postindex ACS), and patients with clinically evident ASCVD and any of the following: diabetes or metabolic syndrome, polyvascular disease (vascular disease in ≥ 2 arterial beds), symptomatic PAD, recurrent MI, MI in past 2 years, previous CABG surgery, LDL-C of at least 2.6 mmol/L or HeFH, and Lp(a) of at least 60 mg/dL (120 nmol/L) in patients whose LDL-C remains above 1.8 mmol/L, despite MTD statins (with or without another LLT).

Drug Under Review

Key characteristics of inclisiran are summarized in Table 3, along with other treatments available for patients with HeFH or patients with nFH with ASCVD.

Inclisiran is administered by SC injection at a dose of 284 mg per 1.5 mL, at baseline, 3 months, and every 6 months thereafter. It is indicated as an adjunct to lifestyle changes, including diet, to further reduce LDL‐C level in adults with the following conditions who are on MTD statins, with or without other LDL‐C‐lowering therapies:

• HeFH

• nFH with ASCVD.

The sponsor’s reimbursement request is consistent with the indication.

Inclisiran is an siRNA that reduces the expression of PCSK9. PCSK9 is a protein that binds to and inhibits the recycling of LDLR, therefore reducing the expression of PCSK9 and increasing the number of LDLRs, and this facilitates the clearance of LDL-C from the circulation.

Inclisiran was previously reviewed by CADTH in February 2022 for the same indication, and the recommendation was to not reimburse.²⁷ Key reasons for this recommendation included the fact that there was insufficient evidence that inclisiran reduces CV morbidity and mortality, or all-cause mortality, as the pivotal trials — ORION-9, ORION-10, and ORION-11 — were not designed to assess these outcomes.²⁷ Additionally, CDEC noted that the long-term efficacy and safety of inclisiran has not been determined, and that there are 2 ongoing studies — ORION-4 and ORION-8 — that are expected to provide evidence to better characterize the pertinent clinical outcomes, as well as provide long-term efficacy and safety data. CDEC also noted that there was no direct comparison of inclisiran to evolocumab or alirocumab, or to other add-on drugs, and that there were limitations to the submitted ITC, including the relatively short follow-up period (24 weeks) in patients with a chronic condition.

The sponsor outlined the basis for its resubmission. To address the lack of evidence for the reduction of CV morbidity and/or mortality and all-cause mortality, the sponsor included a pooled analysis of the ORION-9, ORION-10, and ORION-11 studies, focusing on the risk of MACE with inclisiran versus placebo across the 3 trials. In the posthoc analysis of this exploratory outcome from these 3 trials, inclisiran reduced the risk of MACE versus placebo. To address the issue of the lack of long-term safety data, the sponsor submitted the ORION-3 trial, as well as a pooled analysis of 7 ORION trials. From the ORION-3 study, the sponsor noted that most of the AEs were mild to moderate, and that 1% of patients experienced an SAE that was possibly related to inclisiran. With respect to the pooled analysis, the trajectory of SAEs or AEs did not change with additional years of inclisiran treatment. Finally, the sponsor submitted a revised budget impact model to address CDA-AMC’s concerns from the first recommendation. It focused on the population of patients with nFH with ASCVD who are at high risk and reported a reduction in budget impact of approximately one-third.

Table 3: Key Characteristics of Treatments for Patients With HeFH and With nFH and ASCVD

ApoB = apolipoprotein B; ASCVD = atherosclerotic cardiovascular disease; CVD = cardiovascular disease; ECG = electrocardiogram; HDL-C = high-density-lipoprotein cholesterol; HeFH = heterozygous familial hypercholesterolemia; LDL-C low-density-lipoprotein cholesterol; LLT = lipid-lowering therapy; MI = myocardial infarction; MTD = maximally tolerated dose; nHF = nonfamilial hypercholesterolemia; TG = triglycerides; total-C = total cholesterol; UA = unstable angina.

Sources: Product monograph for inclisiran,⁷⁵ evolocumab,⁶⁷ alirocumab,⁶⁸ atorvastatin calcium,⁷⁶ atorvastatin calcium.⁷⁷

Stakeholder Perspectives

Patient Group Input

This section was prepared by the CDA-AMC review team based on the input provided by patient groups. The full original patient input(s) received by CDA-AMC have been included in the Stakeholder section of this report.

Two patient groups — the CHPA and the HeartLife Foundation — responded to CDA-AMC’s call for patient input for the current review of inclisiran as an adjunct to lifestyle changes, including diet and MTD statins, with or without other LDL-C-lowering therapies, in adult patients with HeFH or nFH with ASCVD who require additional lowering of LDL-C.

The information provided by CHPA was gathered through a survey questionnaire that was in effect from June 8 until July 10, 2023, targeting patients with or at high risk for ASCVD, followed by individual interviews with 10 individuals who had a diagnosis of ASCVD or had experienced a heart attack or stroke and had received inclisiran. The HeartLife Foundation submission was completed by its patient partner executives; it includes data from literature review, 1-on-1 interviews with patients living with the disease, and study review.

Among the 85 CHPA survey respondents, 58% reported having a diagnosis of ASCVD or having experienced a heart attack or stroke, 27% of respondents had symptoms of or were at high risk for ASCVD, 67% reported having a diagnosis of FH, and 25% reported having other lipid disorders.

The patient groups emphasized that living with ASCVD and high levels of LDL-C is very hard to manage, affects the physical and mental well-being, has a significant financial burden on families, and impacts their quality of life. Symptoms like shortness of breath, chest pain, and fatigue were stated by the respondents, who indicated the negative impact of a heart attack, bypass surgery, or stroke on themselves and their families. Many with a family history of heart disease and/or high cholesterol commented on their fear of following a family pattern of early death.

According to the 2 patient inputs, managing hypercholesterolemia requires a low-fat diet and medications including but not limited to statins, ezetimibe, and PCSK9 inhibitors. Although 100% of respondents from the CHPA input indicated that they ate a low-fat diet, more than half of them indicated this was not entirely effective. Among the 92% of respondents who used statins, 81% found them to be effective or somewhat effective to achieve target LDL-C levels; however, 64% experienced moderate-to-severe side effects. Of the 87% who used ezetimibe, only 40% indicated that it was effective, but it has fewer side effects than statins. More than half (57%) of respondents had been prescribed a PCSK9 inhibitor, with about 92% of those on the drug reporting that it worked well or very well to manage their cholesterol levels, and 14% said there were moderate side effects only. The HeartLife Foundation submission added that patient adherence to currently available and publicly reimbursed therapeutic options is acknowledged to be poor, and access to efficacious treatments like PCSK9 inhibitors is very limited.

The patient groups stated that patients seek a safe, tolerable, and effective treatment that can minimize the long-term health consequences of ASCVD in high-risk patients by effectively managing LDL-C levels below the recommended threshold. This, in turn, can reduce the occurrence of MACE, including myocardial (re)infarction, IS, the need for coronary revascularization, and CV death, and ultimately enhance the quality of life for individuals living with ASCVD. Patients also want an accessible therapy with a more affordable and manageable treatment regimen, less frequent dosing, fewer side effects, easier administration, and less disruption to work or daily life.

All the patient partners interviewed for the HeartLife input and patients interviewed for the CHPA input had received inclisiran, and almost all of them stated that the drug was highly effective and improved their overall well-being and quality of life.

Clinician Input

Input From Clinical Experts Consulted by CDA-AMC

All CDA-AMC review teams include at least 1 clinical specialist with expertise in the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 3 clinical specialists with expertise in the diagnosis and management of hypercholesterolemia.

Unmet Needs

The clinical experts agreed that the major issues that affect the treatment of patients with HeFH or with nFH with ASCVD are nonadherence, intolerance to high-intensity statins, inability to reach recommended lipid targets despite MTD statins and ezetimibe, and lack of access to PCSK9 inhibitors. Related to that, a large percentage of patients (much greater than 50%) with HeFH are not able to reach their target LDL-C of less than 2.5 mmol/L, and with nFH with ASCVD are not able to reach their target of less than 1.8 mmol/L. The clinical experts noted that in patients with HeFH, the addition of a PCSK9 inhibitor to statin therapy will help most patients achieve their target; however, only a small number of these patients will receive these drugs.

The clinical experts noted that the adherence issues are compounded by the side effects of the drugs used, and the fact that patients may be reluctant to take a medication on a chronic basis to prevent future events or symptoms. The clinical experts appeared to agree that statins are the major cause of side effects, and they noted that there is evidence suggesting that combining better-tolerated drugs like ezetimibe and PCSK9 inhibitors with statins may be 1 strategy for achieving targets. The clinical experts also noted that ezetimibe is not potent enough to achieve target LDL-C as monotherapy, and that access to the PCSK9 monoclonal antibodies is limited.

Place in Therapy

The clinical experts consider inclisiran as another option among the PCSK9-targeting drugs, equivalent to the monoclonal antibodies that target PCSK9, evolocumab, and alirocumab, which are currently used as adjunctive therapies combined with statins (with or without ezetimibe) in patients unable to reach their target LDL-C. The clinical experts all emphasized the importance of having another option for add-on therapy to statins, and that the infrequent dosing of inclisiran may be an advantage with respect to adherence. The clinical experts were also clear that inclisiran is unlikely to become a first-line therapy, ahead of statins, because of the large body of evidence supporting the use of statins. The clinical experts also noted that, per the indication, patients would be required to have reached the MTD of a statin (which may include 0 mg) before moving to other options like inclisiran. Statin intolerance should be documented, as recommended by CCS guidelines. None of the clinical experts believed that inclisiran will shift the treatment paradigm.

Patient Population

With respect to patients with HeFH, the clinical experts believed that in addition to those unable to reach their LDL-C target despite MTD statins, with or without ezetimibe, patients who would be especially well suited to inclisiran would include those with other risk factors, such as smoking, diabetes, hypertension, or elevated Lp(a).

The clinical experts believed that patients with nFH with ASCVD who meet the indication (LDL-C above threshold despite MTD statins, plus or minus ezetimibe) are particularly well suited to inclisiran and could include those unable to tolerate high-intensity statins, those with early disease onset or recurrent disease, those whose LDL-C is far from threshold, and those with the risk factors.

The clinical experts believed that the patients enrolled in the pivotal ORION trials are consistent with the target population for inclisiran.

Suitable patients would be identified based on laboratory tests (lipid panel and ApoB), according to the clinical experts. The clinical experts noted that although genetic testing could be used to confirm FH, this is not required, nor should it be, to gain access to inclisiran, given the limited availability of such tests in various regions of the country.

The clinical experts also noted that HeFH is underdiagnosed in Canada, with 1 clinical expert estimating that only 10% to 15% of patients with HeFH have been diagnosed.

Assessing the Response to Treatment

The clinical experts agreed that a reduction in lipid metrics, most notably LDL-C, but also non-HDL-C and ApoB, is used to assess response to treatment in the clinic. All these outcomes were assessed in the pivotal ORION trials. The clinical experts noted that clinical outcomes such as CV morbidity and mortality were of paramount importance overall; however, these are clearly not used to monitor treatment response in the clinic. One clinical expert drew attention to the fact that despite guidelines emphasizing that lipids need to be monitored regularly, there is no specific guidance as to how frequently lipid response should be monitored. This clinical expert noted that using 2003 guidance, which is still likely relevant today, the levels of lipids and lipoprotein are expected to reach steady state within 6 weeks of initiating drug therapy, and long-term follow-up after the initial titration phase can be performed every 6 to 12 months. The clinical experts emphasized that reducing LDL-C to below target and keeping it there should be the focus, rather than aiming for an arbitrary percent reduction (such as a 40% reduction, for example).

Discontinuing Treatment

The clinical experts agreed that medication intolerance, loss of coverage, and treatment that no longer aligns with a patient’s goals of care are reasons to discontinue inclisiran. Of course, according to the clinical experts, failure to meet an arbitrary percent reduction in LDL-C while on MTD statins, plus or minus ezetimibe, would also be a reason for stopping or switching treatment.

Prescribing Considerations

Although HeFH is more likely to be diagnosed by a specialist, none of the clinical experts believed that diagnosis requires a specialist, and for patients with nFH with ASCVD, a diagnosis can be made by a specialist or primary care physician. One of the clinical experts was very clear that requiring specialist intervention in diagnosis, management, or monitoring would be unnecessary and counterproductive, and could result in inequities in access to inclisiran, given the inequities in access to specialist care across the country.

Clinician Group Input

This section was prepared by the CDA-AMC review team based on the input provided by clinician groups. The full original clinician group input(s) received by CDA-AMC have been included in the Stakeholder section of this report.

Fourteen clinician groups — Alberta Cardiovascular Disease Prevention Collaborative (8 clinicians contributed to the input); BC Lipid specialists (11 clinicians contributed to the input); le Centre hospitalier universitaire Dr.-Georges-L.-Dumont (6 clinicians contributed to the input); Cambridge Cardiac Rehab Program (6 clinicians contributed to the input); CCS Dyslipidemia Guideline Committee (14 clinicians contributed to the input); Cardiology Association of Niagara (3 clinicians contributed to the input); Egyptian Cardiologists of Niagara (3 clinicians contributed to the input); Kawartha Cardiology Clinic (7 clinicians contributed to the input); Lipid Clinic of McMaster University and Hamilton Health Sciences (1 clinician contributed to the input); Mazankowski Alberta Heart Institute (3 clinicians contributed to the input); Oakville Cardiologists (9 clinicians contributed to the input); Service of cardiology, Internal Medicine Department and Heart Failure Group at St. Thomas Elgin General Hospital (STEGH; 5 clinicians contributed to the input); Western University, Division of Cardiology, Cardiac Rehabilitation and Secondary Prevention Program (3 clinicians contributed to the input); and University of Toronto faculty and clinicians at St. Michael’s Hospital who are actively involved in the treatment of patients with ASCVD and/or lipid disorders (10 clinicians contributed to the input) — responded to CDA-AMC’s call for clinician group input. Information for this input was gathered through a review of the relevant literature and publications, as well as experience and knowledge in this field.

According to the clinician groups, in the Canadian context, the current treatment paradigm for dyslipidemia or high cholesterol levels in patients with ASCVD and FH involves drug therapies, such as statins (first-line therapy), ezetimibe, and PCSK9 monoclonal antibodies, in addition to dietary modifications, consisting of reducing saturated fat intake, increasing fibre intake, and adopting a generally healthy and balanced diet. Other medications, such as fibrates, are not indicated for LDL-C lowering, and bile acid resins are seldom used.

The clinician group input stated that the CCS dyslipidemia guidelines recommend lifestyle modifications to improve lipid parameters and an LDL-C threshold of 1.8 mmol/L or less. However, a high proportion of patients, including those in the high-risk population with dyslipidemia, cannot achieve the recommended lipid threshold because of intolerance to currently available treatments (particularly statins), lack of compliance to treatment, variable response to currently available treatments, and lack of accessibility (i.e., cost) to highly effective PCSK9 inhibitors. Suboptimal therapy increases the risk of MACE. As such, the overarching treatment goals are to reduce the risk of MACE and CV mortality by optimizing the reduction in lipid profiles with efficacious, accessible therapies with fewer side effects and therapies with longer dosing intervals.

The clinician groups agreed that inclisiran can improve lipid profiles by inhibiting PCSK9 production, resulting in the increased expression of hepatic LDL receptors. The difference from other drugs that target the PCSK9 pathway is in the molecular mechanism (siRNA) that leads to the degradation of the messenger RNA encoding PCSK9, specifically in the cytoplasm of hepatocytes. It has the advantage of being administered by SC injection every 6 months rather than every 2 weeks. The drug under review would be used as an add-on therapy to MTD statins with or without additional LLTs in patients who require additional lipid-lowering, per the CCS dyslipidemia guidelines. Patients with or at risk of ASCVD or FH who require additional LLT and who become refractory to statins and ezetimibe, along with those who struggle with compliance, would be best suited for the drug under review. High-risk patients who cannot tolerate high-dose statin therapy due to side effects would also benefit from inclisiran. Furthermore, patients with HeFH who are at risk for ASCVD would benefit from the drug under review, according to BC Lipid specialists; le Centre hospitalier universitaire Dr.-Georges-L.-Dumont; Cambridge Cardiac Rehab Program; CCS; Oakville Cardiologists; and Western University, Division of Cardiology, Cardiac Rehabilitation and Secondary Prevention Program.

According to the clinician groups, the percentage of reduction in lipid parameters (LDL-C, non-HDL-C, and ApoB measurements) 6 months after treatment, and yearly thereafter, are the main outcomes of interest that can be assessed to determine whether a patient is responding to treatment. A clinically meaningful response to treatment would be indicated by at least a 30% reduction in LDL-C or non-HDL-C levels. The clinician groups stated that discontinuation of therapy should be considered in patients with significant intolerance, severe side effects, or a lack of response.

The clinician groups stated that inclisiran should be able to be appropriately used by both primary care and specialist physicians in specialty clinics, community settings, community outpatient clinics, and hospitals.

Drug Program Input

The drug programs provide input on each drug being reviewed through CDA-AMC’s reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CDA-AMC are summarized in Table 4.

Table 4: Summary of Drug Plan Input and Clinical Expert Response

ACS = acute coronary syndrome; ASCVD = atherosclerotic cardiovascular disease; CABG = coronary artery bypass graft; CDEC = Canadian Drug Expert Committee; FH = familial hypercholesterolemia; HeFH = heterozygous familial hypercholesterolemia; LDL-C = low-density-lipoprotein cholesterol; LLT = lipid-lowering therapy; Lp(a) = lipoprotein (a); MI = myocardial infarction; MTD = maximally tolerated dose; PAD = peripheral artery disease.

Clinical Evidence

The objective of CDA-AMC’s Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of inclisiran 284 mg in 1.5 mL for SC injection in the treatment of HeFH and nFH with ASCVD in adults. The focus will be placed on comparing inclisiran to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of inclisiran is presented in 4 sections, with CDA-AMC’s critical appraisal of the evidence included at the end of each section. The first section, the Systematic Review, includes pivotal studies and RCTs that were selected in accordance with the sponsor’s systematic review protocol. The second section includes sponsor-submitted long-term extension studies. The third section includes indirect evidence from the sponsor. The fourth section includes additional studies that were considered by the sponsor to address important gaps in the systematic review evidence.

Included Studies

Clinical evidence from the following is included in the CDA-AMC review and appraised in this document:

• Three pivotal studies or RCTs identified in the systematic review, as well as a posthoc pooled analysis

• Two long-term extension studies

• One ITC

• One additional study addressing gaps in evidence.

Systematic Review

The contents of this section have been informed by materials submitted by the sponsor. The following information has been summarized and validated by the CDA-AMC review team.

Description of Studies

Characteristics of the included studies are summarized in Table 5.

Table 5: Details of Studies Included in the Systematic Review

ApoB = apolipoprotein B; ASCVD = atherosclerotic cardiovascular disease; ASCVD-RE = atherosclerotic cardiovascular disease risk equivalent; CeVD = cerebrovascular disease; CHD = coronary heart disease; CV = cardiovascular; FH = familial hypercholesterolemia; FRS = Framingham Risk Score; HDL-C = high-density-lipoprotein cholesterol; HeFH = heterozygous familial hypercholesterolemia; LDL-C = low-density-lipoprotein cholesterol; LVEF = left ventricular ejection fraction; MACE = major adverse cardiovascular events; MI = myocardial infarction; NA = not applicable; NYHA = New York Heart Association; PAD = peripheral arterial disease; RCT = randomized controlled trial; SC = subcutaneous; TC = total cholesterol.

Sources: ORION-9 Clinical Study Report;²⁸ ORION-10 Clinical Study Report;²⁹ ORION-11 Clinical Study Report.³⁰

A total of 3 studies were identified from the literature for inclusion in this systematic review: ORION-9, ORION-10, and ORION-11. A number of other studies were identified that are ongoing, with no data available yet, and therefore will not be reported in this review (VICTORION-INITIATE, ORION-18, ORION-4, VICTORION-2P, VICTORION-INCEPTION). As ORION-8 is a long-term extension study, it will be described in detail in Long-Term Extension Studies section below.

The ORION-9 Trial²⁸

The primary objectives of the ORION-9 study were to evaluate the effect of inclisiran treatment on LDL-C levels at day 510 and time-adjusted percentage change in LDL-C levels from baseline to the period from after day 90 and up to day 540. Secondary objectives of the ORION-9 study were to evaluate the effect of inclisiran treatment on PCSK9, total cholesterol, ApoB, and non-HDL-C at day 510; LDL-C and PCSK9 levels over time to day 540; the maximum reduction in LDL-C levels; LDL-C and PCSK9 levels over time in individual patients; other lipids, lipoproteins, and apolipoproteins; and the proportion of patients achieving prespecified LDL-C targets; and to evaluate the safety and tolerability profile of inclisiran. Exploratory objectives were to evaluate the effect of inclisiran on CV effects such as CV death, resuscitated cardiac arrest, nonfatal MI, and nonfatal stroke; the proportion of patients in each group with any LDL-C reduction from baseline at any visit (i.e., responders); and the response of LDL-C reduction related to underlying causal mutations of HeFH. ORION-9 was an international, multicenter, phase III, placebo-controlled, double-blind, randomized study. Eligible patients were adults older than 18 years with a diagnosed history of HeFH and elevated LDL-C levels who were either on MTD statins or who had documented evidence of intolerance to at least 2 different statins. The study enrolled 482 patients, was conducted at 47 centres, and screened patients in 8 countries: Canada (3 centres), Czech Republic (3), Denmark (6), Netherlands (5), South Africa (9), Spain (6), Sweden (3), and the US (12). A total of 23 patients were enrolled from Canadian sites: 12 patients randomized to the inclisiran arm and 11 patients randomized to the placebo arm. Patients were randomized by an automated Interactive Response Technology (IRT) only after patient eligibility was confirmed. Treatment allocation was stratified by country and by current use of statins or other LLTs in block sizes of 4. All groups were studied concurrently. Patients were randomized (1:1) to receive either inclisiran sodium 300 mg (equivalent to inclisiran 284 mg) or placebo on top of MTD statins. The study was 18 months in duration, with patients receiving 4 300 mg doses of inclisiran sodium (on day 1, day 90, day 270, and day 450). The screening period occurred between day –14 and day –1 before randomization, and involved confirming eligibility and collecting baseline assessments, such as a physical examination, vital signs, 12-lead electrocardiogram (ECG), fasting lipid profile, limited serum chemistry, hematology, and coagulation, and collecting a pharmacogenetic sample. There was no run-in period in the study. The clinical cut-off date for receiving treatment for the final analysis was August 27, 2019.

The ORION-10 Trial²⁹

The primary objectives of the ORION-10 study were to evaluate the effect of inclisiran treatment on LDL-C levels at day 510 and time-adjusted percentage change in LDL-C levels from baseline to the period from after day 90 and up to day 540. Secondary objectives of the ORION-10 study were to evaluate the effect of inclisiran on PCSK9, total cholesterol, ApoB, and non-HDL-C at day 510; LDL-C and PCSK9 levels over time to day 540; the maximum reduction in LDL-C levels; LDL-C and PCSK9 levels over time in individual patients; other lipids, lipoproteins, and apolipoproteins; and the proportion of patients achieving prespecified LDL-C targets; and to evaluate the safety and tolerability profile of inclisiran. The exploratory objective was to evaluate the effect of inclisiran on CV events such as CV death, resuscitated cardiac arrest, nonfatal MI, and nonfatal stroke (ischemic and hemorrhagic). The ORION-10 trial was a US-based, multicenter, phase III, placebo-controlled, double-blind, randomized study with 1,561 patients. Eligible patients were adults older than 18 years with a diagnosed history of ASCVD (CHD, cerebrovascular disease, or PAD) and elevated LDL-C levels who were either on MTD statins or who had documented evidence of intolerance to at least 2 different statins. The study was conducted in 146 centres in the US. Patients were randomized by an automated IRT only after patient eligibility was confirmed. Treatment allocation was stratified by the current use of statins or other LLTs in block sizes of 4. Patients were randomized (1:1) to receive either inclisiran sodium 300 mg or placebo on top of MTD statins. The study was 18 months in duration, with patients receiving 4 300 mg doses of inclisiran sodium or placebo (on day 1, day 90, day 270, and day 450). The screening period occurred between day –14 and day –1 before randomization and involved confirming eligibility and collecting baseline assessments, such as a physical examination, vital signs, 12-lead ECG, fasting lipid profile, limited serum chemistry, hematology, and coagulation. There was no run-in period in the study. The clinical cut-off date for receiving treatment for the final analysis was September 10, 2019.

The ORION-11 Trial⁷⁸

The primary objectives of the ORION-11 study were to evaluate the effect of inclisiran treatment on LDL-C levels at day 510 and time-adjusted percentage change in LDL-C levels from baseline to the period from after day 90 and up to day 540. Secondary objectives of the ORION-11 study were to evaluate the effect of inclisiran on PCSK9, total cholesterol, ApoB, and non-HDL-C at day 510; LDL-C and PCSK9 levels over time to day 540; the maximum reduction in LDL-C levels; LDL-C and PCSK9 levels over time in individual patients; other lipids, lipoproteins, and apolipoproteins; and the proportion of patients achieving prespecified LDL-C targets; and to evaluate the safety and tolerability profile of inclisiran. The exploratory objective was to evaluate the effect of inclisiran on CV events such as CV death, resuscitated cardiac arrest, nonfatal MI, and nonfatal stroke (ischemic and hemorrhagic). ORION-11 was an international (non-US), multicenter, phase III, placebo-controlled, double-blind, randomized study with 1,617 patients. Eligible patients were adults older than 18 years with a diagnosed history of ASCVD (CHD, CVD, or PAD) or ASCVD-RE (type 2 diabetes, FH, or a 10-year risk of 20% or greater of having a CV event assessed by FRS or equivalent [target LDL-C of < 100 mg/dL]) and elevated LDL-C levels (≥ 1.8 mmol/L [≥ 70 mg/dL] for patients with ASCVD and ≥ 2.6 mmol/L [≥ 100 mg/dL] for patients with ASCVD-RE) who were either on MTD statins with or without other stable (≥ 30 days with no planned change) LLT or who had documented evidence of intolerance to at least 2 different statins. The study was conducted in 72 centres in 8 countries in Europe and South Africa: Czech Republic (2 centres), Germany (5), Hungary (4), Netherlands (1), Poland (19), South Africa (8), Ukraine (9), and the UK (24). Patients were randomized by an automated IRT only after patient eligibility was confirmed. Treatment allocation was stratified by country and by current use of statins or other LLTs in block sizes of 4. Patients were randomized (1:1) to receive either inclisiran sodium 300 mg or placebo on top of MTD statins. The study was 18 months in duration, with patients receiving 4 300 mg doses of inclisiran sodium or placebo (on day 1, day 90, day 270, and day 450). The screening period occurred between day –14 and day –1 before randomization and involved confirming eligibility and collecting baseline assessments, such as a physical examination, vital signs, 12-lead ECG, fasting lipid profile, limited serum chemistry, hematology, and coagulation. There was no run-in period in the study. The clinical cut-off date for receiving treatment for the final analysis was July 31, 2019.

The ORION-9, ORION-10, and ORION-11 trials shared an identical study design; the diagram is presented in Figure 2.

Figure 2: Diagram of Study Design for the ORION-9, ORION-10, and ORION-11 Trials

FUP = follow-up; V = visit.

Sources: ORION-9 Clinical Study Report;²⁸ ORION-10 Clinical Study Report;²⁹ ORION-11 Clinical Study Report.³⁰

Populations

Inclusion and Exclusion Criteria

The key inclusion and exclusion criteria for the ORION-9, ORION-10, and ORION-11 trials were largely identical, apart from the studied population of interest. The ORION-9 trial was conducted in patients with HeFH, the ORION-10 trial was conducted in patients with ASCVD (CHD, cerebrovascular disease, or PAD), and the ORION-11 trial was conducted in patients with ASCVD and ASCVD-RE.^28-30 Notably, the LDL-C cut-off values were different among the studies. For patients with clinical ASCVD, the LDL-C cut-off was 1.8 mmol/L or greater; for those with ASCVD-RE, the cut-off LDL-C was 2.6 mmol/L or greater.^28-30

Interventions

The ORION-9, ORION-10, and ORION-11 trials employed the same interventions for the active and placebo arms.^28-30 In each trial, patients were randomized (1:1) to receive either inclisiran sodium 300 mg or placebo via SC injection on top of MTD statins. Patients received 4 300 mg doses of inclisiran sodium or placebo (on day 1, day 90, day 270, and day 450). All study drugs were administered under aseptic conditions by qualified clinical study site staff and under the supervision of the investigator or a designee. The site of injection was the abdomen, with alternating sites for each injection. It is not clear what the plan was for patients who missed doses.

In each trial, the study drugs were blinded before distribution to each site. Each study drug vial (or prefilled syringe in the ORION-10 trial) contained either inclisiran or placebo and had a yellow shroud to blind the vial. The pharmacist or qualified designee prepared the blinded study drug under aseptic conditions to be administered to the patient on that day. Randomization via an automated IRT was used to assign patients to a blinded study drug. The clinical study site pharmacist maintained the double-blind, according to site-specific procedures and the pharmacy manual. Because inclisiran may be visually distinguishable from placebo, blinded syringes were provided to all study sites and used to maintain the blind.

All patients had the right to withdraw at any point during treatment without prejudice. The investigator could discontinue any patient at any time if medically necessary. Reasons for study discontinuation were considered to constitute 1 of the following:

• AE

• death

• withdrawal of patient consent

• physician decision

• loss to follow-up

• initiation of protocol-prohibited LLT (i.e., an approved PCSK9 inhibitor).

Prior and Concomitant Therapy

For eligible prior and concomitant medications for all 3 ORION trials — including statins and other LLTs (i.e., ezetimibe) — patients were required to have been on stable dose for a minimum of 30 days before screening. Patients receiving statins were to be receiving the MTD. Hormone replacement therapy, prescription medications to treat preexisting medical conditions (such as diabetes or hypertension), and prescription and nonprescription medications to treat AEs at the discretion of the investigator were also permitted.

Medications that were prohibited from being added during all trials included those that are prescribed to lower LDL-C, such as statins, ezetimibe, lomitapide, mipomersen, niacin, colesevelam, bile acid absorption inhibitors, monoclonal antibodies directed toward PCSK9, and any medications taken for the purpose of lipid-lowering, including over-the-counter or herbal therapies.

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Outcomes

A list of efficacy end points assessed in this Clinical Review Report is provided in Table 6, followed by descriptions of the outcome measures. Summarized end points are based on outcomes included in the sponsor’s Summary of Clinical Evidence, as well as any outcomes identified as important to this review by to the clinical expert(s) consulted by CDA-AMC and stakeholder input from patient and clinician groups and public drug plans. Using the same considerations, the CDA-AMC review team selected end points that were considered to be most relevant to CDA-AMC’s expert committee deliberations and finalized this list of end points in consultation with members of the expert committee. These outcomes were not assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

Table 6: Outcomes Summarized From the Studies Included in the Systematic Review

AE = adverse event; ApoB = apolipoprotein B; ASCVD = atherosclerotic cardiovascular disease; CV = cardiovascular; HDL-C = high-density-lipoprotein cholesterol; LDL-C = low-density-lipoprotein cholesterol; Lp(a) = lipoprotein(a); MI = myocardial infarction; SAE = serious adverse event.

^aAll analyses of the primary, key secondary, and other secondary end points were imputed using various multiple imputation methods.

Sources: ORION-9 Clinical Study Report;²⁸ ORION-10 Clinical Study Report;²⁹ ORION-11 Clinical Study Report.³⁰

Patients were in a fasted state for all efficacy laboratory assessments. Parameters assessed were total cholesterol, triglycerides, LDL-C, HDL-C, non-HDL-C, very-low-density-lipoprotein cholesterol, apolipoprotein A1, ApoB, Lp(a), high-sensitivity C-reactive protein, and PCSK9. All laboratory assessments and assays were performed by a central laboratory, except for urinalysis.

The primary outcome of the ORION-9, ORION-10, and ORION-11 trials was the percent change in LDL-C from baseline to day 510. All trials had a coprimary end point of time-adjusted percentage change in LDL-C from baseline to the period from after day 90 and up to day 540, defined as the average percentage change in LDL-C from baseline to the period from after day 90 and up to day 540, reflecting the start of the biannual dosing regimen.

Key secondary efficacy end points of the ORION trials included:

• absolute change in LDL-C from baseline to day 510

• time-adjusted absolute change in LDL-C from baseline to the period from after day 90 and up to day 540

• percentage change from baseline to day 510 in PCSK9, total cholesterol, ApoB, and non-HDL-C.

Key secondary end points were not tested if either of the coprimary efficacy end points’ null hypotheses failed to be rejected.

Other secondary outcomes were consistent across the ORION trials, and included maximum percent change in LDL-C; absolute and percent change in LDL-C from baseline to each assessment time up to day 540; individual responsiveness (defined as the number of patients reaching on-treatment LDL-C levels of < 25 mg/dL, < 50 mg/dL, < 70 mg/dL, and < 100 mg/dL) at day 510; proportion of patients in each group with a greater than or equal to 50% LDL-C reduction from baseline; absolute change and percentage change in other lipids, lipoproteins, apolipoproteins, and PCSK9 from baseline at each subsequent visit to day 540; and the proportion of patients in each group who attain global lipid targets for their level of ASCVD risk.

Exploratory end points included the incidence of CV death, resuscitated cardiac arrest, nonfatal MI, and nonfatal stroke (ischemic and hemorrhagic), and the proportion of patients in each group with any LDL-C reduction from baseline at any visit (responders). In the ORION-9 trial, an additional exploratory outcome consisted of response of LDL-C reduction related to underlying causal mutations of HeFH.

Blood samples were taken at scheduled time points to determine LDL-C concentrations. Aliquots of plasma and serum were collected at each time point and stored for additional analyses, including future analysis of biomarkers of CV risk. Plasma samples were analyzed using a validated enzyme-linked immunosorbent assay to determine PCSK9 protein concentration.

The safety and tolerability of inclisiran was a secondary end point of the study and was measured by AEs, SAEs, vital signs, clinical laboratory values, ECG measurements, and the formation and characterization of ADAs. AEs were defined as any untoward medical occurrence in a patient administered a medicinal product that does not necessarily have a causal relationship with the treatment and were coded using MedDRA Version 20.1. The severity of AEs was assessed by the investigator on a 3-point scale (mild, moderate, or severe).

No patient-reported HRQoL outcomes were assessed in the ORION trials.

Statistical Analysis

Sample Size and Power Calculation

For the ORION-9, ORION-10, and ORION-12 trials, the sample-size calculation was performed with the assumption (based on the observed results from a phase II study) that the difference in change from baseline between the active-dose group and the placebo group for LDL-C will be no less than 30 mg/dL, with a standard deviation of 20 mg/dL. Assuming about a 5% drop out rate, the sample size was approximately 380 patients in the ORION-9 trial and 1,425 patients in the ORION-10 and ORION-11 trials, which is evaluable for efficacy across the placebo and inclisiran groups. The sample size of at least 380 patients provided more than 90% power to detect a 30% reduction of LDL-C in the inclisiran group compared to the placebo group, at 1-sided significance level of 0.025. In the ORION-9 trial, due to faster than expected enrolment, the actual enrolment was 482 patients. This increased sample size contributed additional safety data and did not appreciably affect power calculations.

Statistical Test or Model

The incidence of MACE was a prespecified exploratory end point in the ORION-9, ORION-10, and ORION-11 studies. Relevant AEs (i.e., MACE, MI, and stroke) were identified using standard nomenclature from MedDRA. A basket of MedDRA-defined CV terms was used to define the prespecified, nonadjudicated, exploratory end point of MACE (defined per protocol) as a composite of cardiac death, cardiac arrest, nonfatal MI, and fatal and nonfatal stroke. The analysis of MACE was based on the safety population (N = 3,655 patients representing 2,653 PYs of exposure to inclisiran); data were analyzed using Cox regression methods and Kaplan-Meier survival analysis; and the meta-analysis was conducted using the Mantel-Haenszel approach with the Peto method for study pooling, with the study as a fixed effect in the model. Odds ratios and corresponding 95% CIs were provided for the meta-analysis as overall effect estimates.

In the ORION trials, analysis of the first coprimary outcome (percentage change in LDL-C) was conducted on the intention-to-treat (ITT) population and was based on an analysis of covariance (ANCOVA) model on the percentage change in LDL-C from baseline to day 510 on each multiply imputed dataset (100 total). The model included the fixed effect of treatment group (and for the ORION-11 trial, the current use of statins or other LLTs) and baseline LDL-C as a covariate. Treatment effects from these 100 ANCOVA analyses were combined using Rubin’s method via the SAS PROC MIANALYZE procedure. The difference in LSM between treatment groups and the corresponding 2-sided 95% CI was provided for hypothesis testing.

Analysis of the second coprimary outcome (time-adjusted percentage change in LDL-C) was also conducted on the ITT population and was based on a mixed model for repeated measures (MMRM) on the percentage change in the LDL-C from baseline over all visits on each multiply imputed dataset (100 total). The model included fixed effects for treatment, visit, baseline value, and the interaction between treatment and visit. The restricted maximum likelihood estimation approach was used with the covariance structure set as unstructured. The time-adjusted percentage change in LDL-C from baseline to the period from after day 90 and up to day 540 was calculated from the MMRM. Linear combinations of the estimated means after day 90 and up to day 540 were used to compare treatment effects. Treatment effects from these 100 MMRM analyses were combined using Rubin’s method via the SAS PROC MIANALYZE procedure. The difference in LSM between treatment groups and the corresponding 2-sided 95% CI was provided for hypothesis testing.

Multiple Testing Procedure

The key secondary efficacy end points were not tested if either of the coprimary efficacy end points’ null hypotheses failed to be rejected. The Hochberg procedure was applied to control the familywise type I error rate at a 2-sided alpha significance level of 0.05 for the key secondary end points.

Data Imputation Methods

A control-based pattern-mixture model (PMM) was used to explore the possibility of data missing not at random for patients who discontinued the study. For patients who discontinued the study without further follow-up data, missing values after study discontinuation were imputed under the assumption that their outcome would be similar to those in the placebo group who had similar background characteristics. For patients who did not discontinue the study, intermittent missing values were imputed based on the missing-at-random (MAR) assumption. Multiple imputations were used to account for uncertainty in the imputation process and results from the imputed datasets were combined using Rubin’s method.

A key difference in the multiple imputation washout methodology that is unique to the ORION-11 trial was the addition of a modified multiple imputation washout model, which is believed to be the most appropriate method for the imputation of missing data, as it provides the best estimate of what the values of missing data points would have been if had they been measured. The modified method accounted for patients in the inclisiran group who received all 4 doses of the study drug, had the day 510 value missing, had evaluable data at day 540, and had their intermittent missing day 510 values imputed assuming the missing data were MAR.

Subgroup Analyses

Key prespecified subgroup analyses for the efficacy and safety end points included sex, age, body mass index, race, baseline statin use and intensity, other LLT, baseline triglyceride level, metabolic disease, ASCVD status (ORION-9 and ORION-11 trials only), renal impairment (based on estimated glomerular filtration rate), history of allergy, baseline LDL-C, study centre region, and postbaseline-LDL-C; phenotype and baseline ezetimibe use were only subgroups in the ORION-9 trial.

Sensitivity Analyses

The following sensitivity analyses were performed:

• A control-based PMM, using the same imputed datasets and an MMRM that were used for the second coprimary end point primary analysis, was used to compare treatments at day 510. Multiple imputations were used to account for uncertainty in the imputation process, and results from the imputed datasets were combined using Rubin’s method.

• For both coprimary outcomes, an MMRM analysis without multiple imputation that assumes that missing data are MAR was performed. The model included fixed effects for treatment, visit, baseline value, and the interaction between treatment and visit. The restricted maximum likelihood estimation approach was used with the covariance structure set as unstructured. A linear contrast at day 510 was used to compare treatment groups for the first coprimary outcome, percent change in LDL-C, and a linear combination of estimated means after day 90 and up to day 540 was used to compare treatment groups for the second coprimary outcome, time-adjusted percent change in LDL-C.

• The impact of country and current use of statins or other LLTs was assessed by including country, the treatment-by-country interaction, and the current use of statins or other LLTs (yes or no) as fixed effects in the primary analysis ANCOVA (using multiple imputation washout model data).

• An ANCOVA model without multiple imputation was performed using the modified intention-to-treat (mITT) population. The model included the fixed effect of treatment group and baseline LDL-C as a covariate.

• A tipping-point analysis was performed to search for the tipping point that would reverse the study conclusion. In the tipping-point analysis, the deltas in the treatment group were varied independently (the inclisiran group is progressively worse while the placebo group is not impacted, and the inclisiran group is progressively worse while the placebo group progressively improves) until the hypothesis tests on the coprimary efficacy end points became statistically insignificant.

Secondary Outcomes of the Studies

The absolute change in LDL-C from baseline to day 510 and percentage change from baseline to day 510 in PCSK9, total cholesterol, ApoB, and non-HDL-C were analyzed using an MMRM with covariates. The time-adjusted absolute change in LDL-C from baseline to the period from after day 90 and up to day 540 was analyzed similarly to that of the time-adjusted percentage change in LDL-C from baseline to the period from after day 90 and up to day 540. Missing values were imputed using the control-based PMM on LDL-C, PCSK9, total cholesterol, ApoB, and non-HDL-C, and absolute change or percentage change from baseline was calculated based on imputed data before any analysis was performed. The MMRM without multiple imputation was used in sensitivity analyses for the key secondary end points.

Table 7: Statistical Analysis of Efficacy End Points

ANCOVA = analysis of covariance; ApoB = apolipoprotein B; CI = confidence interval; HDL-C = high-density-lipoprotein cholesterol; LDL-C = low-density-lipoprotein cholesterol; LLT = lipid-lowering therapy; LSM = least squares mean; MAR = missing at random; mITT = modified intention to treat; MMRM = mixed model for repeated measures; MNAR = missing not at random; PMM = pattern-mixture model.

Sources: ORION-9 Clinical Study Report;²⁸ ORION-10 Clinical Study Report;²⁹ ORION-11 Clinical Study Report.³⁰

Analysis Populations

Table 8: Analysis Populations of the ORION-9, ORION-10, and ORION-11 Trials

ITT = intention to treat; LDL-C = low-density-lipoprotein cholesterol; mITT = modified intention to treat.

Sources: ORION-9 Clinical Study Report;²⁸ ORION-10 Clinical Study Report;²⁹ ORION-11 Clinical Study Report.³⁰

Results

Patient Disposition

The ORION-9, ORION-10, and ORION-11 trials shared a similar study design and patient enrolment model.

Table 9 summarizes the patient flow of the ORION trials. In the ORION-9 trial, a total of 617 patients were screened and 482 were randomized. The most common reason for screening failure was that the inclusion or exclusion criteria were not met █████████ ███ ██ ███████████ ███████ █████████████ ████████ ██ █ ███ ███████ A total Of the 2,329 patients screened in the ORION-10 trial, 1,561 were randomized. In the ORION-11 trial, a total of 2,381 patients were screened and 1,617 were randomized. The primary reason for screening failure in the ORION-10 and ORION-11 trials was the patient not meeting the inclusion and/or exclusion criteria, ████████████ ███ ███████████ █████ █████ ████████ ██ █ ████ ██████ ██████ ██████. The proportion of patients that failed screening varied across trials but was more similar in the ORION-10 and ORION-11 trials (32.98% and 32.09%) compared to the ORION-9 trial (21.88%).

Across all studies, 94% of patients or more completed the study (i.e., had a day 540 EOS visit). The discontinuation rate was similar across studies, with the ORION-10 trial having the greatest proportion of patients discontinuing treatment. In all studies, the primary reason for discontinuation was withdrawal of consent. The proportion of patients discontinuing due to death was similar in the ORION-10 and ORION-11 trials but was lower in the ORION-9 trial.

Table 9: Summary of Patient Disposition From the Studies Included in the Systematic Review

FAS = full analysis set; ITT = intention to treat; mITT = modified intention to treat, NR = not reported.

^aOne patient randomized to placebo was given inclisiran.

Sources: ORION-9 Clinical Study Report;²⁸ ORION-10 Clinical Study Report;²⁹ ORION-11 Clinical Study Report.³⁰

Baseline Characteristics

The baseline characteristics outlined in Table 10 are limited to those that are most relevant to this review or were felt to affect the outcomes or interpretation of the study results.

Table 10: Summary of Baseline Characteristics From the ORION-9, ORION-10, and ORION-11 Trials (ITT Population)

ApoB = apolipoprotein B; ASCVD = atherosclerotic cardiovascular disease; CV = cardiovascular; eGRF = estimated glomerular filtration rate; HDL-C = high-density-lipoprotein cholesterol; HeFH = heterozygous familial hypercholesterolemia; IQR = interquartile range; LDL-C = low-density-lipoprotein cholesterol; LDLR = low-density-lipoprotein receptor; NA = not applicable; NR = not reported; SD = standard deviation.

^aIn the ORION-11 trial, patients in this category had type 2 diabetes, FH, or a 10-year risk of a CV event of 20% or greater, as assessed by the FRS for CVD or equivalent.

^| ██████ ███ ████████ ███ ███ █████ ████████ ████ ██ █ █████

Sources: ORION-9 Clinical Study Report;²⁸ ORION-10 Clinical Study Report;²⁹ ORION-11 Clinical Study Report,³⁰ Raal FJ et al.,⁷⁹ Ray KK et al. (2020).¹¹

Exposure to Study Treatments

██ ████████ ████ ████████ ██ ████████ ███ ███ ██████████ ███ ███████ ████ ████ █████ ███ █████ █████ █████████████ ██ ████████ █ █████████ ███ ████ ████████ ██ ████████ ███ ██████████ ███ █████ ███ █████ █████ █████████████ ███ █████ ███ █████ ████ ███ ████████ █████████████ █████ █████████████ ██ ████████ ██ ███████ ████ █████ ███ █████ ██ ██████████ ███ ███████ █████ █████████████ ██ █████████ █████ █████████████ ██ ████████ ███ ██████ ██ ███ ██████████ ███ ███ ██████ ██ ███ ███████ ████ ███ ██████████ ███ ██ ████████ ███ ██████ █████████████ ██ ████████ █████ ███ ███████ ███ ███ ██████ █████████████ ██ █████████ █ ████████ ███████ ██ ███████ ████████ ██ █████████████ ██ ████████ █████████ ███ ████████ ███ █████████ ██ █████ ████████ ███ █████████ ██ Table 11.

Concomitant Medications

There were no medications or cointerventions required during the study. To be eligible for enrolment, participants must have been treated with any of the following statins: atorvastatin 40 mg or 80 mg once daily; rosuvastatin 20 mg or 40 mg once daily; or simvastatin 40 mg once daily, or, if patient was on 40 mg daily for more than 1 year, 80 mg once daily. Lower doses of statins were allowed in cases of partial statin intolerance, defined as intolerance to any of the previously described statins at any of the aforementioned doses. ██████ ███ ████████ ██ ███ ███ ██████████ ███████ ███ ██ █████ ███ ███ █ ███████████ ███████████ ██ █████████████ ████ ███ ███ █████ ███ █████████ ████████ ███████ ███ █████████ ██████.

In the ORION-9 trial, overall, █████ █████████ ██ ████████ ████████ ███, 90.5% (436/482) of patients received statin therapy, 55.4% (267/482) received other LLTs (58.3% [140/240] of patients in the placebo group and 52.5% [127/242] of patients in the inclisiran group), and 3.9% (19/482) received other LLTs and no statins. Overall, 73.9% (356/482) were on a high-intensity statin at baseline. A total of 14.5% (70/482) of patients received a moderate-intensity statin and 1.9% (9/482) patients received a low-intensity statin at baseline. Approximately half (52.3%; 252/482) of patients the were treated with ezetimibe. In the ORION-10 trial, overall, █████ ███████████ ██ ████████ ████████ ███, 89.2% (1,393/1,561) of patients received statin therapy and 31.3% (489/1,561) received other LLTs. Two-thirds (69.4%; 1,084/1,561) of patients were on a high-intensity statin at baseline. A total of 18.7% (292/1,561) of patients received a moderate-intensity statin and 0.8% (12/1,561) received a low-intensity statin at baseline. A total of 9.9% (156/1,561) patients were treated with ezetimibe. In the ORION-11 trial, overall, █████ ███████████ ██ ████████ ████████ ███, 94.7% (1,532/1,617) of patients received statin therapy and 11.8% (191/1,617) received other LLTs. A total of 78.0% (1,261/1,617) of patients were on a high-intensity statin at baseline, 15.5% (251/1,617) of patients were on a moderate-intensity statin at baseline, and 0.4% (6/1,617) were on a low-intensity statin at baseline. A total of 7.1% (114/1,617) patients were treated with ezetimibe.

██ ████████ ████████ █████ ██ ████████ █████████ ███ ██ ███ ██ ███████ ██ ███ ██████ ██████ ███ ██████ █ ███████ ██████ ██ ███ ███████ █████ █████ ███████ ████ █ █████ ██████████ ████████ █████████████ ██ ███████ ██ ███ ██████████ █████ █████ ███████ ████ █ █████ ██████████ ████████ ██████ ███ ██████ ██ █████████ █████ ███████████ ██ ████████ ███ ██ ███ ███ █████ ██ ███████ ██ ███ █████ ██████ ███ ██████ ██████ ██ ██████ █████████ ███ ███████ ██ ████████ ██████ ███████ ███████ ███████ ███ ████████ ██████ ██████████ ██████ ████████ ██████ ███ ██████ █ ████████ ██ ███ ███████ █████ ████ ████ █ █████ ██████████ ████████ ███ ████ █████████████ ██ █████████ ████████ █████ ███████████ ██ ████████ ███ ██ ███ ███ █████ ██ ███████ ██ ███ ███ ██████ ███ ██████ ████████ ████ ███████████████ ████████ ██████ █████████ ███████ ████ ██████████████████ ████████ █████ ████████ ███████████████ ████████ ██████ ████ ████████ ██████████████████ ██████████ ██ ████████ ████ ██████████ █████ ████ ████████

Table 11: Summary of Patient Exposure From the ORION-9, ORION-10, and ORION-11 Trials (Safety Population)

IQR = interquartile range; NR = not reported; SD = standard deviation.

Sources: ORION-9 Clinical Study Report;²⁸ ORION-10 Clinical Study Report;²⁹ ORION-11 Clinical Study Report.³⁰

Efficacy

Major Adverse Cardiovascular Events

In the ORION-9, ORION-10, and ORION-11 trials, the exploratory end point of MACE was defined as the composite of CV death, resuscitated cardiac arrest, nonfatal MI, and nonfatal stroke (hemorrhagic or nonhemorrhagic), using predefined MedDRA search.

As part of its resubmission, the sponsor conducted a pooled analysis of clinical outcomes from the ORION-9, ORION-10, and ORION-11 trials and also provided what was referred to as a sensitivity analysis that pooled data from the ORION-10 and ORION-11 studies. The pooled analysis of all 3 trials is not relevant for this review, as it combines the HeFH and the nFH with ASCVD populations, and these 2 populations are being viewed separately for this review, consistent with the indication. The sensitivity analysis that was conducted to assess the effects of inclisiran (n = 1,494) compared to placebo (n = 1,477) on MACE in the ASCVD and ASCVD-RE populations is relevant.⁸⁰

HeFH Population

The incidence of MACE in the inclisiran and placebo arms of the ORION-9 trial was 10 (4.1%) and 10 (4.2%), respectively; the absolute number of MACE for the inclisiran and placebo arms was 10 and 11, respectively; the corresponding RR was ███ ████ ███ ████ █████

nFH With ASCVD

Results from the posthoc pooled analysis of the ORION-10 and ORION-11 trials showed ███ ██████ patients in the inclisiran arm experienced ███ ██████, while ███ ███████ patients in the placebo arm experienced ███ ██████. The reported HR of ████ ████ ███ █████ █████ for MACE favoured inclisiran over placebo in the ORION-10 and ORION-11 patient population.

The incidence of MACE in the inclisiran and placebo arms of the ORION-10 trial was 58 (7.4%) and 79 (10.2%), respectively; the absolute number of MACE in the inclisiran and placebo arms was 66 and 90, respectively; the corresponding RR was ███ ████ ███ ████ ████. The incidence of MACE in the inclisiran and placebo arms of the ORION-11 trial was 63 (7.8%) and 83 (10.3%), respectively; the absolute number of MACE for the inclisiran and placebo arms was 65 and 100, respectively; the corresponding RR was ███ ████ ███ ████ ████.

Myocardial Infarction:

• Heterozygous Familial Hypercholesterolemia: In the ORION-9 trial, the exploratory end point of nonfatal MI occurred in 9 (3.7%) patients experiencing | events in the inclisiran arm compared to 10 (4.2%) patients experiencing ██ events in the placebo arm.

• nFH With ASCVD: Using a posthoc pooled analysis of the ORION-10 and ORION-11 trials, the effects of inclisiran (n = 1,494) compared to placebo (n = 1,477) on fatal or nonfatal MI outcomes in the ASCVD and ASCVD-RE population showed that ██ ██████ patients in the inclisiran arm experienced ██ ██████, while ██ ██████ patients in the placebo arm experienced ██ ██████. The reported HR was ████ ████ ███ █████ █████ for fatal or nonfatal MI in the ORION-10 and ORION-11 patient population.

Stroke:

• Heterozygous Familial Hypercholesterolemia: In the ORION-9 trial, for the exploratory end point of nonfatal stroke, no patients in either the inclisiran or placebo treatment arms experienced an event.

• nFH With ASCVD: Using a posthoc pooled analysis of the ORION-10 and ORION-11 trials, the effect of inclisiran (n = 1,494) compared to placebo (n = 1,477) on fatal or nonfatal stroke outcomes in the ASCVD and ASCVD-RE population showed that ██ ██████ patients in the inclisiran arm experienced ██ ██████, while ██ ██████ patients in the placebo arm experienced ██ ██████. The HR was ████ ████ ███ █████ █████ for fatal or nonfatal stroke in the ORION-10 and ORION-11 patient populations.

Table 12: Posthoc Pooled Analysis of MACE From the ORION-9, ORION-10, and ORION-11 Trials

ASCVD = atherosclerotic cardiovascular disease; CI = confidence interval; CV = cardiovascular; HR = hazard ratio; MACE = major adverse cardiac events; MI = myocardial infarction; OR = odds ratio; PY = patient-year.

^aThe HR and 95% CI are from a Cox model with treatment and study ID as factors.

^bThe pooled analyses for CV events conducted by Ray et al. (2022)⁸¹ included all patients from the 3 pivotal ORION trials, where a proportion of patients had HeFH; thus, this analysis removed the ORION-9 population and included patients only from the ORION-10 and ORION-11 trials with ASCVD and ASCVD-RE, of whom > 98% had nFH.

^c████████ ████ ██████ ███████ ██████████████████ ███ ██████████████████████ ██████████████████ ██████ █████████ ████ ███ ████████████ ██████ ██████ ████ █████████ ███ █████ ██ ████████ ███████ ██████ ████ ███████ █████ ████ ████ ████████ ████ ███ █████████████ ███████████████ ████ ████████ ████ ██ █████ █████ ███ ██ ██████████████████████ ███████ ██████ ████ ███ ██ ███████ ███ █████████

Sources: Novartis. (2023) Data on File. CKJX839A1 Inc-Pub084;⁸⁰ Ray KK et al. (2022).⁸¹

Low-Density-Lipoprotein Cholesterol

Percent Change in LDL-C From Baseline to Day 510

The first coprimary key end point of percent change in LDL-C from baseline to day 510 was the same in the ORION-9, ORION-10, and ORION-11 trials.

Heterozygous Familial Hypercholesterolemia:

• The between-group difference between inclisiran and placebo in percent reduction in LDL-C in the ORION-9 trial was –47.9% (95% CI, –53.5% to –42.3%; P < 0.0001).

nFH With ASCVD:

• The between-group difference between inclisiran and placebo in percent reduction in LDL-C in the ORION-10 trial was – 52.2% (95% CI, –55.7% to –48.8%; P < 0.0001) and in the ORION-11 trial was –49.9% (95% CI, –53.1% to –46.6%; P < 0.0001).

• Sensitivity analyses conducted using control-based PMM, MMRM, and ANCOVA multiple imputation washout model showed similar results. Of note, the modified multiple imputed washout model analysis was only performed for the ORION-11 trial. Similar statistically significant (P < 0.0001) placebo-adjusted differences were observed regardless of analysis population (ITT, full analysis set, or mITT) used.⁸²

Subgroups:

• Across the studies, placebo-adjusted LDL-C reductions favouring inclisiran were similar in most subgroups. A statistically significant interaction was observed for above and below the median and quartiles of baseline LDL-C and PCSK9 levels. In all subgroups, inclisiran lowered LDL-C more than placebo.

Time-Adjusted Percent Change in LDL-C From Baseline After Day 90 up to Day 540

The second coprimary key end point of time-average percent change in LDL-C from baseline to the period from after day 90 and up to day 540 was the same for the ORION-9, ORION-10, and ORION-11 trials.

Heterozygous Familial Hypercholesterolemia:

• The LSM difference from placebo favoured inclisiran in the ORION-9 trial, at −44.30% (95% CI, −48.48% to −40.12%; P < 0.0001). The results of the sensitivity analyses for time-adjusted percent change in LDL-C from baseline to the period from after day 90 and up to day 540 were consistent with the overall population.

nFH With ASCVD:

• The LSM difference from placebo favoured inclisiran in the ORION-10 trial, at −53.78% (95% CI, −56.23% to −51.33%; P < 0.0001), and in the ORION-11 trial, at −49.17% (95% CI, −51.57% to −46.77%; P < 0.0001). The results of the sensitivity analyses for time-adjusted percent change in LDL-C from baseline to the period from after day 90 and up to day 540 were consistent with the overall population.

Subgroups:

• Subgroup analyses were provided for the coprimary outcome of time-adjusted percent change in LDL-C after day 90 up to day 540 for the ORION-9, ORION-10, and ORION-11 trials. Results of the subgroup analyses of interest to this review, including baseline LDL-C, baseline statin treatment, statin intensity, and LLT use, were consistent with the overall patient population.

Mean Absolute Change in LDL-C From Baseline to Day 510

Heterozygous Familial Hypercholesterolemia:

• In the ORION-9 trial, the key secondary end point of LSM absolute change in LDL-C from baseline to day 510 was −68.89 mg/dL (95% CI, −77.11 to −60.67 mg/dL; P < 0.0001). Sensitivity analysis using an MMRM demonstrated similar results.

nFH with ASCVD:

The key secondary end point of mean absolute change in LDL-C from baseline to day 510 was −54.12 mg/dL (95% CI, −57.37 to −50.88 mg/dL; P < 0.0001) in the ORION-10 trial and −51.87 mg/dL (95% CI, −55.01 to −48.72 mg/dL; P < 0.0001) in the ORION-11 trial. Sensitivity analysis using an MMRM demonstrated similar results.

Time-Adjusted Absolute Change in LDL-C From Baseline After Day 90 up to Day 540

Heterozygous Familial Hypercholesterolemia:

• Compared to placebo, the time-adjusted absolute change from baseline to the period from after day 90 and up to day 540 in the ORION-9 trial was −62.74 mg/dL (95% CI, −69.01 to −56.48 mg/dL; P < 0.0001). Sensitivity analysis using an MMRM demonstrated similar results.

nFH With ASCVD:

• Compared to placebo, the time-adjusted absolute change from baseline to the period from after day 90 and up to day 540 in the ORION-10 trial was –53.28 mg/dL (–55.75 to –50.80 mg/dL; P < 0.0001) and in the ORION-11 trial was −48.94 mg/dL (95% CI, −51.39 to −46.48 mg/dL; P < 0.0001). Sensitivity analysis using an MMRM demonstrated similar results.

Other Lipid Parameters

Percent change in total cholesterol, non-HDL-C, and ApoB from baseline to day 510 is reported in Table 41 in Appendix 1.

Table 13: Summary of Key Lipid Parameters From the ORION-9, ORION-10, and ORION-11 Trials

CI = confidence interval; LDL-C = low-density-lipoprotein cholesterol; LSM = least squares mean; SD = standard deviation.

^aData reported is from the prespecified washout model to account for missing data.

^bData reported is from the prespecified control-based PMM to account for missing data.

Sources: ORION-9 Clinical Study Report;²⁸ ORION-10 Clinical Study Report;²⁹ ORION-11 Clinical Study Report,³⁰ Raal FJ et al.,⁷⁹ Ray KK et al. (2020).¹¹

Harms

Refer to Table 14 for harms data.

Adverse Events

Heterozygous Familial Hypercholesterolemia

The incidence of AEs in patients treated with inclisiran and with placebo was 76.8% and 71.7% in the ORION-9 trial.

In the ORION-9 trial, the most common AEs in the inclisiran and placebo groups were nasopharyngitis (11.6% versus 8.3%), influenza (5.4% versus 8.8%), upper respiratory tract infection (6.6% versus 6.7%), and back pain (7.1% versus 4.2%).

nFH With ASCVD

The incidence of AEs was consistent in patients treated with inclisiran and those treated with placebo, as well as across trials, with 73.5% versus 74.8% patients experiencing at least 1 AE in the ORION-10 trial and 82.7% versus 81.5% experiencing at least 1 AE in the ORION-11 trial.

The most common AEs in the ORION-10 trial were diabetes mellitus (15.4% versus 13.9%), hypertension (5.4% versus 5.4%), back pain (5.0% versus 5.0%), bronchitis (5.9% versus 3.9%), and dyspnea (5.0% versus 4.2%). In the ORION-11 trial, the most common AEs were diabetes mellitus (10.9% versus 11.7%), nasopharyngitis (11.2% versus 11.2%), hypertension (6.5% versus 6.7%), and upper respiratory tract infection (6.4% versus 6.1%).

Serious Adverse Events

Heterozygous Familial Hypercholesterolemia

In the ORION-9 trial, 18 (7.5%) patients in the inclisiran arm and 33 (13.8%) patients in the placebo arm experienced at least 1 SAE. The most common SAEs were unstable angina, myocardial ischemia, acute MI, aortic valve stenosis, and back pain.

nFH With ASCVD

In the ORION-10 trial, 175 (22.4%) patients in the inclisiran arm and 205 (26.3%) patients in the placebo arm experienced at least 1 SAE. The most common SAEs were CAD, cardiac failure (congestive), acute MI, pneumonia, and noncardiac chest pain. In the ORION-11 trial, 181 (22.3%) patients in the inclisiran arm and 181 (22.5%) patients in the placebo arm experienced at least 1 SAE. The most common SAEs were angina pectoris, acute MI, unstable angina, CAD, and atrial fibrillation.

Withdrawal Due to Adverse Events

Heterozygous Familial Hypercholesterolemia

In the ORION-9 trial, 3 (1.2%) patients in the inclisiran group withdrew due to an AE. No patients in the placebo group withdrew due to an AE. ███████ ███████ ██ ██████████ ████ █████ ████ ████ ████████ ███████ █████████ ████ █████████ ███ ███ ████████ ███ ██████ ████ ██ ███ ████████ █████ ███ ███ █████████ ████ ████████ ██████ ████ ██████████ ███████████ ███████ ██ █████████.

nFH With ASCVD

The incidence of WDAEs in the ORION-10 trial was similar across groups, at 2.4% (19 patients) in the inclisiran group and 2.2% (17 patients) in the placebo group. ███ ████ ██████ ███ ██ ████ ███████████ ███ ███████████████ ████████ ███████ ██ ██████████ ████ ██████ █████████ ███ ██ ██████████ █████████████ ███ ████████ ███████████████ ███ ██████████ ██████ █████████ █████ ███ ██████ █████████ █████ ███ ██████ ███████ ██████ █████████ █████ ███ ██████ ███ ███████ █████████ ███ ███ █████████ █████ ██ ███ ██████ ████ █████ ████ ███ ███████ ██ █████████ ██ ██████ ██ ███ █████████████

The incidence of WDAEs in the ORION-11 trial was similar to that in the ORION-10 trial, with 23 (2.8%) and 18 (2.2%) patients in the inclisiran group and the placebo group, respectively, experiencing AEs that led to withdrawal. ███████ ██████ ██ ███ ██████████ ███ ███████ ██████ ███████ ██ ██████████ ██ █████████ ████████ ███████ █████████ █████ ███ ██████ ████████████████ █████████ ███ ███████ █████████ █████ ██████ ███████████████ ███ ██████████ ██████ █████████ █████ ███ ██████ ███ █████████ █████ ███ ██████

Mortality

Heterozygous Familial Hypercholesterolemia

In the ORION-9 trial, only 2 deaths occurred (0.4%), 1 in each trial arm.

nFH With ASCVD

A total of 23 patients died during the ORION-10 study, 12 (1.5%) in the inclisiran group and 11 (1.4%) in the placebo group. In total, 29 (1.8%) patients died during the ORION-11 study, 14 (1.7%) in the inclisiran group and 15 (1.9%) in the placebo group.

Notable Harms

Heterozygous Familial Hypercholesterolemia

██████████ ██████ ███ ██████████████ █████████ ████████ ██ █ ██████ ███ █ ██████ ████████ ██ ███ ██████████ ███ ███████ ██████ ██ ████████ The incidence of AEs at the injection site in the inclisiran and placebo groups was 17.0% (41 patients) versus 1.7% (4 patients) in the ORION-9 trial. Injection-site reactions were mild to moderate, and no severe reactions were seen. One patient withdrew from the study due to an injection-site reaction in the inclisiran group of the ORION-9 trial. ██ ████████ ████████ █████████ █████████ ███ ███ ████████████████ █████████ ████ ██████████ ████ ██ ████████ ██ █████ ██████████████ ███ █████████ ██ ████████████████ █████████ ██ ███████████ ███ ███████████████ ████████ ███ ██ ██████ ███ ██ ██████ ██ ████████ ███ █████████ ██ █████ ██████ ██ ███ ██████████ ███ █████████████ ██ ███████ ███ █ ██████ ███ █ ███████ ███ █████████ ██ ███████ ██████ ███ ██ █ ██████ ███ █ ██████ ██ ███████████ ███ ███████████████ ████████ ██ ████████ ███ ██████ ████ ████ ██ ████████.

nFH With ASCVD

██████████ ██████ ███ ██████████████ █████████ ████████ ██ ██ ██████ ███ ██ ██████ ████████ ██ ███ ██████████ ███ ███████ ██████ ██ █████████ ███ ██ ██████ ██ ██ ██████ ████████ ██ █████████ The incidence of AEs at the injection site in the inclisiran and placebo groups was 6.0% (47 patients) and 1.9% (15 patients), respectively, in the ORION-10 trial, and was 7.6% (62 patients) and 1.7% (14 patients), respectively, in the ORION-11 trial. Injection-site reactions were mild to moderate, and no severe reactions were seen across trials. One patient withdrew from the study due to an injection-site reaction in the inclisiran group in the ORION-10 trial, while 2 patients in the inclisiran group of the ORION-11 trial withdrew from the study due to injection-site reactions. ██ ████████ ████████ █████████ █████████ ███ ███ ████████████████ █████████ ████ ██████████ ████ ██ ████████ ██ █████ ██████████████ ███ █████████ ██ ████████████████ █████████ ██ ███████████ ███ ███████████████ ████████ ███ ██ ██████ ███ ██ ██████ ██ █████████ ███ ██ ██████ ███ ██ ██████ ██ █████████ ███ █████████ ██ █████ ██████ ██ ███ ██████████ ███ ███████ ██████ ██ ████████ ███ ███ ████ ██ ██████ ███ ██ ███████ ███ ██ ██████ ███ ██ ███████ █████████████ ████████ █████ ███ ███████ █████ ████ ██ ███ ███████ ██████ ███ ████ ██ ███ ██████████ ██████ ███ █████████ ██ ███████ ██████ ███ ██ ██████ ███ ██ ███████ ███ ██ ██████ ███ ██ ██████ ██ ███████████ ███ ███████████████ ████████ ██ █████████ ███ ████ █████████████ ███ ██████ ████ ████ ██ █████████

Table 14: Summary of Harms Results From the Studies Included in the Systematic Review

AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CAD = coronary artery disease; COPD = chronic obstructive pulmonary disease; E = event count; GFR = glomerular filtration rate; GGT = gamma glutamyl transpeptidase; INR = international normalized ratio; MI = myocardial infarction; NR = not reported; PAD = peripheral artery disease; SAE = serious adverse event; SOC = system organ class; TEAE = treatment-emergent adverse event; URTI = upper respiratory tract infection; WDAE = withdrawal due to adverse event.

^aOccurring in ≥ 5% of patients in one group.

^bOccurring in ≥ 1% of patients in one group.

^cOccurring in ≥ 0.5% of patients in one group.

Critical Appraisal

Internal Validity

The major piece of new evidence for the systematic review portion of this resubmission was a posthoc pooled analysis of MACE from the ORION-9, ORION-10, and ORION-11 trials. The main issues with this type of analysis are that MACE and its components were only an exploratory outcome from these ORION trials, it is a posthoc analysis, and the pooled analysis that includes all 3 ORION trials mixes the HeFH population from the ORION-9 trial with the nFH with ASCVD populations from ORION-10 and ORION-11 trials. The fact that MACE and its components was an exploratory outcome in these ORION trials also introduces the potential for bias. Sample sizes were not determined based on these outcomes; events were captured via the safety population and definitions may not be inclusive or specific enough; there was no blinded, centralized assessment of events; and the timing was likely insufficient to assess CV events. The use of a posthoc analysis introduces significant potential for bias, as an investigator may be biased by their ability to review the data when deciding what analyses to conduct and how to construct the composite outcome. For example, it is clear from the pooled analysis that an improvement for inclisiran versus placebo is driven entirely by the ORION-10 and ORION-11 trials, whereas there does not appear to be any difference in risk of MACE between the inclisiran and placebo groups in the ORION-9 trial. Therefore, pooling all 3 trials leads 1 to the erroneous conclusion that the risk of MACE was reduced with inclisiran treatment across the ORION-9, ORION-10, and ORION-11 trials, when that was not the case. Finally, combining results from all 3 ORION trials is not appropriate, as this ignores the fact that these trials feature 2 distinct populations, each separately identified within the indication. Additionally, there may even be issues with pooling the ORION-10 and ORION-11 trials, as there are some differences in baseline characteristics between these 2 study populations, most notably that all patients in the ORION-10 trial had ASCVD, whereas approximately 88% of patients in the ORION-11 trial had ASCVD, with the remaining categorized as ASCVD-RE. There was also a higher percentage of patients who discontinued treatment in the ORION-10 trial than in the ORION-11 trial, further reinforcing that these are, indeed, 2 distinct study populations. It is not clear whether the sponsor took steps to adjust for these sources of heterogeneity.

ORION-9, ORION-10, and ORION-11 were all phase III, double-blind, RCTs. Appropriate methods for randomization (using IRT), treatment allocation (stratified by country and the current use of statins or other LLTs in block sizes of 4), and maintenance of blinding to treatment assignment were used in all 3 trials, reducing selection, performance, and detection biases. ████████ ██ ███ ████ ███████ █████ ██ █████ █████████ ██ ███ ████████ █████ ███ █████ ████ ███ ███████ ███ ███ ███████ ███████ ███ █████ ███ ███████ ██ ██ ███████ ██ ██ ███ █████ ████████ ████████ ███ ███████ █████ ██ ███ ████████ ██████ There were no notable differences in baseline characteristics in the studies, and there was no imbalance in discontinuations, suggesting that attrition bias was limited. Moreover, unblinding was only permitted in the event of an emergency or AE for which it was necessary to know the study drug to determine an appropriate course of therapy. Injection-site reactions are known complications of PCSK9 inhibitors and were more frequent in the inclisiran groups across trials, which could have revealed treatment assignment, but overall, reactions were not common, and the effect they would have on the results and unblinding is unclear.

The primary analyses of the ORION trials were conducted in the ITT population. Low dropout rates were seen in all trials; however, the total number of missing data was not reported for any outcomes in the trials, and therefore the extent of missing data in each group at various time points and for each key outcome is unknown. Efforts were made to reduce the amount of missing data, including diligent follow-up. Missing data were imputed in the coprimary end point of percent change in LDL-C from baseline to day 510 using a multiple imputation washout model on actual values with baseline and observed efficacy measures, and the current use of statins or other LLTs as covariates. Missing values in the inclisiran group were imputed under the assumption that their outcome was similar to those in the placebo group with similar background characteristics. This method may be subject to bias, resulting in greater treatment effects in favour of inclisiran. For patients in the inclisiran group only missing day 510 data, values were imputed. For patients in the placebo group, missing values over all visits after early termination were imputed based on the MAR assumption. Again, this may impact the direction of the treatment effect in favour of inclisiran over time. Results of the coprimary and secondary outcomes were consistently large, with minimal differences between observed and imputed values. Numerous sensitivity analyses, with and without multiple imputations, were also employed. Therefore, it is unlikely that missing data would have impacted the LSM percent change in LDL-C.

The prespecified power and sample-size calculation for all ORION trials was identical and was based on the assumption that the difference in change from baseline in LDL-C between the inclisiran and placebo groups would be no less than 30 mg/dL, with a standard deviation of 20 mg/dL; however, the enrolled populations were much higher than the power and sample-size calculation defined. ███████████ ██████ █████ ████ █████████ ███ ████████ ███ ████████ ██ ████ ███ █████ ██████ ████████ █████████████ █████ ████ ████ ████████ ██ ██████ ████ ███ ██ ███████ ██████████ █ ███████ ██ ████ ███████████ ████ ██████████ ████████ ███████ ████████ ███ ████ ███ █████ ██████ ████ ██ ████ █████ ███ ██████ ██ ███ ██████████ ██ ██████████ ██████ ████ ██████ ████ ██████ █████████ The additional enrolled patients in the ORION trials could have led to an overpowering of study results, in which the higher number of patients enrolled could have increased the probability of seeing minuscule differences between groups. However, overpowering is unlikely to have affected the results of the ORION studies, given the large differences in efficacy observed between inclisiran and placebo and given the request by the FDA, so any ethical and resource allocation issues are of no concern for the ORION trials. The higher sample sizes contributed additional safety information for all trials; however, secondary outcomes and CV-related events considered to be of interest to this review were not accounted for.

Acceptable methods to account for multiplicity were used in all trials. The coprimary efficacy outcome was controlled for multiplicity using the familywise error rate and a nested testing procedure, first on the percent change in LDL-C from baseline to day 510, and then on the time-adjusted percentage change in LDL-C from baseline to the period from after day 90 and up to day 540. The Hochberg procedure was applied for key secondary end points.^83-85 Other secondary end points and exploratory end points were not controlled for multiplicity, nor for missing data, including the composite outcome of MACE, which was considered most clinically important to this review. The proportion of patients reaching global lipid targets (LDL-C < 100 mg/dL or < 70 mg/dL) was a secondary end point that was also not controlled for multiplicity or missing data. The sponsor’s evaluation of these outcomes was conducted on the ITT population; however, there was a discrepancy between the number of patients in the ITT population and the reported number of patients at day 510, with the proportion of patients missing from the analysis ranging from 5% to 15% across trials. The resulting missing patients inflated the proportion of patients achieving global lipid targets in both the inclisiran and placebo arms.^13,24,37

Subgroup analyses for efficacy and safety were prespecified in the statistical analysis plan, and missing data were accounted for using the MMRM method but were not adjusted for multiplicity. CIs for most subgroup analyses suggested precision; however, subgroups with a lower number of patients had wider, more imprecise CIs. Subgroups based on risk status (ASCVD or ASCVD-RE) were conducted for the ORION-9 and ORION-11 trials; however, the ASCVD-RE subgroup in the ORION-11 trial was not considered to be of interest, given that it was mostly made up of patients who were not part of the population for which reimbursement was requested by the sponsor (only 11 patients had HeFH and the rest had ASCVD-RE).

External Validity

The ORION-9, ORION-10, and ORION-11 trials aimed to enrol patients with ASCVD and/or ASCVD-RE and specific serum LDL-C and triglyceride cutoffs. ██ ████████ █████ ██ ████████ ████ ██████ █████████ ███ ███ ██ ███████ █████████████ ███ ████ █████ ██ ████████ ███ ████ █████ ███ █████ ██ ██████ ████████ ███ ███ ████ ███ ███████████ █████ █████ █████████ Screening failures and inclusion criteria were considered appropriate for the ORION-10 and ORION-11 trials, given the specified LDL-C cut-points of 1.8 mmol/L and 2.6 mmol/L, which are aligned with current CCS guidelines, and therefore the threat of sampling bias is estimated to be low, given the eligibility criteria. The included patient populations in the ORION studies were mostly reflective of the funding request; however, with the exception of the ORION-10 trial, the ORION trials were multinational trials, and the ORION-9 study was the only study that enrolled patients in Canada (n = 23). The proportion of patients receiving high-intensity statins at baseline was as expected in the HeFH population in the ORION-9 trial (73.9%), as well as in the ASCVD populations in the ORION-10 trial (69.4%) and in the ORION-11 trial (78.0%); however, the clinical expert believed that more patients with HeFH would be receiving ezetimibe than what was seen in the ORION-9 trial (52.3%). Partial or complete intolerance to statins at baseline ranged from 11.4% to 25.3%, which is in line with the proportion of 15% to 20% estimated by the clinical expert. ███ ██████████ ██ ████████ ██ ████ █████ ████ █████ ██ ██ ██████ ████ ████ ████████ ██████ ███████ ███ ███ ████████ ██ ██████ ████████ ███████ ████ ███ ████ █████ ██ ███ ██████████ ██ ███ ██████ The ORION trials excluded patients who experienced MACE in the 3 months before randomization, and the clinical experts believed this made sense, given that the primary outcome was LDL-C, not MACE; given the high risk of recurrence in the short-term (6 months), excluding these patients would eliminate this potential confounder. Additionally, 1 clinical expert believed it to be debatable whether LLT this soon after an event would have any impact on the subsequent risk of clinical events in the short-term. The inclusion criteria for the ORION-9, ORION-10, and ORION-11 studies excluded patients who were currently receiving treatment with PCSK9 monoclonal antibodies or who had received them in the 90 days before screening, and the baseline characteristics of patients in the ORION trials did not include prior treatment with PCSK9 inhibitors. The product monograph for inclisiran states that when transitioning from a PCSK9 inhibitor to inclisiran, the last dose of the PCSK9 inhibitor should be delivered and then, at the next scheduled date, inclisiran can be administered. The effect of switching from other PCSK9 inhibitors to inclisiran on the reduction in LDL-C, CV-related morbidity, and mortality remains uncertain. Despite this, and according to the clinical expert consulted by CDA-AMC, the baseline demographic and medical characteristics of the ORION trials reflect the HeFH and ASCVD populations expected to use inclisiran in Canada.

All ORION trials were placebo-controlled trials and did not include an active comparator, which allows for adequate evaluation of the treatment effect of inclisiran but may overestimate the treatment effects. A demonstration of comparative effectiveness to another PCSK9 inhibitor would have allowed for better interpretation of the efficacy results. Despite this, the clinical expert consulted by CDA-AMC noted that the incremental improvements in LDL-C and the differences between the inclisiran and placebo groups are still clinically meaningful, given that in both the clinical trial and real-world settings, patients with HeFH and/or ASCVD are heavily treated with background medications (e.g., statins, ezetimibe, blood pressure medication, diabetes medications), and therefore the differences seen were still notable. Given that there were no direct comparisons between inclisiran and alirocumab or evolocumab, the 2 available PCSK9 inhibitors available in Canada, the sponsor provided an ITC to address this gap.

The outcomes used to assess the efficacy of inclisiran were chosen based on validated laboratory assessments of lipids, are considered widely accepted surrogates for clinically relevant outcomes, and are reflective and important in guiding treatment decisions in Canadian clinical practice. The duration of the trial (18 months) was also considered appropriate for assessing these outcomes over time, given that trials for PCSK9 inhibitors of alirocumab and evolocumab were 12 weeks to 24 weeks in duration, and effects on lipids are rapidly seen.¹³ However, the included studies were not designed to assess important CV-related outcomes, including reductions in MACE and all-cause and CV-related mortality, as these outcomes were exploratory and not powered for statistical analysis. Across trials, there were no differences between groups and, therefore, there was no cause for concern with these outcomes. However, the impact of inclisiran on these outcomes remains uncertain, and the duration of the trial was considered too short for assessing reductions in these outcomes. Moreover, the product monograph for inclisiran states that the effect of inclisiran on CV morbidity and mortality has not been determined.¹⁷

No HRQoL or patient-reported outcomes were assessed in the ORION trials, and therefore the effect of inclisiran with respect to these outcomes remains unknown.

Long-Term Extension Studies

The contents of this section have been informed by materials submitted by the sponsor. The following information has been summarized and validated by the CDA-AMC review team.

The ORION-3 Trial^31,32

Description of Studies

ORION-3^31,32 is a 4-year, open-label, multicenter extension study of the phase II, 1-year ORION-1 study that was conducted across 52 study sites in 5 countries. The primary objective of this study was to assess the effect of long-term treatment with twice-yearly siRNA therapeutic inclisiran dosing on LDL-C reductions at day 210 compared to baseline. The secondary and exploratory objectives were to assess the effects of inclisiran on cholesterol levels, other lipids levels, and PCSK9 levels up to 4 years in each arm, as well as the long-term safety and tolerability of inclisiran. An additional exploratory objective was to evaluate the effects of transitioning from evolocumab to inclisiran. A total of 382 participants were enrolled from 52 centres in 5 countries: Canada (11), Germany (5), Netherlands (14), the UK (14), and the US (8). In total, 56 patients were enrolled in the study from Canadian centres.

Populations

Patients 18 years and older with prevalent ASCVD or high-risk primary prevention and elevated LDL-C despite MTD statins or other LDL-lowering treatments, or with documented statin intolerance, who had completed 1 year of observation in the ORION-1 trial were eligible for this study. Patients were excluded if they had any uncontrolled or serious medical or surgical condition that reduced life expectancy, had received or were receiving current treatment with a PCSK9 inhibitor, or had recent or planned use of any investigational medicinal products other than inclisiran.

Interventions

Patients who received inclisiran in the ORION-1 trial received twice-yearly 300 mg SC inclisiran sodium throughout the ORION-3 trial (inclisiran-only arm), whereas those who received placebo in the ORION-1 trial received SC evolocumab 140 mg every 2 weeks until day 360 and then transitioned to twice-yearly inclisiran for the remainder of the ORION-3 study (switching arm). Inclisiran was administered as a single SC injection of 300 mg of inclisiran sodium in a 1.5 mL solution by a health care professional at the study site. Evolocumab was self-administered by the patient as a single 1.0 mL SC injection, using a single-use autoinjector containing 140 mg of evolocumab.

Outcomes

The primary efficacy end point was the percentage change in LDL-C with inclisiran from baseline of the ORION-1 trial to day 210 of the ORION-3 trial in the inclisiran-only arm. Secondary and exploratory end points included changes in LDL-C and other lipid parameters up to 4 years in each arm, in addition to individual responses to inclisiran and safety and tolerability outcomes (AEs, SAEs, WDAEs, notable harms).

Statistical Analysis

There was no formal sample-size calculation for this trial. Descriptive statistics, reported as counts and proportions, were used to summarize data. Missing data were not imputed. Patients missing any data required for computing the end point were excluded from the analysis.

As a posthoc analysis, the mean percentage change from the ORION-1 trial baseline in LDL-C averaged over time for the mITT population in the inclisiran-only arm was analyzed for the entire 4-year duration of the ORION-3 trial and for each of the 4 years. The average over time was calculated as the arithmetic mean of the LSM at each study visit, estimated using a MMRM, which included study visits as the fixed effect. For the switching-arm ITT population, the same was analyzed from the ORION-3 trial baseline for year 1, the 3-year period from year 2 to year 4, and each of the previous 3 years. Analyses for the inclisiran-only arm were performed in the ITT and the mITT populations; mITT was the primary population used for presentation whenever available. All patients who received at least 1 dose of inclisiran were included in the safety analysis.

Results

Baseline Characteristics

Baseline characteristics of the inclisiran-only and switching-arm groups in the ORION-3 trial are comparable and are summarized in Table 15.

Table 15: Summary of Baseline Characteristics in the ORION-3 Study

ASCVD = atherosclerotic cardiovascular disease; BMI = body mass index; eGFR = estimated glomerular filtration rate; ITT = intention to treat; LDL = low-density-lipoprotein; mITT = modified intention to treat; SD = standard deviation.

^aFor the inclisiran-only arm, the efficacy baseline is for the mITT population; for the switching arm, the efficacy baseline is for the ITT population. The inclisiran-only arm uses the ORION-1 trial baseline and the switching arm uses the ORION-3 trial baseline.

^bIn the safety population.

Sources: ORION-3 Clinical Study Report,³¹ Ray KK et al. (2023).³²

Patient Disposition

Patient disposition in the treatment arms of the ORION-3 trial is summarized in Table 16. Based on data published for the ORION-1 trial,⁸⁶ of the 483 patients who completed the ORION-1 trial, 382 (79.1%) were enrolled in the ORION-3 trial. Of the 290 patients enrolled in the inclisiran-only arm, 233 (80.3%) completed the study. The primary reason for discontinuation was withdrawal of consent, by 25 (8.6%) patients. Of the 92 patients enrolled in the switching arm, 80 (87.0%) completed the study. The primary reason for discontinuation was also the withdrawal of consent, by 5 (5.4%) patients.

Table 16: Patient Disposition

ITT = intention to treat; mITT = modified intention to treat.

Sources: ORION-3 Clinical Study Report,³¹ Ray KK et al. (2023).³²

Concomitant Medications and Cointerventions

The following medications were permitted during the study: hormone replacement therapy, lipid-lowering medications, prescription medications for the treatment of preexisting medical conditions, and medications to treat an AE at the discretion of the investigator.

There were no required concomitant medications and/or treatments in the ORION-3 trial; however, to be eligible for enrolment in the preceding ORION-1 study, participants must have either been receiving a stable dose of a statin or other LLT. Accordingly, 76% of patients in the inclisiran-only group and 78% of patients in the switching arm were taking a LLT at baseline (Table 17)

Table 17: Summary of LLT Usage During the ORION-3 Trial

LLT = lipid-lowering therapy.

^aNew or changed concomitant LLT is defined as any LLT with a start date after day 1 of the ORION-3 trial.

Source: ORION-3 Clinical Study Report.³¹

Exposure to Study Treatments

There were 1,045.5 PYs of exposure to inclisiran in the inclisiran-only arm during the open-label extension phase, resulting in total cumulative exposure to inclisiran from the beginning of the ORION-1 trial through to the end of the ORION-3 trial of 1,209.6 PYs. The exposure to inclisiran in the switching arm was 250.2 PYs (Table 18). ██ ███████ ██ ███████ █████████ ██ ██████ ███ ████ █████████

Table 18: Patient Exposure (Safety Population Plus Patients Switched to Inclisiran)

IQR = interquartile range; NR = not reported; SD = standard deviation.

Sources: ORION-3 Clinical Study Report,³¹ Ray KK et al. (2023).³²

Efficacy

Percentage Change in LDL-C From Baseline of the ORION-1 Trial to Day 210 of the ORION-3 Trial for the Inclisiran-Only Arm

In the inclisiran-only arm, LDL-C concentrations at day 210 were decreased by 1.56 mmol/L (95% CI, –1.68 to –1.44 mmol/L), reflecting a 47.5% reduction (95% CI, –50.7% to –44.3%) (Table 19). This result was observed approximately 570 days after the first inclisiran exposure in the ORION-1 trial.

Table 19: Change in LDL-C From Baseline in the ORION-1 Trial to Day 210 in the ORION-3 Trial for the Inclisiran-Only Arm

CI = confidence interval; LDL-C = low-density-lipoprotein cholesterol.

Sources: ORION-3 Clinical Study Report,³¹ Ray KK et al. (2023).³²

Secondary Efficacy End Points

Percentage and Absolute Change in LDL-C From Baseline

During the 4 years of the open-label extension, the mean percentage change and mean absolute change in LDL-C concentrations in the inclisiran-only arm ranged between –34.3% and –53.8%, and between –1.13 mmol/L and –1.76 mmol/L, respectively, with the upper limit of the 95% CI at all time points being lower than –30% and excluding 0 (Table 20). The highest reduction was observed for the day 870 to day 900 mean percentage change, at –53.81%.

The mean percentage change and mean absolute change in LDL-C in the switching arm ranged between –38.2% and –65.7%, and between –1.20 mmol/L and –2.00 mmol/L, respectively.

Table 20: Secondary and Exploratory Efficacy End Points of the ORION-3 Trial (Percentage and Absolute Change in LDL-C From Baseline by Treatment Arm and Visit Day^a)

CI = confidence interval; LDL-C = low-density-lipoprotein cholesterol; NA = not applicable.

^aData are n or mean (95% CI).

^bFor the inclisiran-only arm, data were analyzed in the mITT population; for the switching arm, data were analyzed in the ITT population. The inclisiran-only arm uses the ORION-1 trial baseline and the switching arm uses the ORION-3 trial baseline.

^cDay 870 for inclisiran-only arm and day 900 for the switching arm. Per the study protocol, patients in the inclisiran-only arm did not have a day 510 visit, and patients in the switching arm did not have the day 570 visit.

Sources: ORION-3 Clinical Study Report,³¹ Ray KK et al. (2023).³²

Percentage and Absolute Change in Other Efficacy Parameters From Baseline for the Inclisiran-Only Arm

In the inclisiran-only arm, the mean percentage change in total cholesterol ranged from –21.1% to –30.2%, remaining relatively consistent throughout the follow-up period (Table 21). Non-HDL-C, ApoB, and triglycerides also remained consistently decreased throughout the follow-up period. Lp(a) concentration decreased by 16.3% at day 30, with no meaningful changes thereafter.

Harms

AE results are displayed in Table 22. Overall, of the 284 patients in the inclisiran-only arm, 275 (96.8%) patients experienced at least 1 TEAE and 79 (27.8%) patients experienced at least 1 TEAE possibly related to the study drug. A total of 104 (36.6%) patients experienced at least 1 treatment-emergent serious adverse event (TESAE). There were 7 deaths (2.5%) in the inclisiran group, all reported as having no reasonable possibility of being related to the treatment administration by the investigator. Nineteen (6.7%) patients and 12 (4.2%) patients discontinued the study treatment due to TEAEs and TESAEs, respectively.

Table 21: Secondary Efficacy End Points of the ORION-3 Trial (Percentage and Absolute Change in Other Efficacy Parameters From Baseline for the Inclisiran-Only Arm)