CADTH Reimbursement Review

Inclisiran (Leqvio)

Sponsor: Novartis Pharmaceuticals Canada Inc.

Therapeutic area: Primary hypercholesterolemia

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Executive Summary

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

Introduction

Atherosclerotic cardiovascular (CV) diseases (ASCVDs) are a group of disorders of the heart and blood vessels. They are the leading cause of death globally, with an estimated 17.9 million deaths each year.^1-3 CV diseases are generally associated with high blood-cholesterol levels (hypercholesterolemia), resulting in the buildup of cholesterol, specifically low-density lipoprotein (LDL) cholesterol (LDL-C), and fatty deposits inside the arteries leading to atherosclerosis.^3-5

Symptoms of ASCVD depend on the atherosclerotic site and the specific condition; however, typical symptoms of underlying CV issues include pain or pressure, particularly in the chest and/or arms, shortness of breath, lightheadedness or dizziness, cold sweats, and fatigue. More severe manifestations of ASCVD as a result of hypercholesterolemia may include various CV events, such as myocardial infarction (MI) or stroke, which may be fatal.⁵

There are both genetic and acquired or behavioural causes of hypercholesterolemia. Primary hypercholesterolemia can be classified into 2 subtypes: familial hypercholesterolemia (FH) and non-familial hypercholesterolemia (nFH). FH can be further subdivided into heterozygous (HeFH) and homozygous (HoFH) disease, with HoFH being the more severe and rare form of the disease.^6-9

The management of hypercholesterolemia is divided into primary and secondary prevention, where primary prevention is the effort to prevent or delay the onset of ASCVD, while secondary prevention refers to the effort to treat known ASCVD and to prevent or delay the onset of disease manifestations.^10,11

Statins are the primary pharmacological intervention to achieve control of LDL-C in patients with hypercholesterolemia. Most patients with ASCVD should be initiated on the maximum dose of high-intensity statins (atorvastatin or rosuvastatin), with the goal of lowering LDL-C by at least 50%. In cases of primary prevention where the LDL goal is unmet with statin therapy alone, add-on ezetimibe or bile acid sequestrants (or both) is recommended.^10,12,13 Ezetimibe is a cholesterol absorption inhibitor that blocks the absorption of dietary cholesterol and delivery to the liver, resulting in enhanced clearance of LDL-C and further reducing LDL-C by between 10% and 40% (average 20%).¹⁴ In patients with clinical ASCVD, if LDL goals are still not met, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (alirocumab and evolocumab) are available to patients meeting certain criteria as an adjunct treatment to diet, a maximally tolerated dose (MTD) of a statin, and ezetimibe.^8,15

Inclisiran (Leqvio) is a small interfering ribonucleic acid (RNA) conjugated with triantennary N-acetylgalactosamine (GalNAc) to facilitate uptake by hepatocytes and selectively target the liver. Through RNA interference, inclisiran directs catalytic breakdown of PCSK9 messenger RNA, preventing the production of PCSK9 protein and increasing the number of LDL receptors (LDLRs) on hepatocyte surfaces, which results in increased LDL-C uptake and reduction of the LDL-C in circulation. Inclisiran is approved by Health Canada as an adjunct to lifestyle changes, including diet, to further reduce LDL-C levels in adults with HeFH or nFH with ASCVD who are on an MTD of a statin, with or without other LDL-C-lowering therapies.¹⁶

As per the product monograph, the effect of inclisiran on CV morbidity and mortality has not been determined.¹⁶

The objective of the current review is to perform a systematic review of 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 groups that responded to CADTH’s call for patient input and from the clinical expert consulted by CADTH for the purpose of this review.

Patient Input

Two patient groups, the Canadian Heart Patient Alliance (CHPA) and the HeartLife Foundation, provided input for this review. The CHPA is a patient-led non-profit umbrella organization of patients, families, health professionals, and supporters dedicated to reducing CV disease and preventing early death due to cholesterol and other risk factors. Its focus is high cholesterol and other lipids, due to genetic and non-genetic factors, as the leading under-diagnosed and under-treated cause of CV disease and early death. The CHPA is the successor to the FH Canada Patient Network and collaborates with FH Canada, the Heart Healthy Program Prevention Clinic at St. Paul’s Hospital (Vancouver), and the Lipid Genetics Clinic at the London (Ontario) Health Sciences Centre’s University Hospital. The HeartLife Foundation is a patient-driven charity whose mission is to transform the quality of life of people living with heart failure by engaging, educating, and empowering a global community to create lasting solutions and build healthier lives.

The information provided by CHPA was gathered from a total of 262 individuals through an online survey (n = 254) and individual interviews (n = 8). The information provided by the HeartLife Foundation was gathered through discussions held with individual members across Canada. Members include both patients living with heart failure and their family caregivers. The discussions were held as informal group conversations (e.g., via Zoom sessions) or through phone calls with individuals.

About 25% of respondents to the CHPA survey reported regular physical symptoms related to their lipid levels, some minor and some significant, including headaches (like icy picks), chest pains, muscle pains in legs and ankles, shortness of breath, xanthomas (under the skin of the wrists, ankles, or elsewhere), weakness, fatigue, muscle loss, and neuropathy. About 20% also indicated that managing their cholesterol level and keeping it at target was an ongoing challenge; however, 20% said their high cholesterol or other lipid condition had little to no effect on their quality of life. Many reported they had changed their diet and exercise. However, some responses indicated that patients were not always aware of the impact of high cholesterol, in part because they were well managed on treatment and did not experience daily symptoms. Most respondents felt positive about their daily life and had accepted or adapted to living with high cholesterol, including those who have experienced a CV event or have stents. The 2 most frequently mentioned sources of anxiety were:

• uncertainty regarding the effectiveness of the medications or the risk of a CV event in future

• the impact on their children, whether their children had been diagnosed or were at risk.

The majority of respondents to the CHPA survey expressed multiple concerns, largely about treatment schedule, side effects, and the cost of current therapies. For respondents, the most important impact was knowing there was a treatment that could lower their cholesterol levels and keep them closer to target, thereby reducing the risk of further CV events. Public reimbursement for PCSK9 inhibitors in Canada is limited, and access for patients with uncontrolled LDL-C is highly restricted by provincial health benefit program reimbursement criteria.

Clinician Input

Input From the Clinical Expert Consulted by CADTH

According to advice obtained from the clinical expert consulted by CADTH for this review, many patients are unable to meet the pre-specified LDL-C thresholds, outlined in the Canadian Cardiovascular Society (CCS) Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease and the CCS Position Statement on FH, for current treatments, and there is an unmet need for additional treatment options that further reduce LDL-C levels. Statins are considered the standard of treatment for the prevention of ASCVD in high-risk patients and patients with FH or severe hypercholesterolemia; however, the clinical expert pointed out that up to 15% of patients are partially or completely intolerant to statins.

It was also emphasized by the clinical expert that the CCS guidelines should be used as a basis for recommendation in identifying and treating patients (in patients with HeFH without clinical ASCVD whose LDL-C remains above the target LDL-C level of at least 2.5 mmol/L or less than 50% reduction from baseline despite MTD statin therapy with or without ezetimibe therapy, or patients with HeFH and ASCVD whose LDL-C remains above at least 1.8 mmol/L despite MTD statin therapy, with or without ezetimibe), and that suitable patients should match the characteristics of the patients enrolled in the clinical trials included in this review. The clinical expert indicated that the patients least suitable for treatment with the drug under review were those with low-risk ASCVD, patients with low-risk severe hypercholesterolemia that is well controlled with statins, patients with ASCVD who are at their LDL-C goals with current therapies, patients with nFH above a certain age where the treatment would be for primary prevention, and patients with multiple comorbidities that limit lifespan.

The clinical expert stated that the percentage reduction in LDL-C and the absolute level of LDL-C achieved are outcomes used in clinical practice to determine response to treatment. The clinical expert indicated that treatment response should be assessed every 6 months, then yearly. The patients considered most likely to exhibit a response to treatment with inclisiran, according to the clinical expert, were those that achieved a 30% to 40% reduction in LDL-C from baseline levels (while on an optimized statin, with or without ezetimibe therapy) but require further lowering of LDL-C. The clinical expert stated that age, end-stage disease, and/or dementia are important factors that should be considered when deciding to discontinue treatment.

Clinician Group Input

A group of clinicians consisting of lipid specialists working in lipid clinics in British Columbia, including the Healthy Heart Program Prevention Clinic at St. Paul’s Hospital, the lipid clinic at Surrey Memorial Hospital, and the Victoria Lipid Clinic, provided input for this review.

The clinician group noted the tolerability of current treatments, compliance, ability to treat to targeted lipid levels, and accessibility as the current unmet needs in treating patients with HeFH and/or ASCVD. The clinician group described an ideal treatment option as 1 that would reduce levels of LDL-C, non-HDL-C, and apolipoprotein B (ApoB); reduce the risk of major adverse cardiovascular events (MACEs) and CV mortality, and be safe and well tolerated, with properties that promote adherence.

The clinician group noted that patients with the greatest unmet need for intervention are those with HeFH, patients with statin intolerance, and patients with ASCVD with other markers of high risk (e.g., multi-vessel disease, polyvascular disease, diabetes, elevated lipoprotein [a]). Finally, they noted the patients least suitable for treatment with the drug under review would be patients who do not have an indication for the therapy, patients who have achieved LDL targets on other therapies (a statin with or without ezetimibe), and patients who have not attempted a statin.

The clinician group noted that inclisiran may displace other PCSK9 inhibitors as an add-on to statins and ezetimibe if it is more accessible than current treatments and depending on the results of currently ongoing CV outcome trials. It may also fill a void if it is approved for secondary prevention in high-risk patients.

Drug Program Input

The questions the drug plans submitted to the clinical expert for clarification focused on the definitions of specific populations and the variability in treatment according to Canadian guidelines. The clinical expert consulted by CADTH for this review indicated that, overall, initiation criteria for inclisiran may follow that of other PCSK9 inhibitors, with patients first receiving MTD statins followed by ezetimibe, if they are within 20% of their LDL-C target, or PCSK9 if their distance to target is greater than 20%. The cut-point targets of 2.6 mmol/L (> 2.5 mmol/L) for HeFH and 1.8 mmol/L for patients with ASCVD are reflective of the guidelines for these populations. The drug plans were also concerned whether laboratory assessments were appropriate outcomes for assessing effectiveness in the real world. The clinical expert noted that LDL-C, ApoB, and non-HDL-C are guideline-recommended biomarkers for CV outcomes. It was also noted that inclisiran may follow the same initiation and renewal criteria as the currently available PCSK9 inhibitors, and that the occurrence of cardiac events would not warrant discontinuation. Lastly, the drug programs were concerned with whether or not inclisiran would be used in patients who do not have hypercholesterolemia or who had not had a prior heart attack or stroke (i.e., for primary prevention). The clinical expert noted that elevated LDL-C can be caused by other diseases, and that these should be addressed separately and are therefore not within the context of this review.

Clinical Evidence

Pivotal Studies and Protocol Selected Studies

Description of Studies

A total of 3 studies were included in this review: ORION-9, ORION-10, and ORION-11.^17-19 The included studies were all phase III, double-blind, randomized controlled trials (RCTs) comparing inclisiran with placebo in patients with HeFH or ASCVD (or with an ASCVD risk equivalent, i.e., diabetes, FH, or a 20% or greater 10-year risk of a CV event as assessed by the Framingham Risk Score for CV disease or equivalent) who were receiving MTD statins or were statin-intolerant. Patients in the ORION-9 trial were adults (≥ 18 years) with a history of HeFH (with a diagnosis of HeFH 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, or elevated cholesterol or early heart disease, which may indicate FH. Patients enrolled in the ORION-10 trial were adults (≥ 18 years) with a history of ASCVD, and patients enrolled in the ORION-11 trial were adults (≥ 18 years) with a history of ASCVD or with an ASCVD risk equivalent. In all 3 ORION studies, patients were randomized 1:1 to either inclisiran sodium 300 mg or placebo, in addition to MTD statin. The ORION-9, −10, and −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 (1 each on day 1, day 90, day 270, and day 450). The primary outcome of the ORION-9, −10, and −11 trials was the percentage change in LDL-C from baseline to day 510. In all trials, the co-primary end point was the average percentage change in LDL-C from baseline over the period after day 90 up to day 540, reflecting the start of the twice-yearly dosing regimen. Incidences of CV death, resuscitated cardiac arrest, non-fatal MI, non-fatal stroke (ischemic and hemorrhagic) were exploratory outcomes in the ORION trials within the composite outcome of MACEs, and total deaths was a secondary outcome reported as adverse events (AEs) in the ORION studies.

Baseline characteristics were well balanced across groups in each trial. In ORION-9, patients were mostly White (94.0%) with a median age of 56 years, and more than half of the patients were female (52.9%). CV risk factors were balanced between the treatment groups. Overall, 350 patients (72.6%) had an ASCVD risk equivalent and 132 (27.4%) had ASCVD. A total of 356 patients (73.9%) were treated with high-intensity statins at baseline, and just more than half were treated with ezetimibe. Partial or complete intolerance to statins was reported in 122 patients (25.3%).¹⁷ In ORION-10, patients were mostly White (85.7%) and male (69.4%), with a median age of 67 years. All patients had ASCVD, and most had coronary heart disease (CHD) (91.1%). A total of 1,084 patients (69.4%) were on high-intensity statins at baseline, and 156 patients (9.9%) were treated with ezetimibe. Partial or complete intolerance to statins was reported in 344 patients (22.0%).¹⁸

In ORION-11, patients were mostly White (98.1%) and male (71.7%), with a median age of 65 years. CV risk factors were balanced between the treatment groups; 1,414 (87.4%) had ASCVD and 203 (12.6%) had an ASCVD risk equivalent. The non-HeFH, ASCVD risk–equivalent population from ORION-11 was not of interest to this review, as these patients were not included in the funding request. Overall, 1,261 patients (78.0%) were on a high-intensity statin at baseline. A total of 114 patients (7.1%) were treated with ezetimibe. Partial or complete intolerance to statins was reported in 185 patients (11.4%).¹⁹

Efficacy Results

All-cause and CV-related mortality were assessed as AEs in the ORION-9, −10, and −11 trials, and were reported as the incidence of death within the safety population. In ORION-9, only 2 deaths occurred (0.4%), 1 in each treatment group.¹⁷ 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.¹⁸ In total, 29 patients (1.8%) died during the ORION-11 study, 14 (1.7%) in the inclisiran group, and 15 (1.9%) in the placebo group.¹⁹ Most frequently, deaths were related to cardiac disorders as a system organ class, ranging from 1 patient (0.4%) to 7 patients (0.9%) in the ORION-9, −10, and −11 trials.^17-19

Although not referred to as CV-related morbidity in the ORION trials, for the purposes of this review, the incidence of MACEs and its composite components were considered CV-related morbidity and it was an exploratory outcome of the ORION trials. No between-group comparisons were conducted in the ORION-9, −10, or −11 trials for this outcome. The incidence of MACEs in the inclisiran groups was consistently similar to or lower than in the placebo groups across all trials (4.1% versus 4.2%, 7.4% versus 10.2%, and 7.8% versus 10.3%, in ORION-9, −10, −11, respectively). Non-fatal MI was the most frequently occurring individual event across all trials, occurring in 3.7% versus 4.2%, 5.1% versus 8.2%, and 5.8% versus 8.5% of patients in the inclisiran and placebo groups of ORION-9, −10, and −11, respectively.^17-19 No resuscitated cardiac arrests or stroke events occurred in the ORION-9 trial.¹⁷ Other CV-related morbidities of interest to this review, including hospitalizations and minimally invasive CV interventions, were not reported in the ORION trials.

The primary efficacy end point in the ORION-9, −10, and −11 trials was the percentage change in LDL-C from baseline to day 510. In all ORION trials, inclisiran reduced LDL-C levels from baseline to day 510: −41.15% in ORION-9 (95% confidence interval [CI], −44.52 to −37.77), −56.34% in ORION-10 (95% CI, −58.35 to −54.34), and −49.3% in ORION-11 (95% CI, −51.22 to −47.48), while the change from baseline LDL-C levels increased with placebo: 8.37% in ORION-9 (95% CI, 3.96 to 12.77), 1.30% in ORION-10 (95% CI, −1.24 to 3.83), and 4.2% in ORION-11 (95% CI, 1.62 to 6.69).^17-19 Between-group differences were statistically significant in favour of inclisiran in all studies with differences from placebo of −49.52 (95% CI, −55.04 to −43.99) in ORION-9, −57.64 (95% CI, −60.86 to −54.43) in ORION-10, and −53.5 (95% CI, −56.66 to −50.35) in ORION-11 (P < 0.0001 for all).^17-19 The clinical expert consulted by CADTH considered the between-group differences in LDL-C levels to be clinically meaningful.

Results for key secondary outcomes in the ORION trials of absolute change in LDL-C from baseline to day 510, time-adjusted change in LDL-C from baseline after day 90 up to day 540, and percentage change from baseline to day 510 in total cholesterol, ApoB, and non-HDL-C were consistent with the co-primary end points. For absolute change in LDL-C from baseline to day 510, inclisiran displayed a larger absolute reduction in LDL-C: −58.95 mg/dL in ORION-9 (95% CI, −64.75 to −53.15), −56.18 mg/dL in ORION-10 (95% CI, −58.47 to −53.90), and −50.91 mg/dL in ORION-11 (95% CI, −53.14 to −48.67). The between-group differences were statistically significant in favour of inclisiran in all studies: −68.89 mg/dL in ORION-9 (95% CI, −77.11 to −60.67), −54.12 mg/dL in ORION-10 (95% CI, −57.37 to −50.88), and −51.87 mg/dL in ORION-11 (95% CI, −55.01 to −48.72) (P < 0.0001 for all). In all trials, inclisiran was associated with greater absolute reductions in LDL-C from baseline after day 90 and up to day 540: −56.58 mg/dL (95% CI, −60.98 to −52.17) versus 6.17 mg/dL (95% CI, 1.72 to 10.62) in ORION-9, −53.66 mg/dL (95% CI, −55.41 to −51.92) versus −0.39 mg/dL (95% CI, −2.14 to 1.37) in ORION-10, and −48.63 mg/dL (95% CI, −50.37 to −46.89) versus 0.31 mg/dL (95% CI, −1.42 to 2.04) in ORION-11. The mean difference between inclisiran and placebo was statistically significant in all trials (P < 0.0001). Lastly, results for percentage change in total cholesterol, ApoB, and non-HDL-C showed greater percentage changes for the inclisiran groups in all studies, and the mean difference from placebo was statistically significant in all cases (P < 0.0001).^17-19

Other outcomes of interest to this review, including health-related quality of life (HRQoL) and neurocognitive assessments, were not included in the ORION trials.

Harms Results

The incidence of treatment-emergent adverse events (TEAEs) was consistent between inclisiran- and placebo-treated patients as well as across trials, with patients experiencing at least 1 TEAE (76.8% versus 71.7%, 73.5% versus 74.8%, and 82.7% versus 81.5% in ORION-9, −10, and −11, respectively).^17-19 There was no difference in the frequency of treatment-emergent serious adverse events (SAEs) between the treatment groups in ORION-9, −10, and −11. Treatment-emergent SAEs in ORION-9 occurred in 7.5% of inclisiran-treated patients and 13.8% of placebo-treated patients.¹⁷ In ORION-10 and −11, SAEs occurred in 22.4% and 22.3% of inclisiran-treated patients compared with 26.3% and 22.5% of placebo-treated patients.^18,19 In ORION-9, 1.2% of patients in the inclisiran group withdrew due to an AE, while no patients in the placebo group withdrew due to AEs.¹⁷ The incidence of withdrawal due to adverse events (WDAEs) in ORION-10 and −11 were similar, with 2.4% and 2.8% of inclisiran-treated patients and 2.2% of placebo-treated patients in each trial withdrawing due to AEs, respectively.^18,19

No difference in either neurologic events or neurocognitive disorders was observed between inclisiran and placebo in any of the ORION trials; however, the incidence was higher in all placebo groups. In all trials, fewer placebo-treated patients reported TEAEs at the injection site compared with those treated with inclisiran. Injection-site reactions were mild to moderate, and no severe reactions were seen across trials. There were no differences between inclisiran and placebo for other notable harms of hypersensitivity reactions, renal safety, or hepatic safety.^17-19

Critical Appraisal

ORION-9, ORION-10, and ORION-11 were all phase III, double-blind RCTs. There were no notable differences in baseline characteristics within the studies. Given the higher incidence of injection-site reactions in the inclisiran group, it may have been possible to reveal treatment assignment, and it is unclear what effect this would have had on the results; however, it is considered minimal, given the objective nature of the study outcomes. There were no apparent imbalances in discontinuations that may have led to unblinding. Screening failures and inclusion criteria were considered appropriate for the ORION 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. The included patient populations in the ORION studies were mostly reflective of the population for which reimbursement was requested; however, ORION-11 included a proportion of patients with ASCVD-risk equivalences (13%), which were not part of the reimbursement population requested by the sponsor. All ORION trials were placebo-controlled studies; therefore, they lacked comparison to a relevant treatment, increasing the risk of bias in the estimation of treatment effects.

Acceptable methods to account for multiplicity were used in all trials for the co-primary and key secondary efficacy end points. Other secondary and exploratory end points, including CV-related mortality and morbidity, which were of importance to this review, were not controlled for multiplicity; thus, they need to be interpreted with consideration of type I error. Given the large number of comparisons in the study, a statistically significant finding may be attributable to an inflated type I error.

The ORION trials were based on lipid and lipoprotein efficacy outcomes that are well recognized and widely accepted surrogate end points for CV-related outcomes. The clinical expert consulted by CADTH noted that the incremental improvements in LDL-C and the differences between the inclisiran and placebo groups are still clinically meaningful, given that patients are heavily treated with other therapies in both clinical trials and real-world settings. However, important outcomes, including reductions in CV-related morbidity (CV death, MI, stroke, resuscitated cardiac arrest, non-fatal MI, and non-fatal stroke) or the composite of MACEs as well as all-cause and CV-related mortality, were exploratory and not powered for statistical analysis; thus, the impact of inclisiran on these outcomes remains uncertain. Moreover, the duration of the studies (18 months) was not sufficient to measure these outcomes. No HRQoL or patient-reported outcomes were assessed in the ORION trials; therefore, the effect of inclisiran with respect to these outcomes remains unknown.

One outcome considered important to patients was a more appropriate dosing regimen. The majority of patients in the ORION trials completed the study ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. In comparison with current PCSK9 inhibitors, which require injections every 2 weeks, inclisiran is a twice-yearly injection administered by a health care professional. The clinical expert consulted by CADTH for this review indicated that this rate of injection may improve adherence relative to current PCSK9 inhibitors.

Indirect Treatment Comparisons

Description of Studies

The sponsor submitted an indirect treatment comparison (ITC) that compared the efficacy of inclisiran with relevant drug comparators in patients with HeFH or ASCVD (or an ASCVD risk equivalent). The objective of the sponsor-submitted report was to conduct a feasibility assessment through a systematic review of the literature and, if possible, to conduct an ITC 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 an ASCVD risk equivalent).²⁰

The sponsor-submitted ITC was informed by a systematic review of RCTs conducted in April 2020. Thirty-nine studies met the inclusion criteria of the review and feasibility assessment, and 22 studies were sub-selected for inclusion in the ITC based on network connectivity and homogeneity in study characteristics, patient characteristics, or outcomes that were likely modifiers of the relative treatment effects.²⁰

The analyses were conducted using a network meta-analysis (NMA). A selection of both fixed and random effects was conducted for outcomes of interest. Random-effects analyses were selected as the base case, given the number of studies per node and observed heterogeneity in patient and trial characteristics. Three network scenarios were conducted: HeFH patients on an MTD statin, patients with ASCVD or an ASCVD risk equivalent on an MTD statin, and patients with ASCVD or an ASCVD risk equivalent who are intolerant to statins. Efficacy outcomes included the percentage, absolute, and time-adjusted change from baseline in LDL-C and percentage change from baseline in HDL-C, and safety outcomes included total discontinuations and discontinuations due to AEs.²⁰

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 risk–equivalent populations on MTD statins, where 1 closed loop was formed, and 7 trials were included in the network for ASCVD and ASCVD risk–equivalent populations intolerant to statins. In the HeFH population on MTD statins, there was no difference between inclisiran and alirocumab or evolocumab for any efficacy and safety outcomes. In the network for ASCVD and ASCVD risk–equivalent populations on an MTD statin, inclisiran was favoured over ezetimibe for efficacy outcomes related to LDL-C; however, there was no difference between inclisiran and alirocumab or evolocumab for any efficacy or safety outcomes. In the network for ASCVD and ASCVD risk–equivalent populations intolerant to statins, inclisiran was favoured over ezetimibe for efficacy outcomes related to LDL-C but not for safety outcomes. There was no difference between inclisiran and alirocumab or evolocumab in any efficacy or safety outcomes.

Critical Appraisal

There were several limitations with the key assumptions made in the NMA approach with regard to background statin use and the time of assessment of outcomes. This impacted the clinical and methodological heterogeneity, thus limiting the interpretability and generalizability of the results. Though 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 that the use of statins would not bias the results of the NMA; however, based on discussions with the clinical expert consulted by CADTH, this was 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; therefore, no attempt was made to adjust for differences in baseline characteristics due to the number of studies and the inconsistent reporting of characteristics. The NMA used 24 weeks as the time of assessment, which was considered acceptable for lipid and lipoprotein outcomes. End-of-study 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 time of assessment was 24 weeks, may undermine true treatment effects. Additionally, given the twice-yearly dosing regimen of inclisiran, a an assessment at 24 weeks may be insufficient to assess safety outcomes compared with the every-2-weeks 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, the data imputation analysis methods, and the specific background treatments allowed and/or delivered. Unidentified or unknown methodological or clinical (particularly treatment-effect modifiers) heterogeneity needs 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.

Other Relevant Evidence

Two additional relevant studies (ORION-4 and ORION-8) were noted in the sponsor submission and identified in the CADTH screening of clinical trial databases. At the time of this review, no results were available for either of the studies. As such, ORION-4 and ORION-8 were not included in the available evidence discussed earlier. ORION-4 aims to evaluate the efficacy of inclisiran on the number of patients with the major CV events of CHD, MI, fatal or non-fatal ischemic stroke, or urgent coronary revascularization procedure, or the composite of CHD death or MI, and the number of CV deaths in patients with ASCVD. ORION-8 is an extension study of the ORION-5, −9, −10, and −11 trials to evaluate the long-term efficacy, safety, and tolerability of inclisiran in patients with ASCVD, an ASCVD risk equivalent, HeFH, or HoFH who still had elevated LDL-C despite maximally tolerated LDL-C-lowering therapies. Results of these trials are expected to provide further evidence to better characterize the efficacy profile of inclisiran in pertinent clinical outcomes and provide long-term efficacy and safety data for inclisiran.

Conclusions

In all 3 ORION studies, inclisiran demonstrated a statistically significant and clinically meaningful change compared with placebo in the co-primary end points of change in LDL-C from baseline at day 510, and time-adjusted change from baseline after day 90 up to day 540 in patients with HeFH, ASCVD, and ASCVD or an ASCVD risk equivalent, respectively. Results of the key secondary end points were in line with the primary outcome. Together, the lipid and lipoprotein efficacy outcomes were appropriate, and are reflective of clinical practice in Canada. The combined percentage change and absolute change in LDL-C from baseline, as well as the ApoB and non-HDL-C measurements, are guideline-specific and relevant in diagnosing and treating HeFH and ASCVD. None of the ORION studies assessed HRQoL; thus, the effect of inclisiran on HRQoL is uncertain.

Overall, treatment with inclisiran was well tolerated over the study period. Inclisiran did not appear to be associated with more AEs or SAEs compared with placebo. Known AEs of interest, such as injection-site reactions, were more frequent in the inclisiran group; however, there were no concerns. Although the sponsor submitted an ITC evaluating inclisiran and appropriate comparators in the treatment of HeFH and ASCVD, the results of the indirect evidence for the outcomes evaluated were inconclusive on the efficacy and safety of inclisiran compared with relevant treatments. In addition, the sponsor-submitted ITC provides minimal value to assess efficacy compared with either ezetimibe or the other available PCSK9 inhibitor, as it did not evaluate clinical outcomes.

The ORION-9, −10, and −11 trials were not designed to compare between treatment groups for outcomes of critical importance to the review: mortality (all-cause and CV-related) and CV-related morbidity (resuscitated cardiac arrest, non-fatal MI, non-fatal stroke, and MACE); however, there was no apparent difference between inclisiran and placebo. The short follow-up duration of the ORION trials (18 months) did not allow for adequate evaluation of these outcomes. Longer follow-up data obtained from the ORION-8 trial, combined with results from the ORION-4 trial, will provide important insight into the efficacy of inclisiran in reducing CV-related morbidity and mortality.

Introduction

Disease Background

ASCVDs are a group of disorders of the heart and blood vessels. They are the leading cause of death globally, with an estimated 17.9 million deaths each year.^1-3 CV diseases are generally associated with high blood-cholesterol levels (hypercholesterolemia) resulting in the buildup of cholesterol, specifically LDL-C, and fatty deposits inside the arteries leading to atherosclerosis.^3-5 Changes in the endothelial cell lining of the arterial wall lead to an accumulation of lipoproteins and inflammatory cells, resulting in the formation of an atherosclerotic lesion or plaque, which narrows the arterial lumen reducing blood flow. ASCVDs consist of coronary artery disease, cerebrovascular disease, and peripheral artery disease (PAD).

Symptoms of ASCVD depend on the atherosclerotic site and the specific condition; however, typical symptoms of underlying CV issues include pain or pressure, particularly in the chest and/or arms, shortness of breath, lightheadedness or dizziness, cold sweats, and fatigue. More severe manifestations of ASCVD as a result of hypercholesterolemia may include various CV events such as MI or stroke, which may be fatal.⁵

There are both genetic and acquired or behavioural causes of hypercholesterolemia. Primary hypercholesterolemia can be classified into 2 subtypes: FH and nFH. FH is associated with a specific underlying genetic defect resulting in elevated LDL-C levels from birth that persist throughout life and can lead to the early development of atherosclerosis, while nFH is associated with several genetic interactions as well as dietary and lifestyle risk factors. FH can be further subdivided into HeFH and HoFH disease, with HoFH being the more severe and rare form of the disease.^6-9 About 60% to 80% of people with FH have genetic mutations in 1 of 3 known genes: under-expression or alteration of LDLRs of hepatocytes, which encode clearance of LDL and account for approximately 85% of FH cases; defective ApoB resulting in a loss of ligand binding to LDLRs; and a gain-of-function mutation in PCSK9 resulting in more rapid degradation of LDLRs, which increases plasma LDL-C levels and which account for 5% and less than 2% of cases, respectively.^21-24 The general incidence and prevalence of HeFH is likely underestimated, yet it is still believed to affect 30 million people worldwide, or 1 in 311 people, and may be higher in certain groups,^25,26 particularly founder populations of French Canadians. There are an estimated 145,000 patients with FH in Canada.^{6,15,22,27,28}

Hypercholesterolemia and ASCVD are diagnosed by a thorough physical examination, analysis of medical and family history and risk factors, and an array of laboratory tests (e.g., electrocardiogram, echocardiogram, stress tests, and cardiac catheterization) and imaging (CT, MRI). The exact cause of ASCVD remains unclear; however, there are numerous well-known risk factors that increase the chances of developing the disease. Although not the sole cause of ASCVD, elevated LDL-C is the major causal and most readily modifiable factor in developing the disease.²⁹ Other risk factors include hypertension, smoking, diabetes, being overweight or obese, and a family history of CV disease.

Hypercholesterolemia can be defined as LDL-C greater than 190 mg/dL (> 4.9 mmol/L) or greater than 160 mg/dL (> 4.1 mmol/L) with 1 major risk factor, or greater than 130 mg/dL (> 3.4 mmol/L) with 2 CV risk factors.²² In general, LDL-C levels in adult patients with HeFH are greater than 4.9 mmol/L. A clinical diagnosis of FH is made based on high plasma levels of LDL-C, family history of hypercholesterolemia, a history of premature ASCVD, and the presence of tendon xanthomas.^15,30 Left untreated, 50% of men with FH will experience an MI by the age of 50, and 30% of women by the age of 60.²⁴ A reduction of 1 mmol/L (approximately 38.67 mg/dL) in LDL-C is estimated to reduce the relative risk of ASCVD by 20% to 22%.³¹

Multiple diagnostic criteria for FH exist; however, the CCS recommends the proposed criteria developed by FH Canada (Figure 1).^8,27,32 A diagnosis of FH should be considered in patients with a baseline LDL-C of 5 mmol/L or greater for patients who are at least 40 years of age (or LDL-C ≥ 4.0 mmol/L for age < 18 years, or LDL-C ≥ 4.5 mmol/L for age ≥ 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.²⁷ Genetic testing is not necessary for diagnosis, and approximately 30% of patients with a definitive diagnosis of HeFH do not display a monogenic variant.³³ The clinical expert consulted by CADTH for this review indicated that genetic testing through next-generation sequencing is not routinely available in Canadian provinces but is available in Quebec.

The 2021 dyslipidemia guidelines in Canada recommend both non-high-density lipoprotein cholesterol (non-HDL-C) and ApoB as lipid-screening parameters to improve risk stratification and management of ASCVD. In addition to LDL-C levels, both non-HDL-C and ApoB levels provide an additional assessment of the total concentration of atherogenic particles. Non-HDL-C and ApoB levels are both predictors of CV event risk and benefit from lipid-lowering therapy. Non-HDL-C is routinely reported across Canada at no additional cost, based on the simple calculation of total cholesterol minus HDL-C, and ApoB testing is available as an insured laboratory test in all provinces except Ontario.¹¹

Figure 1: Proposed Canadian Definition of FH

ASCVD = atherosclerotic cardiovascular disease; APOB = apolipoprotein B gene; FH = familial hypercholesterolemia; LDL-C = low-density lipoprotein cholesterol; LDLR = low-density lipoprotein receptor gene; PCSK9 = proprotein convertase subtilisin/kexin type 9 gene.

* Secondary causes of high LDL-C should be ruled out (severe or untreated hypothyroidism, nephrotic syndrome, hepatic disease [biliary cirrhosis], and 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 ClinVar database, Human Gene Mutation Database, or Western Database of Lipid Variants in the proband or a first-degree relative.

Source: Ruel et al.³⁴

Standards of Therapy

The management of hypercholesterolemia is divided into primary and secondary prevention, where primary prevention is the effort to prevent or delay the onset of ASCVD, while secondary prevention refers to the effort to treat known ASCVD.¹⁰ The condition of FH is associated with premature death and complications due to accelerated development of ASCVD.³⁵

Early detection of FH is important to reduce the risk of CV events and, as such, initial non-pharmacological interventions for hypercholesterolemia include diet and lifestyle modifications. The lowering of plasma cholesterol levels is known to reduce CV events, CHD mortality, and all-cause mortality.³⁶ Recommended lifestyle modifications, as per the CCS guidelines on the diagnosis and treatment of dyslipidemias, include weight control, reducing the amount of fat to less than 30% of daily calories, consuming 10 g to 20 g of fibre per day, and increased physical activity. Additional lifestyle changes include smoking cessation and limiting alcohol intake.^8,12 Lifestyle and diet changes alone are unlikely to achieve LDL-C goals (estimated reduction in LDL-C concentration of 10% to 15%), and most patients will require pharmacological intervention.^8,14,37

In addition to the recommended lifestyle changes, statins are the primary pharmacological intervention to achieve control of LDL-C in patients with hypercholesterolemia. Most patients with ASCVD should be initiated on the maximum dose of high-intensity statins (atorvastatin or rosuvastatin) with the goal of lowering LDL-C by at least 50%. Lower-intensity statins (reduced dose of atorvastatin or rosuvastatin, or simvastatin or pravastatin), which lower LDL-C by approximately 30%, should be used only in the elderly or frail or those unable to tolerate high-intensity statins.¹⁰ In cases of primary prevention where the LDL goal is unmet with statin therapy alone, add-on ezetimibe or bile acid sequestrants (or both) is recommended.^10,12,13 Ezetimibe is a cholesterol absorption inhibitor that blocks the absorption of dietary cholesterol and its delivery to the liver, resulting in enhanced clearance of LDL-C, further reducing LDL-C between 10% to 40% (average 20%).¹⁴

In patients with ASCVD, if LDL goals are still not met, PCSK9 inhibitors (alirocumab and evolocumab) are available to patients meeting certain criteria as an adjunct treatment to diet, MTD, and ezetimibe.^8,15 In patients with HeFH without ASCVD, Canadian guidelines recommend initiation of a PCSK9 inhibitor to lower LDL-C in patients whose LDL-C remains above the target (i.e., LDL-C ≥ 2.5 mmol/L or < 50% reduction from baseline, or ApoB ≥ 0.85 mg/dL or non-HDL-C ≥ 3.2 mmol/L) despite MTD statin therapy with or without ezetimibe therapy. In patients with HeFH and established ASCVD, PCSK9 inhibitors are to be initiated in those whose LDL-C remains above the threshold of 1.8 mmol/L or greater (or ApoB ≥ 0.7 mg/dL or non-HDL-C ≥ 2.4 mmol/L) despite MTD statin therapy, with or without ezetimibe.¹¹ The addition of PCSK9 inhibitors can lower LDL-C up to 60% for those on statin therapy.²² Reimbursement for both alirocumab and evolocumab are variable in Canada, with most provinces funding them as limited-use options.

Drug

Inclisiran (Leqvio) is a small interfering RNA conjugated with GalNAc to facilitate uptake by hepatocytes and selectively target the liver. Through RNA interference, inclisiran directs catalytic breakdown of PCSK9 messenger RNA, preventing the production of PCSK9 protein and increasing the amount of LDLR on hepatocyte surfaces, which results in increased LDL-C uptake and reduction of the LDL-C in circulation (Figure 2).

Figure 2: Inclisiran Mechanism of Action

ASGPR = asialoglycoprotein receptor; GalNAc = triantennary N-acetylgalactosamine; mRNA = messenger ribonucleic acid; PCSK9 = proprotein convertase subtilisin/kexin type 9; RISC = RNA-induced silencing complex; RNA = ribonucleic acid.

Source: Sponsor submission.¹⁶

Inclisiran is administered subcutaneously by a health care professional (doctor, nurse, pharmacist) in a single 1.5 mL pre-filled syringe (equivalent to 300 mg inclisiran sodium). The recommended dose of inclisiran is 284 mg, initially and again at 3 months, followed by every 6 months thereafter.¹⁶

Inclisiran is indicated by Health Canada as an adjunct to lifestyle changes, including diet, to further reduce LDL-C levels in adults with HeFH or nFH with ASCVD who are on an MTD statin, with or without other LDL-C-lowering therapies.¹⁶ The Health Canada Notice of Compliance was granted on July 26, 2021. The European Medicines Agency granted marketing authorization to inclisiran on December 11, 2020 for the treatment of adults with hypercholesterolemia or mixed dyslipidemia. The FDA issued a complete response letter for inclisiran stating that it could not approve the new drug application due to unresolved facility inspection–related conditions at the third-party manufacturing facility. Resubmission to the FDA was conducted in July 2021, and was approved by the FDA in December 2021.³⁸

The sponsor is requesting that inclisiran be reimbursed as an adjunct to diet and maximally tolerated statin therapy, with or without other lipid-lowering therapies, in adult patients with HeFH or clinical ASCVD who require additional lowering of LDL-C.

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups.

About the Patient Groups and Information Gathered

Two patient groups, the CHPA and the HeartLife Foundation, provided input for this review. The CHPA is a patient-led non-profit umbrella organization of patients, families, health professionals, and supporters dedicated to reducing CV disease and preventing early death due to cholesterol and other risk factors. Its focus is high cholesterol and other lipids, due to genetic and non-genetic factors, as the leading under-diagnosed and under-treated cause of CV disease and early death. The CHPA is the successor to the FH Canada Patient Network and collaborates with FH Canada, the Heart Healthy Prevention Program at St. Paul’s Hospital in British Columbia, and the Lipid Genetics Clinic at the London (Ontario) Health Sciences Centre’s University Hospital. The HeartLife Foundation is a patient-driven charity whose mission is to transform the quality of life of people living with heart failure by engaging, educating, and empowering a global community to create lasting solutions and build healthier lives.

The information provided by CHPA was gathered from a total of 262 individuals through an online survey (n = 254) and individual interviews (n = 8). The web-based English survey was conducted through Survey Monkey from March 18 to April 3, 2021, with a 95% completion rate. The 8 individual interviews were conducted by telephone or Zoom calls, with 6 calls in English and 2 in French. Request for participation in the survey was distributed mainly through the CHPA mailing list, the St. Paul’s Hospital Healthy Heart Program FH patient list, and various social media channels. About 95% of respondents identified themselves as residing in Canada: 61% in British Columbia, 19% in Ontario, 8% in Quebec, 3% in Alberta, and 4% in Manitoba, Saskatchewan, and Yukon. The remaining 5% were residing internationally. The online survey was directed to patients and family members affected by “high lipids,” including HeFH and ASCVD. Overall, 51% of survey respondents indicated they or a family member were affected by HeFH. A small proportion of patients identified as having HoFH (4%), symptoms but not diagnosed with FH (9%), a family history of FH (5%), ASCVD (6%), or other lipid disorders (7%). A total of 13% said they were awaiting diagnosis, unsure, or had multiple indications. The mean age of the patients (not respondents) was 59 years, and the median age was 61 years.

The information provided by the HeartLife Foundation was gathered through discussions held with their members across Canada. Members include both patients living with heart failure and their family caregivers. The discussions were held as informal group conversations (e.g., via Zoom sessions) or through phone calls with individuals. Information was gathered from a total of individuals who were between the ages of 35 and 70.

Disease Experience

As part of the online survey by CHPA, participants were asked an open-ended question regarding the impact of living with high cholesterol, high lipids, or CV disease. Approximately 95% of respondents had received or were still receiving treatment for their condition, with about 90% reporting their LDL-C level as well managed. Of note, CHPA mentioned that these respondents are probably better managed than most patients. About 80% of patient respondents were part of a CV program and received regular follow-up care by a specialist or their family physician. The responses were categorized under several non-exclusive themes:

• Symptoms: About 25% reported regular physical symptoms related to their lipid levels or condition, some minor and some significant, including headaches (like icy picks), chest pains, muscle pains in legs and ankles, shortness of breath, xanthomas (under the skin in wrists, ankles, or elsewhere), weakness, fatigue, muscle loss, and neuropathy.

• Managing cholesterol: About 20% also indicated that managing their cholesterol level and keeping it at target was an ongoing challenge. As 1 patient stated, “Spent 15 years trying to bring my cholesterol down with diet and exercise with little success and living in fear of having a stroke or heart attack.”

• Lifestyle impact: About 20% said their high cholesterol or lipid condition had little or no effect on their quality of life. Many reported they had changed their diet and exercise. However, some responses indicated that patients were not always aware of the impact of high cholesterol, in part because they were well managed on treatment and did not experience daily symptoms. According to 1 patient, “The condition never affected my work, school or social life. It affected my family life by altering our diet.”

• CV events: 75% of the FH patients reported having had at least 1 CV event or intervention, such as heart attack, stroke, angioplasty, bypass surgery, and/or stent insertion. Many have had multiple events requiring multiple interventions. Many expressed anxieties about the “unpredictability” of a CV event and the potential for severe consequences.

• Psychological and family impact: Most respondents felt positive about their daily life and have accepted or adapted to living with high cholesterol, including those who have experienced a CV event or have stents. The 2 most frequently mentioned sources of anxiety were:

  • future uncertainty of the medications not working or the risk of a CV event

  • the impact on their children, whether diagnosed or at risk. According to 1 patient with FH, “It is a relatively symptom free genetic disorder. My only concerns have been related to life expectancy due to the increased risk of heart failure or stroke. I am also concerned with my 2 young children and whether they will develop the condition as they grow older.”

The HeartLife Foundation emphasized that the negative effects of ASCVD on Canadian families and the health system are significant, and that more needs to be done to address CV disease and improve health outcomes for patients.

Experience With Treatment

CHPA collected respondents’ perceptions of their treatments from the open-ended question as well as from 2 rating scales measuring the effectiveness and side effects experienced from about 13 treatments, including drug therapies, diet, and apheresis. Almost all patients on treatment were also following a low-fat diet and exercising. However, most respondents reported they were not well managed using diet or nutritional supplements alone. The majority (about 94%) of respondents had taken or were currently taking statins. In 55% of respondents, statins were reported to have worked well or very well, whereas 18% of respondents reported their cholesterol levels were not managed by statins. Severe or very severe adverse effects from statins were experienced by 25% of respondents.

About 2-thirds of respondents had an additional drug (often ezetimibe) added and about 40% to 50% had switched or added a PCSK9 inhibitor to their treatment regimen. The responses were similar, with approximately 80% who received a PCSK9 inhibitor (Repatha or Praluent) reporting that these therapies worked well or very well; 12% reported that their cholesterol levels were not managed by PCSK9 inhibitors. Between 83% (Repatha) and 95% (Praluent) of patients reported none or very few adverse effects, with 10% (Repatha) reporting some “severe” adverse effects. Less than 10% indicated that none of the drug regimens were effective. The following perspectives on treatment were shared by patients:

“At present, no drug alone or in combination has been successful in managing my cholesterol level and statins have caused severe side effects. The PCSK9 inhibiter, while tolerable without adverse side effects, has shown a small measurable decrease in cholesterol levels but not significant enough to be called successful.”

“My body does not tolerate the many statins I have used and causes significant elevations to my CK and liver levels. Hence, I have been taking PCSK9 along with low doses of Crestor, along with ezetimibe to aggressively manage the LDL levels. These drug use over the years have caused many side effects such as muscle and joint pain, low libido, sleep problems, and headaches over the years. They have led to anxiety and depression. The physical symptoms have made it difficult to engage in regular sports, exercise and personal and intimate relationships in order to enjoy a high-quality life.”

According to the HeartLife Foundation, a large proportion of the population treated with statins cannot achieve LDL-C goals. In addition, patient adherence to currently available and publicly reimbursed therapeutic options is recognized as poor. Public reimbursement for PCSK9 inhibitors in Canada is limited, and access for patients with uncontrolled LDL-C is highly restricted by provincial health benefit program reimbursement criteria.

Improved Outcomes

The majority of respondents to the CHPA survey felt they were well managed on their current therapy but also expressed multiple concerns, largely about treatment schedule, side effects, and cost.

Overall, 10% of respondents knew much or very much about inclisiran (Leqvio). Among those who did know, the response was mostly positive, with inclisiran viewed as an alternative to statins or injections of PCSK9 inhibitors every 2 weeks. Those taking statins expressed hope it would be more effective in controlling cholesterol. For those on PCSK9 inhibitors, the impact on quality of life was considered as the positive aspect. Additionally, several respondents expressed the hope that the cost of twice-yearly injections would be less than the cost of injections administered every 2 weeks. Some expressed caution based on the lack of evidence. The following perspectives on inclisiran were shared by patients:

“I hope there is a drug that could keep us patients in the ‘normal’ range. I also find an injection every 2 weeks impedes my ability to travel or be away when delivery is expected. It is not an easy drug to commit too. I would prefer to go back to a daily pill so I can make personal plans easier.

“I think it’s amazing, especially with patients who may forget to take daily medication or need health care providers. Because I work as a pilot, the daily statins is more reliable, than 2-week injections. But bi-annual injections would be great since I won’t have to remember to carry pills with me all the time between home and travel.”

“It effectively lowers LDL [but] we need to see outcome data with regards decrease HEART ATTACKS, strokes, cardiac death & total mortality.”

The survey also presented a number of paired “trade-off” decisions comparing a daily pill, self-injection every 2 weeks, and twice-yearly injections by a health care provider. Overall, respondents clearly preferred the treatment modality that was most effective (with the fewest side effects), whether pill or injection. When treatments are considered equally effective, there is a small preference for a daily pill over a self-injection every 2 weeks, but a preference for a twice-yearly injection administered by a health care provider over the daily pill. Finally, respondents (76%) preferred a twice-yearly injection administered by a health care provider to a self-injection every 2 weeks.

Additional feedback was received from 10 patients who had experience with inclisiran through clinical trials or an early access program. Four resided in Canada. All were diagnosed with ASCVD or HeFH and reported they had been on maximum statin doses without achieving target cholesterol levels. All had received inclisiran while continuing their statin regimen, and all had experienced a significant reduction in LDL levels with no adverse effects related to inclisiran. For respondents, the most important impact was knowing there was a treatment that could lower their cholesterol levels and keep them closer to target, thereby reducing the risk of further CV events. According to 1 respondent, “I feel good that I am doing something to prevent further lipid build-up and reduce risk of hardening of arteries.”

The HeartLife Foundation stated that the outcome that Canadians deserve is the ability to reduce the long-term ASCVD health consequences in high-risk patients caused by uncontrolled or poorly managed LDL-C levels. The merits of a twice-yearly dosage schedule will reduce pill burden and make it significantly easier for patients to take this drug, resulting in greater adherence and improved control of LDL-C. Many members had expressed significant interest in reducing the number of pills taken and moving toward a twice-yearly medication.

Additional Details

CHPA noted it was surprising and very gratifying to compare responses from their most recent survey to 1 that was conducted 6 years ago. Only 25% of respondents in 2015 reported that their LDL cholesterol levels were kept at desired levels, compared with 90% in the present survey. Among those not at target in 2015, about half had experienced challenges getting the statin dosage correct or access to a supplemental medication. One of the main differences in the respondent populations was the greater number of patients prescribed a PCSK9 inhibitor in the most recent survey. According to CHPA, while these respondents do not represent all Canadians living with high cholesterol, they give a clear picture of what can happen when patients receive an appropriate diagnosis, education, support, and the right medication. This patient group emphasizes that it would be extremely beneficial to introduce an alternative therapy that would be available to those not well managed on current therapies, with immediate access to those not at target, despite a maximum statin dosage.

The HeartLife Foundation noted that the number of people who suffer serious health consequences caused by ASCVD, heart attack, and ischemic strokes, and the number of people that ultimately die from the effects of CV disease, is immense. Risk factors for ASCVD need to be addressed as aggressively as possible with the tools and interventions that are available. According to the HeartLife Foundation, the product under review is 1 of these valuable interventions that should be widely available to Canadians.

Clinician Input

Input From the Clinical Expert Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise regarding 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 1 clinical specialist with expertise in the diagnosis and management of HeFH and ASCVD.

Unmet Needs

In the CCS Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease and CCS Position Statement on FH, strict LDL-C thresholds have been selected based on the available evidence according to the risk of ASCVD and absolute level of LDL-C, non-HDL-C, or ApoB for the initiation of statins, ezetimibe, and PCSK9 inhibitors. Statins are considered the standard of treatment for the prevention of ASCVD in high-risk patients and patients with FH or severe hypercholesterolemia. The clinical expert pointed out that up to 15% of patients are partially or completely intolerant to statins, meaning that despite maximally tolerated statin therapy (here, the dose can be 0 mg), the patient’s LDL-C level still exceeds the threshold as described in the CCS guidelines. In these cases, ezetimibe is recommended but might be insufficient to treat optimally, following which PCSK9 inhibitors are considered. The clinical expert noted that treatment with PCSK9 inhibitors has been shown to reduce MACEs (CV death, non-fatal MI, and strokes), and there is a trend toward reduction in CV mortality. Patients unable to meet the pre-specified LDL-C thresholds with current treatments have unmet need for additional treatment options.

Place in Therapy

Decreasing atherogenic lipoprotein levels directly addresses the pathophysiology of ASCVD and modifies the natural course of the disease. The overall aim of treatment is to reduce MACEs. After lifestyle modifications, statins plus or minus ezetimibe remain the first-line approach and must be optimized before a PCSK9 inhibitor is considered. The clinical expert consulted by CADTH explained that PCSK9 inhibitors complement statin therapy and should be considered only if the patient has not reached the appropriate guideline-mandated goals of therapy. Rarely, PCSK9 inhibitors may be used alone.

Patient Population

The clinical expert also emphasized that the CCS guidelines should be used as a basis for identifying and treating patients. The clinical expert consulted by CADTH did express, however, that the characteristics of appropriate patients should match the clinical study data (i.e., age, presence of CV disease or severe hypercholesterolemia), and that stage of disease may be relevant in patients who are elderly or have end-stage disease. In the case of inclisiran, the indications would be similar to those expressed for PCSK9 inhibitors in the CCS Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease and CCS Position Statement on FH.

Lastly, the patients noted by the clinical expert as least suitable for treatment with the drug under review were those with low-risk ASCVD, those with low-risk severe hypercholesterolemia well controlled with statins, patients with ASCVD at LDL-C goals with current therapies, patients above a certain age taking the drug for primary prevention, and patients with multiple comorbidities that limit lifespan.

Assessing Response to Treatment

In line with the CCS guidelines highlighted previously, the clinical expert stated that a reduction from baseline of 50% in LDL-C and in the absolute level of LDL-C achieved below the target (LDL-C < 2.5 mmol/L for HeFH, or LDL-C < 1.8 mmol/L for ASCVD) are relevant outcomes used in clinical practice to determine response. The clinical expert indicated that treatment response should be assessed every 6 months, then yearly.

The clinical expert considered the patients most likely to exhibit a response to treatment were those that achieved a 30% to 40% reduction in LDL-C from baseline levels while on an optimized statin, with or without ezetimibe therapy.

Discontinuing Treatment

The clinical expert stated that age, end-stage disease, and/or dementia are important factors that should be considered when deciding to discontinue treatment.

Prescribing Conditions

The clinical expert noted that treatment settings would initially be specialized lipid clinics, with diagnoses and treatment confirmed by cardiologists and endocrinologists; however, throughout treatment and follow-up, treatment would migrate to internal medicine and general practice. The clinical expert also noted that in patients with (suspected) FH, genetic testing should be considered to confirm the diagnosis.

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by clinician groups.

The clinician group that provided input for this project was an informal group consisting of lipid specialists and physicians working in lipid clinics in British Columbia, including the Healthy Heart Program Prevention Clinic at St. Paul’s Hospital, the Surrey Lipid Clinic at Surrey Memorial Hospital, and the Victoria Lipid Clinic. This group frequently communicates to share best practices, collaborate on research and educational projects, and meets through various forums, including advisory boards, conferences, and continuing medical education events.

The information for this submission was based on a review of relevant literature and publications as well as background knowledge in the area.

Unmet Needs

The clinician group noted the following unmet needs:

1. Tolerability of current treatments: Many patients have side effects to statins and ezetimibe, leading to therapy discontinuation. Therefore, therapies with lower rates of perceived side effects are needed.

2. Compliance: Drugs that optimize patient adherence to treatment are needed. It is well known that daily dosing regimens (of current treatments) are seldom fully adhered to.

3. Ability to treat to target: Despite existing therapies, many patients do not reach their guideline-recommended lipid target. This issue is increasing in importance because the latest version of many guidelines (including the 2020 CCS lipid guidelines) recommends treating LDL-C to even lower levels in high-risk patients. Add-on therapies are therefore needed to allow patients to reach their lipid targets.

4. Accessibility: Due to the high cost of PCSK9 inhibitors and the lack of coverage for the ASCVD indication in all Canadian provinces, therapies with greater accessibility to the large population of patients that would benefit because of their high CV risk are needed. Additionally, many patients with FH who have a high lifelong CV risk may require access to alternatives to PCSK9 inhibitors.

The clinician group described an ideal treatment option as 1 that would reduce LDL-C, non-HDL-C, and ApoB; reduce the risk of MACEs and CV mortality, and be safe and well tolerated, with properties that promote adherence.

Place in Therapy

The clinician group noted that current Health Canada–approved treatments include statins, ezetimibe, and PCSK9 monoclonal antibodies, in addition to dietary therapy consisting of reduced intake of saturated fat and dietary cholesterol. All of these therapies are routinely used in clinical practice and endorsed in the 2021 CCS dyslipidemia guidelines.

The clinician group noted that statins are likely to remain the cornerstone of therapy for these patients, given the amount of data supporting them and, as such, inclisiran would most likely be used after a patient has already been optimized (taking an MTD statin or no statin in fully statin-intolerant patients). Alternative LDL-C-lowering add-on drugs (e.g., ezetimibe) may sometimes be effective if LDL-C levels are close to optimal levels whereas, when residual LDL-C remains high, the most appropriate statin add-on would have to be more potent (e.g., PCSK9 inhibitor or inclisiran). Therefore, inclisiran would most likely be used as an add-on to MTDs of statins (and/or ezetimibe) in patients who require additional lipid lowering.

Inclisiran is a first-in-class small interfering RNA that works by inhibiting PCSK9 synthesis, thereby diminishing liver excretion into circulation and subsequently increasing the expression of hepatic LDLRs. The clinician group noted that inclisiran may displace other PCSK9 inhibitors as an add-on to statins and ezetimibe if it is more accessible than current treatments and depending on the results of currently ongoing CV outcome trials. It may also fill a void if it is approved for secondary prevention in high-risk patients.

Patient Population

The clinician group noted that patients with the greatest unmet need for intervention are those with HeFH, patients with statin intolerance, and patients with ASCVD with other markers of high risk (e.g., recent MI, coronary artery bypass graft, multi-vessel disease, polyvascular disease, diabetes, elevated lipoprotein[a]).

Based on the available data, the clinician group noted that inclisiran would be suited to all patients who require additional lowering of LDL. Patients would be identified for treatment based on their diagnosis (FH or ASCVD) and the results of lipid testing (LDL-C, non-HDL-C, ApoB), which is widely available and already used in clinical practice. In terms of patients who could benefit most from treatment with inclisiran, the clinician group noted that patients with either lifetime or short-term high risk, in particular (e.g., patients requiring secondary ASCVD prevention, patients with FH, and patients with high risk, such as those with diabetes mellitus or a high Framingham Risk Score). The clinician group also noted that asymptomatic patients should be treated in specific circumstances, such as patients with FH, patients with documented atherosclerotic disease who have not yet had a clinical event, and other guideline-recommended groups considered to have high CV risk amenable to the benefits of LDL lowering (e.g., patients with a high Framingham Risk Score, diabetes mellitus, or chronic kidney disease).

Finally, they noted that the patients least suitable for treatment with the drug under review would be patients who do not have an indication for the therapy, patients who have achieved LDL targets on other therapies (statin with or without ezetimibe), and patients who have not attempted a statin.

Assessing Response to Treatment

The clinician group noted that LDL-C, non-HDL-C, and ApoB measurements are all included in typical Canadian clinical practice and are endorsed by national guideline recommendations. A reduction in LDL-C or non-HDL-C of at least 30% would be considered a clinically meaningful response to treatment, and treatment response should be assessed at least every 6 months when beginning therapy. Treatment response could then possibly be assessed every year, once the patient is on stable treatment.

Additionally, with regard to identifying patients who are most likely to exhibit a response to treatment with inclisiran, because the response to inclisiran is fairly uniform, the issue of non-response is likely not particularly relevant.

Discontinuing Treatment

The clinician group noted that the factors to consider when deciding whether to discontinue treatment would include a lack of response (which is expected to be very rare), treatment intolerability, or if another treatment option were to become more accessible or available (e.g., a PCSK9 inhibitor).

Prescribing Conditions

The clinician group noted that the settings that would be appropriate for treatment with inclisiran include specialty clinics, community settings, and hospital or community outpatient clinics and that, in theory, inclisiran should be able to be used appropriately by both primary care and specialist physicians. In practice, however, FH is infrequently diagnosed in primary care, so identification of these patients may require a specialist who is familiar with this. Many patients with ASCVD are followed by specialists (e.g., internist, cardiologist), and it is expected that this would be the most likely scenario in which inclisiran would be initiated.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’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 expert consulted by CADTH are summarized in Table 4.

Clinical Evidence

The clinical evidence included in the review of inclisiran (Leqvio) is presented in 3 sections. The first section, the systematic review, includes pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those studies that were selected according to an a priori protocol. The second section includes indirect evidence from the sponsor and indirect evidence selected from the literature that met the selection criteria specified in the review. The third section includes sponsor-submitted long-term extension studies and additional relevant studies that were considered to address important gaps in the evidence included in the systematic review.

Systematic Review (Pivotal and Protocol Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of inclisiran in adults with primary hypercholesterolemia (HeFH and nFH).

Methods

Studies selected for inclusion in the systematic review included pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 5. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

Of note, the systematic review protocol presented in Table 5 was established before the granting of a Notice of Compliance from Health Canada.

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist.⁴¹

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946‒) through Ovid and Embase (1974‒) through Ovid. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concept was inclisiran. Clinical trials registries were searched: the US National Institutes of Health’s clinicaltrials.gov, the WHO’s International Clinical Trials Registry Platform (ICTRP) search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. See Appendix 1 for the detailed search strategies.

The initial search was completed on April 15, 2021. Regular alerts updated the search until the meeting of the CADTH Canadian Drug Expert Committee on August 18, 2021.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool for Searching Health-Related Grey Literature checklist.⁴² Included in this search were the websites of regulatory agencies (FDA and European Medicines Agency). Google was used to search for additional internet-based materials. See Appendix 1 for more information on the grey literature search strategy.

Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion.

Findings From the Literature

A total of 3 studies were identified from the literature for inclusion in the systematic review (Figure 3).^17-19 The included studies are summarized in Table 6. A list of excluded studies is presented in Appendix 2.

Figure 3: Flow Diagram for Inclusion and Exclusion of Studies

Description of Studies

A total of 3 studies were included in this review: ORION-9, ORION-10, and ORION-11.^17-19 The included studies were all phase III, double-blind RCTs comparing inclisiran with placebo in patients with HeFH or ASCVD (and/or an ASCVD risk equivalent) who were receiving MTD statins or were statin-intolerant. All 3 studies were funded by the sponsor.

ORION-9 was a phase III, double-blind, multinational, randomized, placebo-controlled trial designed to assess the efficacy, safety, and tolerability of inclisiran 284 mg versus placebo in patients with HeFH and elevated LDL-C despite maximum tolerated dose of LDL-C-lowering therapies. ORION-9 was conducted in 47 centres in 8 countries: Canada, Czech Republic, Denmark, Netherlands, South Africa, Spain, Sweden, and the US. Three Canadian study centres were included in the ORION-9 study, which enrolled 23 patients.^17,35

ORION-10 was a phase III, double-blind, multi-centre, randomized, placebo-controlled trial designed to assess the efficacy, safety, and tolerability of inclisiran 284 mg versus placebo in patients with ASCVD (CHD, CV disease, PAD) and elevated LDL-C despite an MTD of LDL-C-lowering therapies. ORION-10 was conducted in 146 sites across the US. No Canadian study sites or patients were included in the ORION-10 study.^18,43

ORION-11 was an international, multi-centre, phase III, placebo-controlled, double-blind, randomized study to determine the efficacy, safety, and tolerability in patients with ASCVD or an ASCVD risk equivalent (e.g., diabetes and FH) and elevated LDL-C despite MTD statin therapy. The study was conducted within 72 centres in European countries and South Africa. No Canadian study sites or patients were included in the ORION-11 study.^19,43

In all 3 ORION studies, patients were randomized 1:1 to either inclisiran sodium 300 mg or placebo on top of MTD statin. The ORION-9, −10, and −11 trials enrolled 482, 1,561, and 1,617 patients, respectively. The studies were all 18 months in duration, with patients receiving a 300 mg dose of inclisiran sodium on 4 days: day 1, day 90, day 270, and day 450. The ORION-9, −10, and −11 trials shared an identical study design, which is displayed in Figure 4.^17-19

Figure 4: Schematic Overview of the ORION-9, ORION-10, and ORION-11 Trial Schema

EOS = end of study; FUP = follow up; V = visit.

Source: Clinical Study Reports for ORION-9,¹⁷ ORION-10,¹⁸ and ORION-11.¹⁹

Key eligibility criteria for the ORION-9, −10, and −11 studies are summarized in Table 6. Briefly, eligible patients in ORION-9 included adults (≥ 18 years) with a history of HeFH and/or a documented history of untreated high LDL-C (> 190 mg/dL), and a family history of FH, elevated cholesterol, or early heart disease, which may indicate FH. Patients eligible for ORION-10 were adults (≥ 18 years) with a history of ASCVD. Patients eligible for ORION-11 were adults (≥ 18 years) with a history of ASCVD or an ASCVD risk equivalent.^17-19

The minimum follow-up and duration of all 3 ORION trials was 18 months. The last observation and data cut-off (end of study) for the ORION-9, −10, and −11 trials was at visit 9 (day 540), which was 90 days following the last dose of the study drug at visit 8 (day 450).^17-19

Populations

Inclusion and Exclusion Criteria

The inclusion and exclusion criteria for the 3 ORION trials are summarized in Table 6. Overall, the 3 trials had similar inclusion criteria, with slight differences specific to the included population and disease of interest. In the ORION-9 trial, eligible patients were required to have a family history of HeFH, elevated cholesterol, or early heart disease, or HeFH diagnosed by genetic testing or phenotypic Simon Broome criteria and/or a documented history of untreated high LDL-C (> 190 mg/dL).¹⁷ In contrast, the ORION-10 study enrolled patients with a history of ASCVD, including CHD, CV disease, or PAD.¹⁸ Lastly, the ORION-11 trial included patients with a history of ASCVD (CHD, CV disease, or PAD) or an ASCVD risk equivalent (e.g., type II diabetes, or FH).¹⁹ All trials required patients to be receiving the MTD of a statin, defined as the maximum dose that can be taken on a regular basis without AEs; for those not receiving a statin, documented evidence of intolerance to all doses of at least 2 different statins was required.^17-19

The trials shared the same exclusion criteria. Patients were ineligible if they had New York Heart Association (NYHA) class IV heart failure or a last known left ventricular ejection fraction of less than 25%, cardiac arrhythmia within 3 months before randomization that was not controlled by medication or through ablation, or an MACE within 3 months before randomization.^17-19

Baseline Characteristics

Baseline characteristics for each included trial are summarized in Table 7. Baseline characteristics were well balanced across groups in each trial. Patients enrolled in the ORION-10 and −11 trials were more similar than those enrolled in the ORION-9 trial.

In ORION-9, approximately half of the included patients (227; 47.1%) were male, and the median age was 56 years old.¹⁷ The majority of patients in ORION-10 and −11 were male (69.4% and 71.7%, respectively), and the mean age was 65 to 67 years.^18,19 The majority of patients in all 3 trials were White (range = 83.6 to 98.6%).^17-19 The mean and median age of patients in the ORION-9 trial were approximately 10 years younger than those included in the ORION-10 and −11 trials, and the majority of patients were 65 years of age or older in the ORION-10 (n = 931; 59.6%) and ORION −11 (n = 884; 54.7%) trials compared with the ORION-9 trial, where the majority were younger than 65 years (n = 374; 77.6%).^17-19 Across all 3 trials, the majority of patients also had renal impairment (63.5%, 76.4%, and 71.1% in ORION-9, −10, and −11, respectively).^17-19

In ORION-9, 350 patients (72.6%) had an ASCVD risk equivalent, of which 238 (93.2%) had HeFH, while 132 (27.4%) had ASCVD. Half of the patients had baseline LDL-C levels below, and half above, 138.5 mg/dL, with a mean of 151.4 mg/dL and 154.7 mg/dL in the inclisiran and placebo groups, respectively.³⁵ Conversely, in ORION-10, all patients had ASCVD, and in ORION-11, 1,414 (87.5%) had ASCVD and 203 (12.6%) had an ASCVD risk equivalent, of which only 11 (5.4%) had HeFH. In these trials, patients were evenly balanced for mean baseline LDL-C levels, with a mean LDL-C level of 104.5 mg/dL and 107.2 mg/dL in the inclisiran groups, and 104.8 mg/dL and 103.7 mg/dL in the placebo groups.⁴³ The ASCVD risk–equivalent population of ORION-11 was not of interest to this review, as this population was not included in the reimbursement request. Of those with ASCVD, the proportion of patients with |||||||||| was |||||||||| in the ORION-9 trial, occurring in |||||||||| of patients in the placebo group and |||||||||| in the inclisiran group. Conversely, the ORION-10 and −11 trials reported |||||||||||||||||||| of patients with |||||||||||| ranging from ||||||||||, CV disease ranging from ||||||||||||||||, and |||||||||| ranging from |||||||||||||||||| compared with |||||||||||||||||||||||||||| in ORION-9. Lower rates of |||||||||||||||||||||||| hypertension were seen in the ORION-9 trial (|||||||||| 42.1%, ||||||||||||||), compared with the ORION-10 and −11 trials (|||||||||||||||||||||||||| 90.6%, and 80.5%, respectively).^17-19

In ORION-9, 356 patients (73.9%) were on a high-intensity statin at baseline, and 135 patients (55.8%) and 120 patients (50.0%) in the inclisiran and placebo groups, respectively, were treated with ezetimibe.^17,35 In ORION-10, 1,084 patients (69.4%) were on high-intensity statins at baseline, and a total of 80 (10.2%) and 74 patients (9.5%) in the inclisiran and placebo groups, respectively, were treated with ezetimibe.^18,43 In ORION-11, 1,261 patients (78.0%) were on a high-intensity statin at baseline based on the FDA feedback on September 13, 2019, where simvastatin 40 mg was considered a moderate-intensity statin. A total of 52 (6.4%) and 62 patients (7.7%) in the inclisiran and placebo groups, respectively, were treated with ezetimibe.^19,43

In the ORION-9, −10, and −11 trials, 122 (25.3%), 344 (22.0%), and 185 patients (11.4%) were partially or completely intolerant to statins, respectively.

Interventions

Treatments Administered

ORION-9, −10, and −11 were all double-blind RCTs. Patients were randomized 1:1 by automated interactive response technology to receive either inclisiran sodium subcutaneous injection as the investigational product in all 3 ORION trials, delivered at a dose of 284 mg or placebo as normal sterile saline (0.9% sodium chloride in water for injection). Patients were administered inclisiran or placebo as a single subcutaneous injection in the abdomen for a total of 4 doses, on study days 1, 90, 270, and 450.^17-19

Inclisiran was provided as a unit dose of 300 mg/1.5 mL per 2 mL glass vial, and placebo was provided in a matching glass vial, both manufactured by Alcami (formerly AAI Pharma) prepared and administered by a pharmacist or qualified clinical study site staff. Inclisiran was also administered as a 2.25 mL pre-filled syringe for doses 3 and 4 in ORION-10.^17-19

Treatment allocation was stratified by country and by current use of statins or other lipid-modify therapies (LMTs) in block sizes of 4. The principal investigators were authorized to unblind a patient through interactive response technology 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. The investigator was advised not to reveal the study treatment assignment to any other site or sponsor personnel.^17-19

Patients were required to fast for at least 8 hours for all visits for fasting lipids and glucose blood samples, refrain from unaccustomed strenuous physical exercise for 48 hours before the screening and any study visit until the follow-up had been completed, and were not permitted to donate blood at any time during the study.^17-19

Prior and Concomitant Therapy

Eligible prior and concomitant medications for all 3 ORION trials included statins and other lipid-lowering therapies (e.g., ezetimibe); patients were required to have been on a 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 pre-existing medical conditions such as diabetes or hypertension, and prescription and non-prescription medications to treat AEs at the discretion of the investigator were also permitted.^17-19

All of the trials prohibited adding any medications that are prescribed to lower LDL-C during the trial. This included 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 and herbal therapies.^17-19

||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

Outcomes

The efficacy end points identified in the CADTH review protocol that were assessed in the clinical trials included in this review are listed and summarized in Table 8.

Patients were in a fasted state for all efficacy laboratory assessments. The parameters assessed were total cholesterol, triglycerides, LDL-C, HDL-C, non-HDL-C, very low–density lipoprotein cholesterol, apolipoprotein A1, ApoB, lipoprotein (a), high-sensitivity C-reactive protein, and PCSK9. All laboratory assessments and assays were performed by a central laboratory, with the exception of urinalysis.^17-19

The primary outcome of the ORION-9, −10, and −11 trials was the percentage change in LDL-C from baseline to day 510. All trials had a co-primary end point of time-adjusted percentage change in LDL-C from baseline after day 90 and up to day 540, defined as the average percentage change in LDL-C from baseline over the period after day 90 and up to day 540, reflecting the start of the twice-yearly dosing regimen.^17-19

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 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 1 of the co-primary efficacy end points’ null hypotheses failed to be rejected.^17-19

Other secondary outcomes were consistent across the ORION trials and included all of the following:

• maximum percentage change in LDL-C

• absolute and percentage 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 less than 25 mg/dL, less than 50 mg/dL, less than 70 mg/dL, and less than 100 mg/dL at day 510)

• the proportion of patients in each group with a reduction in LDL-C from baseline of 50% or greater

• absolute change and percentage change in other lipids, lipoproteins, and apolipoproteins

• PCSK9 change from baseline at each subsequent visit to day 540

• the proportion of patients in each group who attained global lipid targets for their level of ASCVD risk

Exploratory end points included incidence of CV death, resuscitated cardiac arrest, non-fatal MI, and non-fatal stroke (ischemic and hemorrhagic), and proportion of patients in each group with any LDL-C reduction from baseline at any visit (responders).^17-19 In ORION-9, an additional exploratory outcome consisted of response of LDL-C reduction by underlying causal mutations of HeFH.¹⁷

Blood samples were taken at scheduled time points to determine LDL-C concentrations. Additional 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.^17-19

Safety and tolerability of inclisiran was a secondary end point of the study and was measured by AEs, SAEs, vital signs, clinical laboratory values, electrocardiogram measurements, and formation and characterization of anti-drug antibodies. Adverse events, defined as any untoward medical occurrence in a patient administered a medicinal product where the AE does not necessarily have a causal relationship with the treatment, were coded using the Medical Dictionary for Regulatory Activities (MedDRA) v20.1. The severity of AEs was assessed by the investigator on a 3-point scale of mild, moderate, or severe.^17-19

No patient-reported HRQoL outcomes were assessed in the ORION trials.^17-19

Statistical Analysis

Sample Size and Power Calculation

The sample size calculations for the ORION-9, −10, and −11 trials were identical and were based on the observed results of the phase II study. Calculations were performed under the assumption that the difference in change from baseline between the active-dose group and the placebo group for LDL-C would be no less than 30 mg/dL, with a standard deviation of 20 mg/dL.^17-19

Assuming a 5% dropout rate, the sample size was approximately 380 patients in ORION-9, and 1,425 patients in both ORION-10 and −11 who were evaluable for efficacy across the placebo and inclisiran dose groups. This sample size of at least 380, 1,425, and 1,425 evaluable patients, respectively, provided more than 90% power to detect a 30% reduction of LDL-C levels in the inclisiran group compared with the placebo group at a 1-sided significance level of 0.025.^17-19 Due to faster-than-expected enrolment in the ORION-9 trial, the actual enrolment was 482 patients.¹⁷ ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.⁴⁴

Interim and Final Analyses

No interim analyses of efficacy were performed for ORION-9, ORION-10, or ORION-11. An independent data monitoring committee (IDMC) reviewed safety data after the first 40 patients received the first subcutaneous injection of inclisiran or placebo and completed 1 month of follow-up. In all ORION trials, an IDMC reviewed safety data 90 days after the first 40 patients received the first injection of inclisiran or placebo. Thereafter, the IDMC reviewed safety data approximately every 3 months until the end of study, unless requested otherwise by the IDMC.^17-19

Statistical and Analytical Plans

In all cases, the statistical analysis plan was finalized before database lock; however, changes were requested by the FDA. For ORION-10 and −11, an addendum and changes to the statistical analysis plan were requested by the FDA as well as other changes in analyses after the statistical analysis plan was finalized, the database locked, and the study unblinded.^17-19

All study-collected data were summarized by treatment group using descriptive statistics, graphs, and/or raw data listings. Categorical variables were summarized using counts and percentages. Percentages were based on the number of patients in the analysis set for whom there were non-missing data, unless otherwise specified. Continuous variables, including changes from day 1, were summarized using descriptive statistics. All P values were 2-sided and rounded to 3 decimal places. All P values rounded to 0.000 were presented as “< 0.001” and P values that round to 1.000 were presented as “1.000.”^17-19

Absolute change and percentage change from baseline were calculated as follows^17-19:

• Absolute change = (value at day χ) minus baseline value

• Percentage change = (absolute change ÷ baseline value) × 100%

Primary Efficacy End Point Analyses

The intention-to-treat (ITT) population was the primary population for the efficacy analysis in all ORION trials. The statistical hypothesis for the co-primary end points was that the difference between patients treated with inclisiran and placebo in the least squares mean (LSM) percentage change and mean time-adjusted change in LDL-C from baseline at day 510 was 0. The co-primary end points were controlled for multiplicity using the family-wise type I error rate which was controlled at a 1-sided alpha significance level of 0.05 by using a nested testing procedure. A sequential testing procedure was used to assess the percentage change in LDL-C from baseline to day 510. If the null hypothesis was rejected at a 2-sided alpha significance level of 0.05 and superiority of inclisiran over placebo was claimed, then the time-adjusted percentage change in LDL-C from baseline after day 90 and up to day 540 was tested, also at a 2-sided alpha significance level of 0.05.^17-19

The primary end points used a reflexive LDL-C measurement approach. LDL-C was calculated based on the Friedewald formula. If the calculated LDL-C was less than 40 mg/dL (1.0 mmol/L), or triglycerides were greater than 400 mg/dL (4.5 mmol/L), or calculated LDL-C was missing, directly measured (using ultracentrifugation) LDL-C was used.^17-19

A multiple imputation washout model was used to impute missing data for the percentage change in the LDL cholesterol level from baseline to day 510. The washout model can be thought of as a modified control-based pattern-mixture model (PMM) that was used to explore the possibility of data missing not at random for patients who discontinued the study early. Percentage change for each visit was calculated after the missing data imputation was performed.^17-19 In ORION-11, the multiple imputation washout model was modified such that patients in the inclisiran group who received all 4 doses of the study drug who had the day 510 value missing and had evaluable data at day 540, had their intermittent missing day 510 values imputed assuming the missing data were missing at random (MAR).¹⁹

The primary analysis was based on an analysis of covariance (ANCOVA) model on each multiply imputed dataset (100 total). The model included the fixed effect of treatment and baseline LDL-C as a covariate. Treatment effects from these analyses were then combined using the Rubin method.⁴⁵ The difference in the LSM between treatment groups and the corresponding 2-sided 95% CI were provided for hypothesis testing.^17-19

For the co-primary end point of time-adjusted percentage change in the LDL cholesterol level between day 90 and day 540, a control-based PMM was used to impute any missing values. A mixed-effects model for repeated measures (MMRM) was used for data obtained during all visits on each multiply imputed dataset. The model included fixed effects for treatment, visit, baseline LDL-C, and the interaction between treatment and visit. Linear combinations of the estimated means after day 90 and up to day 540 were used to compare treatment effects. Note that day 90 was excluded from the MMRM.^17-19

The 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 any 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. For patients who did not discontinue the study, missing values were imputed based on the MAR assumption. Multiple imputations were used to account for uncertainty in the imputation process and results from the imputed datasets were combined using the Rubin method as with the primary end point.^17-19

Sensitivity Analyses

Sensitivity analyses of the co-primary end points was conducted to support the robustness of the conclusions. Three sensitivity analyses were conducted for the percentage change in LDL-C from baseline to day 510, as follows^17-19:

• A control-based PMM using the same imputed datasets and MMRM that was used for the second co-primary efficacy end point.

• An MMRM was used that included fixed effects for treatment, visit, baseline value, and interaction between treatment and visit. The ORION-11 study included the current use of statins or other LMT as fixed effects, as well.

• An ANCOVA model was used to assess the impact of country (ORION-9 and ORION-11) as fixed effects and use of statins or other LMT (ORION-9). The model used the modified ITT population, including the fixed effect of treatment group and baseline LDL-C, as a covariate (ORION-9 and ORION-10).

For time-adjusted percentage change in LDL-C from baseline to day 90 and up to day 540, sensitivity analyses included^17-19:

• An MMRM was used that assumed data are MAR and included fixed effects for treatment, visit, baseline value, interaction between treatment and visit in ORION-9, and −10. The current use of statins or other LMTs was also included as a fixed effect in ORION-11.

• A second MMRM assessed the impact of country (ORION-9 and ORION-11) and current use of statins (ORION-9 and ORION-10) or other LMT as fixed effects.

• A 2-sample t-test was performed to test the treatment difference between inclisiran and placebo for time-adjusted percentage change, which was calculated by taking the arithmetic mean of the percentage change in LDL-C from baseline at each visit after day 90 through day 540.

Secondary Efficacy End Point Analyses

Analyses of the secondary end points were performed only after the analyses of the 2 primary end points were completed and the null hypotheses were rejected. The key secondary end points of this study were^17-19:

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

• time-adjusted absolute change in LDL-C from baseline 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 efficacy end points were not tested if either 1 of the co-primary efficacy end points’ null hypotheses failed to be rejected. Key secondary end points were controlled for multiplicity using the Hochberg procedure,⁴⁶ which was applied to control the family-wise type I error rate at 2-sided alpha significance level of 0.05. Missing values were imputed using the control-based PMM on LDL-C, PCSK9, total cholesterol, ApoB, and non-HDL-C; absolute change or percentage change from baseline was calculated based on imputed data before any analysis was performed.^17-19

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 after day 90 and up to day 540 was analyzed similarly to the analysis of the time-adjusted percentage change in LDL-C from baseline after day 90 and up to day 540. In ORION-11, as 94.7% of patients were currently using statins or other LMT at baseline, a revised model that excluded statins and other LMTs as a covariate was performed. This change did not affect the placebo-adjusted change from baseline in any of the analyses; therefore, key secondary end points using the PMM excluded statins and other LMTs as a covariate.¹⁹ An MMRM without multiple imputation was used as a sensitivity analysis for the key secondary end points.^17-19

The 2-sided 95% CI for LSMs was provided for continuous variables at a single point using an ANCOVA model or using MMRM methods for variables measured over time. The odds ratio and 95% CI were provided for binary variables using logistic regression models. Nominal P values were provided when applicable. Descriptive and graphical summaries by treatment group were also presented.^17-19

Exploratory Efficacy End Point Analyses

Major CV events were defined as the composite of CV death, resuscitated cardiac arrest, non-fatal MI, and stroke (ischemic or hemorrhagic). The number and percentage of patients with an MACE or any of the individual events were presented by treatment group. Events were identified using predefined MedDRA terms, including fatal SAEs in cardiac disorders and fatal SAEs in general-disorder system organ classes, including preferred terms for death, sudden cardiac death, cardiac death, and apparent death.^17-19

For the proportion of patients in each group with any LDL-C reduction from baseline at any visit (responders), the number and percentage of patients with any LDL-C reduction at any visit were presented by treatment group. The odds ratio and 95% CI for the odds ratio were provided using a logistic regression model. The number and percentage of patients with any LDL-C reduction was also summarized at each visit.^17-19

In ORION-9, the absolute change and percentage change in LDL-C and PCSK9 from baseline to day 510 were summarized descriptively by HeFH mutation type and treatment group.¹⁷ The results of that analysis were not included in this report.

Safety Analyses

Safety analyses were based on observed values. Any missing safety data, including laboratory data, were not imputed. For common TEAEs, serious TEAEs, and TEAEs leading to the withdrawal of the study drug, risk ratios along with 95% CIs were presented to compare treatment groups with respect to risk.^17-19

Subgroup Analyses

Analyses of efficacy and safety were performed for the following pre-specified subgroups of interest in all 3 ORION trials using MMRM to account for missing data: gender (male, female), age (< 65 versus ≥ 65 years, and < 75 versus ≥ 75 years,), BMI (≤ the median versus > the median, and quartiles), race (White, Black, other), baseline statin use (yes, no), baseline statin intensity (high intensity, not high intensity), other LMT (any statin with other LMT, other LMT but no statin, no LMT), baseline triglyceride level (< 200 mg/dL versus ≥ 200 mg/dL, and ≤ the median versus > the median), metabolic disease (diabetes, metabolic syndrome without diabetes, neither), renal impairment by eGFR categories (eGFR in mL/min/1.73 m² = ≥ 15 to < 30, ≥ 30 to < 60, ≥ 60 to < 90, and ≥ 90), history of allergy (yes, no), baseline LDL-C (≤ the median versus > the median, and quartiles), and post-baseline LDL-C (≤ 25 at any time point versus > 25 mg/dL at all time points).^17-19

Additional subgroups of phenotype (FH, nFH), and baseline ezetimibe use (yes, no) were assessed in ORION-9.¹⁷ ASCVD status (ASCVD, ASCVD risk equivalent), study centre (North America, Europe, South Africa) were evaluated in ORION-9 and ORION-11, but not ORION-10.^17,19 The ORION-10 study also included a subgroup of ethnicity (Hispanic, non-Hispanic).¹⁸

The subgroups identified in the review protocol included prior CV event (MI, stroke, unstable angina, hospitalization), concomitant treatments (statin, ezetimibe, other LMT), baseline LDL-C level, and patients who are not candidates for or are intolerant to statins.

Analysis Populations

The following analysis populations were defined in ORION-9, ORION-10, and ORION-11^17-19:

• ITT population: This included all patients who were randomized into the study. The ITT population was used for the analysis of the primary and secondary end points.

• Full analysis set: This consisted of all patients who were randomized into the study, took any study drug, and had at least 1 post-treatment lipid data measured.

• Modified ITT: This consisted of all randomized patients who received at least 1 dose of the study drug and had both the baseline and the day 510 follow-up LDL-C assessment.

• Safety population: This comprised all patients who received at least 1 dose of the study drug. This was the primary population for the safety analyses.

The ORION-10 trial also included a pharmacokinetic analysis population¹⁸ that is not described in this report.

Protocol Amendments and Deviations

A total of 4 global protocol amendments occurred in ORION-9. Any potentially relevant changes were made before the enrolment of patients; therefore, there was no impact on the conduct of the study or on the results of the statistical analyses. A total of 4 global protocol amendments also occurred in ORION-10, and 2 global protocol amendments |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| for ORION-11.^17-19 The amendments had no major impact on the studies, as the enrolment and statistical analyses were not completed before the amendments, and changes made to the statistical analysis plan did not impact the study conduct.

In ORION-9, 1 protocol deviation occurred in 11.4% of patients. The most common protocol deviations were prohibited concomitant medication or change in baseline statin or dose of other lipid-lowering therapy (3.7% versus 5.8% for the inclisiran and placebo groups, respectively) and inclusion and/or exclusion criteria violation (3.3% each in the inclisiran and placebo groups).¹⁷ In ORION-10, 1 protocol deviation occurred in 22.1% of patients. The most common protocol deviations were prohibited concomitant medication or change in baseline statin or dose of other lipid-lowering therapy (11.9% versus 12.2%) and mis-dosing for any reason other than patient safety or withdrawal (3.0% versus 5.4%). Inclusion and exclusion criteria violations were low and similar in patients taking placebo (2.6%) and patients taking inclisiran (4.4%).¹⁸ In ORION-11, 1 protocol deviation occurred in 15.2% of patients. The most common protocol deviations were prohibited concomitant medication or change in baseline statin or dose of other lipid-lowering therapy (8.0% versus 10.0%) and mis-dosing for any reason other than patient safety or withdrawal (3.3% versus 2.7%). Inclusion and exclusion criteria violations were low and similar in patients taking placebo (1.9%) and patients taking inclisiran (1.4%).¹⁹

Results

Patient Disposition

The ORION-9, −10, and −11 trials shared a similar study design and patient enrolment. Table 9 summarizes the patient flow of the ORION trials. In ORION-9, a total of 617 patients were screened and 482 were randomized. The most common reason for screening failure was “inclusion/exclusion criteria not met” ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. A total of 2,329 patients were randomized in ORION-10, of which 1,561 were randomized. In ORION-11, a total of 2,381 patients were screened and 1,617 were randomized. The primary reason for screening failure in ORION-10 and −11 was patient not meeting inclusion or exclusion criteria, ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. The proportion of patients who failed screening varied across trials but was more similar in the ORION-10 and −11 trials (32.98% and 32.09%) compared with ORION-9 (21.88%).^17-19

Across all studies, 89% of patients or more completed the study (i.e., had a day 540 end-of-study visit). The discontinuation rate was similar across studies, with ORION-10 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 −11 trials but was lower in the ORION-9 trial.^17-19

Exposure to Study Treatments

All study drugs were administered by staff at the clinical study site. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||　|||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.^17-19

Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported subsequently. See Appendix 3 for detailed sensitivity and subgroup efficacy data.

Mortality (All-Cause and CV-Related)

All-cause and CV-related mortality were measured as AEs in the ORION-9, −10, and −11 trials. The list of deaths as AEs in the ORION trials is summarized in Table 11.

In ORION-9, only 2 deaths occurred (0.4%), 1 in each trial arm.¹⁷ 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.¹⁸ In total, 29 patients (1.8%) died during the ORION-11 study, 14 (1.7%) in the inclisiran group, and 15 (1.9%) in the placebo group.¹⁹ |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. No deaths were attributed to the study drug in any of the studies.^17-19

CV-Related Morbidity

Incidence of Resuscitated Cardiac Arrest, Non-Fatal MI, and Stroke

CV-related morbidity outcomes, including the incidence of resuscitated cardiac arrest, non-fatal MI, and stroke, were included as a compound end point of MACE and was an exploratory outcome in the ORION-9, −10, and −11 trials. Incidences of events are summarized in Table 12. Non-fatal MI was the most frequently occurring individual event across all trials, occurring in 3.7% versus 4.2%, 5.1% versus 8.2%, and 5.8% versus 8.5% of patients in the inclisiran and placebo groups of ORION-9, −10, and −11, respectively; however, there were no apparent differences between groups. No resuscitated cardiac arrest or stroke events occurred in the ORION-9 trial,¹⁷ and results were similar between groups in ORION-10 and ORION-11.^18,19 The overall incidence of MACEs in the inclisiran groups was consistently similar to or lower than in placebo groups across all trials (4.1% versus 4.2%, 7.4% versus 10.2%, and 7.8% versus 10.3%, in ORION-9, −10, −11, respectively).^17-19

Hospitalizations and minimally invasive CV interventions were not reported in ORION-9, ORION-10, or ORION-11.

Percentage and Absolute Change in LDL-C

Percentage Change in LDL-C From Baseline to Day 510

The primary efficacy end point of the ORION-9, −10, and −11 trials was the percentage change in LDL-C from baseline to day 510, which is summarized in Table 13. In all ORION trials, inclisiran reduced LDL-C levels from baseline to day 510: −41.15% in ORION-9 (95% CI, −44.52 to −37.77), −56.34% in ORION-10 (95% CI, −58.35 to −54.34), and −49.3% in ORION-11 (||||||||||||||||||||||||||||||), while the change from baseline LDL-C levels increased with placebo: 8.37% in ORION-9 (95% CI, 3.96 to 12.77), 1.30% in ORION-10 (95% CI, −1.24 to 3.83), and 4.2% in ORION-11 (||||||||||||||||||||||).^17-19 The washout-imputed values, which took missing data into consideration, were similar, albeit the LSM percentage change from baseline was slightly smaller than the observed values.

In all trials, the LSM difference from placebo in percentage change in LDL-C from baseline favoured inclisiran for both the observed and washout-imputed values. The observed values were −49.52 in ORION-9 (95% CI, −55.04 to −43.99), −57.64 in ORION-10 (95% CI, −60.86 to −54.43), and −53.5 in ORION-11 (95% CI, −56.66 to −50.35). The washout-imputed values were −47.89 in ORION-9 (95% CI, −53.52 to −42.26), −52.24 in ORION-10 (95% CI, −55.65 to −48.83), and −49.9 in ORION-11 (95% CI, −53.07 to −46.64). All P values were less than 0.0001,^17-19 with observed values, not accounting for missing data, showing a larger percentage reduction in LDL-C from baseline (Table 13).

Sensitivity Analyses

Results of the 3 additional sensitivity analyses (PMM, MMRM, and an ANCOVA with country and current use of statins or other LMT as fixed effects) for percentage change in LDL-C from baseline to day 510 yielded results similar to the primary end point, with inclisiran demonstrating a reduction in LDL-C and placebo showing an increase in LDL-C levels. The between-group difference was consistent with the base-case scenario and the results were statistically significant (P < 0.0001).^17-19 Detailed outcome data for the sensitivity analyses are summarized in Table 29, Table 30, and Table 32 in Appendix 3.

Subgroup Analysis

Subgroup analyses were provided for the co-primary outcome of the percentage change in LDL-C from baseline to day 510 for the ORION-9, −10, and −11 trials. Results of the subgroup analyses for subgroups of interest, including baseline LDL-C, baseline statin treatment (on treatment versus not on treatment), statin intensity (high versus not high), LMT use (any statin or other LMT versus no statin or LMT), were consistent with the overall patient population and there was no evidence for effect modification within subgroups, with the percentage change from baseline ranging from −42.7% to −55.7% in ORION-9, −69.8% to −45.9% in ORION-10, and −60.8% to −38.2% in ORION-11.^17-19 In the ORION-9 and −11 trials, subgroups based on risk category (patients with ASCVD or an ASCVD risk equivalent) were reported. In both trials, the subgroup results were consistent with the overall population, with an LSM percentage difference in LDL-C of −53.6% (95% CI, −64.8 to −42.3) in ORION-9, and −53.3% (95% CI, −56.6 to −50.1) in ORION-11 for patients with ASCVD, and −47.4% (95% CI, −53.7 to 41.1) and −47.2% (95% CI, −56.1 to −38.3) for the ASCVD risk equivalent subgroup in ORION-9 and −11, respectively.^17,19 The population in ORION-11 with an ASCVD risk equivalent was considered not of interest, as the majority of the population was not included in the funding request.

Comprehensive forest plots summarizing the results of all subgroups evaluated in the ORION-9, ORION-10, and ORION-11 trials for percentage change in LDL-C from baseline at day 510 are provided in Figure 8, Figure 10, and Figure 12 in Appendix 3.

Time-Adjusted Percentage Change in LDL-C From Baseline After Day 90 and Up to Day 540

The time-adjusted percentage change in LDL-C from baseline after day 90 and up to day 540 was the co-primary end point of the ORION-9, −10, and −11 trials. Results are summarized in Table 13. Inclisiran showed greater reductions in LDL-C compared with placebo in all 3 trials: −38.08% (95% CI, −41.03 to −35.14) versus 6.22% (95% CI, 3.26 to 9.17), in ORION-9, −51.27% (95% CI, −53.00 to −49.54) versus 2.51% (95% CI, 0.77 to 4.25) in ORION-10, and −45.82% (95% CI, −47.52 to −44.13) versus 3.35% (95% CI, 1.65 to 5.05) in ORION-11.^17-19

The LSM difference from placebo also favoured inclisiran in all trials: −44.30% (95% CI, −48.48 to −40.12) in ORION-9, −53.78% (95% CI, −56.23 to −51.33) in ORION-10, and −49.17% (95% CI, −51.57 to −46.77) in ORION-11 (P < 0.0001 for all).^17-19

Sensitivity Analyses

The results of the sensitivity analyses for time-adjusted percentage change in LDL-C from baseline after day 90 and up to day 540 were consistent with the overall population.^17-19 Detailed outcome data for the sensitivity analyses are summarized in Table 29, Table 31, and Table 32 in Appendix 3.

Subgroup Analysis

Subgroup analyses were provided for the co-primary outcome of the time-adjusted percentage change in LDL-C after day 90 up to day 540 for the ORION-9, −10, and −11 trials. Results of the subgroup analyses of interest to this review, including baseline LDL-C, baseline statin treatment, statin intensity, and LMT use, were consistent with the overall patient population, ranging from −59.7% to −33.0% in ORION-9, −67.0% to −44.9% in ORION-10, and –58.7% to −35.4% in ORION-11.^17-19

In the ORION-9 and −11 trials, subgroups based on risk category (patients with ASCVD or an ASCVD risk equivalent) were reported. In both trials, subgroup results were consistent with the overall population, with an LSM percentage difference in LDL-C of −47.9% (95% CI, −56.2 to −39.6) and −50.9% (95% CI, −53.4 to −48.8) for the ASCVD populations in ORION-9 and −11, respectively, and −43.7% (95% CI, −48.5 to −38.9) and −42.3% (95% CI, −49.2 to −35.3) for the ASCVD risk–equivalent populations in ORION-9 and −11, respectively.^17,19 The ASCVD risk–equivalent population in ORION-11 was considered not of interest, as the majority of the population was not included in the funding request.

A comprehensive forest plot summarizing the results of all subgroups evaluated in the ORION-9, ORION-10, and ORION-11 trials for time-adjusted percentage change in LDL-C from baseline after day 90 and up to day 540 is provided in Figure 9, Figure 11, and Figure 13 in Appendix 3.

Absolute Change in LDL-C From Baseline to Day 510

Absolute change in LDL-C from baseline to day 510 was a key secondary outcome of the ORION trials, and the results are summarized in Table 13. The absolute reduction in LDL-C in the inclisiran groups was −58.95 mg/dL (95% CI, −64.75 to −53.15) in ORION-9, −56.18 mg/dL (95% CI, −58.47 to −53.90) in ORION-10, and −50.91 mg/dL (95% CI, −53.14 to −48.67) in ORION-11 while, in the placebo groups, the reduction was 9.94 mg/dL (95% CI, 4.10 to 15.78) in ORION-9, −2.06 mg/dL (95% CI, −4.36 to 0.24) in ORION-10, and 0.96 mg/dL (95% CI, −1.26 to 3.18) in ORION-11. The LSM difference from placebo favoured inclisiran in all trials; −68.89 mg/dL (95% CI, −77.11 to −60.67) in ORION-9, −54.12 mg/dL (95% CI, −57.37 to −50.88) in ORION-10, and −51.87 mg/dL (95% CI, −55.01 to −48.72) in ORION-11 (P < 0.0001 for all). ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.^17-19

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

The time-adjusted absolute change from baseline in LDL-C after day 90 up to day 540 was a secondary efficacy outcome of the ORION-9, −10, and −11 trials, and is summarized in Table 13. In the time-adjusted analyses for all trials, inclisiran demonstrated greater reductions in LDL-C compared with placebo: −56.58 mg/dL (95% CI, −60.98 to −52.17) versus 6.17 mg/dL (95% CI, 1.72 to 10.62) in ORION-9, −53.66 mg/dL (95% CI, −55.41 to −51.92) versus −0.39 mg/dL (95% CI, −2.14 to 1.37) in ORION-10, and −48.63 mg/dL (95% CI, −50.37 to −46.89) versus 0.31 mg/dL (95% CI, −1.42 to 2.04) in ORION-11. Compared with placebo, the time-adjusted absolute change from baseline after day 90 and up to day 540 ranged from −62.74 mg/dL (95% CI, −69.01 to −6.48) to −48.94 mg/dL (95% CI, −51.39 to −46.48) (P < 0.0001 for all). ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.^17-19

Global Lipid LDL-C Targets

At day 510, 158 (65.3%), 651 (83.4%), and 661 (81.6%) of inclisiran-treated patients in the ORION-9, −10, and −11 trials reached an LDL-C level of less than 100 mg/dL compared with 21 (8.8%), 387 (49.6%), and 425 (52.7%) placebo-treated patients, respectively. Similarly, 99 (40.9%), 581 (74.4%), and 564 (69.6%) of inclisiran-treated patients in the ORION-9, −10, and −11 trials reached LDL-C level of less than 70 mg/dL compared with 3 (1.3%), 119 (15.3%), and 104 (12.9%) placebo-treated patients, respectively. Note that some patients were counted under multiple categories.^17-19

In the ORION-9 study, a total of 159 (66.0%) inclisiran-treated patients achieved a 50% or greater reduction in LDL-C from baseline at any visit over the course of the study compared with 9 (3.8%) placebo-treated patients.¹⁷ In ORION-10, and ORION-11, 701 (91.4%) and 658 (81.9%) inclisiran-treated patients reached a 50% or greater reduction in LDL-C from baseline compared with 50 (6.5%) and 47 (5.9%) placebo-treated patients.^18,19

In ORION-9, at any visit, 186 (77.2%) inclisiran-treated patients achieved their corresponding LDL-C targets (LDL-C < 100 mg/dL or < 70 mg/dL) compared with 44 (18.4%) placebo-treated patients. In ORION-10, 722 (94.1%) inclisiran-treated patients achieved their LDL-C targets at any visit compared with 277 (36.1%) placebo-treated patients. In ORION-11, 741 (92.4%) inclisiran-treated patients achieved their corresponding LDL-C targets at any visit compared with 335 (41.9%) placebo-treated patients. In patients with ASCVD, at day 510, 31 (52.5%), 581 (84.1%), and 522 (81.7%) inclisiran-treated patients achieved their LDL-C target (LDL-C < 70 mg/dL) in ORION-9, −10, and −11, respectively, compared with 1 (1.4%), 119 (17.9%), and 103 (16.0%) placebo-treated patients, respectively.^17-19 In patients with HeFH (ORION-9), 115 (66.9%) inclisiran-treated patients and 14 (8.9%) placebo-treated patients achieved their LDL-C target (LDL-C < 100 mg/dL) at day 510.^17,19

Health-Related Quality of Life

No patient-reported outcomes or HRQoL outcomes were evaluated in the included trials.

Neurocognitive Assessments

Neurocognitive testing was not conducted in the ORION trials.

Change in Laboratory Parameters

Change in laboratory parameters, including the percentage change in total cholesterol, ApoB, non-HDL-C, and triglycerides from baseline to day 510, were key secondary outcomes in the ORION-9, −10, and −11 trials. Results are summarized in Table 14. In ORION-9, −10, and −11, the percentage reduction in total cholesterol using PMM for inclisiran was −25.11 (95% CI, −27.83 to −22.39), −33.56 (95% CI, −35.09 to −32.03), and −28.00 (95% CI, −29.40 to −26.60), respectively, with a mean difference from placebo of −31.77 (95% CI, −35.59 to −27.94; P < 0.0001), −33.13 (95% CI, −35.30 to −30.97; P < 0.0001), and −29.79 (95% CI, −31.78 to −27.81; P < 0.0001), respectively.^17-19 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. In ORION-9, −10, and −11, the percentage reduction in ApoB using PMM for inclisiran was −33.14 (95% CI, −35.91 to −30.36), −44.81 (95% CI, −46.52 to −43.10) and −38.15 (95% CI, −39.76 to −36.54), respectively, with mean differences from placebo of −36.06 (95% CI, −39.99 to −32.14; P < 0.0001), −43.09 (95% CI, −45.50 to −40.67; P < 0.0001), and −38.94 (95% CI, −41.21 to −36.67; P < 0.0001), respectively.^17-19 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. In ORION-9, −10, and −11, the percentage reduction in non-HDL-C for inclisiran using PMM was −34.93 (95% CI, −38.46 to −31.40), −47.41 (95% CI, −49.44 to −45.38), and −41.16 (95% CI, −43.09 to −39.24), respectively, with mean differences from placebo of −42.36 (95% CI, −47.32 to −37.40; P < 0.0001), −47.36 (95% CI, −50.25 to −44.47; P < 0.0001), and −43.32 (95% CI, −46.04 to −40.60; P < 0.0001), respectively.^17-19 ||||||||||||||||||||||||||||||||||||||||||||||||||||||. The percentage change in triglyceride levels was greater in the inclisiran groups compared with the placebo groups in all ORION trials, with a placebo-adjusted difference of 11.8%, 12.6%, and 7.0% in ORION-9, −10, and −11, respectively. Triglyceride levels were not key secondary end points and did not take into account the multiplicity of testing and the Hochberg procedure therefore, statistical significance was not assessed.^35,43

Harms

Only those harms identified in the review protocol are reported subsequently. Table 15 contains detailed harms data.

Treatment-Emergent Adverse Events

The incidence of TEAEs was consistent between inclisiran- and placebo-treated patients as well as across trials, with patients in both groups experiencing at least 1 TEAE (inclisiran versus placebo): 76.8% versus 71.7%, 73.5% versus 74.8%, and 82.7% versus 81.5% in ORION-9, −10, and −11, respectively.^17-19

The incidence and type of common TEAEs were similar in the placebo and inclisiran groups in all trials; however, the most common TEAEs varied across the 3 ORION trials. In ORION-9, the most common TEAEs 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%).¹⁷ The most common TEAEs in ORION-10 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%).¹⁸ In ORION-11, the most common TEAEs 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%).¹⁹ ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.^17-19

Serious Adverse Events

Treatment-emergent SAEs in ORION-9 occurred in 18 (7.5%) inclisiran-treated patients and 33 (13.8%) placebo-treated patients.¹⁷ The incidence of SAEs was higher in ORION-10 and −11, occurring in 175 (22.4%) and 181 (22.3%) inclisiran-treated patients, respectively, compared with 205 (26.3%) and 181 (22.5%) placebo-treated patients.^18,19 There was no difference in the frequency of treatment-emergent SAEs between the treatment groups in ORION-9, ORION-10, and ORION-11. Treatment-emergent SAEs in ORION-9 included mostly CV events; the most common events included unstable angina (1.0%) and myocardial ischemia (0.8%).¹⁷ The most common SAEs in ORION-10 were CV-related, with 2.4%, 1.7%, and 1.7% of patients experiencing coronary artery disease, congestive cardiac failure, or acute MI, respectively.¹⁸ As with the 2 other ORION trials, the most common SAEs in ORION-11 were also CV-related and included angina pectoris (1.7%), acute MI (1.4%), and unstable angina (1.4%).¹⁹ ||||||||||||||||||||||||||||||||||||||||||||　||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.^17-19

Withdrawal Due to Adverse Events

In ORION-9, 3 patients (1.2%) in the inclisiran group withdrew due to an AE. No patients in the placebo group withdrew due to an AE. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.¹⁷

The incidence of WDAEs in ORION-10 was similar across groups, occurring in 19 inclisiran-treated patients (2.4%) and 17 placebo-treated patients (2.2%). |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.¹⁸

The incidence of WDAEs in ORION-11 was similar to ORION-10, with 23 (2.8%) and 18 (2.2%) inclisiran- and placebo-treated patients, respectively, experiencing TEAEs that led to withdrawal. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||¹⁹

Notable Harms

Neurologic Events

Neurologic events and neurocognitive disorders are summarized in Table 15. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||　|||||||||||||||||||||||||||||||||.^17-19

Injection-Site Reactions

Injection-site reactions are summarized in Table 15. In all trials, fewer placebo-treated patients reported TEAEs at the injection site than those treated with inclisiran. The incidence of TEAEs at the injection site for inclisiran- and placebo-treated patients was 41 (17.0%) versus 4 (1.7%) in ORION-9, 47 (6.0%) versus 15 (1.9%) in ORION-10, and 62 (7.6%) versus 14 (1.7%) in ORION-11. Injection-site reactions were mild to moderate, and no severe reactions were seen across trials. One patient withdrew from the study due to injection-site reactions in the ORION-9 and ORION-10 inclisiran groups, while 2 patients in the ORION-11 inclisiran group withdrew from the study due to injection-site reactions. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.

Hypersensitivity Reactions

Hypersensitivity reactions are summarized in Table 15. TEAEs related to hypersensitivity did not differ between groups in all 3 trials. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||　||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.^17-19

Renal and Hepatic Safety

Renal and hepatic safety is summarized in Table 15. Renal events were not different between inclisiran and placebo groups across trials, |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.^17-19

||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||^17-19

Clinical Laboratory Evaluations

The incidence of clinically significant creatinine kinase changes was recorded as part of the clinical laboratory evaluation in ORION-9, −10, and −11. A detailed summary of clinically significant creatinine kinase changes at the end of the study is provided in Table 35 in Appendix 3. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.¹⁹

Critical Appraisal

Internal Validity

ORION-9, ORION-10, and ORION-11 were all phase III, double-blind RCTs. Appropriate methods for randomization (using interactive response technology), treatment allocation (stratified by country and current use of statins or other LMTs 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 within the studies and there was no imbalance in discontinuations, suggesting that attrition bias was limited. Moreover, unblinding was permitted only 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; overall, injection-site reactions were not common, and it is unclear what effect this would have had on the results and unblinding.

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 were 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 co-primary end point of percentage 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 current use of statins or other LMTs as covariates. Missing values in the inclisiran group were imputed under the assumption that their outcome was similar to the outcomes 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 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 treatment effect in favour of inclisiran over time. Results of the co-primary 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 percentage change in LDL-C.

The pre-specified power and sample size calculation for all ORION trials was identical and was based on the difference in change from baseline in LDL-C between the inclisiran and placebo groups being no less than 30 mg/dL, with a standard deviation of 20 mg/dL; however, the enrolled populations were much higher than what was defined by the power and sample size calculation. |||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. The additional patients enrolled in the ORION trials could have led to the overpowering of study results, whereby the higher number of patients enrolled may increase 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, any ethical or 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 of interest to this review were not accounted for.

Acceptable methods to account for multiplicity were used in all trials. The co-primary efficacy outcome was controlled for multiplicity using the family-wise error rate using a nested testing procedure first on the percentage change in LDL-C from baseline to day 510, and then on the time-adjusted percentage change in LDL-C from baseline after day 90 and up to day 540. The Hochberg procedure was applied for key secondary end points.^18,19,46 Other secondary end points and exploratory end points were not controlled for multiplicity or missing data, including the composite outcome of MACE, which was considered of clinical importance to this review. The proportion of patients reaching global lipid targets (LDL-C < 100 mg/dL or < 70 mg/dL) were secondary end points that were 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 proportions of patients achieving global lipid targets in both the inclisiran and placebo arms.^11,29,47

Subgroup analyses for efficacy and safety were pre-specified 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, those subgroups with a lower number of patients had wider, more imprecise CIs. Subgroups based on risk status (ASCVD or an ASCVD risk equivalent) were conducted for ORION-9 and ORION-11; however, the ASCVD risk–equivalent subgroup in ORION-11 was not considered 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 an ASCVD risk equivalent).

External Validity

The ORION-9, −10, and −11 trials aimed to enrol patients with ASCVD and/or an ASCVD risk equivalent and within specific cut-offs for serum LDL-C and triglyceride. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. Screening failures and inclusion criteria were considered appropriate for the ORION-10 and −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; 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, ORION-11 included a proportion of patients with ASCVD risk equivalents (13%), which were not part of the reimbursement population requested by the sponsor.

With the exception of ORION-10, the ORION trials were multinational; however, ORION-9 was the only study that enrolled Canadian patients (n = 23). The proportion of patients receiving high-intensity statins at baseline was as expected for patients with HeFH in ORION-9 (73.9%), as well as for the patients with ASCVD in ORION-10 (69.4%) and −11 (78.0%); however, the clinical expert believed that more patients with HeFH would be receiving ezetimibe compared with what was seen in ORION-9 (52.3%). Partial or complete intolerance to statins at baseline ranged from 11.4% to 25.3%, which was in line with the 15% to 20% proportion estimated by the clinical expert. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. The inclusion criteria in the ORION-9, −10, and −11 studies excluded patients if they had previously received or were currently receiving treatment with PCSK9 monoclonal antibodies within 90 days of screening, and the baseline characteristics of patients in the ORION trials did not include the proportion of patients who had prior treatment with PCSK9 inhibitors. The product monograph for inclisiran states that when transitioning from a PCSK9 inhibitor to inclisiran, the last dose of PCSK9 should be delivered and then, at the next scheduled date, inclisiran can be administered; however, the efficacy of switching from other PCSK9 inhibitors to inclisiran in terms of reducing LDL-C, CV-related morbidity, and mortality, remains uncertain. Despite this and, according to the clinical expert consulted by CADTH, the baseline demographic and medical characteristics of the ORION trials reflect the HeFH and ASCVD populations that are expected to use inclisiran in Canada.

All of the ORION studies were placebo-controlled trials and did not include an active comparator. This allows for adequate evaluation of the treatment effect of inclisiran; however, it may overestimate the treatment effects. Demonstration of effectiveness compared with another PCSK9 inhibitor would have allowed for better interpretation of efficacy results. Despite this, the clinical expert consulted by CADTH noted that the incremental improvements in LDL-C and differences between inclisiran and the 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 (i.e., statins, ezetimibe, blood pressure medication, diabetes medications); therefore, the differences seen were still notable. Given 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 inform on the efficacy of inclisiran were chosen based on validated laboratory assessments of lipids. They are considered widely accepted surrogates for clinically relevant outcomes and are reflective of 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 the trials for the PCSK9 inhibitors alirocumab and evolocumab were 12 to 24 weeks in duration and that effects on lipids are rapidly seen.¹¹ However, the included studies were not designed to assess important CV-related outcomes, including reductions in MACEs 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 for 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.¹⁶

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.

Indirect Evidence

Objectives and Methods for the Summary of Indirect Evidence

Due to the lack of direct evidence comparing inclisiran with other existing therapies as monotherapy, or as add-on therapy in the treatment of adult patients with HeFH or ASCVD, the sponsor submitted an ITC that was used to inform the pharmacoeconomic model.²⁰ The objective of this section is to summarize and critically appraise the methods and findings of the sponsor-submitted ITC comparing inclisiran with relevant drug comparators for the treatment of adult patients with HeFH or ASCVD with high LDL-C that is uncontrolled by MTD statins, with or without ezetimibe, or those with uncontrolled LDL-C who are statin-intolerant or contraindicated, with or without ezetimibe.

A focused literature search for NMAs dealing with hypercholesterolemia was run in MEDLINE All (1946–) and Embase (1974–) on April 14, 2021. No limits were applied to the search. Retrieval was not limited by publication date or by language. Articles were screened by 1 researcher for ITCs that met the patient, intervention, comparator, and outcome criteria listed in Table 5. In addition, the sponsor-submitted ITC was reviewed.

The literature search for NMAs identified 103 articles; however, no studies evaluated the efficacy and safety of inclisiran in patients with HeFH or ASCVD against relevant comparators.

Description of Indirect Comparison(s)

The sponsor submitted an ITC that compared the efficacy of inclisiran with relevant drug comparators in patients with HeFH or ASCVD (or an ASCVD risk equivalent). The sponsor first conducted a systematic literature review to evaluate various efficacy, safety, and HRQoL outcomes to assess the feasibility of conducting an NMA. Thirty-nine studies met the inclusion criteria of the systematic review and feasibility assessment, and 22 studies were sub-selected for inclusion in the NMA based on network connectivity and whether there were any differences in the study, patient, or outcome characteristics that were likely modifiers of the relative treatment effects.²⁰ Table 16 summarizes the available selection criteria specific to the ITC and NMA, as well as the methods for study selection for the systematic literature review.

ITC Methods

Objectives

The objective of the sponsor-submitted report was to conduct a feasibility assessment through a systematic literature review and, if possible, to conduct an ITC 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 who had an ASCVD risk equivalent).²⁰

Study Selection Methods

The sponsor-submitted NMA was informed by a systematic review of RCTs conducted in April 2020. The sponsor provided the protocol and plan for analyses in a separate report. Briefly, eligible publications were full-text, peer-reviewed RCTs. The planned method for identifying citations was through searches of MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials databases, among others. Study selection and data extraction were planned to be conducted by 2 independent reviewers with discrepancies resolved by discussion using the Covidence online screening tool.²⁰ Assessment of the quality of included studies was planned using the Cochrane risk-of-bias assessment tool; however, no quality assessment was included in the NMA report.

Table 17 summarizes the predefined study selection criteria for the systematic review in the sponsor-submitted ITC and NMA. The list of comparators and outcomes of interest included in the literature review was broader than that of the NMA; otherwise, the patient population was similar. No limitations on publication language were applied. The eligible patient population for the review included adults with HeFH or ASCVD with inadequate LDL-C control on MTD statins or who are statin-intolerant or contraindicated, which was identical to the NMA population. Multiple networks were constructed based on the HeFH, ASCVD, and ASCVD risk–equivalent population. The outcomes of interest to the NMA were percentage and absolute change in LDL-C at 24 weeks, total discontinuations and discontinuations due to AEs at 24 weeks, and percentage change in HDL-C at 24 weeks.²⁰

Feasibility Assessment

A feasibility assessment was conducted to review the studies identified in the systematic literature review, which included the following criteria:

• determination of a connected network comparing the treatments of interest regarding the outcomes of interest

• differences in the study, patient, or outcome characteristics across comparisons that are likely modifiers of the relative treatment effects.

The primary outcomes of interest for the NMA were percentage, absolute, and time-adjusted change from baseline in LDL-C; percentage change from baseline in HDL-C; total discontinuations; and discontinuations due to AEs.²⁰ Several study design, patient, and intervention characteristics were identified a priori as potential treatment-effect modifiers. Key assumptions and recommendations from the feasibility assessment for the approach used in the sponsor-submitted NMA are summarized in Table 18 and included the following:

Background Ezetimibe and Statins

||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. In the NMA, it was assumed that individual statins (atorvastatin, rosuvastatin, and simvastatin) had similar efficacy as background therapy, regardless of dose, and would not bias the results of the NMA. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.²⁰

CV Risk and Severity

Studies included in the feasibility assessment were inconsistent in their reporting of CV risk and severity, and definitions of risk equivalent varied across trials. Populations in the ORION trials included patients considered to have an ASCVD “risk equivalent,” defined by the presence of type 2 diabetes, FH, or a 20% or greater 10-year risk of a CV event as assessed by the Framingham Risk Score for CV disease or equivalent. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.²⁰

Treatment Dosing

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Time of Assessment and Follow-Up

Follow-up for the ORION trials were 540 days; however, other PCSK9 inhibitors had much shorter durations of follow-up. Twenty-four weeks was selected as the preferred base-case time point for multiple reasons. |||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||| 　|　 ||||||||||||||||||||||||||||| | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| | |||||| ||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. For safety outcomes, results were presented at end of study and, given the variation in follow-up, end-of-study outcomes were considered comparable if the duration of follow-up was 24 weeks or longer. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||.²⁰

ITC Analysis Methods

The NMA methods are briefly summarized in Table 19. The analyses were conducted within a Bayesian framework. A selection of both fixed- and random-effects analyses was 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, ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||.²⁰

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Results of the ITC

Summary of Included Studies

The results of the systematic review were included in a separate report. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

Results

HeFH Populations

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The network for the HeFH population on MTD statins is shown in Figure 5. A total of 7 trials were included in the network. ||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

Figure 5: Network Diagram for HeFH Populations on MTD Statin

HeFH = heterozygous familial hypercholesterolemia; LDL-C = low-density lipoprotein cholesterol; MTD = maximally tolerated dose.

Note: Interventions and placebo arms are in addition to background statin with or without other lipid-lowering therapy; no network is feasible for statin-intolerant patients.

Red text indicates the trial was excluded in a sensitivity analysis.

* Subgroup data for patients with HeFH were used in the analysis.

Source: Sponsor-submitted network meta-analysis.²⁰

Base-Case Results

Base-case results for the percentage change in LDL-C at 24 weeks, absolute change in LDL-C at 24 weeks, total discontinuations at 24 weeks or greater, discontinuations due to AEs at 24 weeks or greater, and percentage change in HDL-C at 24 weeks in the HeFH populations on MTD statin are summarized in Table 20.

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Sensitivity Analysis

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ASCVD and ASCVD Risk–Equivalent Populations on MTD Statins

The network for the ASCVD and ASCVD risk–equivalent populations on MTD statins is displayed in Figure 6. A total of 13 studies were included in the base-case network. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||　|　 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

Figure 6: Network Diagram for ASCVD and ASCVD Risk–Equivalent Populations on MTD Statin

ASCVD = atherosclerotic cardiovascular disease; MTD = maximally tolerated dose.

Note: Interventions and placebo arms are in addition to background statin with or without other lipid-lowering therapy.

Red text indicates the trial was excluded in a sensitivity analysis.

Grey text indicates the trial was included only in a sensitivity analysis.

Source: Sponsor-submitted network meta-analysis.²⁰

Base-Case Results

Base-case results for the percentage change in LDL-C at 24 weeks, absolute change in LDL-C at 24 weeks, total discontinuations at 24 weeks or greater, discontinuations due to AEs at 24 weeks or greater, and the percentage change in HDL-C at 24 weeks in the ASCVD and ASCVD risk–equivalent populations on MTD statins is summarized in Table 22.

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Sensitivity Analysis

The results of the sensitivity analyses, for percentage and absolute change in LDL-C at 24 weeks, are summarized in Table 23.

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ASCVD and ASCVD Risk–Equivalent Populations Intolerant to Statins

A total of 7 trials were included in the network for ASCVD and ASCVD risk–equivalent populations intolerant to statins (Figure 7). There were no closed loops.

Figure 7: Network Diagram for ASCVD and ASCVD Risk–Equivalent Populations Intolerant to Statins

ASCVD = atherosclerotic cardiovascular disease.

Note: Interventions and placebo arms are in addition to background statin with or without other lipid-lowering therapy.

Grey text indicates the trial was included only in a sensitivity analysis.

* Subgroup data for statin-intolerant patients to be used in the analysis.

Source: Sponsor-submitted network meta-analysis.²⁰

Base-Case Results

Table 24 summarizes the base-case results for the percentage change in LDL-C at 24 weeks, absolute change in LDL-C at 24 weeks, total discontinuations at 24 weeks or greater, discontinuations due to AEs at 24 weeks or greater, and percentage change in HDL-C at 24 weeks in the ASCVD and ASCVD risk–equivalent populations on MTD statins.

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