CADTH Reimbursement Review

Evinacumab (Evkeeza)

Sponsor: Ultragenyx Pharmaceutical Inc.

Therapeutic area: Homozygous familial hypercholesterolemia

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Ethics Review

Stakeholder Input

Clinical Review

Executive Summary

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

Table 1: Background Information of Application Submitted for Review

NOC = Notice of Compliance; q.4.w. = every 4 weeks.

Introduction

Familial hypercholesterolemia (FH) is a genetic disease characterized by markedly elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) from birth that persist throughout life and can lead to the early development of atherosclerotic cardiovascular disease (ASCVD). FH can be further subdivided into heterozygous FH (HeFH) and homozygous FH (HoFH), with HoFH being the more severe and rare form of the disease.^1-4 HoFH is characterized by profoundly elevated plasma levels of LDL-C from birth, putting people with HoFH at a significantly increased risk of early CV events (including myocardial infarction [MI], stroke, and heart failure); if HoFH is left untreated, people with the condition can be at risk of sudden cardiac death as early as childhood or adolescence.^5-10

Diagnosis of HoFH can be based on clinical criteria or genetic confirmation, though HoFH has historically been more commonly diagnosed based on clinical presentation, due to the limited availability of genetic testing in Canada. The Canadian Cardiovascular Society (CCS) position statement on FH¹ lacks specific guidance on diagnostic differentiation between HeFH and HoFH; however, clinicians in Canada use the clinical diagnostic features of HoFH outlined in the 2023 European Atherosclerosis Society (EAS) guidelines. These diagnostic features include untreated LDL-C levels greater than 10.0 mmol/L (400 mg/dL) or LDL-C levels greater than or equal to 8 mmol/L (300 mg/dL) while on conventional lipid-lowering therapies (LLTs). Additional clinical features include the presence of xanthomas before age 10 years of age or the presence of HeFH in both parents. Genetic confirmation of diagnosis is based on the identification of biallelic pathogenic variants at the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), PCSK9, or LDLRAP1, or in at least 2 such variants at different loci.¹¹

There are an estimated 145,000 people with FH in Canada,^3,5,9,12,13 though recent studies in unselected general populations suggest that HoFH may affect as many as 1 in 300,000 people,^3,14-17 and incidence may be higher in populations with a founder effect, such as has been observed in French Canadians, with an estimated prevalence of 1 in 250,000.¹⁸ There are approximately 80 known cases of HoFH in Canada; in 2022 there were 52 people with confirmed HoFH enrolled on the Canadian HoFH registry, with a majority (69%) found in Quebec, attributable predominantly to founder effects.¹⁹

People with HoFH are at a 100-fold elevated risk for MI compared to those without the condition.²⁰ People with untreated HoFH who have a complete loss of low-density lipoprotein (LDL) function rarely survive beyond their second decade, while those who have partial LDLR activity have a better prognosis, though most develop clinically significant ASCVD by age 30 years if the HoFH is left untreated.¹⁴

The overarching goal of therapy for HoFH is to lower LDL-C and, subsequently, the risk of ASCVD. The lowering of plasma cholesterol levels is known to reduce cardiovascular (CV) events, coronary heart disease (CHD) mortality, and all-cause mortality.²¹ Recommended lifestyle modifications, per the CCS guidelines on the diagnosis and treatment of dyslipidemias, include weight control, restriction of fat consumption to less than 30% of daily calories, consumption of 10 g to 20 g of fibre per day, and increased physical activity. Additional lifestyle changes may include smoking cessation and limiting alcohol intake.^22,23

Statins are the primary pharmacological intervention used to achieve control of LDL-C in patients with hypercholesterolemia. Most patients with hypercholesterolemia should be initiated on the maximally tolerated dose (MTD) of high-intensity statins (atorvastatin or rosuvastatin), with the goal of lowering LDL-C by at least 50%. When the LDL-C goal is unmet with statin therapy alone, treatment with add-on ezetimibe or bile acid sequestrants (or both) is recommended, with the goal of reducing LDL-C between 10% and 40% (average 20%).^24-27 If LDL-C goals are still not met, PCSK9 inhibitors (evolocumab) are available to patients meeting certain criteria as an adjunct treatment to diet, MTD statin, and ezetimibe.^1,12 However, given that traditional LLTs such as statins and PCSK9 inhibitors act by upregulating LDLR expression, they have little efficacy in patients with HoFH and virtually no efficacy in patients with 2 null LDLR alleles. Nearly all patients with HoFH will require extracorporeal LDL-C removal, particularly if LDL-C levels remain greater than 5 mmol/L despite treatment or if ASCVD is present. Either plasmapheresis or, preferably, LDL apheresis should be started as soon as technically feasible, usually before age 5 years and at least by age 8 years.¹

Evinacumab (Evkeeza) is a recombinant human monoclonal antibody that binds to and inhibits ANGPTL3, a member of the angiopoietin-like protein family that is expressed primarily in the liver and plays a role in the regulation of lipid metabolism by inhibiting lipoprotein lipase and endothelial lipase. Inhibition of ANGPTL3 via evinacumab lowers triglycerides and high-density lipoprotein cholesterol (HDL-C) by releasing lipoprotein lipase and endothelial lipase. Evinacumab reduces LDL-C independent of LDLR by promoting very low-density lipoprotein (VLDL) processing and clearance of VLDL remnants upstream of LDL formation through an endothelial lipase–dependent mechanism.

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of evinacumab (Evkeeza) 15 mg/kg every 4 weeks as an adjunct to diet and other LDL-C–lowering therapies for the treatment of adult and pediatric patients aged 5 years and older with HoFH.

Stakeholder Perspectives

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

Patient Group Input

CADTH reviewed 1 joint patient input from the Canadian Heart Patient Alliance and the Canadian Organization for Rare Disorders. Information was gathered via an online survey that ran from April 12 to May 7, 2023, as well as individual interviews conducted with patients with HoFH and their caregivers. All respondents (N = 18) resided in Canada, mostly in Ontario (12 [66.7%]), with 3 (16.7%) each in British Columbia and Quebec. About 75% of respondents had experienced severe (very high) levels of LDL-C, and 25% reported moderate levels of LDL-C. Around 50% of respondents reported that they had experienced moderate or severe CV events, including atherosclerosis, stroke, atrial fibrillation, and/or cardiac infarction, and half the patients had experienced severe chest pains and had xanthomas. Patients and caregivers highlighted that living with HoFH was associated with stress due to the physical symptoms and the uncertainty or unpredictability of the future, with younger patients noting that HoFH impacts their education and social life, partly because of the time required for treatment. Patients expressed the need for treatment options that can reliably, consistently, and sustainably control LDL-C at normal or near-normal levels, allowing them to experience fewer spikes, reducing the frequency and the need for apheresis, and reducing the risk of CV events. Patients questioned the effectiveness of current treatment options (apheresis, statins, and other medications) in managing their LDL-C levels and highlighted concerns about having to undergo surgery because of future CV events, further impacting their quality of life (QoL) and life expectancy. Of the 18 respondents who provided input, 6 reported having access to or experience with evinacumab through a clinical trial, compassionate access program, or research study. Patients indicated that they were satisfied with evinacumab, as treatment consistently lowered their LDL-C levels and improved their health-related quality of life (HRQoL) through reduced frequency of apheresis, improvements in energy, and the ability to participate in social and family events and attend school. Additionally, there were no reports of serious adverse events (SAEs) following the use of evinacumab.

Clinician Input

Input From Clinical Experts Consulted by CADTH

The information in this section is based on input received from a panel of 4 clinical specialists consulted by CADTH for the purpose of this review.

HoFH is a rare disease, diagnosed based on standard, well-established clinical and genetic criteria, although genetic confirmation is not required. People with HoFH present at an early age with extremely elevated LDL-C levels (untreated LDL-C greater than or equal to 10 mmol/L), as well as other clinical characteristics, including the presence of xanthomas. The clinical experts noted that there are currently multiple established guidelines for the management of dyslipidemia and highlighted the recent publication of the EAS consensus statement on HoFH. The experts noted that current guideline-recommended LDL-C thresholds are pragmatic and remain well above the acceptable level for patients without hypercholesterolemia. Per the current guidelines, the target LDL-C level for patients with HoFH is below 2.5 mmol/L; however, the experts agreed that this value is pragmatic and arbitrary, being based on other treatments and clinical trial criteria.

The clinical experts highlighted that survival for patients with HoFH has nearly doubled in a generation due to the LLTs available; however, they noted that repeated CV events, including MI, aortic valve stenosis, aortic root disease, and the need for revascularization, have increased. As such, the clinical experts emphasized that the main goal of treatment for patients with HoFH is to reduce LDL-C aggressively and safely over the longest term possible to prevent premature CV disease (CVD). In the pediatric population, the goal of LDL-C–lowering treatment is to prevent or delay ASCVD and obviate the need for or reduce apheresis. For adults, the goal of LDL-C–lowering treatment is to slow or halt ASCVD and potentially reverse it and its progression to clinically manifest CVD.

Most currently available pharmacological treatments only target the function of LDLR, rendering them less effective in patients with HoFH; they are more effective in patients with residual LDLR function, rather than “null” mutations (i.e., where there is no functional LDLR). The clinical experts noted that once a patient is diagnosed with HoFH, they are immediately put on MTD statin and on ezetimibe therapy. In most cases, this combination is insufficient to achieve the desired LDL-C goals. To further reduce LDL-C levels, PCSK9 inhibitors may be tried; however, the experts noted that given the pathophysiology of HoFH and the mechanism of action of PCSK9 inhibitors, response may be limited, though treatment with PCSK9 inhibitors should still be attempted. Often statins, ezetimibe, and PCSK9 inhibitors do not achieve sustained and significant reductions of LDL-C to levels below 2.5 mmol/L and/or a 50% lowering of LDL-C. If LDL-C levels are still above the goal, other treatment options — including lomitapide with or without extracorporeal removal of circulating LDL-C — may be attempted. However, these other treatment options have a notable impact on HRQoL: lomitapide is associated with the need for severe dietary restrictions as well as with adverse reactions and poor tolerability or compliance; extracorporeal removal of LDL-C, while effective, is extremely invasive, burdensome, and associated with a rebound period where LDL-C levels rise to baseline, requiring recurrent and sustained treatment cycles. The experts highlighted the need for a drug that is safe and effective and can lower baseline levels to a similar degree to that achieved with pheresis, without the same burden. The experts also noted that not all patients are able to access the full armamentarium of treatments available, and access to pheresis may be limited in Canada, with only 4 centres in the country (Toronto, London, Quebec City, and Edmonton). An alternative, plasmapheresis, which is more widely available, is considered a less optimal substitute for LDL apheresis.

The experts highlighted that evinacumab would likely be used as an add on to MTD statin, ezetimibe, and/or PCSK9 inhibitors, with the hope of supplanting lomitapide and either delaying or reducing the frequency of pheresis.

The experts highlighted that the selection of patients most in need of intervention with evinacumab is not entirely based on disease characteristics but that intervention with evinacumab would be preferred in patients with an LDL-C level greater than 2.5 mmol/L, despite receiving maximally tolerated therapy. The experts further noted that evinacumab would be preferentially used in patients receiving or being considered for lomitapide or those on or being considered for apheresis, owing to the poor risk-benefit profile of lomitapide and the burden of extracorporeal LDL-C removal. Per the clinical experts, the patients most likely to benefit from treatment with evinacumab are those diagnosed with HoFH who have had limited or inadequate response to available LLTs. In addition to the treatments available, patients with ASCVD, aortic valve disease, or genetic documentation of 2 pathogenic variants are subsets of patients at high risk for whom evinacumab might be considered. The experts noted that there are no patients with HoFH that they would not consider for treatment with evinacumab and that it is highly unlikely that patients with HoFH would be able to achieve desirable LDL-C targets on conventional statin and ezetimibe therapy alone.

The clinical experts agreed that the most important outcome of treatment is the reduction of CV morbidity or mortality; however, they noted that reduction in LDL-C is the most reasonable surrogate outcome used by clinicians to avoid all downstream ASCVD complications. Additionally, the clinical experts noted that current clinical trials aim to address important outcomes used in clinical practice and that measuring event-driven outcomes is unreasonable in this population due to the rarity of the disease and the length of time before events arise. Additionally, from a functional perspective, avoidance of pheresis options would be a measure of success, though there are currently no data to demonstrate this potential benefit. While acknowledging the lack of data, the experts mentioned that patients should be stable on evinacumab for 6 months before any attempt to reduce the frequency of or remove pheresis.

The clinical experts agreed that treatment would be discontinued in patients who experienced severe adverse events (AEs), including anaphylactic or infusion reactions, that are unable to be managed. Additionally, the experts agreed that any new AEs identified could be cause for discontinuation, given the small sample size included in the trials for evinacumab. The experts noted that progression of atherosclerosis, major adverse cardiac events, or lack of response to treatment may still occur with sustained treatment; however, the experts stated that such progression would not prompt discontinuation of treatment. Although there is no strict definition for lack of response in this population, the experts highlighted that arbitrary LDL-C cut offs would be chosen to determine an acceptable LDL-C reduction, though this would be contextual for each patient. However, the experts also emphasized that it would be inappropriate to discontinue or deny access to therapies that provide any safe lowering of LDL-C. For example, the experts noted that a treatment offering patients a 20% reduction in LDL-C might be less than an arbitrary 30% cut-off; however, the experts agreed that they would not likely discontinue treatment in such as case and would not consider a 20% reduction in LDL-C as a lack of efficacy.

Patients with HoFH are under the care of specialists with special qualifications in dyslipidemia (e.g., endocrinologists, cardiologists, lipidologists), and treatment would occur within the specialist facilities of that individual or facilities accessible to that individual. Patients with HoFH are also under the care of a lipid specialist and are seen as often as every 3 months, and at minimum every 6 months. During pheresis therapy, lipid profiles are conducted before and following pheresis treatment; as such, LDL-C is routinely tracked. The experts noted that because of the IV infusion, an infusion setting is required as infusion reactions and flu-like reactions may occur. For patients receiving pheresis treatments, evinacumab would be easiest to administer where extracorporeal machines are located. The experts also noted that vascular access in children may pose a potential challenge. Given the dispersion of the patient population, the experts noted that co-management with general practitioners could be envisioned and that administration of evinacumab may be possible, though under the remote supervision of a specialist. The experts also highlighted that experience with evinacumab is limited; thus, moving treatment into the community setting may be possible in the future, though not likely to occur yet.

Clinician Group Input

One clinician group, Familial Hypercholesterolemia Canada, provided input for this review. Information from this group was gathered through the collective clinical experience of 7 clinical experts, published literature, and congress proceedings. Overall, the clinician group noted that there is an unmet need for equitably accessible therapies that safely and effectively treat HoFH. The clinician group highlighted that current treatment options (statins, ezetimibe, and PCSK9 inhibitors, with or without plasmapheresis or apheresis) are inadequate in lowering LDL-C in patients with HoFH due to lack of efficacy and differences in mechanism of action (statins, ezetimibe, and PCSK9 inhibitors), lack of tolerability (lomitapide), and invasiveness in the form of reduced HRQoL and disruption to patients’ and families’ daily lives (apheresis and plasmapheresis). Additionally, the clinician group highlighted the lack of availability of LDL apheresis and plasmapheresis, which are limited to major academic centres, resulting in additional travel burden and creating inequities in level of care based on patients’ geographic location across Canada. Patients best suited for treatment with evinacumab, according to the clinician group, are those in whom target levels of LDL-C are not reached with current treatments or those with progressive CVD, despite the use of current treatments. The clinician group indicated that evinacumab would likely be used as a fourth-line therapy, after statins, ezetimibe, and PCSK9 inhibitors, and suggested that evinacumab may eliminate or reduce the need for plasmapheresis or apheresis, and possibly for lomitapide. In line with the clinical experts consulted by CADTH, the clinicians from Familial Hypercholesterolemia Canada considered reduction in LDL-C levels to be the most important outcome of treatment. The clinician group cited a sustained reduction in LDL-C greater than 20% to 30% to be a meaningful response to treatment. Additional important outcomes for assessing response to treatment included reduction in the frequency of apheresis or plasmapheresis. The clinician group noted that intolerable side effects would be the primary factor when deciding to discontinue treatment.

Drug Program Input

The drug programs identified the following jurisdictional implementation issues: relevant comparators, considerations for initiation of therapy, considerations for prescribing of therapy, generalizability, and care provision issues. Refer to Table 5 for more details.

Clinical Evidence

Systematic Review

Description of Studies

Two studies — the CL-1629 (ELIPSE) trial and the CL-17100 trial — were included in this review. The ELIPSE trial was a pivotal, phase III, double-blind, randomized placebo-controlled trial designed to evaluate the efficacy and safety of evinacumab versus placebo in pediatric and adult patients with HoFH. A total of 65 patients were randomized 2:1 to evinacumab 15 mg/kg every 4 weeks or matching placebo. A total of 3 patients were enrolled from Canadian investigative sites. The primary outcome of the ELIPSE trial was the change from baseline in LDL-C at week 24. Secondary outcomes included the percent change from baseline to week 24 in Apo B, non-HDL-C, and total cholesterol; the proportion of patients with a greater than or equal to 30% and a greater than or equal to 50% reduction in LDL-C at week 24; the absolute change from baseline in LDL-C to week 24; the proportion of patients with LDL-C less than 100 mg/dL (2.59 mmol/L) at week 24; and the proportion of patients who meet European Union (EU) or US apheresis eligibility criteria at week 24.

The CL-17100 study, which was considered a supportive trial for this review, included 3 parts (Parts A, B, and C). Part A was a phase Ib, single-arm, single-dose, pharmacokinetic and pharmacodynamic study consisting of a 16-week open-label treatment period; it enrolled 6 patients with HoFH. Only Parts B and C were of interest to this review. Part B was a 24-week, phase III, single-arm, open-label study to assess the efficacy and safety of evinacumab in patients aged 5 to 11 years with HoFH. A total of 14 patients were enrolled into Part B, and no patients from Part A were enrolled into Part B. Upon completion of Part B, all patients continued into Part C. Part C is an ongoing extension period that consisted of the 20 patients who completed Part A (N = 6) and Part B (N = 14). Part C consisted of a 48-week treatment period and a 24-week follow-up period after the last dose of evinacumab. The dosage in Part C was the same as the dosage in Part B: 15 mg/kg IV every 4 weeks. The data cut-off dates for Parts B and C were January 31, 2022, and June 2, 2022, respectively. The primary outcomes of Parts B and C were identical to the ELIPSE trial, with secondary outcomes of percent change from baseline to week 24 in Apo B, non-HDL-C, and total cholesterol; the proportion of patients with a greater than or equal to 50% reduction in LDL-C at week 24; the absolute change from baseline in LDL-C to week 24; and the proportion of patients with LDL-C less than 100 mg/dL (2.59 mmol/L) at week 24.²⁸

In the ELIPSE trial, there was a difference between the evinacumab and placebo groups in terms of age at baseline, with a mean age of 44.3 years (standard deviation [SD] = 16.8) in the evinacumab group compared to 36.7 years (SD = 11.52) in the placebo group. Only 1 patient in each treatment group was younger than 18 years. In line with the difference in age, there was also a difference in mean time from diagnosis of HoFH to randomization: 16.15 years (SD = 14.562) in the evinacumab group compared to 10.65 years (SD = 12.537) in the placebo group. A total of 48.8% of patients had homozygous LDLR mutations in the evinacumab group compared to only 31.8% in the placebo group, while fewer patients had compound heterozygous LDLR mutations in the evinacumab group than in the placebo group (27.9% versus 36.4%). Most patients received at least 3 LLTs at baseline (69.8% in the evinacumab group versus 50.0% in the placebo group), consisting mostly of the combination of statin plus ezetimibe and a PCSK9 inhibitor (48.8% in the evinacumab group versus 36.4% in the placebo group). More patients in the evinacumab group received lomitapide than in the placebo group (25.6% versus 13.6%). The patients’ lipid parameters at baseline were comparable across treatment groups. (For the evinacumab group versus the placebo group, the mean values of these parameters were as follows: LDL-C = 259.5 mg/dL versus 246.5 mg/dL; Apo B = 169.1 mg/dL versus 175.9 mg/dL; non-HDL-C = 281.9 mg/dL versus 269.9 mg/dL; and total cholesterol = 325.6 mg/dL versus 315.9 mg/dL.)²⁹

The CL-17100 study was conducted in patients aged 5 to 11 years with HoFH. The mean age of the patients enrolled in Part B of the CL-17100 study was 9.1 years (SD = 1.94). Most patients (57.1%) were white females. Most patients (71.4%) had compound heterozygous mutations, and only 50% of patients had received prior apheresis at baseline. Nearly all patients were treated with statins (85.7%) and ezetimibe (92.9%) at baseline, and only 2 patients (14.3%) received lomitapide. The patients’ lipid parameters at baseline were similar to those in the ELIPSE trial, with mean values as follows: LDL-C of 263.7 mg/dL, Apo B of 168.2 mg/dL, non-HDL-C of 282.2 mg/dL, and total cholesterol of 315.5 mg/dL.²⁸

Efficacy Results

Percent Change From Baseline in LDL-C

During the 24-week double-blind period of the ELIPSE trial, the least squares mean (LSM) percent change from baseline with evinacumab was –47.1% (standard error [SE] = 4.6), compared to 1.9% (SE = 6.5) with placebo. The LSM difference (LSMD) between evinacumab and placebo in percent change from baseline in LDL-C at 24 weeks was –49.0% (95% confidence interval [CI], –65.0 to –33.1), favouring evinacumab. During the open-label treatment period of the ELIPSE trial, the LSM percent change in LDL-C at 48 weeks in the open-label treatment period was –46.31% |||| ||||||. Results of the sensitivity analyses and subgroup analyses by background LLT, apheresis status, baseline LDL-C level, and HoFH genotype were consistent with the primary analysis, in favour of evinacumab.²⁹

In the CL-17100 study, the results for LSM change from baseline in LDL-C with evinacumab from Part B and from the pooled Part B and C were consistent with the double-blind period of the ELIPSE trial, with a percent change of –48.32% |||| ||||||| ||| ||||||| |||| ||||||| at 24 weeks, respectively.²⁸

Absolute Change From Baseline in LDL-C

The absolute change from baseline in LDL-C during the 24-week double-blind treatment period of the ELIPSE trial was –134.7 mg/dL (SE = 12.4) in the evinacumab group compared to –2.6 mg/dL (SE = 17.6) in the placebo group, favouring evinacumab (LSMD = –132.1 mg/dL; 95% CI, –175.3 to –88.9; P < 0.0001). In the open-label treatment period, the LSM absolute change from baseline in LDL-C at 48 weeks was –134.3 mg/dL (SD = 117.33).²⁹

In Part B of the CL-17100 study, the LSM absolute change from baseline in LDL-C was –131.9 mg/dL (SD = 30.0).²⁸

Proportion of Patients With Greater Than or Equal to 30% Reduction in LDL-C

In the 24-week double-blind treatment period of the ELIPSE trial, 83.7% of patients in the evinacumab group and 18.2% of patients in the placebo group experienced a greater than or equal to 30% reduction in LDL-C, favouring evinacumab (odds ratio [OR] = 25.2; 95% CI, 5.7 to 110.5; P < 0.0001).²⁹

The proportion of patients with a greater than or equal to 30% reduction in LDL-C at week 24 was not evaluated in the open-label treatment period of the ELIPSE trial or in the CL-17100 study.

Percent Change From Baseline in Apo B

In the ELIPSE trial, during the 24-week double-blind treatment period, the LSM percent change from baseline in Apo B was –41.4% (SE = 3.3) with evinacumab compared to –4.5% (SE = 4.8) with placebo, favouring evinacumab (LSMD = –36.9%; 95% CI, –48.6 to –25.2). The LSM percent change from baseline in Apo B at 48 weeks in the open-label treatment period was –40.83% (SD = 26.150).²⁹

In the CL-17100 study, the LSM percent change from baseline in Apo B with evinacumab for Part B and for the pooled Part B and C was –41.32% (SD = 33.541) ||| ||||||| |||| |||||||, respectively.²⁸

Proportion of Patients With LDL-C Less Than 100 mg/dL (2.59 mmol/L)

In the double-blind period of the ELIPSE trial, the proportion of patients with LDL-C less than 100 mg/dL (2.59 mmol/L) at 24 weeks was 46.5% in the evinacumab group compared to 22.7% in the placebo group (OR = 5.7; 95% CI, 1.3 to 24.9; P = 0.0203).²⁹

The proportion of patients with LDL-C less than 100 mg/dL was not evaluated in the open-label treatment period of the ELIPSE trial or in the CL-17100 study.

Proportion of Patients With LDL-C Less Than 70 mg/dL (1.81 mmol/L)

In the double-blind period of the ELIPSE trial, the proportion of patients with LDL-C less than 70 mg/dL (1.81 mmol/L) at 24 weeks was 27.9% in the evinacumab group compared to 4.5% in the placebo group (OR = 20.9; 95% CI, 1.6 to 276.8; P = 0.0209).²⁹

The proportion of patients with LDL-C less than 70 mg/dL was not evaluated in the open-label treatment period of the ELIPSE trial or in the CL-17100 study.

Proportion of Patients Who Met US Apheresis Criteria

In the double-blind period of the ELIPSE trial, the proportion of patients who met US apheresis eligibility criteria at 24 weeks was 7.0% in the evinacumab group compared to 22.7% in the placebo group (OR = 0.1; 95% CI, 0.0 to 0.3; P = 0.0845). Statistical hypothesis testing was terminated at this end point in the ELIPSE trial because statistical significance was not reached.²⁹

The proportion of patients who met US apheresis eligibility criteria was not evaluated in the open-label treatment period of the ELIPSE trial or in the CL-17100 study.

Proportion of Patients Who Met EU Apheresis Criteria

In the double-blind period of the ELIPSE trial, the proportion of patients who met EU apheresis eligibility criteria at 24 weeks was 32.6% in the evinacumab group compared to 77.3% in the placebo group (OR = 0.1; 95% CI, 0.0 to 0.3).²⁹

The proportion of patients who met EU apheresis eligibility criteria was not evaluated in the open-label treatment period of the ELIPSE trial or in the CL-17100 study.

EQ-5D

In the double-blind period of the ELIPSE trial, the mean EQ-5D utility score at 24 weeks was |||||| points (SD = ||||) for evinacumab and |||||| points (SD = ||||) for placebo, representing a mean change from baseline of ||||||| points (SD = ||||) with evinacumab and ||||||| points (SD = ||||) with placebo.²⁹

Quality of life was not evaluated in the open-label treatment period of the ELIPSE trial or in the CL-17100 study.

Mortality (All-Cause and CV-Related)

All-cause and CV-related mortality were not evaluated in the ELIPSE or CL-17100 studies.

CV-Related Morbidity

CV-related morbidity outcomes, such as the incidence of resuscitated cardiac arrest, nonfatal MI, and stroke, were not evaluated in the ELIPSE or CL-17100 studies.

Harms Results

In the ELIPSE trial, the incidence of treatment-emergent adverse events (TEAEs) was lower for patients in the evinacumab group than for patients in the placebo group during the double-blind treatment period (65.9% versus 81.0%). In the open-label treatment period of the ELIPSE trial, the incidence of TEAEs for patients receiving evinacumab (73.4%) was higher than in the double-blind treatment period. The most common TEAEs by preferred term in patients treated with evinacumab versus placebo were nasopharyngitis (15.9% versus 23.8%) and influenza-like illness (11.4% versus 0.0%). In the open-label treatment period, the most frequently reported TEAEs included nasopharyngitis and headache (9.4% each). SAEs in the ELIPSE trial occurred in 2 patients (4.5%) in the evinacumab group and consisted of urosepsis (1 [2.3%]) and attempted suicide (1 [2.3%]). There were no SAEs in the placebo group. There were no withdrawals due to AEs and no deaths reported during the ELIPSE trial. In terms of notable harms, 4 patients (9.1%) and 3 patients (14.3%) experienced allergic events and 3 patients (6.8%) and 1 patient (4.8%) experienced infusion-related reactions (IRRs) in the evinacumab and placebo groups, respectively, of the double-blind treatment period of the ELIPSE trial.²⁹

In the CL-17100 study, nearly all patients treated with evinacumab experienced at least 1 TEAE (||||%). The most frequent individual AEs by preferred term included headache (||||%) and nasopharyngitis (||||%). |||||||||| ||||||| experienced an SAE of tonsillitis. There were |||| withdrawals due to AEs or deaths reported during the CL-17100 study. Notable harms of general allergic events occurred in ||||| patients (||||%), and |||| patients had IRRs.²⁸

Critical Appraisal

The ELIPSE trial was a first-in-class, phase III, placebo-controlled randomized controlled trial (RCT) that included both double-blind and open-label treatment periods. Appropriate methods were used for randomization (using interactive response technology), treatment allocation (stratified by apheresis treatment and by region), and maintenance of blinding to treatment assignment, thereby reducing selection, performance, and detection biases. The CL-17100 study was an open-label, single-arm study of evinacumab in patients with HoFH aged 5 to 11 years. The choice to conduct a single-arm trial in the younger population was justified considering the rarity of the indication and the age of the participants; however, the noncomparative nature negates the ability to draw definitive conclusions on the effectiveness of evinacumab due to the small sample size and the chronic progression of HoFH. As such, the strength and interpretability of the results for this group of patients are limited. Dropouts and missing data in the ELIPSE and CL-17100 studies were low. The primary end point of the ELIPSE trial used a mixed-effect model with repeated measures (MMRM) to account for missing data under the missing at random assumption, which may not hold in this trial setting and may lead to overconfidence in the effect size. The sensitivity analyses used a pattern mixture model (PMM) to account for nonignorable missingness; overall, though, the amount of missing data was minimal and unlikely to impact the results. Acceptable methods to account for multiplicity were used in the ELIPSE trial. The primary and key secondary end points were controlled for multiplicity at the 0.05 level using a hierarchical testing sequence. However, statistical significance was not achieved for the end point of proportion of patients who meet US apheresis eligibility criteria; thus, the multiple testing procedure failed, and all subsequent outcomes (proportion of patients with LDL-C less than 100 mg/dL and proportion of patients who meet EU apheresis eligibility criteria) should only be viewed as supportive. Though they generally supported the primary analysis, the subgroup analyses in the ELIPSE trial and the CL-17100 study were not statistically powered to detect within-group or between-group differences; thus, the results from the subgroup analyses should be interpreted as supportive evidence only for the overall effect of evinacumab.

The clinical experts consulted by CADTH considered the inclusion and exclusion criteria for the ELIPSE and CL-17100 studies appropriate, though the clinical experts highlighted that genetic confirmation of HoFH does not always occur. Both the ELIPSE and CL-17100 studies were multinational studies; however, the ELIPSE trial was the only study to enrol patients living in Canada (N = 3), though given the low number of patients living in Canada enrolled, generalizability based on geography cannot be assumed. HoFH is a rare disease, which expectedly resulted in the small sample sizes in the ELIPSE and CL-17100 studies. The ELIPSE trial included 65 patients with HoFH, and the CL-17100 study included 20 patients with HoFH. The clinical experts noted that, in their experience, the populations included in the trials, with regard to the age of the patients and the LDL-C levels at baseline, were generally in line patients treated in clinical practice in Canada. The chosen comparator of placebo in the ELIPSE study was appropriate and aligned with the recommended standard of care guidelines for HoFH in Canada; the clinical experts noted that standard of care consists of MTD statin, ezetimibe, and a PCSK9 inhibitor. The clinical experts noted that the proportion of patients receiving LLTs was in line with the general population of patients with HoFH in Canada, though the proportion of patients in the ELIPSE trial receiving PCSK9 inhibitors was higher than in Canadian clinical practice owing to the difficulty in accessing PCSK9 inhibitors in Canada. There were minor differences in lomitapide use at baseline, with only 11 patients (25.6%) in the evinacumab group and 3 patients (13.6%) in the placebo group receiving lomitapide, though this was potentially related to the rarity of the disease and to the study design, as differences among patients may be more noticeable in studies with small sample sizes. The outcomes used to provide information on the efficacy of evinacumab in the ELIPSE and CL-17100 studies were based on validated laboratory assessments of lipids and are widely accepted surrogates for clinically relevant CV outcomes and are important in guiding treatment decisions in Canadian clinical practice in patients with HoFH. In addition to the well-established lowering of LDL-C, the most valuable outcomes to patients with HoFH include reduction in the risk of CV events and reduction of the need for apheresis. The included studies were not designed to assess important CV-related outcomes, including reductions in major adverse cardiac events and in all-cause and CV-related mortality, though the clinical experts consulted by CADTH noted that measuring event-driven outcomes such as these is difficult in HoFH due to the rarity of the disease. Additionally, impact on HRQoL was an exploratory outcome of the ELIPSE trial and was not evaluated in the CL-17100 study. The clinical experts noted that reduction in the burden of apheresis requirements is believed to improve patients’ HRQoL; however, the measurement of this in the available evidence was not captured. The clinical experts emphasized that the duration of the ELIPSE and CL-17100 studies (24 weeks) was considered appropriate for assessing lipid-related outcomes given that the effects on lipids are rapidly seen; however, they noted that the 24-week duration of the included studies was insufficient to determine the impact of evinacumab on CV-related morbidity and mortality and on HRQoL.

GRADE: Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For the pivotal studies and RCTs identified in the sponsor’s systematic review, Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) was used to assess the certainty of the evidence for the outcomes considered most relevant to inform CADTH’s expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE working group.^30,31 Under the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.

The selection of outcomes for the GRADE assessment was based on the sponsor’s summary of clinical evidence, consultation with clinical experts, and input received from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members: reduction in LDL-C levels (percent change from baseline in LDL-C at 24 weeks, absolute change in LDL-C at 24 weeks, proportion of patients with ≥ 30% reduction in LDL-C at 24 weeks, proportion of patients who meet US apheresis eligibility criteria at 24 weeks, proportion of patients with LDL-C < 100 mg/dL [2.59 mmol/L] at 24 weeks, proportion of patients who meet EU apheresis eligibility criteria at 24 weeks, proportion of patients with LDL-C < 70 mg/dL [1.81 mmol/L] at 24 weeks); reduction in other lipid parameters (percent change from baseline in Apo B at 24 weeks); and improved HRQoL (change from baseline in EQ-5D utility score at 24 weeks).

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null. The target of the certainty of evidence assessment was the presence of a clinically important reduction of LDL-C (percent and absolute change in LDL-C) against thresholds informed by treatment guidelines and clinical expert opinion. Other targets for the certainty of evidence assessment were the presence or absence of any (non-null) effect for the proportion of patients achieving lipid targets (i.e., percent change from baseline in Apo B, proportion of patients with a ≥ 30% reduction in LDL-C, proportion of patients with LDL-C < 100 mg/dL or < 70 mg/dL, proportion of patients who meet US or EU apheresis criteria, and HRQoL measured by the EQ-5D).

Results of GRADE Assessments

Table 2 shows the detailed GRADE summary of findings for evinacumab versus placebo for outcomes in the pivotal ELIPSE trial of adolescent and adult patients with HoFH. Table 3 shows the narrative GRADE summary of findings for evinacumab in the pediatric population of the CL-17100 study and the outcomes from the ELIPSE trial that were unable to be populated in Table 2.

Long-Term Extension Studies

Description of Studies

The CL-1719 study was a key long-term extension study submitted by the sponsor. The CL-1719 study is an ongoing long-term extension study evaluating the safety, tolerability, and efficacy of evinacumab in patients with HoFH, some of whom had previously participated in an evinacumab study (the continue evinacumab group) and some of whom were naive to evinacumab (the new evinacumab group). All patients received 15 mg/kg of evinacumab, intravenously, every 4 weeks for 24 months. The study consisted of a run-in phase, a screening phase, a treatment period, and a 24-week follow-up period. The study duration ranged from 26 weeks up to approximately |||| years. By the interim data cut-off date (||||| ||| ||||), ||| patients had been enrolled in the total study population (consisting of the adult and adolescent populations), || patients (||||%) had completed the treatment period, || patients (||||%) were ongoing in the treatment period, and || patients (||||%) had discontinued. The mean age of the patients was |||| years; || adolescent patients (||||%) had been enrolled.

Efficacy Results

Reductions in lipid parameters observed early in the treatment course in the total study population were maintained with longer-term evinacumab treatment of up to at least ||| weeks (mean percent change from baseline at week ||| was ||||||% for LDL-C and ||||||% for Apo B).||||| |||| |||||||||| || ||||||||||| |||||||| || ||||| ||||| ||| || ||| ||||| |||||||| |||||||||||| || ||| |||||||| ||| ||||||||||| || |||||||| ||||||| || |||||||||| ||||||||| ||| |||||||| |||||||| |||| ||| ||||||||||||| |||||||||| |||||| ||||||

The reductions from baseline in LDL-C and other lipid parameters in the adolescent population were consistent with those in the total study population. Treatment with evinacumab resulted in consistent reductions in mean percent change from baseline for LDL-C (||||||%) and Apo B (||||||%) at week 24 in this study, which were maintained for up to || weeks (mean percent change from baseline at week |||| was ||||||% for LDL-C and ||||||% for Apo B).

Table 2: Detailed Summary of Findings for Evinacumab Versus Placebo for Adolescent and Adult Patients With HoFH (ELIPSE Trial)

Apo B = apolipoprotein B; CI = confidence interval; DBTP = double-blind treatment period; EU = European Union; HoFH = homozygous familial hypercholesterolemia; HRQoL = health-related quality of life; IRR = infusion-related reaction; LDL-C = low-density lipoprotein cholesterol; LSM = least squares mean; NA = not applicable; NR = not reported; OLTP = open-label treatment period; RCT = randomized controlled trial; RR = risk ratio; SAE = serious adverse event; SE = standard error.

Note: Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

^aRated down 1 level for serious imprecision. Although the sample size was adequate based on the sample size calculation for the primary end point, the small size raises concern about prognostic imbalance and potential overestimation of the true effect.³² Downgrading for risk of bias was considered due to the potential for spurious correlations when estimating percent change outcomes, but supportive evidence was sufficient to not downgrade.³³

^bRated down 1 level for serious imprecision. Based on the sample size (and baseline imbalances indicating that randomization may not have ensured prognostic balance), rating down 2 levels would also be an option (–1 for imprecision and –1 for study limitations).

^cThis end point failed to meet statistical significance in the statistical hierarchy.

^dThis end point was not tested for superiority due to earlier failure of the statistical hierarchy. The potential for type I error is increased, and the findings should be considered as supportive evidence.

^eThis end point was an exploratory outcome. The potential for type I error is increased, and the findings should be considered as supportive evidence.

^fRated down 1 level for serious indirectness due to insufficient duration of follow-up for the outcome according to clinical expert input.

^gRated down 2 levels for very serious imprecision due to the absence of or very low number of events and small sample size.

Source: ELIPSE Clinical Study Report.²⁹

Table 3: Narrative Summary of Findings for Evinacumab for Pediatric Patients With HoFH (CL-17100 Study)

Apo B = apolipoprotein B; HoFH = homozygous familial hypercholesterolemia; IRR = infusion-related reactions; LDL-C = low-density lipoprotein cholesterol; LSM = least squares mean; SAE = serious adverse event; SD = standard deviation; vs. = versus.

Note: Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes. For single-arm trials, all serious concerns with study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias are documented in the table footnotes.

^aIn the absence of a comparator group, conclusions about efficacy relative to any comparator cannot be drawn; the certainty of evidence therefore starts at “very low” and cannot be rated up.

^bRated down 2 levels for very serious imprecision due to the absence of or very low number of events and small sample size.

^cRated down 1 level for serious risk of bias due to potential for bias in favour of evinacumab arising from the open-label nature of the study and the subjective nature of the outcome. Rated down 1 level for serious imprecision as the small sample size raises concerns about prognostic imbalance and potential overestimation of the true effect. There is no known minimally important difference, and the target of certainty assessment was any effect.

Source: CL-17100 Clinical Study Report.²⁸

Harms Results

Most patients experienced at least 1 TEAE; ||| of || (||||%) were reported in the new evinacumab group, || of || (|||||%) in the continue evinacumab group, and || of ||| (||||%) in the total study population. The most frequently reported TEAEs for the total study population were nasopharyngitis, headache, influenza-like illness, arthralgia, COVID-19 infection, back pain, and nausea. The TEAE profile in the adolescent population was similar to that in the total study population. |||||| patients experienced at least 1 TEAE. ||||||||||| patients (||||%) in the total study population experienced serious TEAEs. In the adolescent population, |||| patient (|||%) experienced a serious TEAE. ||||| patients had documented TEAEs leading to discontinuation of the study drug. ||| patients in the total study population experienced cardiac-related TEAEs resulting in death that were considered unrelated to the study drug. No deaths were reported in the adolescent population.

Critical Appraisal

The lack of an internal comparator limits the interpretation of the treatment effect observed in the CL-1719 trial as it is uncertain whether the magnitude of the effect observed for evinacumab as an adjunct to background LLT in patients continuing with evinacumab and in new patients is attributable to evinacumab, due to variations in patient health status (continuing and new patients enrolled), residual effects from the use of evinacumab (for patients entering study from an evinacumab study, the impact of ongoing treatments on the effect of evinacumab efficacy), or other unidentified prognostic factors. The single-arm design does not allow for the symptoms of underlying HoFH to be differentiated from treatment-related AEs.

There were no established hypothesis tests or clear thresholds for the secondary variables assessed in the trial. A lack of hypothesis testing against clear thresholds reduces the internal validity of the efficacy findings as it introduces bias in the interpretation of the findings. The open-label design may have also introduced bias in the assessment of subjective outcomes such as the reporting of AEs. Missing data and the lack of methods to account for missing data in the analysis may have impacted the internal validity of the results. There were variabilities in some lipoprotein profiles reported at later follow-up points, and these were attributed to missing or lack of patient data.

Study CL-1719 enrolled ||| patients from Canada, though it was unclear if the results were generalizable to patients with HoFH in Canada due to the small sample size and study design. The outcomes investigated were appropriate and reflective of current clinical practice. The follow-up duration was considered appropriate and more reflective of real-world practice. The use of concomitant medication and background LLT reported among patients was in line with that reported in the ELIPSE and CL-17100 studies. The concomitant medications used were also reflective of current clinical practice in Canada.

Indirect Comparisons

Description of Studies

No direct evidence comparing evinacumab to relevant comparators was available, and to support the pharmacoeconomic model for evinacumab, the sponsor submitted an indirect treatment comparison (ITC) that aimed to estimate the relative effect of evinacumab compared with relevant comparator treatments for adult and adolescent patients (aged 12 years and older) with HoFH to estimate the relative efficacy, safety, and tolerability of evinacumab compared with lomitapide, ezetimibe, evolocumab, and LDL apheresis.³⁴

The sponsor-submitted ITC first conducted a systematic literature review (SLR) to identify existing studies conducted in patients with HoFH. Patient-level data from the evinacumab and placebo arms of the ELIPSE trial were compared to aggregate data from the identified trials using Bucher ITCs and matching-adjusted indirect comparison (MAIC) methods for the outcomes of percent change in LDL-C, proportion of patients with a greater than or equal to 50% reduction in LDL-C, proportion of patients who experienced any SAEs, and proportion of patients discontinuing the study due to any cause.³⁴

Efficacy Results

The SLR identified 23 studies reporting data on unique patient groups as potentially relevant for inclusion in the ITCs. The studies were assessed for heterogeneity based on study design, eligibility criteria, baseline characteristics, and availability of end point data. Following assessment of heterogeneity, 3 studies from the SLR (Cuchel et al. [2013], Raal et al. [2015], and Gagne et al. [2002]), as well as the ELIPSE study, were identified for inclusion in the ITCs, for a total of 4 studies.

The unadjusted naive Bucher ITC comparing data for evinacumab from the ELIPSE trial and for evolocumab from the Raal et al. (2015) study was only conducted for the end point of percent change from baseline in LDL-C at 12 weeks. The results demonstrated that evinacumab was favoured over evolocumab for percent change from baseline in LDL-C (mean difference = –24.33%; 95% CI, –47.50 to –1.15).³⁴

In the MAICs of the ELIPSE trial (evinacumab) to the Cuchel et al. (2013) study (lomitapide) and of the ELIPSE trial (evinacumab) to the Gagne et al. (2002) study (ezetimibe), after adjustment, there were no imbalances between the selected baseline characteristics, though the effective sample size for evinacumab was only 9.9 patients in the comparison with lomitapide and 22.3 patients in the comparison with ezetimibe. The results of the MAIC for the mean difference in percent change from baseline in LDL-C suggested that there was no difference between evinacumab and lomitapide after adjustment (mean difference = 5.08%; 95% CI, –25.46 to 15.29), though evinacumab was favoured over ezetimibe (mean difference = –34.35%; 95% CI, –46.06 to –22.64). For the proportion of patients with a 50% or greater reduction in LDL-C, there was no difference between evinacumab and lomitapide after adjustment (relative risk = 1.42; 95% CI, 0.84 to 2.41).³⁴

Critical Appraisal

The feasibility of conducting an ITC and subsequent analyses was informed by an SLR; however, no information was provided on the SLR methods with regard to the databases searched, the method of study selection or data extraction (e.g., duplicate reviewers), or quality assessment. Thus, CADTH is unable to comment on whether appropriate methods were taken to identify studies for inclusion in the ITCs. Two types of ITC were conducted: a MAIC and a Bucher ITC. Bucher ITCs were used for the comparison of evinacumab to evolocumab based on the connection of the studies via a placebo arm, though the sponsor did not consider evolocumab to be an appropriate comparator to evinacumab due to the lack of available data on effect modifiers and the overall low numbers available for LDLR mutation status. Two MAICs were conducted, 1 each for the comparators of ezetimibe and lomitapide, but none for PCSK9 inhibitors or statins. The focus of the analyses was to evaluate treatments given at second line or later; thus, statins alone were excluded. The exclusion of PCSK9 inhibitors from the analyses was considered inappropriate, as PCSK9 inhibitors are also standard of care in the treatment of HoFH.

The clinical experts consulted by CADTH could not confirm or refute that the prognostic factors and treatment effect modifiers consisting of age, presence of CHD, baseline LDL-C, and LDLR mutation status (defective/defective or null/null) were the only relevant variables in this disease. The key limitation of the unanchored MAICs, which is a limitation inherent to all unanchored MAICs, is that the assumption that all effect modifiers and prognostic factors are accounted for in the model is unlikely met.

The choice to conduct an unanchored MAIC was motivated by the lack of a common comparator across studies. However, there were important differences in the study designs (RCT and single arm), populations, and times of outcome assessment (12 weeks to 26 weeks) of the comparator studies that limited the ability to draw strong inferences about the efficacy of evinacumab compared with other treatments in HoFH. There were also differences in population characteristics in the trials that may impact the comparability of the studies, notably the variation in the proportion of patients with CHD at baseline, the variation in the proportion of patients receiving apheresis at baseline, differences in LDLR mutation status across populations, and overall differences in lipid parameters (including LDL-C, Apo B, and non-HDL-C). Following adjustment for prognostic factors and treatment effect modifiers, the resulting effective sample size for the evinacumab group was decreased 77% and 47% for the comparisons versus lomitapide and ezetimibe, respectively. This is a result of the considerable heterogeneity across studies and may affect the numerical stability of the MAIC estimates, which increases the uncertainty of the results. In the absence of all prognostic factors and treatment effect modifiers, the National Institute for Health and Care Excellence Decision Support Unit considers the amount of bias in an unanchored MAIC likely to be substantial.³⁵ Overall, given the substantial loss in sample size after weighting, the results may not be generalizable to the population of patients with HoFH living in Canada.

The outcomes evaluated in the ITCs are relevant to the clinical management of HoFH. The sponsor conducted a Bucher ITC between evinacumab and evolocumab for the outcome of percent change from baseline in LDL-C, though no formal statistical analyses or adjustments were conducted; thus, the results of this analysis should be interpreted with caution. MAICs were conducted for the outcomes of percent change from baseline in LDL-C and proportion of patients with a greater than or equal to 50% reduction in LDL-C. Additional naive ITCs were conducted for safety outcomes including the proportion of patients who experienced any SAEs and proportion of patients discontinuing the studies due to any cause; however, as these analyses were only descriptive, no conclusion could be drawn on the comparative safety. After adjustment, there was no evidence of preference for evinacumab over lomitapide for the outcome of percent change from baseline in LDL-C, but evinacumab was favoured over ezetimibe. However, in all cases, 95% CIs were wide, suggesting notable imprecision in comparative efficacy estimates.

Studies Addressing Gaps in the Evidence From the Systematic Review

Description of Study

The study by Stefanutti et al. (2022) assessed the long-term efficacy and safety of evinacumab in a cohort of patients with HoFH who were on and off background LDL apheresis (and other LLTs) in a real-world setting. The patients received evinacumab 15 mg/kg every 4 weeks for a duration of 24 months.

Efficacy Results

The mean percent change from baseline in LDL-C following the use of evinacumab and LDL apheresis treatment was −54.4%, −48.9%, −49.4%, and −46.8%, respectively, at 6, 12, 18, and 24 months (P < 0.001 for all, compared with baseline). One patient discontinued LLT due to hospitalization. Four patients experienced an LDL-C reduction of 50% or more, with 2 of these patients having an on-treatment LDL-C level of less than 2.5 mmol/L (97 mg/dL).

Evinacumab (With or Without LDL Apheresis) Versus LDL Apheresis Alone

The LDL-C–lowering effect of evinacumab with or without background LDL apheresis treatment was greater than with LDL apheresis alone (i.e., without evinacumab treatment). With LDL apheresis alone, the time-average LDL-C was reduced by 27.2% in the 6 patients who received LDL apheresis during the normal course of their therapy before initiation of evinacumab treatment.

Harms Results

No discontinuations due to severe AEs were reported following the use of evinacumab. There were also no CV events observed during the 24-month follow-up period and subsequent compassionate extension period (12 months) with evinacumab. There were no reports of symptoms related to common AEs (pharyngitis, nasal congestion, myalgia, diarrhea, and arthralgia) during the 24-month follow-up period and 12-month extension period. Overall, plasma aspartate aminotransferase, alanine aminotransferase, and creatinine kinase concentrations for individual patients with HoFH remained stable during treatment with evinacumab.

Critical Appraisal

The lack of comparator and the open-label design were the main limitations of the study. There was no control group for comparison; thus, the benefit observed cannot be attributed to treatment with evinacumab. The sample size was considered too small to assess the magnitude of effects, and no sample size calculations were provided. There was little information provided related to the eligibility criteria for patients to be included in the study. There is a risk of detection bias for subjective outcome measurements, such as AE reporting, due to the open-label nature of the study, as patients and providers were aware of the treatment. The study duration (24 months) was considered sufficiently long to assess the beneficial effects of evinacumab in the patient population. No HRQoL data were presented. It is uncertain whether evinacumab impacted patient outcomes in the real-world setting.

There was limited generalizability in terms of genetic confirmation of HoFH diagnosis. The clinical diagnosis criterion was not used in the study, which may not be reflective of Canadian practice guidelines. It was unclear what background LLTs were used alongside LDL apheresis.

Conclusions

HoFH is a rare disease, and there is an unmet need for new, safe, and effective treatments for this population of patients who have depleted all other options and require additional LDL-C lowering. Evinacumab is a first-in-class treatment that acts in an LDLR-independent manner to reduce LDL-C levels. Two studies were included in this review — the phase III, double-blind, randomized ELIPSE trial and the single-arm, open-label CL-17100 study — evaluating the efficacy and safety of evinacumab as adjunct to diet and stable maximum doses of LLTs in pediatric and adult patients with HoFH.

The ELIPSE study demonstrated that evinacumab likely resulted in a clinically important decrease (improvement) in LDL-C levels when compared with placebo beyond the threshold for clinically important reductions of 30%, as defined by clinical experts and clinical practice guidelines, which was further supported by the CL-17100 study. Treatment with evinacumab was well tolerated over the study period and did not appear to be associated with more AEs or SAEs than placebo. Known AEs of interest, such as IRRs, were slightly more frequent in the evinacumab group; however, there were no concerns. The included studies had a short treatment duration of only 24 weeks, which was sufficient to address the primary outcome of change in LDL-C but precluded the ability to assess long-term efficacy and safety, as well as HRQoL. Though considered outcomes of importance to patients, reduction in CV risk (including CV-related morbidity and mortality), as well as reduction in the need for and frequency of apheresis, were not evaluated in the included studies; thus, the impact of evinacumab on these outcomes is unknown.

There were important technical limitations in the conduct of the ITCs: the included studies varied in design, did not include all relevant standard of care treatments, and had differences between the included populations. As such, the results of the ITCs were inconclusive and imprecise given the large reduction in sample sizes and wide 95% CIs.

Overall, the results of the included studies were generally positive, supporting the use of evinacumab in pediatric and adult patients with HoFH; however, there were important limitations in the studies — such as the small sample size, the short duration of follow-up, the single-arm open-label design of the CL-17100 study, and the lack of direct comparative evidence — that limit the generalizability of the study results to a broader population with HoFH.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of evinacumab, 150 mg/mL solution for IV infusion, as an adjunct to diet and other LDL-C–lowering therapies for the treatment of adult and pediatric patients aged 5 years and older with HoFH.

Disease Background

The content within this section has been informed by materials submitted by the sponsor and clinical expert input. The following has been summarized and validated by the CADTH review team.

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.^36-38 CVDs 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.^38-40 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, thereby reducing blood flow. 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, light-headedness or dizziness, cold sweats, and fatigue. More severe manifestations of ASCVD because of hypercholesterolemia include CV events such as MI or stroke, which may be fatal.⁴⁰

FH is a genetic disease characterized by markedly elevated plasma levels of LDL-C from birth that persist throughout life and can lead to the early development of atherosclerosis. FH can be further subdivided into HeFH and HoFH disease, with HoFH being the more severe and rare form of the disease.^1-4 HoFH is characterized by profoundly elevated plasma levels of LDL-C from birth, putting people with HoFH at a significantly increased risk of early CV events (including MI, stroke, and heart failure); if HoFH is left untreated, people with the condition can be at risk of sudden cardiac death as early as childhood or adolescence.^5-10 More than 90% of HoFH cases are caused by mutations in the LDLR gene. The remaining cases are caused by mutations in the PCSK9, APOB, and LDLRAP1 genes.¹⁴ The amount of residual LDLR activity that a patient has contributes to the severity of disease. The lower the LDLR activity, the more severe the disease and the harder it is to treat with the available treatment options, as many treatments rely on functional LDLR to reduce LDL-C levels.^14,41,42

There are an estimated 145,000 people with FH in Canada,^3,5,9,12,13 though recent studies in unselected general populations suggest that HoFH may affect as many as 1 in 300,000 people,^3,14-17 and may be higher in populations with a founder effect such as has been observed in French Canadians, with an estimated prevalence of 1 in 250,000.¹⁸ There are approximately 80 known cases of HoFH in Canada; in 2022, there were 52 patients with confirmed HoFH enrolled in the Canadian HoFH registry, with a majority (69%) found in Quebec, attributable predominantly to founder effects.¹⁹

Diagnosis of HoFH can be made based on clinical criteria or genetic confirmation, though HoFH has historically been more commonly diagnosed based on clinical presentation, due to the limited availability of genetic testing in Canada. The CCS position statement on FH¹ lacks specific guidance on diagnostic differentiation between HeFH and HoFH; however, clinicians in Canada use the clinical diagnostic features of HoFH outlined in the 2023 EAS guidelines. These features include untreated LDL-C levels greater than 10.0 mmol/L (400 mg/dL) or LDL-C levels greater than or equal to 8 mmol/L (300 mg/dL) while on conventional LLTs. Additional clinical features include the presence of xanthomas before age 10 years or the presence of HeFH in both parents. Genetic confirmation of diagnosis is based on the identification of biallelic pathogenic variants at the LDLR, APOB, PCSK9, or LDLRAP1, or at least 2 such variants at different loci.¹¹

People with HoFH are at a 100-fold elevated risk for MI compared to those without the condition.²⁰ If HoFH is not adequately treated, many people with the condition will experience an MI before age 10 years. People with untreated HoFH who have a complete loss of LDL function rarely survive beyond their second decade, while those who have partial LDLR activity have a better prognosis, though most develop clinically significant ASCVD by age 30 years if the HoFH is left untreated.¹⁴

Standards of Therapy

The content within this section has been informed by materials submitted by the sponsor and clinical expert input. The following has been summarized and validated by the CADTH review team.

The condition of FH is associated with premature death and complications due to accelerated development of ASCVD. Early detection of FH is important to reduce the risk of CV events; initial non-pharmacological interventions for hypercholesterolemia include diet and lifestyle modifications. The overarching goal of therapy for HoFH is to lower LDL-C and, subsequently, the risk of ASCVD. The lowering of plasma cholesterol levels is known to reduce CV events, CHD mortality, and all-cause mortality.²¹ If HoFH is left untreated, people with the condition can be at risk of sudden cardiac death as early as childhood or adolescence. The CCS recommends that patients with HoFH be referred to specialized lipid clinics for genetic analysis, for evaluation of the presence of ASCVD, and for initiation of aggressive LLTs, potentially including extracorporeal LDL-C removal, lomitapide, and PCSK9 inhibitors.¹

Recommended lifestyle modifications, as per the CCS guidelines on the diagnosis and treatment of dyslipidemias, include weight control, reduction of fat consumption to less than 30% of daily calories, consumption of 10 g to 20 g of fibre per day, and increased physical activity. Additional lifestyle changes may include smoking cessation and limiting alcohol intake.^22,23 Lifestyle and diet changes alone are unlikely to achieve LDL-C goals (generally result in an estimated reduction in LDL-C of 10% to 15%), and most patients will require pharmacological intervention.^1,24,43

Statins are the primary pharmacological intervention used to achieve control of LDL-C in patients with hypercholesterolemia. Most patients with hypercholesterolemia should be initiated on the MTD 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, rosuvastatin, simvastatin, or pravastatin), which lower LDL-C by approximately 30%, should be used only in older adults or frail or patients who are unable to tolerate high-intensity statins.²⁷ When the LDL-C goal is unmet with statin therapy alone, treatment with add-on ezetimibe or bile acid sequestrants (or both) is recommended.^25-27 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% and 40% (average 20%).²⁴ If LDL-C goals are still not met, PCSK9 inhibitors (evolocumab) and lomitapide are available to patients meeting certain criteria as an adjunct treatment to diet, MTD statin, and ezetimibe.^1,12 However, given that traditional LLTs such as statins and PCSK9 inhibitors act by upregulating LDLR expression, they have little efficacy in patients with HoFH and virtually no efficacy in patients with 2 null LDLR alleles.

Nearly all patients with HoFH will require extracorporeal LDL-C removal, particularly if LDL-C levels remain greater than 5 mmol/L despite treatment or if ASCVD is present. Either plasmapheresis or, preferably, LDL apheresis should be started as soon as technically feasible, usually before age 5 years and at least by age 8 years.¹

Drug Under Review

Evinacumab (Evkeeza) is a recombinant human monoclonal antibody that binds to and inhibits ANGPTL3, a member of the angiopoietin-like protein family that is expressed primarily in the liver and plays a role in the regulation of lipid metabolism by inhibiting lipoprotein lipase and endothelial lipase. Inhibition of ANGPTL3 via evinacumab lowers triglycerides and HDL-C by releasing lipoprotein lipase and endothelial lipase. Evinacumab reduces LDL-C independent of LDLR by promoting VLDL processing and clearance of VLDL remnants upstream of LDL formation through an endothelial lipase–dependent mechanism.

Evinacumab is administered intravenously at a dosage of 15 mg/kg every 4 weeks over 60 minutes. Each vial contains 345 mg/2.3 mL or 1,200 mg/8 mL (150 mg evinacumab per mL) solution in single-dose vials.

The reimbursement request for evinacumab is in line with the proposed Health Canada indication as an adjunct to diet and other LDL-C–lowering therapies for the treatment of adult and pediatric patients aged 5 years and older with HoFH. The Health Canada Notice of Compliance was granted on September 22, 2023. Evinacumab has not previously been reviewed by CADTH. Evinacumab has also been reviewed by other major regulatory bodies, including the FDA and the European Medicines Association, and is currently under review by the National Institute for Health and Care Excellence, though only for patients aged 12 years and older.⁴⁴

The key characteristics of evinacumab and of other treatments available for HoFH are summarized in Table 4.

Table 4: Key Characteristics of Evinacumab and Other Pharmacologic Therapies

CAD = coronary artery disease; CHD = coronary heart disease; CV = cardiovascular; HDL-C = high-density lipoprotein cholesterol; HeFH = heterozygous familial hypercholesterolemia; HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme-A; HoFH = homozygous familial hypercholesterolemia; LDL = low-density lipoprotein; LDL-C = low-density lipoprotein cholesterol; PCI = percutaneous coronary intervention; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; q.d. = every day; SC = subcutaneous; VLDL = very low-density lipoprotein.

Sources: Sponsor submission;⁴⁵ evinacumab product monograph;⁴⁶ inclisiran clinical review.⁴⁷

Stakeholder Perspectives

Patient Group Input

This section was prepared by the CADTH review team based on the input provided by patient groups. The full original patient input received by CADTH has been included in the Stakeholder section of this report.

CADTH received 1 joint patient input from the Canadian Heart Patient Alliance and the Canadian Organization for Rare Disorders, which was summarized for this review. The Canadian Heart Patient Alliance is a patient-led nonprofit umbrella organization of patients, families, health professionals, and supporters dedicated to reducing CVD and preventing early deaths due to genetic, environmental, lifestyle, and other risk factors; the organization focuses on improving awareness, screening, testing, diagnosis, care, and treatment of all CVDs. The Canadian Organization for Rare Disorders is Canada’s national network for organizations representing rare disorders, providing a strong common voice to advocate for health policy and a health care system that work for those with rare disorders. The organization works with governments, researchers, clinicians, and industry to promote research, diagnosis, treatment, and services for all rare disorders in Canada.

Information was gathered via an online survey that ran from April 12 to May 7, 2023, as well as individual interviews conducted with patients with HoFH and caregivers. Twelve online surveys were completed — 10 by patients with HoFH and 2 by caregivers — and 6 interviews were conducted with 5 patients with HoFH and 1 caregiver. Of the 18 respondents, 10 (56%) were male and 8 (44%) were female. Six patients (33%) were aged between 40 and 60 years, 6 (33%) were aged between 30 and 39 years, and 6 (33%) were aged between 18 and 29 years. All patients resided in Canada, mostly in Ontario (12 [66.7%]), with 3 (16.7%) each in British Columbia and Quebec.

About 75% of respondents had experienced severe (very high) levels of LDL-C, and 25% reported moderate levels of LDL-C. Around 50% of respondents reported that they had experienced moderate or severe CV events, including atherosclerosis, stroke, atrial fibrillation, and/or cardiac infarction, and half the patients had experienced severe chest pains and had xanthomas. Most patients had undergone multiple surgeries throughout their lifetime. Patients also expressed that HoFH negatively impacted their HRQoL. Patients and caregivers highlighted that living with HoFH was associated with stress due to the physical symptoms and the uncertainty or unpredictability of the future, with younger patients noting that HoFH impacts their education and social life, partly because of the time required for treatment.

The patients questioned the effectiveness of current treatment options (apheresis, statins, and other medications) in managing their LDL-C levels, highlighting concerns about having to undergo surgery because of future CV events, further impacting their QoL and life expectancy. Of the 18 respondents who provided input, 6 reported having access to or experience with evinacumab through a clinical trial, compassionate access program, or research study. Patients indicated that they were satisfied with evinacumab, as treatment consistently lowered their LDL-C levels and improved their HRQoL through reduced frequency of apheresis, improvements in energy, and the ability to participate in social and family events and attend school. Additionally, there were no reports of SAEs following the use of evinacumab.

Patients expressed the need for treatment options that can reliably, consistently, and sustainably control LDL-C levels at normal or near-normal levels, allowing them to experience fewer spikes, reducing the frequency and the need for apheresis, and reducing the risk of CV events.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise in the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). As part of the review of evinacumab, a panel of 4 clinical experts from across Canada was convened to characterize unmet therapeutic needs, assist in identifying and communicating situations where there are gaps in the evidence that could be addressed through the collection of additional data, promote the early identification of potential implementation challenges, gain further insight into the clinical management of patients living with the condition, and explore the potential place in therapy of the drug (e.g., potential reimbursement conditions). A summary of this panel discussion follows.

Unmet Needs

In patients with HoFH, ASCVD occurs very early and progresses aggressively throughout life. Most currently available pharmacological treatments only target the function of LDLR, rendering them less effective in patients with HoFH. The clinical experts highlighted that survival for patients with HoFH has nearly doubled in a generation due to the LLTs available; however, they noted that repeated CV events, including MI, aortic valve stenosis, aortic root disease, and the need for revascularization, have increased. As such, the clinical experts emphasized that the main goal of treatment for patients with HoFH is to aggressively reduce LDL-C early, adequately, and safely over the longest term possible to prevent premature CVD. Current treatment options, including statins, ezetimibe, and PCSK9 inhibitors, do not achieve sustained and significant reductions of LDL-C to levels below 2.5 mmol/L and/or a 50% lowering of LDL-C. Other treatment options, including lomitapide, are associated with adverse reactions and poor tolerability and/or compliance, limiting their effectiveness; extracorporeal removal of LDL-C, while effective, is extremely invasive and burdensome. Additionally, the experts noted that access to pheresis may be limited in Canada and that pheresis treatments are also associated with a rebound period where LDL-C levels rise to baseline, requiring recurrent and sustained treatment cycles. The experts highlighted the need for a drug that is safe and effective and can lower baseline LDL-C levels to a similar degree to that achieved with pheresis, without the same burden.

In addition to current therapies being unable to adequately reduce LDL-C to target levels, the experts noted that not all patients are able to access the full armamentarium of treatments available and that some therapies have a notable impact on HRQoL. Treatment for HoFH requires multiple and ongoing medical visits, with the experts highlighting that patients requiring pheresis treatments must adhere to a strict and burdensome treatment schedule, impacting their ability, and their caregivers’ ability, to attend school or work.

Place in Therapy

The clinical experts noted that there are currently multiple established guidelines for the management of dyslipidemia and highlighted the recent publication of the EAS consensus statement on HoFH; however, current treatment options are more effective in patients with residual LDLR function than in patients with “null” mutations (i.e., where there is no functional LDLR). The experts noted that current guideline-recommended LDL-C thresholds are pragmatic and remain well above the acceptable level for patients without hypercholesterolemia; thus, the overall aim of treatment is to achieve the lowest possible LDL-C level safely.

Though diagnosis of HoFH is relatively straightforward, based on clinical and genetic criteria, patients require the care of lipid specialists. The clinical experts noted that once a patient is diagnosed with HoFH, they are immediately put on MTD tatin and on ezetimibe therapy. In most cases, this combination is insufficient to achieve the desired LDL-C goals. To further reduce LDL-C levels, PCSK9 inhibitors may be tried; however, the experts noted that, given the pathophysiology of HoFH and the mechanism of action of PCSK9 inhibitors, response may be limited, though treatment with PCSK9 inhibitors should still be attempted.

If LDL-C levels are still above the goal, lomitapide with or without extracorporeal removal of circulating LDL-C may be attempted; however, lomitapide is associated with the need for severe dietary restrictions, as well as undesirable side effects. The clinical experts noted that in their experience, only half of patients can tolerate lomitapide therapy and those who can are on a very low dose with limited efficacy. With regard to pheresis, only 4 centres in Canada can perform LDL apheresis (Toronto, London, Quebec City, and Edmonton); an alternative, plasmapheresis, which is more widely available, is considered a less optimal substitute for LDL apheresis.

The experts highlighted that evinacumab would likely be used as an add on to MTD statin, ezetimibe, and/or PCSK9 inhibitors, with the hope of supplanting lomitapide and either delaying or reducing the frequency of pheresis.

Patient Population

HoFH is a rare disease, and patients with HoFH are diagnosed based on standard, well-established clinical, and genetic criteria, although genetic confirmation is not required. Patients present at an early age with extremely elevated LDL-C levels (untreated LDL-C greater than or equal to 10 mmol/L), as well as other clinical characteristics, including the presence of xanthomas. In conjunction with primary care physicians, lipid specialists aim to reduce LDL-C levels to prevent downstream CVD, particularly in younger patients. Per the current guidelines, the target LDL-C level for patients with HoFH is below 2.5 mmol/L; however, the experts agreed that this value is pragmatic and arbitrary, being based on other treatments and clinical trial criteria.

Treatments for HoFH are additive, with the goal of safely driving down LDL-C levels as low as possible, regardless of the thresholds specified in the guidelines. In the pediatric population, the goal of LDL-C–lowering treatment is to prevent or delay ASCVD and to obviate the need for or reduce apheresis. For adults, the goal of LDL-C–lowering treatment is to slow or halt ASCVD and potentially reverse it and its progression to clinically manifest CVD.

The experts highlighted that the selection of patients most in need of intervention with evinacumab is not entirely based on disease characteristics but that intervention with evinacumab would be preferred in patients with an LDL greater than 2.5 mmol/L, despite receiving maximally tolerated therapy. They further noted that evinacumab would be preferentially used in patients receiving or being considered for lomitapide or those on or being considered for apheresis, owing to the poor risk-benefit profile of lomitapide and the burden of extracorporeal LDL-C removal.

Per the clinical experts, the patients most likely to benefit from treatment with evinacumab are those diagnosed with HoFH who have had limited or inadequate response to available LLTs. In addition to the treatments available, patients with ASCVD, aortic valve disease, or genetic documentation of 2 pathogenic variants are subsets of patients at high risk for whom evinacumab might be considered.

The experts noted that there are no patients with HoFH that they would not consider for treatment with evinacumab and that it is highly unlikely that patients with HoFH would be able to achieve desirable LDL-C targets on conventional statin and ezetimibe therapy alone.

Assessing the Response to Treatment

The clinical experts agreed that the most important outcome of treatment is the reduction of CV morbidity or mortality; however, they noted that LDL-C level is the most reasonable surrogate outcome used by clinicians to avoid all downstream ASCVD complications. Additionally, the clinical experts noted that current clinical trials aim to address important outcomes used in clinical practice and that measuring event-driven outcomes is unreasonable in this population due to the rarity of the disease and the length of time before events arise. Major adverse CV events may still occur with sustained treatment; however, the experts stated that this would not be a reason to discontinue treatment.

The experts noted that other lipid parameters, such as Apo B or non-HDL-C, are routinely measured in clinical practice, particularly by academic institutions; however, they emphasized that these parameters would not likely alter treatment decisions in HoFH given the underlying pathology related to the LDLR, so LDL-C level is the most appropriate biomarker. Additionally, from a functional perspective, avoidance of pheresis options would be a measure of success, though there are currently no data to demonstrate this potential benefit.

The clinical experts noted that evinacumab has been administered in the medical short stay unit of hospitals and that achieving the LDL-C threshold of 2.5 mmol/L has not been an unrealistic goal; the experts stated that this treatment provides a new hope for patients with HoFH. The experts also noted that no safety concerns have been identified for evinacumab to date. One expert shared the example of a patient with extensive xanthomas that were not resolving with pheresis treatment; however, once the patient was put on evinacumab, the xanthomas regressed. The experts mentioned that patients should be stable on evinacumab for 6 months before an attempt to reduce the frequency of or remove pheresis. Patients with HoFH are under the care of a lipid specialist and are seen as often as every 3 months, and at minimum every 6 months. During pheresis therapy, lipid profiles are conducted before and following pheresis treatment; as such, LDL-C is routinely tracked.

The experts noted that improvement in symptoms or impact of ischemia on daily living is difficult to establish in patients with HoFH and that, generally, by the time symptoms occur, intervention such as revascularization is needed. The experts noted that in more severe cases, imaging techniques may be used to assess the extent of disease, but that imaging would not be appropriate to gauge response to treatment.

Discontinuing Treatment

The clinical experts agreed that treatment with evinacumab would be discontinued in patients who experience severe AEs, including anaphylactic or infusion reactions that are unable to be managed. Additionally, the experts agreed that any new AEs identified could be cause for discontinuation, given the small sample size included in the trials for evinacumab.

The experts noted that progression of atherosclerosis or lack of response to treatment would not prompt discontinuation of treatment. Although there is no strict definition for lack of response in patients with HoFH, the experts highlighted that arbitrary LDL-C cut-offs would be chosen to determine an acceptable LDL-C reduction, though this would be contextual for each patient. However, the experts also emphasized that it would be inappropriate to discontinue or deny access to therapies that provide any safe lowering of LDL-C. For example, the experts noted that a treatment offering patients a 20% reduction in LDL-C might be below an arbitrary 30% cut-off; however, the experts agreed that they would not likely discontinue treatment and would not consider a 20% reduction in LDL-C as a lack of efficacy.

The experts considered that quantifying the reduction in LDL-C may be a challenge in patients undergoing extracorporeal removal of LDL-C, due to the pattern of LDL-C reduction and rebound inherent in this cyclic therapy; thus, determining response (or lack of response) to treatment requires a sufficient passage of time to observe changes.

Additionally, the experts noted that pregnancy, or contemplation of pregnancy, would also be a consideration for discontinuation of treatment with evinacumab.

Prescribing Considerations

The experts indicated that diagnosis of HoFH is relatively straightforward, and that diagnosis can be made by any practitioner based on well-established clinical findings, family history, laboratory values, and genetic criteria. However, the experts noted that awareness of HoFH is low; therefore, patients with HoFH are generally identified through referral or in a more specialized setting. As such, patients with HoFH are under the care of specialists with special qualifications in dyslipidemia (e.g., endocrinologists, cardiologists, lipidologists), and treatment would occur within the specialist facilities of that individual or facilities accessible to that individual.

Evinacumab is administered through IV infusion; thus, an infusion setting is required. The experts noted that infusion reactions and flu-like reactions may occur and that for patients receiving pheresis treatments, evinacumab would be easiest to administer where extracorporeal machines are located. The experts also noted that vascular access in children may be a potential challenge.

Given the dispersion of the patient population, the experts noted that co-management with general practitioners could be envisioned. The experts highlighted that in some cases where remote consultation is available, administration of evinacumab may be possible, though under the remote supervision of a specialist. The experts also highlighted that experience with evinacumab is limited; thus, moving treatment into the community setting may be possible in the future, though not likely to occur imminently.

Clinician Group Input

This section was prepared by the CADTH review team based on the input provided by clinician groups. The full original clinician group input received by CADTH has been included in the Stakeholder section of this report.

Input from 1 clinician group, Familial Hypercholesterolemia Canada, was submitted for this review. Familial Hypercholesterolemia Canada is a national group of pediatric and adult lipid specialists in Canada whose purpose is to improve the care of patients with FH and reduce CV risks associated with this very high–CV risk condition. Information from this group was gathered through the collective clinical experience of 7 clinical experts, published literature, and congress proceedings.

The clinician group highlighted that HoFH presents in early childhood and is very challenging to treat across the patient’s lifespan, noting that current treatment options are inadequate in lowering LDL-C in patients with HoFH due to lack of efficacy and differences in mechanism of action (statins, ezetimibe, and PCSK9 inhibitors), lack of tolerability (lomitapide), and invasiveness in the form of reduced HRQoL and disruption to patients’ and families’ daily lives (apheresis and plasmapheresis). Additionally, the clinician group highlighted the lack of availability of LDL apheresis and plasmapheresis, which are limited to major academic centres, resulting in additional travel burden and creating inequities in level of care based on patients’ geographic location across Canada. Overall, the clinician group noted that there is an unmet need for equitably accessible therapies that safely and effectively treat patients with HoFH.

According to the clinician group input, patients best suited for treatment with evinacumab are those with HoFH in whom target levels of LDL-C are not reached with current treatments (statins, ezetimibe, and PCSK9 inhibitors, with or without plasmapheresis or apheresis) or those with progressive CVD, despite the use of current treatments. As such, the clinician group indicated that evinacumab would likely be used as a fourth-line therapy, after statins, ezetimibe, and PCSK9 inhibitors. The clinician group also suggested that evinacumab may eliminate or reduce the need for plasmapheresis or apheresis, and possibly for lomitapide.

According to the clinician group, ideal treatments for HoFH would be well tolerated with few side effects, have no significant drug interactions and have minimal impact on health care resources and would not place a burden on patients and their families.

In line with the clinical experts consulted by CADTH, the clinicians from Familial Hypercholesterolemia Canada considered reduction in LDL-C levels to be the most important outcome of treatment. The clinician group noted that a reduction in LDL-C would translate to reduced CV events and improved survival. Specifically, the clinician group cited a sustained reduction in LDL-C greater than 20% to 30% to be a meaningful response to treatment. Additional important outcomes for assessing response to treatment included reduction in the frequency of apheresis or plasmapheresis. The clinician group noted that intolerable side effects would be the primary factor when deciding to discontinue treatment.

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 experts consulted by CADTH are summarized in Table 5.

Table 5: Summary of Drug Plan Input and Clinical Expert Response

CDEC = CADTH Canadian Drug Expert Committee; CV = cardiovascular; HoFH = homozygous familial hypercholesterolemia; LDL = low-density lipoprotein; LDL-C = low-density lipoprotein cholesterol; LDLR = low-density lipoprotein receptor; MTD = maximally tolerated dose; q.4.w. = every 4 weeks.

Clinical Evidence

The objective of CADTH’s Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of evinacumab 150 mg/mL IV infusion in the treatment of pediatric and adult patients with HoFH. The focus will be placed on comparing evinacumab to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of evinacumab is presented in 4 sections, with CADTH’s critical appraisal of the evidence included at the end of each section. The first section, the systematic review, includes the pivotal studies and RCTs that were selected according to the sponsor’s systematic review protocol. CADTH’s assessment of the certainty of the evidence in this first section, using the GRADE approach, follows the critical appraisal of the evidence. The second section includes sponsor-submitted long-term extension studies. The third section includes indirect evidence from the sponsor. The fourth section includes additional studies that were considered by the sponsor to address important gaps in the systematic review evidence.

Included Studies

Clinical evidence from the following is included in the CADTH review and appraised in this document:

• Two pivotal studies or RCTs identified in the systematic review (the CL-1629 study [ELIPSE] and the CL-17100 study [pediatric study])^28,29

• One long-term extension study (the CL-1719 study)⁴⁸

• One sponsor-submitted ITC³⁴

• One additional study addressing gaps in evidence (Stefanutti et al. [2022]).⁴⁹

Systematic Review

The content within this section has been informed by materials submitted by the sponsor. The following has been summarized and validated by the CADTH review team.

Description of Studies

Characteristics of the included studies are summarized in Table 6.

A total of 2 studies were included in this review: the pivotal CL-1629 (ELIPSE) trial and the indication criteria expansion study, CL-17100, supporting the use of evinacumab in children aged 5 to 11 years.

Table 6: Details of Studies Included in the Systematic Review

ADA = antidrug antibody; ALT = alanine aminotransferase; Apo B = apolipoprotein B; Apo CIII = apolipoprotein C-III; AST = aspartate aminotransferase; AUC_tau = area under the plasma concentration-time curve over dosing interval; CABG = coronary artery bypass grafting; C_max maximum concentration; CPK = creatine phosphokinase; C_trough = concentration at the trough; DBP = diastolic blood pressure; DBTP = double-blind treatment period; eGFR = estimated glomerular filtration rate; EU = European Union; HADS = Hospital Anxiety and Depression Scale; HDL-C = high-density lipoprotein cholesterol; HeFH = heterozygous familial hypercholesterolemia; HoFH = homozygous familial hypercholesterolemia; ID = identification; IND = investigational new drug; LDL-C = low-density lipoprotein cholesterol; LDLR = low-density lipoprotein receptor; LLT = lipid-lowering therapy; Lp(a) = lipoprotein (a); mAb = monoclonal antibody; MI = myocardial infarction; NA = not applicable; NYHA = New York Heart Association; OLTP = open-label treatment period; PCI = percutaneous coronary intervention; PK = pharmacokinetic; q.4.w. = every 4 weeks; RNA = ribonucleic acid; SBP = systolic blood pressure; SOC = standard of care; SS = steady state; TC = total cholesterol; TEAE = treatment-emergent adverse event; TIA = transient ischemic attack; TSH = thyroid-stimulating hormone; ULN = upper limit of normal.

Sources: ELIPSE Clinical Study Report;²⁹ CL-17100 Clinical Study Report.²⁸

CL-1629 Study (ELIPSE Trial)

The ELIPSE trial was a phase III, double-blind, randomized placebo-controlled trial designed to evaluate the efficacy and safety of evinacumab versus placebo in pediatric and adult patients with HoFH. A total of 65 patients were randomized 2:1 to evinacumab 15 mg/kg every 4 weeks or matching placebo via an interactive web response system (IWRS). Randomization was stratified by prior apheresis treatment (yes versus no) and by geographical region (Japan versus rest of world). The ELIPSE trial was conducted in 30 centres in 11 countries: Australia, Austria, Canada, France, Greece, Italy, Japan, the Netherlands, South Africa, Ukraine, and the US. A total of 3 patients were enrolled from Canadian investigative sites. The ELIPSE trial consisted of an 8-week run-in period for patients who did not have a functional diagnosis of HoFH and opted to undergo genotyping for confirmation or for patients whose background LLT or apheresis schedules were not stable before the 2-week screening period. The run-in period was followed by a 24-week double-blind treatment period and a 24-week open-label treatment period. During the 24-week open-label treatment period, all patients received evinacumab 15 mg/kg IV every 4 weeks. The data cut-off date for the 24-week double-blind treatment period of the ELIPSE trial was July 29, 2019, and for the open-label treatment period was January 12, 2020. Patients then had the option to enter the long-term, open-label extension study (the CL-1719 study), and those who chose not to enter the extension study were followed for 24 weeks.²⁹

CL-17100 Study

The CL-17100 study was a single-arm, open-label study that included 3 parts:²⁸

• Part A: phase Ib, single-arm, single-dose pharmacokinetic and pharmacodynamic study

• Part B: phase III, single-arm, 24-week, open-label efficacy and safety study

• Part C: phase III, 48-week treatment period and 24-week follow-up period

Part A was a phase Ib, single-dose, open-label study to determine the safety, pharmacokinetics, and pharmacodynamics of a single dose of evinacumab 15 mg/kg IV in 6 patients aged 5 to 11 years with HoFH.²⁸ Results for Part A will not be discussed in this report.

Part B was a phase III, single-arm, open-label study to assess the efficacy and safety of evinacumab in patients aged 5 to 11 years with HoFH. A total of 14 patients were enrolled in Part B, none of whom had participated in Part A. Part B of the CL-17100 study was conducted in Australia, Austria, the Netherlands, Taiwan, and the US. Part B consisted of up to 4 periods: an up to 8-week run-in period, an up to 2-week screening period, and a 24-week open-label treatment period, and a follow up period. Since all patients entered Part C, the follow up period of Part B was not applicable. Upon completion of Part B, all patients continued into Part C.²⁸

Part C is an ongoing extension period that consists of the 20 patients who completed Part A or Part B. Part C consists of a 48-week treatment period and a 24-week follow-up period after the last dose of evinacumab. The final dosage in Part C was the same as the dosage in Part B: 15 mg/kg IV every 4 weeks.²⁸

The data cut-off dates for Part B and Part C were January 31, 2022, and June 2, 2022, respectively.²⁸

Populations

Inclusion and Exclusion Criteria

The inclusion and exclusion criteria for the 2 trials are summarized in Table 6. The inclusion criteria for both trials were similar, enrolling patients with either a genetically or clinically confirmed diagnosis of HoFH;^28,29 however, patients in the ELIPSE trial were aged 12 years or older,²⁹ while patients enrolled in Part B of the CL-17100 study were aged 5 to 11 years.²⁸ Additionally, patients in the CL-17100 study were required to have an LDL-C level greater than 130 mg/dL (approximately 3.4 mmol/L) at screening,²⁸ while patients in the ELIPSE trial with LDL-C were only required to have an LDL-C level greater than 70 mg/dL (1.81 mmol/L) at screening.²⁹

In general, patients in both trials were expected to be on the MTD of LLTs at screening; however, this was only specified as an inclusion criterion for the CL-17100 study. Maximally tolerated therapy included daily statin, ezetimibe, and PCSK9 inhibitor antibody (evolocumab or alirocumab), unless the patient had a documented history of tolerability issues, little to no response to therapy, or other documented reason for not receiving these therapies. Lipid-modifying therapy could also include other LLTs, such as LDL apheresis.^28,29

Interventions

Interventions, run-in treatments, background therapy, and prior and concomitant therapies were similar across the ELIPSE and CL-17100 studies.^28,29 In the ELIPSE trial, patients in the double-blind treatment period were randomized 2:1 to receive evinacumab at a dose of 15 mg/kg or matching placebo through a 60-minute IV infusion. The last dose of the double-blind study drug was administered at week 20. In the open-label period of the study, all patients received evinacumab at 15 mg/kg IV every 4 weeks starting at week 24 until the last dose at week 44.²⁹

In Parts B and C of the open-label CL-17100 study, patients received evinacumab 15 mg/kg every 4 weeks administered as an IV infusion over 65 minutes.²⁸

Run-In Treatment

The ELIPSE trial highlighted that patients undergoing apheresis therapy must have initiated LDL apheresis at least 3 months before screening and be on a stable weekly or every other week (i.e., every 7 days or every 14 days) schedule and/or stable settings for at least 8 weeks before screening.²⁹ In the CL-17100 study, there was no time limit for initiation of LDL apheresis,²⁸ though the schedule and setting requirements were the same as for the ELIPSE trial. Patients with an unstable schedule and/or unstable apheresis settings for at least 8 weeks before the screening visit entered an 8-week run-in period before the screening period. Patients on background LLT that had not been stable for at least 4 weeks (6 weeks for fibrates [ELIPSE trial only]; 8 weeks for PCSK9 inhibitor antibodies) before the screening visit entered a 4-week (6-week for fibrates; 8-week for PCSK9 inhibitor antibodies) run-in period to stabilize their LLT before entering the screening period.^28,29

Background Treatments

In both studies, patients were on a maximally tolerated LLT regimen (statin, PCSK9 inhibitor antibody, ezetimibe, lomitapide, mipomersen, probucol, and so on), unless the patient had a documented history of tolerability issues. Lipid-modifying treatments could have also included other LLTs, including LDL apheresis. Patients receiving background LLT undergoing apheresis had to also maintain stable LLT and a stable apheresis schedule throughout the duration of the study, from screening to the end of the double-blind treatment period and continuing through to the end of the open-label treatment period.^28,29

For patients who entered Part C of the CL-17100 study and were receiving lipid apheresis, the frequency of apheresis could be reduced based on the investigator’s judgment.²⁸

Concomitant and Prohibited Medications

In the ELIPSE trial, any treatment administered, including apheresis, from the time of informed consent to the end of the treatment period or final study visit was considered concomitant medication. The use of all medications and nutritional supplements known to alter serum lipids, such as statins, ezetimibe, fibrates, niacin, bile acid resins, red yeast rice, lomitapide, mipomersen, and PCSK9 inhibitor antibodies, was permitted as long as that therapy had been stable for at least 4 weeks (6 weeks for fibrates, 8 weeks for PCSK9 inhibitor antibodies, 12 weeks for lomitapide, and 24 weeks for mipomersen) before the screening visit. Patients had to continue background LLT for the duration of the study, starting at screening and continuing through to the end of the open-label treatment period (week 48). Similarly, patients had to maintain their apheresis regimen (if applicable), starting at screening and continuing through to the end of the open-label treatment period (week 48). Patients on thyroid replacement therapy could be included if the dose had been stable for at least 12 weeks before the screening visit.²⁹

In the ELIPSE trial, the following concomitant medications and procedures were prohibited through to the end of the double-blind treatment period and through to the end of the open-label treatment period:²⁹

• Background LLT that has not been stable for at least 4 weeks (6 weeks for fibrates) before the screening visit (unless participating in the run-in period to stabilize).

• Background mipomersen treatment that has not been stable for 24 weeks before the screening visit or background lomitapide at a MTD that has not been stable for 12 weeks before the screening visit. Recent discontinuation of lomitapide had to be washed out for at least 8 weeks before the screening visit.

• Background PCSK9 inhibitor antibody that has not been stable for at least 8 weeks before the screening visit.

• Apheresis schedule that is not weekly or every other week or that has not been stable for at least 8 weeks before screening.

• Plasma exchange.

• Nutraceuticals or over-the-counter therapies known to affect lipids at a dose or amount that has not been stable for at least 4 weeks before the screening visit.

• Systemic corticosteroids, unless used as replacement therapy for pituitary or adrenal disease with a stable regimen for at least 6 weeks before the screening visit.

• Thyroid replacement therapy, unless the dosage of replacement therapy has been stable for at least 12 weeks before the screening visit.

The concomitant and prohibited medications in the CL-17100 study were similar; however, mipomersen was not included in the list of prohibited medications.²⁸

Dose Modification

Dose modifications for individual patients were not permitted in either study.^28,29

Patients who permanently discontinued use of the study drug during the double-blind treatment period in the ELIPSE study remained in the study and underwent all study visits and procedures. At the time of study drug discontinuation in either the double-blind or open-label treatment period, the patient would have an unscheduled visit within 5 days of discontinuation of the study drug, if possible, and then resume the original study schedule until end of the double-blind treatment period or have end-of-study assessments at least 24 weeks after their last dose of the study drug in the open-label treatment period.²⁹

In the CL-17100 study, patients in Part B and Part C who prematurely discontinued the study drug and agreed to remain in the study would undergo all study visits and procedures except for study drug dosing. At the time of study drug discontinuation, the patient would have an unscheduled visit as soon as possible, with assessments normally planned at the week 24 end-of-treatment visit (Part B patients) or the week 48 visit (Part C patients) and then resume the original study schedule until the end-of-study visit.

In both studies, evinacumab dosing was permanently stopped in the event of the following (although other reasons may also be possible):^28,29

• evidence of pregnancy

• acute systemic infusion reactions with AEs, such as anaphylaxis, laryngeal or pharyngeal edema, severe bronchospasm, chest pain, seizure, or severe hypotension

• need for a prohibited concomitant medication during the double-blind treatment period (although, after discussion with the study monitor, treatment could be continued or could be only temporarily discontinued)

• withdrawal of consent.

The CL-17100 study also noted specific types of liver dysfunction as a reason for discontinuation.²⁸

In both studies, the investigators could also permanently discontinue evinacumab dosing at any time, even without consultation with the medical monitor if the urgency of the situation required immediate action and if this was determined to be in the patient’s best interest.^28,29

Outcomes

A list of efficacy end points assessed in this Clinical Review Report is provided in Table 7, followed by descriptions of the outcome measures. The summarized end points are those included in the sponsor’s summary of clinical evidence as well as additional outcomes identified as important to this review by the clinical experts consulted by CADTH and by the stakeholder input from patient and clinician groups and public drug plans. Using the same considerations, the CADTH review team selected end points that were considered most relevant to inform CADTH’s expert committee deliberations and finalized this list of end points in consultation with members of the expert committee. All the summarized efficacy end points were assessed using GRADE. Select notable harms outcomes considered important for informing CADTH’s expert committee deliberations were also assessed using GRADE.

Table 7: Outcomes Summarized From the Studies Included in the Systematic Review

Apo B = apolipoprotein B; CV = cardiovascular; EU = European Union; LDL-C = low-density lipoprotein cholesterol; NA = not applicable.

^aStatistical testing for these end points was adjusted for multiple comparisons (e.g., hierarchal testing).

^bA patient is considered as meeting US apheresis eligibility criteria if their LDL-C level is greater than or equal to 300 mg/dL (7.77 mmol/L) (Goldberg [2011]).

^cA patient with primary CV disease prevention is considered as meeting EU apheresis eligibility criteria if their LDL-C level is greater than 160 mg/dL (4.2 mmol/L); a patient with secondary CV disease prevention is considered as meeting EU apheresis eligibility criteria if their LDL-C level is greater than 120 mg/dL (3.1 mmol/L) (Schettler [2012]).

^dCV-related events including morbidity and mortality were of interest to this review but were not evaluated in the included trials.

Sources: ELIPSE Clinical Study Report;²⁹ CL-17100 Clinical Study Report.²⁸

Efficacy Outcomes

According to the clinical expert input and clinician group input, reduction in circulating LDL-C levels is the hallmark of treatment for patients with hypercholesterolemia and is an important outcome in the management of HoFH, with the aim of slowing or halting ASCVD and its progression to clinically manifest CVD. Therefore, outcomes related to LDL-C reduction were included as outcomes to be assessed using GRADE. In the included studies, these outcomes consisted of percent and absolute change from baseline in LDL-C, as well as the proportion of patients achieving lipid targets of 30% reduction, LDL-C reduction to less than 100 mg/dL, LDL-C reduction to less than 70 mg/dL, and proportion of patients meeting the US and EU apheresis criterion per LDL-C level.

While HRQoL was identified as an important outcome in patients with HoFH, the clinical experts noted that improvements in LDL-C levels are not directly linked to improvements in HRQoL; rather, the benefits of reduced LDL-C in patients with HoFH may be seen in a reduction in the frequency of or need for apheresis, though this would not necessarily be realized in the short duration of a clinical trial. Regardless, HRQoL outcomes from the included trials (i.e., EQ-5D) were included in the GRADE assessment.

Primary Efficacy Outcome

The primary outcome of the ELIPSE and CL-17100 studies was the percent change from baseline in LDL-C to week 24, where LDL-C was calculated using the Friedewald formula and percent change was defined as:^28,29

100 × (LDL-C value at week 24 – LDL-C value at baseline) / LDL-C value at baseline

Secondary Efficacy Outcomes

Key secondary efficacy end points of the ELIPSE trial included percent change from baseline in Apo B, non-HDL-C, and total cholesterol to week 24; proportion of patients with a greater than or equal to 30% and a greater than or equal to 50% reduction in LDL-C at week 24; absolute change from baseline in LDL-C to week 24; proportion of patients with LDL-C less than 100 mg/dL (2.59 mmol/L) at week 24; and proportion of patients who meet EU or US apheresis eligibility criteria at week 24. Patients were considered as meeting US apheresis eligibility criteria if their LDL-C levels were greater than or equal to 300 mg/dL (7.77 mmol/L). Patients being treated for primary CVD prevention were considered as meeting EU apheresis eligibility criteria if their LDL-C levels were greater than 160 mg/dL (4.2 mmol/L), and patients being treated for secondary CVD prevention were considered as meeting EU apheresis eligibility criteria if their LDL-C levels were greater than 120 mg/dL (3.1 mmol/L). Other secondary end points included percent change from baseline in triglycerides, lipoprotein A, and apolipoprotein C-III to week 24; absolute change from baseline in Apo B, non-HDL-C, and total cholesterol to week 24; and proportion of patients with LDL-C less than 70 mg/dL (1.81 mmol/L) at week 24.²⁹

Similar lipid measures were selected as secondary outcomes for the CL-17100 study, with the omission of the proportion of patients with a greater than or equal to 30% reduction in LDL-C at week 24 and the proportion of patients meeting US or EU apheresis criteria.²⁸

All lipid parameters were collected by investigators and sent to a central laboratory for evaluation.^28,29

Exploratory Outcomes

HRQoL was an exploratory outcome of the ELIPSE trial. The measures used to evaluate HRQoL in the ELIPSE trial were the EQ-5D and the Hospital Anxiety and Depression Scale.²⁹ HRQoL measured by the Hospital Anxiety and Depression Scale was not considered in this review.

The EQ-5D is a standardized measure of health status developed by the EuroQol Group to provide a simple, generic measure of health for clinical and economic appraisal. The EQ-5D, as a measure of HRQoL, defines health in terms of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 3 ordinal levels of severity: no problems (1), some problems (2), severe problems (3). The overall health state is defined as a 5-digit number. Health states defined by the 5-dimensional classification can be converted into corresponding index scores that quantify health status, where 0 represents “death” and 1 represents “perfect health.”²⁹

Harms Outcomes

The safety of evinacumab was a secondary end point of the ELIPSE and CL-17100 studies and was measured by AEs, SAEs, AEs of special interest (AESIs), vital signs, Tanner stages, clinical laboratory values, electrocardiogram measurements, and the formation and characterization of antidrug antibodies. AEs were recorded by the investigator from the time the informed consent was signed to the end of the study using the currently available version of the Medical Dictionary for Regulatory Activities by preferred term and system organ class.^28,29

AEs were defined as any untoward medical occurrence in a patient administered a study drug that may or may not have a causal relationship with the study drug. SAEs were defined as any untoward medical occurrence that results in death, is life threatening, requires admission to a hospital or emergency department for longer than 24 hours or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly, or is an important medical event. Severe TEAEs were also reported as SAEs.^28,29

AESIs were AEs of scientific and medical concern specific to the study drug. AESIs for evinacumab included anaphylactic reactions, allergic reactions and/or local injection site reactions, increase in alanine aminotransferase or aspartate aminotransferase greater than or equal to 3 times the upper limit of normal, symptomatic overdose with evinacumab, neurocognitive events, new onset of diabetes, and pancreatitis.^28,29

The clinical experts consulted by CADTH indicated that many of the AESIs defined in the included trials were borne from other LLTs used in hypercholesterolemia. However, given the method of administration of evinacumab, the clinical experts indicated that it would be important to consider allergic reactions and IRRs associated with evinacumab.

Statistical Analysis

Sample Size and Power Calculation

ELIPSE Trial

For the primary efficacy outcome of percent change from baseline in LDL-C, a sample size of 57 patients (38 on evinacumab and 19 on placebo) would be powered at 90%, based on a 2-sample t test, to reject a null hypothesis of no difference between treatment groups at the 0.05 significance level, assuming a group difference in mean percent change from baseline in LDL-C of 38% and a common SD of 35%. This sample size was adjusted for a 5% non-evaluable patient rate and a 15% dropout rate.²⁹

CL-17100 Study

Given the design of the CL-17100 study, no sample size calculation was conducted.²⁸

Interim and Final Analyses

ELIPSE Trial

For the ELIPSE trial, no formal interim analysis was planned. Efficacy and safety analyses for the primary and secondary efficacy end points of the ELIPSE trial were performed in 2 steps. The first step included the efficacy analyses up to week 24. This analysis was conducted on all randomized patients once all data through week 24 had been collected and validated. The second step, considered the final analysis, was conducted at the end of the study and consisted of the final efficacy and safety analyses at time points beyond the week 24 visit.²⁹

CL-17100 Study

No interim analyses were planned for the CL-17100 study; however, an interim Clinical Study Report was provided by the sponsor, presenting data for Part A (data cut-off: February 11, 2021), Part B (data cut-off: January 31, 2022), and Part C (data cut-off: June 2, 2022).²⁸

Statistical and Analytical Plans

ELIPSE Trial

Efficacy analysis: Efficacy in the included trials was assessed through multiple lipid parameters, which have been previously described previously. All lipid parameters were collected over the course of the study and sent to a central laboratory for evaluation.²⁹

For statistics where international and conventional units would not impact the results (i.e., percent change from baseline, summary test statistics, proportions of patients below a threshold), statistical models were implemented using conventional units. For other statistics (e.g., descriptive statistics at baseline and over time, absolute change from baseline), results were presented in both international and conventional units.²⁹

The intention-to-treat (ITT) population was the primary population for the efficacy analysis in the ELIPSE trial, which used an MMRM approach. All postbaseline data available within the week 2 to week 24 efficacy analysis window were used, and missing data were assumed missing at random. The baseline was defined as the last available measurement before the date of the first double-blind study treatment administration. The calculated LDL-C at week 24 was the LDL-C value obtained within the week 24 analysis window, regardless of adherence to treatment and of subsequent therapies. The model included an individual-level random intercept and fixed categorical effects for the treatment group (evinacumab versus placebo) for the following: randomization strata (apheresis [yes or no] and region [Japan or rest of world]), each time point (weeks 2, 4, 8, 12, 16, 20, and 24), treatment by time point interaction and strata by time point interaction, as well as the continuous covariates of baseline calculated LDL-C value and baseline value by time point interaction. The model parameters were estimated using the restricted maximum likelihood estimator with the Newton-Raphson algorithm and an unstructured correlation matrix to permit within-patient dependence. Denominator degrees of freedom were estimated using the Satterthwaite approximation. Within-treatment-group LSMs and SEs were adjusted using weights equal to the observed proportion of patients in the previously noted strata variable levels across the study population (i.e., population weight), rather than equal weights. Population weights were considered more appropriate than equal coefficients due to potential imbalances observed in the study population between levels of the randomization stratification factors. Prior to performing the primary efficacy analysis, statistical analysis method assumptions were checked for baseline homogeneity of LDL-C levels between treatment groups, normality of the LDL-C percent change distribution for each treatment group, and equality of variances between treatment groups using a residual plot.²⁹

During the open-label treatment period, efficacy variables were explored through descriptive statistics at each scheduled visit for all patients administered the open-label study treatment, as well as for the patient subgroups (by study treatment received) in the double-blind treatment period. Formal statistical testing was not planned. Descriptive statistics included the observed values of the same parameters described for each variable in the double-blind treatment period.²⁹

Sensitivity analyses: Robustness of the primary analysis was assessed through the following sensitivity analyses:²⁹

• Sensitivity to stratification at randomization: To assess stratification mistakes made at the time of randomization, the MMRMs were rerun, replacing the IWRS strata with the actual recorded strata.

• Sensitivity to on-treatment calculated LDL-C values: To assess the more clinically relevant treatment comparisons of the percent change from baseline in calculated LDL-C to week 24, the modified ITT population (refer to Table 9) was used during the efficacy treatment period (on-treatment estimand).

• Sensitivity to non–good clinical practice (GCP)–compliant sites: To assess the impact of non–GCP-compliant sites on the primary efficacy end point, the primary efficacy analysis excluded non–GCP-compliant sites. Sites known to be non–GCP compliant at the time of database lock were identified for this analysis before database lock. Any additional sites determined to be non–GCP compliant postdatabase lock were separately identified.

• Sensitivity to the handling of missing data: To assess the handling of missing data through visual examination and using a PMM, postbaseline LDL-C levels (in the ITT population) were described and were graphed according to the following groups:

  • LDL-C available at week 24 (i.e., primary efficacy end point available)

  • LDL-C available at week 20 but missing at week 24

  • LDL-C available at week 16 but missing from week 20

  • LDL-C available at week 12 but missing from week 16

  • LDL-C available at week 8 but missing from week 12

  • LDL-C available at week 4 but missing from week 8

  • LDL-C available at week 2 but missing from week 4

  • LDL-C missing from week 2.

Sensitivity analysis to explore the impact of nonignorable missingness on the primary efficacy analysis was also conducted using the PMM approach. In the PMM approach, different imputation strategies were applied to LDL-C values missing during the double-blind, on-treatment period (i.e., within the period from the first double-blind study treatment administration up to the day of the last double-blind administration, plus 35 days) versus LDL-C values missing due to treatment discontinuation after the on-treatment period (i.e., after the day of the last double-blind administration, plus 35 days) based on the following assumptions:²⁹

• For patients within 35 days after their last study treatment (double-blind treatment period), treatment administration would continue to show benefit similar to that observed at the scheduled time point. Therefore, missing LDL-C values during the on-treatment period (e.g., samples obtained outside the specified window, no blood sample available although visit was performed) should be considered “missing at random” and imputed based on other observed measurements in the on-treatment period.

• Patients who stopped taking their study treatment no longer benefited from it after discontinuation, and thus tended to have LDL-C values returning to baseline. Therefore, LDL-C values missing after the on-treatment period should be imputed based on the patient’s own baseline value.

Missing data from the randomized population were imputed 100 times to generate 100 complete datasets, using a Markov chain Monte Carlo method, and were used for the sensitivity analysis of the primary efficacy analysis. For the percent change from baseline in LDL-C end point, the 100 complete datasets of observed and imputed LDL-C data at week 24 were analyzed using an analysis of covariance model, with treatment group and randomization strata as fixed effects and the baseline LDL-C value as a continuous covariate. The MIANALYZE procedure was used to generate valid statistical inferences by combining results from the 100 analyses using the Rubin formulas.²⁹

Subgroup Analyses: To assess the homogeneity of the treatment effect across various subgroups, the treatment by subgroup factor, the time point by subgroup factor, and the treatment by time point by subgroup factor interaction terms and a subgroup factor term were added to the primary MMRM. The significance level of the treatment by subgroup factor interaction term at week 24 was provided for each factor for descriptive purposes. To handle imbalances between randomization stratification factor levels, population weights were used, as they were for the primary analysis model.²⁹

The following subgroups of interest were preplanned: baseline apheresis status (yes, no); geographical region (Japan, rest of world); sex (female, male); age (< 65 years, ≥ 65 years); race; ethnicity; baseline LDL-C (< 130 mg/dL, ≥ 130 mg/dL); HoFH genotype (homozygous, compound heterozygous, double heterozygous); receptor-negative mutation in both LDLR alleles, where receptor-negative is defined as a mutation resulting in termination codons, splice site mutations, frame shifts, and large insertions or deletions (yes, no).²⁹

Secondary end point efficacy analysis: Statistical analyses for the key secondary efficacy end points and other secondary efficacy end points were performed in the ITT population. For the descriptive summaries, percent change and, when appropriate, absolute change from baseline in LDL-C, Apo B, total cholesterol, triglycerides, non-HDL-C, lipoprotein A, and apolipoprotein C-III were estimated at each time point for each treatment group.²⁹

Continuous secondary variables anticipated to have a normal distribution were analyzed using the same fixed-effect MMRM described for the primary end point. Specifically, the model contained the categorical effects of treatment group, randomization strata (as per IWRS), planned time points up to week 24, strata by time point interaction, and treatment by time point interaction, as well as the continuous covariates of corresponding baseline value and baseline value by time point interaction.²⁹

Continuous secondary efficacy variables anticipated to have a non-normal distribution (i.e., triglycerides and lipoprotein A) were analyzed using the multiple imputation approach for handling of missing values, with data log-transformed before the imputation process and then back-transformed to create the imputed datasets. The percent change from baseline at the time point of interest was derived from observed and imputed lipid values at this time point. Multiple imputed datasets were modelled using a simple regression to compare treatment group differences,⁵¹ with the end point of interest as the response variable. The mean treatment response was estimated using a robust M-estimation within treatment group, randomization strata, and corresponding baseline values. Combined means estimates for both treatment groups, as well as the differences in these estimates, with their corresponding SEs, 95% CIs, and P values, were provided.²⁹

Binary secondary efficacy end points were analyzed using the multiple imputation approach to account for missing values. The binary end point at the time point of interest was derived from observed and imputed lipid values at this time point. Multiple imputed datasets were modelled using stratified logistic regression. The logistic regression procedure was used to compare treatment group differences, with the model containing treatment group and corresponding baseline values as covariates, stratified by randomization strata. Combined estimates of OR versus placebo, 95% CI, and P value were provided.²⁹

Sensitivity Analyses

Sensitivity analyses of key secondary end points were conducted using the modified ITT population, and the ITT estimand was replaced by the on-treatment estimand, defined as all key secondary efficacy end point values collected during the efficacy treatment period.²⁹

Multiple testing: In the ELIPSE trial, to handle multiple key secondary end points during the double-blind treatment period, a hierarchical inferential approach was used to control the overall type I error at the level of 0.05. The hierarchical testing sequence included the primary efficacy variable (percent change from baseline in LDL-C to week 24), followed by key secondary end points: percent change from baseline in Apo B, non-HDL-C, and total cholesterol to week 24, proportion of patients with a greater than or equal to 30% reduction in LDL-C at week 24, proportion of patients with a greater than or equal to 50% reduction in LDL-C at week 24, absolute change from baseline in LDL-C to week 24, and proportion of patients who meet US and EU apheresis eligibility criteria. No further adjustments were made for other secondary end points, and P values were provided for reference only.²⁹

Safety analysis: Safety results were presented separately for the double-blind and open-label treatment periods, unless otherwise noted. Safety summaries for the double-blind treatment period were presented by treatment group, containing patients from the double-blind safety analysis set (SAS). No formal inferential testing was performed, and summaries were descriptive in nature.²⁹

An independent data monitoring committee composed of members who were independent from the sponsor and the study investigators monitored patient safety by conducting formal reviews of the accumulated safety data.²⁹

CL-17100 Study

Efficacy analysis: Efficacy analyses are only reported for Part B of the CL-17100 study. The primary end point of percent change from baseline in LDL-C at week 24 was summarized descriptively for all patients in the ITT population using mean, SE, and 95% CI. Missing data were imputed using a PMM approach, as described in the section on the sensitivity analysis for the ELIPSE trial.²⁸

Missing LDL-C change data from the ITT population were imputed 100 times to generate 100 complete datasets using a Markov chain Monte Carlo method. The 100 completed datasets of observed and imputed LDL-C data will be used for the primary analysis. For the percent change from baseline in LDL-C end point, the 100 complete datasets of observed and imputed LDL-C data at week 24 were analyzed using the MEANS procedure. The MIANALYZE procedure was used to combine the results from the 100 analyses using the Rubin formulas. Combined estimates of the mean at week 24 were provided with the SE and the 95% CI. Formal statistical testing was not planned.²⁸

Sensitivity analyses: Sensitivity analyses were conducted similarly to the ELIPSE trial, removing non–GCP-compliant sites, using the MMRM approach, as defined for the primary end point of the ELIPSE trial, and using the modified ITT population.²⁸

Subgroup analyses: The following subgroups of interest were planned: sex (female, male), age (≥ 5 to < 10 years, ≥ 10 to ≤ 12 years), race, ethnicity, baseline apheresis status (yes, no), receptor-negative mutation in both LDLR or LDLRAP1 alleles (yes, no), and LDLR activity (null/null [LDLR activity ≤ 15%], not null/null [LDLR activity > 15%]).²⁸

Secondary efficacy analysis: For the secondary efficacy end points, descriptive summaries and analyses were performed in the ITT population, using values obtained regardless of adherence to the study treatment and of subsequent therapies.²⁸

Continuous secondary end points anticipated to have a normal distribution were analyzed using the ITT population and the PMM approach for missing data as described for the primary efficacy end point. Continuous secondary efficacy variables anticipated to have a non-normal distribution were analyzed identically to in the ELIPSE trial.²⁸

Binary secondary efficacy end points were descriptively summarized using the ITT population, along with the proportion and 95% CI. Missing data were imputed using the same PMM approach as described for the primary efficacy end point.²⁸

Multiple testing: No formal statistical testing was performed for this open-label study, as such control for multiplicity was not applicable.²⁸

Safety analysis: Safety summaries were descriptive in nature, and no formal inferential testing was performed.²⁸

An independent data monitoring committee composed of members who were independent from the sponsor and the study investigators monitored patient safety by conducting formal reviews of the accumulated safety data.²⁸

Table 8: Statistical Analysis of Efficacy End Points

Apo B = apolipoprotein B; Apo CIII = apolipoprotein C-III; CI = confidence interval; DBTP = double-blind treatment period; EU = European Union; HADS = Hospital Anxiety and Depression Scale; HDL-C = high-density lipoprotein cholesterol; ITT = intention to treat; LDL-C = low-density lipoprotein cholesterol; LOCF = last observation carried forward; Lp(a) = lipoprotein (a); mITT = modified intention to treat; MMRM = mixed-effect model with repeated measures; PMM = pattern mixture model; TC = total cholesterol.

Sources: ELIPSE Clinical Study Report;²⁹ CL-17100 Clinical Study Report.²⁸

Analysis Populations

The analysis populations for the ELIPSE and CL-17100 studies are summarized in Table 9. The ELIPSE trial included an ITT population, a modified ITT population, an SAS in both the double-blind and open-label treatment phases, and a quality of life analysis set.²⁹ The CL-17100 study included an ITT, a modified ITT, and an SAS population.²⁸

Table 9: Analysis Populations of ELIPSE and CL-17100 Studies

DBTP = double-blind treatment period; HADS = Hospital Anxiety and Depression Scale; ITT = intention to treat; LDL-C = low-density lipoprotein cholesterol; mITT = modified intention to treat; OLTP = open-label treatment period; SAS = safety analysis set.

Sources: ELIPSE Clinical Study Report;²⁹ CL-17100 Clinical Study Report.²⁸

Protocol Amendments and Deviations

Protocol Amendments

The original global study protocol for the ELIPSE trial, dated May 7, 2017, was amended |||| times. |||||||| ||||||||| || |||||||| ||| |||||| ||||||||| ||||||| |||||||| ||| |||||||| || ||||| ||| |||| || |||||||||| ||| ||||||||||| ||||||||| || ||||| |||||||||| || ||| || |||| ||||||||||| ||| ||||||||||||| || ||| ||| |||||||||| ||| ||||||| ||||||| || |||||||| || ||||||| ||| ||||||| ||||| ||||||||| ||| ||||||||| ||||||| |||||| ||| |||||| ||||||| ||| |||||||||| || |||| ||||||||| ||||| ||||||||| |||||||| ||| |||| ||| |||||||| ||| |||||||||| |||| ||||| |||||||||||| || |||| |||||| ||| |||| |||||||| |||||| || |||||||||| ||||||||| ||||||| || ||||| ||||||||| |||||||| ||||||||||||| |||| ||||||||| |||||||||||||| ||||||||| |||||||| |||| ||||| ||||| ||| ||||| || |||| || ||| |||| ||| || ||||||||| |||||||| ||| |||| || ||||| ||| ||||||||||| ||| ||||||||||||||||| ||| ||| ||||| ||||||||| |||||||| ||||||||| || |||||||| ||| |||||||||||| |||||||||| || ||| ||||||||||| || |||||||||| ||| ||||| ||||||||||| ||||||||| |||||||||| ||| ||| ||||||||| || |||||||| |||| ||||| ||| ||||||||| ||| ||||||||||| |||||||||||| || ||||||||| |||| |||||||| |||||||| |||||| |||| |||||||||||| |||| ||| ||| ||||||||||| |||||||| ||| |||| |||||| ||| |||| |||||||| ||||||||| |||| |||||||||||| |||| |||||||| || ||||||| |||||||||| ||| || |||||||||| |||||||| ||||||||| || ||| ||||||||| || |||||||| || |||||| |||||||||||| |||||||| || ||||||| || ||||||| ||| |||||||| |||||| |||| |||||||| || ||| |||||||| || |||||||||||||||||||||||| |||||||| ||| |||||||| ||| ||||| || |||| || ||||| |||||| || ||||||| |||| ||||||||. Dates for protocol amendments in the ELIPSE trial were not provided; therefore, it is unclear whether the amendments had any major impact on the conduct of the study.

The protocol for the CL-17100 study was amended twice. Amendment 1 included changes to the study design by |||||||| ||| ||||||||| |||||| || ||||||| || ||||| || || |||||, added the absolute change from baseline in LDL-C to week 24 as an end point, and amended the list of AESIs. The second protocol amendment ||||||||| ||| |||||| |||| ||| |||||| || || || |||||||| ||| || ||||||||||| ||||||||||||| ||| ||||||| |||||||| ||| ||||| |||| ||| ||||||||||||| ||| ||||||| || ||||| |||||| ||||||| || ||||| ||| ||||||||| |||||| || ||| |||||.²⁸ Dates for protocol amendments were not provided; therefore, it is unclear whether the amendments had any major impact on the conduct of the study.

Protocol Deviations

Protocol deviations in the ELIPSE and CL-17100 studies are summarized in Table 10. For the ELIPSE trial, protocol deviations are summarized for both the double-blind and open-label treatment periods. For the CL-17100 study, protocol deviations are summarized as a group for Parts A, B, and C. In the ELIPSE trial, protocol deviations occurred in || patients (||||%) and || patients (||||%)in the evinacumab and placebo groups, respectively. In the CL-17100 study, protocol deviations occurred in ||| patients (|| [|||||%]). In both studies, the most common cause of protocol deviations was procedural irregularities, occurring in || patients (||||%) and ||| patients (||||%) in the ELIPSE trial evinacumab and placebo groups, respectively, and in || patients (||||%) in the CL-17100 study. Other protocol deviations in the ELIPSE trial and the CL-17100 study included those related to the definition of “women of childbearing potential” and lipid apheresis schedule issues, respectively.^28,29

Table 10: Protocol Deviations in ELIPSE (ITT) and CL-17100 (Enrolled Patients) Studies

Sources: ELIPSE Clinical Study Report;²⁹ CL-17100 Clinical Study Report.²⁸

Results

Patient Disposition

The ELIPSE and CL-17100 studies shared a similar patient population for enrolment, though the designs varied. In the ELIPSE trial, 75 patients were screened and 65 were randomized 2:1 to evinacumab (n = 43) or matching placebo (n = 22), making up the ITT population. Ten patients failed screening: 8 violated the eligibility criteria, and 2 withdrew consent. Of the 65 patients randomized and treated, 64 (98.5%) completed the 24-week double-blind treatment period. One patient (1.5%) from the placebo group withdrew consent after receiving 1 dose of the study drug and was not considered to have completed the study. There were no AEs that led to treatment discontinuation during the double-blind treatment period.²⁹

Table 11: Summary of Patient Disposition From Studies Included in the Systematic Review

DBTP = double-blind treatment period; ITT = intention to treat; mITT = modified intention to treat; QoL = quality of life.

Sources: ELIPSE Clinical Study Report;²⁹ CL-17100 Clinical Study Report.²⁸

The CL-17100 study screened a total of 23 patients for enrolment in Parts A, B, and C. A total of 14 patients were enrolled in, treated in, and completed Part B of the CL17100 study; 13 (92.9%) continued to Part C. A total of || patients (6 from Part A, and 14 from Part B) were treated in Part C. As of the interim cut-off date (|||| || ||||), |||| patients (||||%) had completed Part C and || patients (||||%) were ongoing in the Part C treatment period. Overall, |||| patients (||||%) have completed the study and || are ongoing.²⁸

Baseline Characteristics

Baseline characteristics for the ELIPSE and CL-17100 studies are summarized in Table 12. The baseline characteristics included in the table are limited to those that are most relevant to this review or were felt to affect the outcomes or interpretation of the study results.

ELIPSE Trial

In the ELIPSE trial, patients were randomized 2:1 to either evinacumab (n = 43) or placebo (n = 22). A total of 22 patients (33.8%) were randomized and treated in EU member countries and 43 patients (66.2%) in non–EU member countries. There was a difference between the evinacumab and placebo groups in terms of age at baseline, with a mean age of 44.3 years (SD = 16.8) in the evinacumab group compared to 36.7 years (SD = 11.52) in the placebo group. Only 1 patient in each treatment group was below age 18 years. In line with the difference in age, there was also a difference in the mean time from diagnosis of HoFH to randomization: 16.15 years (SD = 14.562) in the evinacumab group compared to 10.65 years (SD = 12.537) in the placebo group. Patients in the evinacumab and placebo groups were mostly female (55.8% and 50.0%) and white (72.1% and 77.3%). There was also a difference in body mass index across patient groups, with the body mass index being less than 30 kg in 32 patients (74.4%) in the evinacumab group and 19 patients (86.4%) in the placebo group.²⁹

A total of 48.8% of patients had homozygous LDLR mutations in the evinacumab group compared to only 31.8% in the placebo group, while fewer patients had compound heterozygous LDLR mutations in the evinacumab group than in the placebo group (27.9% versus 36.4%). Most patients received at least 3 LLTs at baseline (69.8% in the evinacumab group versus 50.0% in the placebo group), mostly statin plus ezetimibe and a PCSK9 inhibitor (48.8% in the evinacumab group versus 36.4% in the placebo group). Nearly all patients were treated with any statin (95.3% in the evinacumab group and 90.9% in the placebo group), and most patients also received ezetimibe (76.7% in the evinacumab group versus 72.7% in the placebo group) or PCSK9 inhibitors (79.1% in the evinacumab group versus 72.7% in the placebo group). More patients in the evinacumab group received lomitapide than in the placebo group (25.6% versus 13.6%). The patients’ lipid parameters were comparable across treatment groups in terms of mmol/L, though the evinacumab group tended to have higher levels of the following than the placebo group: LDL-C (259.5 mg/dL versus 246.5 mg/dL), non-HDL-C (281.9 mg/dL versus 269.9 mg/dL), and total cholesterol (325.6 mg/dL versus 315.9 mg/dL). This was not true of Apo B, for which the mean levels at baseline were lower in the evinacumab group than in the placebo group (169.1 mg/dL versus 175.9 mg/dL).²⁹

CL-17100 Study

The CL-17100 study was conducted in patients aged 5 to 11 years with HoFH. The mean age of the patients enrolled in Part B of the CL-17100 study at baseline was 9.1 years (SD = 1.94). Most patients (57.1%) were white females. Most patients (71.4%) had compound heterozygous mutations, and only 50% of patients had received prior apheresis at baseline. Nearly all patients were treated with statins (85.7%) and ezetimibe (92.9%) at baseline, and only 2 patients (14.3%) received lomitapide. The patients’ lipid parameters at baseline were similar to those in the ELIPSE trial, with mean values as follows: LDL-C of 263.7 mg/dL, Apo B of 168.2 mg/dL, non-HDL-C of 282.2 mg/dL, and total cholesterol of 315.5 mg/dL.²⁸

Table 12: Summary of Baseline Characteristics From Studies Included in the Systematic Review

Apo B = apolipoprotein B; BMI = body mass index; CHD = coronary heart disease; CV = cardiovascular; HDL-C = high-density lipoprotein cholesterol; HoFH = homozygous familial hypercholesterolemia; ITT = intention to treat; LDL-C = low-density lipoprotein cholesterol; LDLR = low-density lipoprotein receptor; LLT = lipid-lowering therapy; NR = not reported; SAS = safety analysis set; SD = standard deviation; TC = total cholesterol.

Sources: ELIPSE Clinical Study Report;²⁹ CL-17100 Clinical Study Report.²⁸

Exposure to Study Treatments

Exposure to study treatments in the ELIPSE trial and the CL-17100 study is summarized in Table 13.

ELIPSE Trial

In the ELIPSE trial, a total of 38 patients (86.4%) in the evinacumab group and 17 patients (81.0%) in the placebo group completed the double-blind treatment period. The mean number of infusions was similar in the evinacumab group |||| |||| ||||||| and the placebo group ||||| |||| |||||||, as was the duration of study drug exposure (evinacumab: ||||| ||||| ||| |||||||| |||||||| ||||| ||||| |||| ||||||).²⁹

||| |||||| patient receiving evinacumab had infusion interruptions at ||||||||| |||| || ||| |||| ||, while ||||| patients receiving placebo had infusion interruptions at ||||||||. There were || infusion interruptions after week 8. ||| ||||||| in the evinacumab group experienced an infusion interruption ||| || ||| ||||||||| |||| |||||||||. The full dose of the study drug was administered in all cases, despite infusion interruptions.²⁹

Table 13: Summary of Patient Exposure From ELIPSE and CL-17100 Studies

ITT = intention to treat; SAS = safety analysis set; SD = standard deviation.

Sources: ELIPSE Clinical Study Report;²⁹ CL-17100 Clinical Study Report.²⁸

CL-17100 Study

In Part B of the CL-17100 study, all 14 patients had a mean of |||| ||||||||| |||| |||||| for a mean duration of ||||| ||||| |||| |||||||. A total of |||||||||| patients had their infusions interrupted at the baseline visit; ||| || || || ||||||||||| |||||| || |||||. ||| |||||| patient had their infusion interrupted at the week 12 visit due to ||||||||| |||||||. Infusions were resumed in all cases within minutes of the interruption. In the pooled population for Parts B and C, the mean number of infusions was ||||| ||||||||| |||| |||||| over an exposure of ||||| ||||| |||| ||||||²⁸

||| |||||| patient had their infusion interrupted at both the week 12 and week 32 visits. ||| |||||| patient had their infusion interrupted at the week 4 visit. In all |||| cases, the reasons for the infusion interruptions were |||||||, and the infusions were resumed following the interruption.²⁸

Efficacy

Efficacy results for the ELIPSE and CL-17100 studies are summarized in Table 14.

Percent Change From Baseline in LDL-C

The primary efficacy end point of the ELIPSE and CL-17100 studies was percent change from baseline in LDL-C to week 24. The results for the LSM percent change from baseline in LDL-C during the double-blind treatment period of the ELIPSE trial are summarized in Figure 1. The LSM percent change from baseline with evinacumab was –47.1% (SE = 4.6), compared to 1.9% (SE = 6.5) with placebo. In the double-blind treatment period, the LSMD between evinacumab and placebo in percent change from baseline in LDL-C was –49.0% (95% CI, –65.0 to –33.1), favouring evinacumab.²⁹

Figure 1: Least Squares Mean Percent Change From Baseline in LDL-C (MMRM Analysis; ITT Population, ELIPSE)

LDL-C = low-density lipoprotein cholesterol; LS = least squares; ITT = intention to treat; MMRM = mixed-effect model with repeated measures; Q4W = every 4 weeks; SE = standard error.

Source: ELIPSE Clinical Study Report.²⁹

The results for the mean percent change from baseline in LDL-C during the open-label treatment period of the ELIPSE trial are summarized in Figure 3. For patients that entered the open-label period from the evinacumab group of the double-blind treatment period, the percent change from baseline in LDL-C to week 48 was –42.70% (SD = 40.0). For patients who received placebo in the double-blind treatment period followed by evinacumab in the open-label treatment period, the percent change in LDL-C at week 48 was –55.80% (SD = 22.45). The overall percent change in LDL-C at 48 weeks in the open-label treatment period was –46.31% (SD = 36.31).²⁹

The results for LSM change from baseline in LDL-C with evinacumab from Part B and the pooled Parts B and C of the CL-17100 study were consistent with the double-blind period of the ELIPSE trial: –48.32% (SD = 39.052) and ||||||| |||| |||||||| respectively.²⁸

Sensitivity Analyses

A sensitivity analysis was performed using the actual stratification factors in place of the interactive voice or web response system strata. However, there were no incorrect stratifications per interactive voice or web response system in the ELIPSE study; thus, the results for the sensitivity analysis were identical to those for the primary analysis. An additional sensitivity analysis was conducted to explore the impact of nonignorable missingness using a PMM. Only 1 patient (4.5%) in the placebo group did not have a LDL-C value at week 24. The LSMD between the evinacumab and placebo groups was –48.2% (95% CI, –63.6 to –32.8). The LSM percent change from baseline in LDL-C to week 24 was –47.1% (SE = 4.6) in the evinacumab group and 1.1% (SE = 6.4) in the placebo group.²⁹

In the CL-17100 study, the results of the sensitivity analysis using the MMRM approach were consistent with the primary analysis, with a percent change from baseline in LDL-C of –48.3% (95% CI, –65.4 to –31.2). There were no non–GCP-compliant sites or missing data, so no sensitivity analyses were conducted for these categories.²⁸

Subgroup Analysis

Subgroup analyses were provided for the primary outcome of percent change from baseline in LDL-C. Subgroup analyses of interest to this review included prior LLT, prior or concomitant apheresis, baseline LDL-C level, and HoFH genotype. Subgroup analyses from the ELIPSE trial and the CL-17100 study are summarized in Table 26, Table 27, and Table 28 of Appendix 1.

Background LLT: Background LDL-C–lowering therapy was not a prespecified subgroup of interest, though the results of the subgroup analysis for the double-blind treatment period of the ELIPSE trial are summarized in Table 26. The percent change from baseline in LDL-C in the evinacumab group when receiving background statins (N = 41), ezetimibe (N = 33), PCSK9 inhibitors (N = 34), or lomitapide (N = 11) was –47.29% (SD = 30.58), –53.07% (SD = 20.97), –49.45% (SD = 31.87), and –49.64% (SD = 22.55), respectively. In the placebo group, the percent change from baseline in LDL-C while on background statins (N = 19), ezetimibe (N = 16), PCSK9 inhibitors (N = 15), or lomitapide (N = 3) was 2.17% (SD = 32.34), –1.95% (SD = 30.58), 1.73% (SD = 30.34), and –17.22% (SD = 47.62), respectively. Subgroup results for patients with no statin, ezetimibe, PCSK9 inhibitor, or lomitapide background therapy were generally similar, though the number of patients without LLTs at baseline was small.²⁹

Subgroup analyses by background LLT were not conducted in the open-label treatment period of the ELIPSE trial or in the CL-17100 study.

Apheresis status: In the subgroup of patients from the double-blind treatment period of the ELIPSE trial who had received apheresis at baseline (Table 27) in the evinacumab (N = 14) and placebo (N = 8) groups, the LSMD compared to placebo was –38.3% (95% CI, –65.1 to –11.5), representing a LSM change from baseline in LDL-C of –46.5% (SE = 8.8) for evinacumab and –8.3% (SE = 11.6) for placebo. In the subgroup of patients who had not received apheresis at baseline in the evinacumab (N = 29) and placebo (N = 14) groups, the LSMD compared to placebo was –55.2% (95% CI, –75.1 to –35.4), representing an LSM change from baseline in LDL-C of –47.3% (SE = 5.9) for evinacumab and 7.9% (SE = 8.4) for placebo.²⁹

In the open-label treatment period, the percent change from baseline in LDL-C in patients who received baseline apheresis and in those who did not was consistent with that in the double-blind treatment period, as well as with that in the primary analysis of the open-label treatment period.²⁹

In the CL-17100 study, the percent change from baseline in LDL-C for patients who had, or had not received prior apheresis was consistent with that in the primary analysis and with the results from both the double-blind and open-label treatment periods of the ELIPSE trial.²⁸

Baseline LDL-C Level: The subgroup analysis by baseline LDL-C level is summarized in Table 27. In the double-blind treatment period of the ELIPSE study, 9 patients with LDL-C less than 130 mg/dL at baseline were randomized to the evinacumab group and 5 such patients were randomized to the placebo group. The LSMD for evinacumab compared to placebo was –22.7% (95% CI, –56.6 to 11.2), representing an LSM change from baseline in LDL-C of –27.3% (SE = 10.2) with evinacumab and –4.6% (SE = 13.4) with placebo. In the subgroup of patients in the evinacumab (N = 34) and placebo (N = 17) groups with baseline LDL-C greater than or equal to 130 mg/dL, the LSMD for evinacumab compared to placebo was –57.3% (95% CI, –75.3 to –39.4), representing an LSM change from baseline in LDL-C of –52.5% (SE = 5.2) and 4.8% (SE = 7.4) for the evinacumab and placebo groups, respectively.²⁹

Subgroup analyses by baseline LDL-C were not conducted in the open-label treatment period of the ELIPSE trial or in the CL-17100 study.²⁸

HoFH genotype: The subgroup analyses by HoFH genotype are summarized in Table 28. In the double-blind treatment period of the ELIPSE trial, the results of the subgroup analyses by HoFH genotype were consistent with the primary analysis across most genotypes, including homozygous (LSMD = –64.4%; 95% CI, –89.6 to –39.2) and compound heterozygous (LSMD = –43.7%; 95% CI, –72.2 to –15.2), as well as negative/negative (LSMD = –48.7%; 95% CI, –85.0 to –12.4) and null/null mutations (LSMD = –59.6%; 95% CI, –88.6 to –30.5), suggesting greater reductions in LDL-C with evinacumab than with placebo, but not for patients with the double heterozygous genotype or other mutations. In the open-label treatment period, analyses for this subgroup were only conducted for negative/negative and null/null mutations, with the results being consistent with the double-blind treatment period.²⁹

In the CL-17100 study, the analyses for this subgroup were only conducted for negative/negative and null/null mutations, with a percent change from baseline in LDL-C of –67.7% (SD = 6.5) in patients with negative/negative mutations (N = 3) and of –57.2% (SD = not applicable) in patients with null/null mutations (N = 1).²⁸

Absolute Change From Baseline in LDL-C

Absolute change from baseline in LDL-C level to week 24 was a secondary outcome of the ELIPSE study. The LSM absolute change in LDL-C during the double-blind treatment period was –134.7 mg/dL (SE = 12.4) in the evinacumab group, while in the placebo group, the LSM absolute change in LDL-C was –2.6 mg/dL (SE = 17.6), and the LSMD versus placebo favoured evinacumab (–132.1 mg/dL; 95% CI, –175.3 to –88.9; P < 0.0001). In the open-label treatment period, the LSM absolute change from baseline in LDL-C at 48 weeks was –134.3 mg/dL (SD = 117.33).²⁹

In Part B of the CL-17100 study, the LSM absolute change from baseline in LDL-C was –131.9 mg/dL (SD = 30.0).²⁸

Proportion of Patients With Greater Than or Equal to 30% Reduction in LDL-C

The proportion of patients with a greater than or equal to 30% reduction in LDL-C at week 24 was a key secondary outcome of the ELIPSE study but was not evaluated in the open-label treatment period or in the CL-17100 study. In the double-blind treatment period of the ELIPSE trial, 83.7% of patients in the evinacumab group and 18.2% of patients in the placebo group experienced such a reduction, favouring evinacumab (OR = 25.2; 95% CI, 5.7 to 110.5; P < 0.0001).²⁹

Percent Change From Baseline in Apo B

The percent change from baseline in Apo B to week 24 was a key secondary efficacy end point of the ELIPSE and CL-17100 studies. In the double-blind treatment period of the ELIPSE trial, the LSM percent change from baseline in Apo B with evinacumab was –41.4% (SE = 3.3), compared to –4.5% (SE = 4.8) with placebo. The LSMD between evinacumab and placebo in percent change from baseline in Apo B was –36.9% (95% CI, –48.6 to –25.2), favouring evinacumab.²⁹

For patients that entered the open-label period of the ELIPSE trial from the evinacumab group of the double-blind treatment period, the percent change from baseline in Apo B to week 48 was –37.10% (SD = 27.716). For patients who received placebo in the double-blind treatment period followed by evinacumab in the open-label treatment period, the percent change in LDL-C at week 48 was –49.92% (SD = 19.784). The overall percent change in LDL-C at 48 weeks in the open-label treatment period was –40.83% (SD = 26.150).²⁹

The results for LSM change from baseline in Apo B with evinacumab from Part B and the pooled Parts B and C of the CL-17100 study were consistent with those in the double-blind period of the ELIPSE trial, at –41.32% (SD = 33.541) and –39.27% (SD = 29.438), for Part B and the pooled Parts B and C, respectively.²⁸

Global Lipid LDL-C Targets

Proportion of Patients With LDL-C Less Than 100 mg/dL (2.59 mmol/L)

The proportion of patients with LDL-C less than 100 mg/dL (2.59 mmol/L) was a key secondary end point of the ELIPSE trial. In the double-blind treatment period, the proportion of patients with LDL-C less than 100 mg/dL at 24 weeks was 46.5% in the evinacumab group, compared to 22.7% in the placebo group (OR = 5.7; 95% CI, 1.3 to 24.9; P = 0.0203).²⁹

The proportion of patients with LDL-C less than 100 mg/dL was not evaluated in the open-label extension study or the CL-17100 study.

Proportion of Patients With LDL-C Less Than 70 mg/dL (1.81 mmol/L)

The proportion of patients with LDL-C less than 70 mg/dL (1.81 mmol/L) was a secondary end point of the ELIPSE trial. In the double-blind treatment period, the proportion of patients with LDL-C less than 70 mg/dL at 24 weeks was 27.9% in the evinacumab group, compared to 4.5% in the placebo group (OR = 20.9; 95% CI, 1.6 to 276.8; P = 0.0209).²⁹

The proportion of patients with LDL-C less than 70 mg/dL was not evaluated in the open-label extension study or the CL-17100 study.

Proportion of Patients Who Meet US Apheresis Criteria

The proportion of patients who meet US apheresis eligibility criteria was a key secondary end point of the ELIPSE trial. In the double-blind treatment period, at 24 weeks, 7.0% of patients in the evinacumab group met the US apheresis eligibility criteria, compared to 22.7% in the placebo group (OR = 0.1; 95% CI, 0.0 to 0.3; P = 0.0845). Statistical hypothesis testing was terminated at this end point in the ELIPSE trial because statistical significance was not reached.²⁹

The proportion of patients who meet US apheresis eligibility criteria was not evaluated in the open-label extension study or the CL-17100 study.

Proportion of Patients Who Meet EU Apheresis Criteria

The proportion of patients who meet EU apheresis eligibility criteria was a key secondary end point of the ELIPSE trial. In the double-blind treatment period, at 24 weeks, 32.6% of patients in the evinacumab group met the EU apheresis eligibility criteria, compared to 77.3% in the placebo group (OR = 0.1; 95% CI, 0.0 to 0.3).²⁹

The proportion of patients who meet EU apheresis eligibility criteria was not evaluated in the open-label extension study or the CL-17100 study.

EQ-5D

HRQoL measured by the EQ-5D was an exploratory outcome of the ELIPSE trial. At baseline, the mean utility score in the evinacumab (N = 43) and placebo (N = 20) groups was |||||| points (SD = ||||) and |||||| points (SD = ||||), respectively. At week 24, the mean utility score was |||||| points (SD = ||||) for evinacumab and |||||| points (SD = ||||) for placebo, representing a mean change from baseline of ||||||| points (SD = ||||) with evinacumab and ||||||| points (SD = ||||) with placebo.²⁹

HRQoL was not measured in the open-label treatment period of the ELIPSE trial or in the CL-17100 study.

Mortality (All-Cause and CV-Related)

All-cause and CV-related mortality were not evaluated in the ELIPSE or CL-17100 studies.

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

Apo B = apolipoprotein B; CFB = change from baseline; CI = confidence interval; DBTP = double-blind treatment period; EU = European Union; ITT = intention to treat; LDL-C = low-density lipoprotein cholesterol; LS = least squares; LSMD = least squares mean difference; NA = not applicable; NR = not reported; OLTP = open-label treatment period; OR = odds ratio; SAS = safety analysis set; SD = standard deviation; SE = standard error; vs. = versus.

^aValues for CFB are as of week 24.

^bValues for CFB are as of week 48 of open-label treatment.

^cValues for CFB in the open-label treatment period of ELIPSE and for the CL-17100 study are SD.

^dStatistical hypothesis testing terminated at this end point because statistical significance was not reached. All other reported differences between treatment groups reported for secondary end points in subsequent rows are nominal.

Sources: ELIPSE Clinical Study Report;²⁹ CL-17100 Clinical Study Report.²⁸

CV-Related Morbidity

CV-related morbidity outcomes, such as the incidence of resuscitated cardiac arrest, nonfatal MI, and stroke, were not evaluated in the ELIPSE or CL-17100 studies.

Harms

Important harms reported in the ELIPSE and CL-17100 studies are summarized in Table 15.

Adverse Events

In the ELIPSE trial, the incidence of TEAEs was lower for patients in the evinacumab group than in the placebo group during the double-blind treatment period (65.9% versus 81.0%). In the open-label treatment period of the ELIPSE trial, the incidence of TEAEs for evinacumab was higher than in the double-blind treatment period (73.4%). The most frequently occurring TEAEs in the double-blind treatment period of the ELIPSE trial in the evinacumab and placebo groups by system organ class were infections and infestations (27.3% versus 28.6%); general disorders and administration site conditions (20.5% versus 14.3%); respiratory, thoracic, and mediastinal disorders (18.2% versus 4.8%); gastrointestinal disorders (15.9% versus 23.8%); musculoskeletal and connective tissue disorders (15.9% versus 9.5%); and nervous system disorders (11.4% versus 23.8%). The most common TEAEs by preferred term in patients treated with evinacumab versus placebo were nasopharyngitis (15.9% versus 23.8%) and influenza-like illness (11.4% versus 0.0%). In the open-label treatment period, the most frequently reported TEAEs were nasopharyngitis and headache (9.4% each). The majority of TEAEs experienced during the double-blind treatment period were classified as mild or moderate in intensity.²⁹

In the CL-17100 study, nearly all patients treated with evinacumab experienced at least 1 TEAE (|||||). The most frequently occurring TEAEs by system organ class in the CL-17100 study included |||||||||| ||| |||||||||||| |||||||| |||||||||||||||| ||||||||| |||||||| ||| ||||||| ||||||||| ||| |||||||||||||| |||| |||||||||| |||||||| The most frequent individual TEAEs by preferred term included |||||||| |||||||| ||| ||||||||||||||| |||||||.²⁸

Serious AEs

In the ELIPSE study, SAEs were reported as severe TEAEs and were infrequently reported, occurring in only |||||| patients in the evinacumab group during the double-blind treatment period and consisting of urosepsis (1 [2.3%]) and attempted suicide (1 [2.3%]). There were no SAEs in the placebo group. In the open-label treatment period, ||||||| patients had SAEs, which included angina pectoris; carotid artery restenosis; congestive cardiac failure; unstable angina and coronary artery disease; pyelonephritis and nephrocalcinosis; and cardiac procedure complication, aortic stenosis, and acute MI (1 [1.16%] each), all of which were considered severe in severity.²⁹

In the CL-17100 study, only |||||| patient experienced an SAE of |||||||||||.²⁸

Withdrawals due to AEs

There were no withdrawals due to AEs in the ELIPSE or CL-17100 studies; however, in the open-label treatment period of the ELIPSE study, 1 patient in the evinacumab group had a pregnancy that led to discontinuation of study treatment, though the patient completed the study.^28,29

Mortality

There were no deaths reported during the ELIPSE or CL-17100 studies.^28,29

Notable Harms

The AESIs to this review were general allergic reactions, IRRs, new onset diabetes, musculoskeletal and connective tissue disorders, creatinine kinase changes, and liver function. In the evinacumab and placebo groups of the double-blind treatment period of the ELIPSE trial, 4 patients (9.1%) and 3 patients (14.3%), respectively, experienced allergic events; 3 patients (6.8%) and 1 patient (4.8%) experienced IRRs; |||||| ||||||||| patients had new onset diabetes; ||||| ||| ||||| patient in each treatment group had diabetic complications; and 7 patients (15.9%) and 2 patients (9.5%) experienced musculoskeletal and connective tissue disorders. |||||| ||||||||| patients experienced increases in creatine kinase and increased aspartate aminotransferase, and ||||| ||| ||||| patient in each treatment group had increased alanine aminotransferase and increased bilirubin. AESIs in the open-label treatment period were similar to those in the double-blind treatment period.²⁹

In the CL-17100 study, general allergic events occurred in ||||||| patients, and || patients had IRRs, new onset diabetes, diabetic complications, or increases in liver enzymes. Musculoskeletal and connective tissue disorders and increases in creatinine kinase were not reported.²⁸

Table 15: Summary of Harms Results From Studies Included in the Systematic Review

ALT = alanine aminotransferase; AST = aspartate aminotransferase; DBTP = double-blind treatment period; HLGT = high-level group term; HLT = higher level term; IRR = infusion-related reaction; MI = myocardial infarction; NR = not reported; OLTP = open-label treatment period; PT = preferred term; SAE = serious adverse event; SAS = safety analysis set; TEAE = treatment-emergent adverse event; ULN = upper limit of normal.

^aTEAEs that occurred at a rate of greater than or equal to 5%.

Sources: ELIPSE Clinical Study Report;²⁹ CL-17100 Clinical Study Report.²⁸

Critical Appraisal

Internal Validity

Two studies were included in this review: the ELIPSE study and the CL-17100 study. The ELIPSE study was a first-in-class, phase III, placebo-controlled RCT that included both double-blind and open-label treatment periods. Appropriate methods for randomization (using interactive response technology), treatment allocation (stratified by apheresis treatment and by region), and maintenance of blinding to treatment assignment were used, reducing selection, performance, and detection biases. Overall, there was only 1 discontinuation in the evinacumab group during the double-blind treatment period, and there was not a substantial difference in AEs across groups; thus, it was unlikely that blinding was impacted during treatment.

The CL-17100 study was an open-label, single-arm study of evinacumab in patients aged 5 to 11 years with HoFH. The choice to conduct a single-arm trial in the younger population was justified by the rarity of the indication and the age of the participants; however, the noncomparative nature negates the ability to draw a statistical association between the reported results and evinacumab due to the small sample size and the chronic progression of HoFH. As such, the strength and interpretability of the results for this group of patients is limited. Further, single-arm trials are generally not considered confirmatory for efficacy and are subject to several limitations that complicate their interpretation; in particular, it is difficult to isolate whether the effect is due to placebo, natural history, or unidentified prognostic factors that could affect the study outcomes. These sources of potential bias are also applicable to the open-label phase of the ELIPSE study.

The original study protocol for the ELIPSE trial was amended | times, and the protocol for the CL-17100 study was amended |||||. It was unclear how many patients were enrolled at each protocol amendment; therefore, the impact of potential biases due to protocol amendments remains unknown. Overall, important protocol deviations in the ELIPSE study (||||% versus ||||%) and the CL-17100 study (|||%) were high, primarily due to procedural irregularities with the apheresis schedule for the ELIPSE trial (listed under “other” important protocol deviations for CL-17100) and due to pharmacokinetic issues in the CL-17100 study, though it remains unclear what impact these deviations may have had on the treatment effect.

As previously noted, dropouts in the ELIPSE and CL-17100 studies were low. The primary end point of the ELIPSE trial used an MMRM to account for missing data under the missing at random assumption, which may have overestimated the precision of the effect estimates. The sensitivity analyses used a PMM to account for nonignorable missingness and showed that the missing data are unlikely to have greatly biased the results. Overall, the amount of missing data was low, as evidenced by the results of the sensitivity analysis, which were nearly identical to those of the primary efficacy analysis. The use of an MMRM was appropriate due to the heterogeneity of the patient population in terms of LDL-C at baseline. However, the implementation of the model may have included too many covariates, which could lead to numerical instability given the small sample size. Information on missingness was reported for secondary end point results and exploratory HRQoL results; thus, the impact of missing data for these outcomes remains unknown.

Acceptable methods to account for multiplicity were used in the ELIPSE trial. The primary end point (percent change from baseline in LDL-C) and key secondary end points (percent change from baseline in Apo B, non-HDL-C, and total cholesterol; proportion of patients with a ≥ 30% reduction in LDL-C at week 24; proportion of patients with a ≥ 50% reduction in LDL-C at week 24; absolute change from baseline in LDL-C to week 24; proportion of patients who meet US apheresis eligibility criteria; proportion of patients with LDL-C < 100 mg/dL; and proportion of patients who meet EU apheresis eligibility criteria) were controlled for multiplicity at the 0.05 level using a hierarchical testing sequence. However, statistical significance was not achieved for the end point of proportion of patients who meet US apheresis eligibility criteria; thus, the multiple testing procedure failed, and all subsequent outcomes (proportion of patients with LDL-C < 100 mg/dL and proportion of patients who meet EU apheresis eligibility criteria) should only be viewed as supportive. In the CL-17100 study, no inferential statistical testing was performed for the efficacy outcomes and no multiple testing procedure was conducted; hence, the results should only be considered supportive of the overall effect of evinacumab.

Predefined sensitivity analyses were conducted in both studies to evaluate the robustness of the primary end point, and these analyses were supportive of the primary end point. Additionally, various prespecified subgroup analyses were conducted in the ELIPSE and CL-17100 studies. Though they generally supported the primary analysis, the subgroup analyses were not statistically powered to detect within-group or between-group differences; thus, the results from the subgroup analyses should be interpreted as supportive evidence only for the overall effect of evinacumab.

External Validity

The clinical experts engaged by CADTH considered the inclusion and exclusion criteria for the ELIPSE and CL-17100 studies appropriate, though the clinical experts highlighted that genetic confirmation of HoFH does not always occur. Both the ELIPSE and CL-17100 studies were multinational studies; however, the ELIPSE trial was the only study to enrol patients living in Canada (N = 3), though given the low number of patients living in Canada enrolled, generalizability based on geography cannot be assumed.

HoFH is a rare disease. The ELIPSE trial included 65 patients with HoFH and the CL-17100 study included 20 patients with HoFH. The clinical experts consulted by CADTH noted that, in their experience, the populations included in the trials were generally in line with those seen in clinical practice in Canada with regard to age and that the LDL-C levels at baseline were reflective of the patients seen by the clinical experts in practice, whose LDL-C levels on MTD statin, ezetimibe, and PCSK9 inhibitors were consistently above 5.0 mmol/L. The experts did note, however, that the distribution of race was not reflective of Canadian clinical practice as the majority of patients in the ELIPSE trial identified as white.

The chosen comparator of placebo in the ELIPSE study was appropriate and aligned with the recommended standard of care guidelines for HoFH in Canada; the experts noted that standard of care consists of MTD statin, ezetimibe, and a PCSK9 inhibitor. All patients in the included studies had received prior LLT, consisting of some combination of statin, ezetimibe, PCSK9 inhibitor, lomitapide, and apheresis. The clinical experts consulted by CADTH noted that the proportion of patients receiving LLTs was in line with the general population of patients with HoFH in Canada, though the proportion of patients in the ELIPSE trial receiving PCSK9 inhibitors was higher than in Canadian clinical practice owing to the difficulty in accessing PCSK9 inhibitors in Canada. There were minor differences in lomitapide use between groups at baseline, with only 11 patients (25.6%) in the evinacumab group and 3 patients (13.6%) in the placebo group receiving lomitapide, though this was potentially related to the rarity of the disease and to the study design, as differences in patients may be more noticeable in studies with small sample sizes.

The outcomes used in the included studies were similar, with identical primary outcomes of percent change from baseline in LDL-C to week 24. The outcomes used to provide information on the efficacy of evinacumab in the ELIPSE and CL-17100 studies were based on validated laboratory assessments of lipids. According to the clinical experts, the selected lipid-related outcomes are considered widely accepted surrogates for clinically relevant CV outcomes and are important in guiding treatment decisions for patients with HoFH in Canadian clinical practice. In addition to the well-established lowering of LDL-C, the most valuable outcomes to patients with HoFH included reduction in the risk of CV events and reduction of the need for apheresis. The included studies were not designed to assess important CV-related outcomes, including reductions in major adverse cardiac events and in all-cause and CV-related mortality, though the clinical experts consulted by CADTH noted that measuring event-driven outcomes such as these is difficult in HoFH due to the rarity of the disease. Additionally, impact on HRQoL was an exploratory outcome of the ELIPSE trial but was not evaluated in the CL-17100 study. The clinical experts consulted by CADTH noted that reduction in the burden of apheresis is believed to improve patients’ HRQoL; however, reduction of apheresis was not captured in the available evidence. The clinical experts consulted by CADTH emphasized that the duration of the ELIPSE and CL-17100 studies (24 weeks) was considered appropriate for assessing lipid-related outcomes given that the effects on lipids are rapidly seen; however, the experts noted that the 24-week duration of the included studies was insufficient to determine the impact of evinacumab on CV-related morbidity and mortality and on HRQoL.

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For the pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for the outcomes considered most relevant to inform CADTH’s expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group:^30,31

• High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate certainty: We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. We use the word “likely” for evidence of moderate certainty (e.g., “X intervention likely results in Y outcome”).

• Low certainty: Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect. We use the word “may” for evidence of low certainty (e.g., “X intervention may result in Y outcome”).

• Very low certainty: We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of the effect. We describe evidence of very low certainty as “very uncertain.”

Under the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.

Although no guidance is available on applying GRADE to noncomparative studies, the CADTH review team assessed the pivotal single-arm trial for study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias to present these important considerations. Because the lack of a comparator arm does not allow for a conclusion to be drawn on the effect of the intervention versus any comparator, the certainty of evidence for single-arm trials started at very low certainty, with no opportunity for rating up.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null. The target of the certainty of evidence assessment was the presence of a clinically important reduction of LDL-C (percent and absolute change in LDL-C) against thresholds informed by treatment guidelines and clinical expert opinion. Other targets for the certainty of evidence assessment were the presence or absence of any (non-null) effect for the proportion of patients achieving global lipid targets (i.e., percent change from baseline in Apo B, proportion of patients with a ≥ 30% reduction in LDL-C, proportion of patients with LDL-C < 100 mg/dL or < 70 mg/dL, proportion of patients that meet US or EU apheresis criteria, and HRQoL measured by the EQ-5D).

The ELIPSE and CL-17100 studies were assessed individually, given the differences in design: the ELIPSE trial was a comparative RCT of evinacumab versus placebo, and the CL-17100 study was a single-arm study of evinacumab, which had different methods of evaluating treatment effect. Additionally, the ELIPSE trial included adolescent and adult populations (aged 12 years and older), while the CL-17100 study had a pediatric patient population (aged 5 to 11 years).

Results of GRADE Assessments

Table 2 shows the detailed GRADE summary of findings for evinacumab versus placebo for outcomes in the pivotal ELIPSE trial of adolescent and adult patients with HoFH. Table 3 shows the narrative GRADE summary of findings for evinacumab in the pediatric population of the CL-17100 study and the outcomes from the ELIPSE trial that were unable to be populated in Table 2.

Long-Term Extension Studies

The content within this section has been informed by materials submitted by the sponsor. The following has been summarized and validated by the CADTH review team.

CL-1719 Study

The CL-1719 study is an ongoing, long-term, open-label study, with a primary aim of evaluating the safety, tolerability, and efficacy of evinacumab 15 mg/kg administered intravenously every 4 weeks in adults and adolescents with HoFH receiving a background LLT (where adolescents were aged 12 years or older, but younger than 18 years). As its secondary objectives, the trial aims to evaluate the effect of evinacumab 15 mg/kg on lipid parameters (i.e., LDL-C, Apo B, non-HDL-C, total cholesterol, and triglycerides).⁴⁸

An interim analysis was conducted on ||||| ||| ||||, at a data lock date of ||| ||| ||||. The study duration varied for every patient, ranging from 26 weeks up to approximately | years. The study is ongoing in 12 countries in Europe, North America (|| patients in Canada), Africa, and Asia. By the data cut-off date, ||| patients had been enrolled in the total study population (consisting of the adult and adolescent populations), || patients (||||%) had completed the treatment period, || patients (||||%) were ongoing in the treatment period, and || patients (||||%) had discontinued. The mean age of the patients was |||| years; || adolescent patients (||||%) had been enrolled; ||||% of the population was male and ||||% was female; and the majority of patients were white (||||%). Of the ||| patients in the total study population, ||| (||||%) had a history and/or risk factors for CVD.⁴⁸ Figure 2 presents the study design of the CL-1719 study.

Figure 2: Study Design of the CL-1719 Study

Q4W = every 4 weeks.

¹ Patients who may require homozygous familial hypercholesterolemia genotyping and patients whose background lipid-lowering therapy or apheresis settings and/or schedule were not stable before baseline (day 1) entered an up to 10-week run-in period.

² All patients who were on a stable background lipid-lowering therapy entered a 2-week screening period, except for those from a previous evinacumab study, who completed an end-of-study visit within 7 days before the baseline (day 1) visit for this open-label study.

³ Patients who completed an end-of-study visit in a previous evinacumab study within 7 days of the baseline (day 1) visit for this open-label study did not have to undergo the screening visit and could enrol directly into this study. The end-of-study visit from the previous study could serve as the baseline (day 1) visit for this open-label study, and overlapping assessments did not need to be repeated in this study. Only those assessments and procedures not done in the previous study were to be conducted at the baseline visit.

⁴ Starting on day 1 (baseline), patients received evinacumab 15 mg/kg IV administered every 4 weeks.

⁵ Patients are followed for 24 weeks after receiving the last dose of the study drug.

Source: CL-1719 Clinical Study Report.⁴⁸

Inclusion and Exclusion Criteria

Male and female patients aged 12 years and older with documented HoFH who were receiving a maximally tolerated background LLT (which could include statin, ezetimibe, PCSK9 inhibitors, lomitapide, and/or LDL apheresis) were included in the CL-1719 study. HoFH diagnosis was based on a genetic criterion (documented functional mutations in both LDLR alleles or documented homozygous or compound heterozygous mutations in APOB or PCSK9) and on clinical criteria (untreated total cholesterol > 12.93 mmol/L and triglycerides < 3.39 mmol/L and both parents with documented total cholesterol > 6.47 mmol/L, or cutaneous or tendinous xanthoma before age 10 years).⁴⁸ The participants enrolled in the CL-1719 trial were broadly classified into 2 groups based on:

• Age: Patients aged 18 years and older were considered the adult population; patients aged 12 years and older but younger than 18 years were considered the adolescent population.

• Prior exposure to evinacumab, which included the following subgroups:

  • patients who entered the study directly without prior enrolment in an evinacumab study (the new evinacumab group)

  • patients who had previously completed any 1 study (the ELIPSE or CL-1331 studies) where evinacumab was administered (the continue evinacumab group)

  • new patients on evinacumab and those continuing with evinacumab (the total evinacumab group).

Interventions

At baseline (day 1), patients were administered 15 mg/kg of evinacumab, intravenously, every 4 weeks (± 5 days). Patients who were receiving 150 mg alirocumab, administered subcutaneously, in any previous study, could opt to continue to receive the drug every 2 weeks in the CL-1719 extension study as background LLT.⁴⁸

Patients entering the CL-1719 study after completing a prior study evaluating the safety and efficacy of alirocumab in patients with HoFH but who had not participated in any prior evinacumab study were allowed to choose whether to remain on alirocumab as part of their background LLT.⁴⁸ Patients were allowed, at the investigator’s and patient health care provider’s discretion, to:

• continue treatment with alirocumab supplied by the sponsor as part of their background LLT

• discontinue alirocumab before enrolling in this study

• change to a commercially available PCSK9 inhibitor antibody before enrolling in this study.

Patients receiving evinacumab in the extension study continued until:

• clinical development of evinacumab for the indication was discontinued

• clinical development of evinacumab was terminated

• risk-benefit of evinacumab in this patient population was deemed unfavourable

• evinacumab was approved by the regulatory authority governing the location of the study site.

Patients who discontinued the study drug prematurely were required to return to the clinic (within 5 days) for end-of-treatment assessments.⁴⁸

Medications and nutritional supplements that could alter serum lipids, such as statins, ezetimibe, fibrates, niacin, bile acid resins, red yeast rice, lomitapide, mipomersen, and PCSK9 inhibitors, were permitted if treatment had been initiated before the baseline visit (day 1) and had been stable for at least 4 weeks (6 weeks for fibrates, 8 weeks for PCSK9 inhibitors, 12 weeks for lomitapide, and 6 months for mipomersen). Lipoprotein apheresis was permitted if the patient’s schedule and setting had been stable for at least 8 weeks before the baseline visit.⁴⁸ Patients receiving background LLT (e.g., statins, ezetimibe, PCSK9 inhibitor antibodies) maintained a stable regimen for at least 24 weeks and throughout the study. Patients on other LLTs (e.g., apheresis, lomitapide) had their regimens adjusted after week 24 based on LDL-C levels and CV risk factors and at the investigator’s discretion. Patients were also recommended to follow a heart-healthy diet throughout the study.⁴⁸

Outcomes

TEAEs, physical examination, vital signs monitoring, electrocardiogram, and clinical safety laboratory tests were the safety objectives investigated in the study. The efficacy of evinacumab was assessed using lipid levels collected at prespecified times throughout the study. Vascular imaging conducted in the adolescent population was an exploratory objective.⁴⁸

Statistical Analysis

No sample size calculation was performed and no formal hypothesis was tested for this study. A population of approximately 120 patients was planned for the study, and 116 patients were enrolled by the interim data cut-off. Fourteen patients aged 12 years or older but younger than 18 years were planned to be enrolled; based on the feasibility of identifying patients, the sample size was considered practical.⁴⁸

Of the 4 datasets defined in the analysis, only the SAS is of interest for this review. The SAS included all patients who were enrolled and had received at least 1 dose or part of a dose of the open-label study treatment in this study. Data in the SAS population are presented as follows:

• Continue evinacumab group: patients who received evinacumab in a previous study (i.e., completed the ELIPSE or CL-1331 studies)

• New evinacumab group: patients without previous exposure to evinacumab

• Total evinacumab group: all patients, regardless of prior evinacumab exposure

Descriptive statistics were used to summarize continuous variables (number of patients reflected in the calculation (n), mean, median, SD, quartiles 1 and 3, minimum, and maximum). Categorical or ordinal data were summarized using frequencies and percentages. The percent and absolute changes in lipid data (e.g., LDL-C, Apo B, triglycerides) were summarized for each visit for each of the groups determined by previous evinacumab exposure for all patients in the SAS and for the subpopulation of adolescent patients in the SAS. A within-patient t test (for lipids with a normal distribution) or Wilcoxon signed rank test (a nonparametric test for lipids with a non-normal distribution such as triglycerides) was conducted for secondary efficacy end points to compare each patient’s week 24 assessment to their baseline assessment. Missing data were not imputed.⁴⁸ The baseline values used to determine the percent and absolute change for each time frame were defined as follows:

• For patients who had participated in the ELIPSE study, the baseline was defined as the last obtained value before the first dose of the double-blind study drug in the ELIPSE study.

• For patients who had participated in the previous evinacumab study (the CL-1331 study) or who had not participated in any previous evinacumab study, the baseline was defined as the last obtained value before the first dose of the study drug in the CL-1719 study.⁴⁸

Patient Population

Baseline Characteristics

Table 16 presents the baseline and demographic characteristics of the population enrolled in the CL-1719 study. The total study population (adult and adolescent populations) consisted of || patients who were new to evinacumab (new evinacumab group) and || patients who were continuing on evinacumab from a previous study (continue evinacumab group). The mean age in the total study population was |||| years, with || adolescent patients (||||%) included. There was an even distribution of males (||||%) and females (||||%) in the study, and the majority of patients were white (||||%). There were more adolescent patients in the new evinacumab group than in the continue evinacumab group and more patients aged 65 years and older in the continue evinacumab group than in the new evinacumab group. Of the ||| patients in the total study population, ||| (||||%) had a history of and/or risk factors for CVD.⁴⁸ The most common CV risk factors reported (> ||% of patients) were cutaneous or tendinous xanthoma (|||||) and family history of premature CHD (||||%). Patients in the total study population had either homozygous (||||%) or compound heterozygous (||||%) mutations in the LDLR gene. In the adolescent population, there were || patients who were new to evinacumab and |||| patients who were continuing evinacumab from a previous study. In the adolescent population, the mean age was |||| years; there were more males (||||%) than females (||||%); the majority of patients were white (||||%); || patients (||||%) had a history of CV events and/or risk factors for CVD; and most patients had either homozygous (||||%) or compound heterozygous (||||%) mutations in the LDLR gene.⁴⁸

Table 16: Baseline Characteristics (CL-1719 Study)

Apo B = apolipoprotein B; BMI = body mass index; CHD = coronary heart disease; CV = cardiovascular; CVD = cardiovascular disease; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; LDLR = low-density lipoprotein receptor; LLT = lipid-lowering therapy; SD = standard deviation; TC = total cholesterol.

^a“CHD risk equivalents” refers to people with a 10-year risk of coronary death or nonfatal myocardial infarction at least as high as those who have known CHD (including those with stable angina or prior myocardial infarction), which generally exceeds 20%.

^bNumbers refer to concomitant use.

^cNumbers refer to treatment history.

Source: CL-1719 Clinical Study Report.⁴⁸

||| patients (||||%) were on a statin at baseline in the total study population, of whom || (||||%) were on a high-intensity statin regimen. The most frequently used LLTs besides statin were ezetimibe (|| |||||||), PCSK9 inhibitor (|| [||||%]), and apheresis (|| [||||%]).⁴⁸ |||||||||||| patients (||||%) had a history of lomitapide use. In the adolescent population, ||| || patients (|||%) were on a statin, of whom || (||||%) were on a high-intensity statin regimen; the most frequently used LLTs at baseline were ezetimibe (|| [||||%]) and PCSK9 inhibitors (|| [||||%]).⁴⁸

Patient Disposition

Table 17 presents the patient disposition (total population and adolescent population) in the CL-1719 extension study. By the interim data cut-off date, || patients (||||%) had completed the treatment period, || patients (||||%) were still receiving treatment in the treatment period, and || patients (||||%) had discontinued the treatment period. The continue evinacumab group consisted of || patients (||||%) previously enrolled in the ELIPSE study and | patients (|||%) previously enrolled in the CL-17100 study. The remaining || patients (||||%) were naive to treatment with evinacumab. |||||||| adolescent patients were enrolled and treated in the study. At the data cut-off date, |||| patients (||||%) had completed the treatment period, |||| patients (||||%) were ongoing in the treatment period, and || patients (||||%) had discontinued.⁴⁸

Table 17: Patient Disposition (CL-1719 Study)

Note: Percentages are calculated with the number of treated patients in each group as the denominator.

Source: CL-1719 Clinical Study Report.⁴⁸

Exposure to Study Treatments

Table 18 presents data on treatment exposure in the adolescent and total study populations. In the total study population, the mean number of evinacumab infusions reported at the data cut-off was |||||, the mean duration of exposure was |||||| weeks, and patients had at least || weeks’ exposure to evinacumab. In the adolescent population, the mean number of study treatment infusions was ||||, the mean study duration was |||| weeks, and all treated patients had at least || weeks’ exposure to evinacumab.⁴⁸

Table 18: Exposure to Evinacumab (CL-1719 Study)

SD = standard deviation.

^aDuration of study treatment exposure in weeks was defined as follows: (last evinacumab treatment administration date) + 28(first evinacumab treatment administration date) / 7. Unplanned intermittent discontinuations in study treatment were accounted for.

Source: CL-1719 Clinical Study Report.⁴⁸

Results

Efficacy

Table 19 presents a summary of efficacy parameters assessed in the CL-1719 study in the total and adolescent populations.

Low-Density Lipoprotein Cholesterol

Treatment in the total study population resulted in an absolute mean (SD) change from baseline in LDL-C at week 24 of |||||| mg/dL (|||||| mmol/L). The mean percent change from baseline at week 24 was ||||||%. The reductions from baseline in LDL-C were maintained to at least week ||| (mean percent change from baseline at week ||| of ||||||%), after which time the results were more variable due to the smaller number of patients contributing to the data. The changes from baseline in LDL-C in the adolescent population aligned with those in the total study population (absolute mean change from baseline to week 24 was |||||| mg/dL [|||||| mmol/L]; percent mean change from baseline at week 24 was ||||||%).⁴⁸

Apolipoprotein B

The absolute mean change from baseline to week 24 in Apo B in the total study population was ||||| mg/dL (|||||| g/L). The mean percent change from baseline at week 24 was ||||||%. The reductions from baseline in Apo B were maintained to at least week |||, after which time the results were more variable due to the smaller number of patients contributing to the data. The changes from baseline in Apo B in the adolescent population aligned with those in the total study population (absolute mean change from baseline to week 24 was ||||| mg/dL [|||||| g/L]; mean percent change from baseline to week 24 was ||||||%). The reductions from baseline in Apo B were maintained in the adolescent population to at least week ||, after which time the results were more variable due to the smaller number of patients contributing data.⁴⁸

Table 19: Summary of Efficacy Parameters (LDL-C and Apo B) for the Total and Adolescent Populations (CL-1719 Study)