Summary Basis of Decision (SBD) for Evkeeza

Clinical Pharmacology

The submitted clinical pharmacology data support the use of Evkeeza (evinacumab) for the recommended indication.

Richly sampled pharmacokinetic data for evinacumab were derived from three Phase I stand-alone studies in healthy subjects with elevated triglyceride levels, whereas sparsely sampled pharmacokinetic data were collected in the Phase III studies R1500-CL-1629 (ELIPSE-HoFH) and R1500-CL-1719 (ELIPSE-OLE) in patients with homozygous familial hypercholesterolemia (the Phase III studies are described in the Clinical Efficacy section). The data were used to develop a population pharmacokinetic model and an exposure-response model in adult patients with homozygous familial hypercholesterolemia. Consistent with the efficacy endpoint of the Phase III studies, the lowering of low-density lipoprotein cholesterol (LDL-C) levels was used as a response endpoint metric in the models. The population pharmacokinetic model was subsequently reparameterized and extended for pediatric patients based on data from study R1500-CL-17100 conducted in this patient population.

The most parsimonious structural population pharmacokinetic model (i.e., a model with the fewest number of estimated parameters to appropriately fit the observed data) for evinacumab was a two-compartment model with parallel linear and non-linear elimination. The non-linear elimination is attributed physiologically to target-mediated drug disposition; however, this was modelled using a simple non-linear Michaelis-Menten equation. While the population pharmacokinetic model provides an appropriate fit to the data with no evidence of model bias, its future predictive power may be limited in the absence of any additional refinement to improve the modelling of the effect of target-mediated drug disposition on the elimination of evinacumab.

The proposed dosage regimen of 15 mg/kg administered intravenously every 4 weeks provides an approximately maximal lowering of LDL-C levels compared with 5 mg/kg every 4 weeks or 20 mg/kg every 4 weeks. Steady-state exposures to evinacumab were reached after four doses, with an accumulation ratio of approximately 2 based on the area under the concentration-time curve (AUC).

No clinically meaningful covariate effects on the evinacumab exposure were identified. However, adult patients with homozygous familial hypercholesterolemia have slower weight-normalized evinacumab clearance than pediatric patients. The population pharmacokinetic model-predicted mean steady-state AUC and maximum concentration (C_max) were larger in adults with homozygous familial hypercholesterolemia (11,222 mg*day/L and 718 mg/L) compared with those in children aged 5 to 11 years (7,187 mg*day/L and 444 mg/L).

No treatment-emergent anti-drug antibodies (ADAs) were detected in the evinacumab-treated patients in the placebo-controlled period of study R1500-CL-1629 (ELIPSE-HoFH), whereas in the open-label study R1500-CL-1719 (ELIPSE-OLE), 2 of 116 patients had treatment-emergent ADAs. In the open-label study R1500-CL-17100, 1 of 20 children (5 to 11 years of age) had treatment-emergent ADAs. In all cases, the treatment-emergent ADA responses were transient and of low titre. No clinically meaningful effect on the safety, efficacy or pharmacokinetics of evinacumab was observed in patients who exhibited treatment-emergent ADA responses compared to those in whom no treatment-emergent ADAs were detected.

For further details, please refer to the Evkeeza Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The primary evidence of efficacy of Evkeeza in reducing LDL-C levels in patients with homozygous familial hypercholesterolemia, when Evkeeza is used as an adjunct to diet and other lipid-lowering therapies, was provided from one well-designed placebo-controlled Phase III clinical study, R1500-CL-1629 (ELIPSE-HoFH), including its open-label extension. The trial was conducted in a limited population of 63 adult patients and 2 pediatric patients aged 12 to 17 years (i.e., adolescents). More data supporting the efficacy of Evkeeza in adults and adolescents were derived from the open-label Phase III clinical study, R1500-CL-1719 (ELIPSE-OLE), whereas data for the pediatric subpopulation aged 5 to under 11 years were provided from the open-label study R1500-CL-17100.

In all patients enrolled in the studies, the diagnosis of homozygous familial hypercholesterolemia was determined by genetic testing or by the presence of the following clinical criteria: i) history of an untreated total cholesterol level higher than 12.93 mmol/L (500 mg/dL) and ii) the presence of xanthoma before 10 years of age or evidence of total cholesterol levels higher than 6.47 mmol/L (250 mg/dL) in both parents. All patients included in the trials were receiving background lipid-lowering therapies.

Placebo-controlled study R1500-CL-1629 (ELIPSE-HoFH)

Study R1500-CL-1629 (ELIPSE-HoFH) was a multicentre, double-blind, randomized, placebo-controlled Phase III trial that evaluated the efficacy of Evkeeza compared to placebo in 65 patients with homozygous familial hypercholesterolemia. Patients were randomized to receive Evkeeza 15 mg/kg intravenously every 4 weeks (42 adults, 1 adolescent) or placebo intravenously every 4 weeks (21 adults, 1 adolescent). After the 24-week double-blind treatment period, 64 of the 65 patients entered a 24-week open-label treatment period during which all patients received Evkeeza 15 mg/kg intravenously every 4 weeks. At baseline, 94% of patients were on statins, 75% on ezetimibe, 77% on a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, 22% on lomitapide, and 34% were undergoing lipoprotein apheresis. The mean LDL-C at baseline was 6.61 mmol/L (255.1 mg/dL). Fifty-one percent of patients had limited LDL receptor (LDLR) function, defined as lower than 15% LDLR function measured by in vitro assays, or minimal or no LDLR function predicted by mutation analyses. The patients’ mean age at baseline was 42 years (range: 12 to 75 years) and 12% of patients were 65 years of age or older. Fifty-four percent of patients were female. The majority of patients were White (74%), 15% were Asian, 3% were Black, and 8% were categorized as “other”.

The primary efficacy endpoint of the study was the percent change in the calculated LDL-C level from baseline to Week 24. Key secondary endpoints included the absolute change in LDL-C from baseline to Week 24, and the percent changes in apolipoprotein B, non-high-density lipoprotein cholesterol, and total cholesterol from baseline to Week 24.

At Week 24, the percent change in calculated LDL-C from baseline was -47.1% in the Evkeeza group and 1.9% in the placebo group. This translates into a between-group least-squares mean difference of -49% (95% confidence interval [CI]: -65% to -33%; p<0.0001). The key secondary endpoint results supported the primary endpoint findings.

In the open-label treatment extension of the study, among the 58 patients with available baseline and post-baseline LDL-C values, the mean percent changes in calculated LDL-C from baseline to Week 48 ranged from -43% to -56%.

Open-label study R1500-CL-1719 (ELIPSE-OLE)

The open-label, multicentre Phase III study R1500-CL-1719 (ELIPSE-OLE) was designed to assess the long-term safety and efficacy of Evkeeza. The study enrolled 116 patients aged 12 years and older with homozygous familial hypercholesterolemia who were either Evkeeza naïve (46 patients) or have participated in other studies (70 patients). All patients received 15 mg/kg of Evkeeza intravenously every 4 weeks as an adjunct to other lipid-lowering therapies (statins, ezetimibe, PCSK9 inhibitors, lomitapide, and/or lipoprotein apheresis). In the group of 86 patients with available post-baseline LDL-C values at Week 24, the mean percent change in calculated LDL-C from baseline was -44%.

The study population included 14 pediatric patients aged 12 to 17 years (i.e., adolescents), 12 of whom were Evkeeza naïve, whereas two patients entered the study after completing study R1500-CL-1629 (ELIPSE-HoFH). The mean age of the adolescent population was 14.4 years and 64% of patients were male. At baseline, all 14 adolescents were receiving a statin, 71% were receiving ezetimibe, 43% were receiving a PCSK9 inhibitor, and 64% were undergoing lipoprotein apheresis. The mean baseline LDL-C level in the adolescent patients was 7.88 mmol/L (300.4 mg/dL). In the group of 12 adolescent patients with available post-baseline LDL-C values at Week 24, the mean percent change in calculated LDL-C compared to baseline was -55%.

Open-label study R1500-CL-17100

Study R1500-CL-17100 was a multicentre, three-part, single-arm, open-label study of Evkeeza in pediatric patients 5 to 11 years of age with homozygous familial hypercholesterolemia. Part A of the study assessed the safety, pharmacokinetics, and pharmacodynamics of a single dose of Evkeeza 15 mg/kg administered intravenously in 6 patients with homozygous familial hypercholesterolemia, followed by a 16-week observational period to determine the dose for the rest of the study. Part B of the study evaluated the efficacy and safety of Evkeeza 15 mg/kg administered intravenously every 4 weeks for 24 weeks in 14 patients with homozygous familial hypercholesterolemia. All the patients from Part A and Part B entered the Part C, which included an open-label treatment with Evkeeza 15 mg/kg administered intravenously every 4 weeks for 48 weeks and a 24-week follow-up period (ongoing at the time of the review). Part C is designed to assess the long-term safety and efficacy of Evkeeza.

In the overall population of 20 patients (6 from Part A and 14 from Part B), the mean age at baseline was 9 years (range: 5 to 11 years) and 12 patients (60%) were female. Fourteen patients (70%) were White, 1 patient (5%) was Black, 2 patients (10%) were Asian, 1 patient (5%) was American Indian or Alaska Native, and 2 patients (10%) were categorized as “other”. The mean body weight was 37.9 kg, and the mean body mass index was 18.8 kg/m². The mean LDL-C at baseline was 7.8 mmol/L (301.9 mg/dL).

In Part B, the primary efficacy endpoint was the percent change in calculated LDL-C from baseline to Week 24. Data available for all 14 patients in Part B showed that at Week 24, the mean percent change in calculated LDL-C from baseline to Week 24 was -48% (95% CI: -69% to -28%).

Indication

The New Drug Submission for Evkeeza was filed by the sponsor with the following proposed indication:

Evkeeza (evinacumab) is indicated as an adjunct to diet and other low-density lipoprotein cholesterol (LDL-C)-lowering therapies for the treatment of adult and pediatric patients aged 5 years and older with homozygous familial hypercholesterolemia (HoFH).

Based on the data reviewed, Health Canada revised the proposed indication to include a caveat statement conveying specifically that the effects of Evkeeza on cardiovascular morbidity and mortality have not been determined. Accordingly, Health Canada approved the following indication:

Evkeeza (evinacumab for injection) is indicated as an adjunct to diet and other low-density lipoprotein cholesterol (LDL-C)-lowering therapies for the treatment of adult and pediatric patients aged 5 years and older with homozygous familial hypercholesterolemia (HoFH).

The effects of Evkeeza on cardiovascular morbidity and mortality have not been determined.

For more information, refer to the Evkeeza Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

In clinical trials, 138 patients with homozygous familial hypercholesterolemia were treated with Evkeeza 15 mg/kg intravenously every 4 weeks for at least 24 weeks, 120 patients were treated for at least 52 weeks, and 78 patients were treated for at least 104 weeks.

The safety of Evkeeza was primarily evaluated based on the pooled placebo-controlled data from two placebo-controlled, 24-week, randomized, double-blind studies (R1500-CL-1629 [ELIPSE-HoFH] described in the Clinical Efficacy section and R1500-CL-1643, a Phase II, dose-ranging study which enrolled adult patients with persistent hypercholesterolemia). There were 117 patients randomized to Evkeeza treatment: 44 patients with homozygous familial hypercholesterolemia and 73 patients with persistent hypercholesterolemia. Eighty-one of the randomized patients received Evkeeza 15 mg/kg intravenously every 4 weeks and 35 received Evkeeza 5 mg/kg intravenously every 4 weeks; one patient was not treated with Evkeeza. The age of patients ranged from 12 to 76 years.

The most frequently reported adverse reactions in Evkeeza-treated adults and adolescents and more frequently reported than in the placebo group (54 patients) were nasopharyngitis (13.7% vs. 13.0%), influenza‑like illness (7.7% vs. 5.6%), dizziness (6% vs. 0%), back pain (5.1% vs. 3.7%), and nausea (5.1% vs. 1.9%). Anaphylaxis was reported in 1 (0.9%) patient treated with Evkeeza. Infusion reactions (e.g., infusion-site pruritus) were reported in 9 (7.7%) patients treated with Evkeeza and in 2 (3.7%) patients treated with placebo. Infusion reactions led to discontinuation of treatment in 2 (1.7%) patients treated with Evkeeza. All hypersensitivity reactions were reversible upon drug discontinuation. The risk of anaphylaxis and infusion reactions can be clinically monitored as Evkeeza is administered in a health care setting.

The safety profile of Evkeeza observed in 13 adolescent patients was consistent with that characterized in adult patients with homozygous familial hypercholesterolemia.

The safety of Evkeeza was also assessed in 20 pediatric patients aged 5 to 11 years with homozygous familial hypercholesterolemia in the open-label study R1500-CL-17100 (described in the Clinical Efficacy section). Other than the additionally reported adverse reaction of fatigue, the safety profile of Evkeeza in the pediatric patients was consistent with that identified in adults and adolescents with homozygous familial hypercholesterolemia.

Appropriate warnings and precautions are in place in the approved Evkeeza Product Monograph to address the identified safety concerns.

For more information, refer to the Evkeeza Product Monograph, approved by Health Canada and available through the Drug Product Database.

The medicinal ingredient in Evkeeza, evinacumab, is a recombinant human monoclonal antibody which specifically binds to and inhibits angiopoietin-like protein 3 (ANGPTL3). Angiopoietin-like protein 3 plays a prominent role in the regulation of lipid metabolism by inhibiting lipoprotein lipase and endothelial lipase activities.

The submitted non-clinical data for evinacumab included primary pharmacodynamic, repeat-dose toxicity, reproductive and developmental toxicity, and juvenile toxicity studies.

In primary pharmacodynamic studies, evinacumab was shown to bind to human ANGPTL3 and block the ANGPTL3-induced inhibition of lipoprotein lipase and endothelial lipase.

Consistent with the expected pharmacological activity of evinacumab, intravenous or subcutaneous administration of evinacumab to animals resulted in decreases in circulating triglyceride, total cholesterol, high-density lipoprotein cholesterol (HDL-C), and/or low-density lipoprotein cholesterol (LDL-C) concentrations.

No adverse effects were observed in repeat-dose toxicity studies conducted in adult rats and cynomolgus monkeys administered evinacumab subcutaneously or intravenously at doses of up to 100 mg/kg body weight once weekly. Similarly, no adverse effects were seen at the same doses of evinacumab used in a toxicity study in juvenile rats. However, in a toxicity study conducted in juvenile rabbits, an increase in mortality was observed at an intravenous dose of 300 mg/kg body weight once every 5 days. This adverse effect was not seen at the lower intravenous doses of 30 and 100 mg/kg body weight once every 5 days. Exposures to evinacumab at the no-observed-adverse-effect levels (NOAELs) ranged from 5-fold to 30-fold the human exposure at the maximum recommended human dose (MRHD) of 15 mg/kg body weight administered intravenously every 4 weeks.

No adverse effects on female fertility were observed in rats administered evinacumab subcutaneously at doses of 30 and 100 mg/kg body weight every 3 days (exposures to evinacumab at both doses were below the human exposure at the MRHD). In a fertility study in rabbits administered evinacumab intravenously at doses of 100 or 300 mg/kg body weight every 5 days (exposures to evinacumab were 11-fold and 30-fold the human exposure at the MRHD, respectively), there were no adverse effects on male fertility. However, an anti-drug antibody (ADA) response was observed in a few animals of each dose group, resulting in moribundity that necessitated early euthanasia. Adverse kidney effects (mesangioproliferative glomerulonephritis and interstitial nephritis) were also observed at both doses in surviving males.

In developmental toxicity studies (described below), exposures to evinacumab at all doses administered to animals during pregnancy and lactation were below the human exposure at the MRHD. Therefore, there are no margins of safety for the observed effects of evinacumab on development.

In an embryo-fetal development study in rabbits, subcutaneous administration of evinacumab to pregnant rabbits at doses greater than or equal to 5 mg/kg body weight every 3 days during the period of organogenesis resulted in teratogenicity (as evidenced by various types of external, visceral, and skeletal fetal malformations). Specifically, fetal malformations consisting of domed head, dilation of lateral and third ventricles of the brain, cleft palate, and flexed forepaws occurred at high incidences. Reductions in litter size and number of live fetuses, increases in post-implantation loss and resorptions, and reduced fetal weights were also observed. Maternal toxicity (maternal death, abortion, premature delivery, adverse clinical signs and weight loss) was observed at all doses used (1, 5, 10, and 30 mg/kg body weight every 3 days during the period of organogenesis).

In an embryo-fetal development study in rats, no adverse effects on embryo-fetal development were observed following subcutaneous administration of evinacumab to pregnant rats at doses of 5, 10, 30, and 100 mg/kg body weight every 3 days. However, maternal toxicity (manifested as maternal deaths and abortions) was observed at the high subcutaneous dose of 100 mg/kg body weight every 3 days. In a prenatal and postnatal development study in rats, there were also no adverse effects on prenatal and postnatal development following subcutaneous administration of evinacumab to pregnant and lactating rats at doses of 30 and 100 mg/kg body weight every 3 days.

Evinacumab was detected in the sera of rabbit and rat fetuses and in rabbit offspring, indicating that the antibody crosses the placental barrier and may be excreted in milk.

Carcinogenicity and genotoxicity studies were not performed, which was considered acceptable and in accordance with relevant guidelines.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Evkeeza Product Monograph. In view of the intended use of Evkeeza, there are no pharmacological or toxicological issues within this submission to preclude authorization of the product.

For more information, refer to the Evkeeza Product Monograph, approved by Health Canada and available through the Drug Product Database.

Characterization of the Drug Substance

Evinacumab, the medicinal ingredient in Evkeeza, is a recombinant human immunoglobulin G4 (IgG4) monoclonal antibody that targets angiopoietin-like 3 (ANGPTL3). It has a molecular weight of 146.08 kDa.

Detailed characterization studies were performed to provide assurance that evinacumab consistently exhibits the desired characteristic structure and biological activity.

The product- and process-related impurities that were reported and characterized were found to be within established limits.

Manufacturing Process of the Drug Substance and Drug Product and Process Controls

Evinacumab is a secreted product of a genetically engineered Chinese hamster ovary (CHO) cell line.

The manufacturing process of evinacumab starts with the thawing of a single vial of the working cell bank. Cells are expanded through a series of bioreactors and transferred into the fed-batch production bioreactor. Evinacumab protein is expressed by the cells and subsequently secreted into the culture medium. The culture is harvested by filtration, after which the secreted protein is purified by a series of chromatography, viral inactivation, and filtration steps. Following concentration and formulation, the formulated drug substance is dispensed into polycarbonate bottles and stored at or below -30 °C.

The manufacturing process of the drug product consists of thawing, pooling, and mixing of the formulated drug substance, followed by bioburden reduction filtration, sterile filtration, aseptic filling of vials, stoppering, capping, and visual inspection of each vial (100% inspection). The vials are stored at 2 °C to 8 °C.

Acceptable ranges for process parameters and controls of critical steps of the drug substance manufacturing process were appropriately established during development. They are based on the product quality attribute assessment, process risk assessment, and process characterization studies. The drug substance manufacturing process was validated by the manufacture of three consecutive commercial-scale batches in two manufacturing suites (process areas) resulting in six process performance qualification batches. Three consecutive batches of the 345 mg/2.3 mL (150 mg/mL) drug product presentation and three consecutive batches of the 1,200 mg/8.0 mL (150 mg/mL) drug product presentation were manufactured to validate the drug product manufacturing process. The drug substance and drug product manufacturing processes were controlled within the defined process parameter ranges. The results of the process performance qualification studies demonstrate that the manufacturing processes are capable of consistently manufacturing evinacumab and Evkeeza of the desired quality.

Control of the Drug Substance and Drug Product

The drug substance release and stability specifications were established based on the evaluation of clinical and manufacturing experience, stability trends, and statistical analyses. In-process limits and specification acceptance criteria were suitably justified and ensure the safety, identity, strength, potency, and purity of the drug substance.

The drug product release and stability specifications were established based on relevant International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, product and process knowledge, attribute criticality, and clinical experience.

In-house analytical methods were validated according to relevant ICH guidelines. All drug substance and drug product batches met the release and stability acceptance criteria.

Evkeeza is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory.

The stability data support the proposed shelf life of 48 months for evinacumab, when it is stored protected from light at or below -30 °C, and 36 months for Evkeeza, when the drug product is stored protected from light at 2 °C to 8 °C. If the diluted solution is not administered immediately, it may be stored at 2 °C to 8 °C for no more than 24 hours from the time of infusion preparation to the end of the infusion or at room temperature up to 25 °C for no more than 6 hours from the time of infusion preparation to the end of the infusion.

The compatibility of the drug product with the primary container closure system was demonstrated through stability studies and extractables and leachables studies.

Facilities and Equipment

The design, operations, and controls of the facilities and equipment involved in the production are considered suitable for the activities and products manufactured. The manufacturing sites are compliant with good manufacturing practices. On-site evaluations of the drug substance and drug product manufacturing facilities were not deemed necessary.

Adventitious Agents Safety Evaluation

The evinacumab manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control.

No raw materials of human or animal origin are directly used in the evinacumab manufacturing process other than the CHO-derived cell line. Relevant information was provided to demonstrate the safety of animal-derived materials used during the cell line development with respect to the risks of introduction of viral adventitious agents and transmissible spongiform encephalopathy agents.

Extensive testing of the master cell bank, working cell bank, and unprocessed bulk is conducted to confirm that the cell substrate and starting materials for the drug substance manufacturing process are free of detectable adventitious agents (bacteria, fungi, mycoplasma, and viruses). The cell culture process includes in-process tests to monitor for bioburden, mycoplasma, and viruses. Scaled-down viral clearance studies demonstrate that the downstream purification process is capable of inactivating or removing model viruses with a broad range of biochemical and biophysical properties.

The excipients used in the drug product formulation are not of animal or human origin.