Summary Basis of Decision for Nilemdo

Clinical Pharmacology

Bempedoic acid, the medicinal ingredient in Nilemdo, is an adenosine triphosphate citrate lyase inhibitor that lowers low-density lipoprotein cholesterol (LDL-C) by the inhibition of cholesterol synthesis in the liver.

The pharmacokinetics and pharmacodynamics of bempedoic acid were evaluated in a series of Phase I and Phase II studies. The oral administration of bempedoic acid 180 mg in healthy subjects resulted in a time to maximum plasma concentration of approximately 3.5 hours. Bempedoic acid is reversibly converted to its pharmacologically active metabolite, ESP15228, by aldo-keto reductase. Bempedoic acid (a prodrug) and ESP15228 require coenzyme A activation by very long chain acyl-CoA synthase 1 to form bempedoyl-CoA and ESP15228-CoA. Both bempedoic acid and ESP15228 are converted to inactive glucuronide conjugates by uridine 5'-diphospho-glucuronosyltransferase-2B7 (UGT2B7). Most of the administered bempedoic acid is metabolized and eliminated in the form of metabolites, with less than 5% of the dose excreted as unchanged bempedoic acid in the urine and feces. Approximately 62.1% and 25.4% of the administered dose is excreted in the urine and feces, respectively, indicating that renal clearance is the main route of elimination for bempedoic acid.

The oral administration of bempedoic acid 180 mg in healthy subjects resulted in a mean half-life of 21 hours, supporting the once daily dosing regimen. In in vitro studies, plasma protein binding of bempedoic acid, ESP15228, and the glucuronide metabolite of bempedoic acid were 99.3%, 99.2%, and 98.8%, respectively. Bempedoic acid does not partition into the cellular components of blood. The steady-state volume of distribution for bempedoic acid was 18 L. The pharmacokinetic parameters were linear across the investigated doses of 120 mg to 240 mg.

The pharmacokinetics of bempedoic acid were not altered by race, body mass index, or baseline disease (i.e., type 2 diabetes mellitus or familial or non-familial hypercholesterolemia). A slightly higher exposure (less than 1.5-fold) of bempedoic acid was observed in females, subjects with lower body weight, and elderly patients. However, these differences were no longer observed when the composite co-variate effect was used. As a result, no dosage adjustment is required based on age, sex, or weight. The exposure of bempedoic acid increased 1.4- and 1.9-fold in subjects with mild (an estimated glomerular filtration rate [eGFR]of 60 to 89 mL/min/1.73 m²) and moderate (an eGFR of 30 to 59 mL/min/1.73 m²) renal impairment, respectively, compared to subjects with normal renal function. No dose adjustment is recommended for patients with mild and moderate renal impairment, as no changes to safety and efficacy endpoints were observed in these subpopulations compared to patients with normal renal function. Limited data in patients with severe renal impairment (an eGFR of less than 30 mL/min/1.73 m²) demonstrated a 2.4-fold increase in the area under the concentration-time curve (AUC) of bempedoic acid. Patients with end-stage renal disease (an eGFR of less than 15 mL/min/1.73 m²) and patients undergoing hemodialysis were not studied. The exposure (AUC) of bempedoic acid was reduced by 22% and 16% in patients with mild (Child Pugh A) and moderate (Child Pugh B) hepatic impairment, respectively, compared with patients with normal hepatic function. Based on safety and efficacy evaluations, no dosage adjustment is required in these subpopulations. Bempedoic acid was not studied in patients with severe hepatic impairment (Child Pugh C).

In drug-drug interaction studies, bempedoic acid was not a substrate of cytochrome P450 (CYP) enzymes. The drug was not observed to inhibit CYP enzymes and moderately induced CYP 2C8 at 5-fold the human exposure. Bempedoic acid and its glucuronide weakly inhibited organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 at clinically relevant concentrations. Therefore, the co-administration of bempedoic acid with substrates of OATP1B1 or OATP1B3 (e.g., bosentan, statins, glecaprevir) may result in an increased plasma concentration of these substrates. Bempedoic acid inhibits organic anion transporter (OAT) 2 in vitro, which may be the mechanism responsible for minor elevations noted in serum creatinine and uric acid. The administration of bempedoic acid with probenecid, an UGT2B7 inhibitor, resulted in a 1.7-fold increase in bempedoic acid exposure. As this was considered a weak interaction (less than a 2-fold increase in AUC), no dosing adjustments are required. Bempedoic acid did not have clinically significant effects on the pharmacokinetics of metformin, oral contraceptives, or ezetimibe. Clinical drug-drug interaction studies revealed an increase in the exposure of statins with concomitant administration of bempedoic acid180 mg. Since the exposure was less than 2-fold for pravastatin, rosuvastatin, and atorvastatin, no dose adjustments are required. However, the dose adjustment or interruption of a statin should be considered if statin-related myopathy is observed during concomitant administration. The administration of a single dose of simvastatin 40 mg with steady state bempedoic acid 180 mg resulted in a 2-fold increase in simvastatin acid exposure. Therefore, concomitant use of more than simvastatin 40 mg with bempedoic acid is contraindicated.

The cardiac safety profile of bempedoic acid was evaluated in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines through both clinical and non-clinical assessments. A dedicated thorough QT study in healthy subjects demonstrated no clinically meaningful effects on corrected QT (QTc), PR, QRS, or heart rate intervals on an electrocardiogram. Although the study did not reach the conventional 2 to 4 times supratherapeutic exposure, this limitation was addressed in the Product Monograph for Nilemdo. Complementary in vitro human ether-a-go-go-related gene assay data further support the absence of proarrhythmic risk.

The results from a food effect study demonstrated that the administration of a single dose of bempedoic acid 180 mg in 15 subjects after a high-fat, high-calorie meal resulted in a comparable rate and extent of absorption when compared with the administration of bempedoic acid 180 mg under fasted conditions. Therefore, Nilemdo can be taken with or without food.

Overall, the clinical pharmacology data support the use of Nilemdo for the recommended indication.

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

Clinical Efficacy

The clinical efficacy of Nilemdo was investigated in four pivotal, multicentre, randomized, double-blind, placebo-controlled, primary hyperlipidemia studies (Studies 1002-040, 1002-047, 1002-046, and 1002-048) involving 3,623 adult patients with hyperlipidemia, of whom 2,425 were randomized to Nilemdo 180 mg orally once daily. In all studies, patients were receiving stable background lipid lowering therapy, including a maximally tolerated dose of a statin. In the two 52-week studies (studies 1002-040 and 1002-047), over 3,000 patients with atherosclerotic cardiovascular disease and/or heterozygous familial hypercholesterolemia were randomized, of which at least 90% of patients received a statin with approximately 50% of patients in both studies receiving a high intensity statin. In the two studies in patients with statin intolerance (studies 1002-046 and 1002-048), 614 patients were receiving no statin, or a maximally tolerated statin dose no more than low intensity statin (dose did not exceed an average daily dose below the lowest approved starting dose).

The key clinical studies in support of the hyperlipidemia indication were Studies 1002-040 and 1002-047. Studies 1002-040 and 1002-047 enrolled patients at a high risk for cardiovascular events and with elevated LDL-C, despite being treated with maximally tolerated lipid-lowering therapy, including statin drugs. In Study 1002-040, 2,230 patients were randomized 2:1 to receive Nilemdo (1,488 patients) or placebo (742 patients) once daily in addition to ongoing background lipid-lowering therapy. In Study 1002-047, 779 patients were randomized 2:1 to receive Nilemdo (522 patients) or placebo (257 patients) once daily in addition to ongoing background lipid-lowering therapy. Both studies used placebo-corrected mean percentage change in LDL-C from baseline to Week 12 as the primary efficacy analysis. Additional key efficacy endpoints included placebo-corrected mean percentage change in LDL-C from baseline to Week 24 to determine the durability of the lipid-lowering response, and mean percent change from baseline in non-high density lipoprotein cholesterol (non-HDL-C), total cholesterol, and apolipoprotein B at Week 12.

Studies 1002-046 and 1002-048 evaluated the effects of Nilemdo 180 mg once daily in statin-intolerant patients with elevated LDL-C. In Study 1002-046, 345 patients on stable lipid-lowering therapy were randomized 2:1 to receive Nilemdo (234 patients) or placebo (111 patients). In Study 1002-048, 269 patients on background ezetimibe 10 mg daily only were randomized 2:1 to receive Nilemdo (181 patients) or placebo (88 patients). Both studies used placebo-corrected mean percentage change in LDL-C from baseline to Week 12 as the primary efficacy analysis.

In Studies 1002-040 and 1002-047, mean baseline LDL-C values were 103 mg/dL (2.7 mmol/L) and 120 mg/dL (3.1 mmol/L), respectively. At Week 12, daily treatment with Nilemdo 180 mg resulted in a placebo-corrected mean percent reduction in LDL-C from baseline of -18.1% (p<0.001) in Study 1002-040 and -17.4% (p<0.001) in Study 1002-047. At Week 24, Study 1002-040 reported a placebo-corrected mean percent reduction in LDL-C from baseline of -14.9% (p<0.001) and Study 1002-047 reported a placebo-corrected mean percent reduction in LDL-C from baseline of -14.8% (p<0.001). At Week 12, other placebo-corrected mean lipid values were also decreased from baseline, including non-HDL-C (-13.3% and -13.0%), total cholesterol (-11.1% and -11.2%), and apolipoprotein B (-11.9% and -13.0%), all with a p<0.001.

At Week 12, Study 1002-046 reported a placebo-corrected mean percent reduction in LDL-C from baseline of -21.4% (p<0.001), while Study 1002-048 reported a placebo-corrected mean percent reduction in LDL-C from baseline of -28.5% (p<0.001).

Further, to support the additional indication of reduction of cardiovascular risk, the sponsor conducted Study 1002-043 (also known as the CLEAR OUTCOMES study), a Phase III, long-term, randomized, placebo-controlled, double-blind, large, cardiovascular study with at least a 90% power to detect a 15% reduction in the primary endpoint of major adverse cardiovascular events (MACE). In total, 13,970 patients at a high risk of adverse cardiovascular events were enrolled, defined by a history of a previous adverse cardiovascular event (e.g., myocardial infarction or ischemic stroke) or without a history of adverse cardiovascular events but with clinical features of high cardiovascular risk. Prior to randomization, patients were also determined to be statin-intolerant, whether absolute, or on a relative basis, and thus unable to tolerate guideline-directed doses of statin drugs. At baseline, 41% of patients were taking at least one lipid-lowering therapy, including ezetimibe (12%) and a very low dose of statins (23%). Patients were randomized 1:1 to receive Nilemdo 180 mg once per day (6,992 patients) or placebo (6,978 patients), alone, or as an add-on to other background lipid-lowering therapies. The median follow-up period was 3.4 years.

In Study 1002-043, treatment with Nilemdo resulted in a statistically significant reduction in the risk of a first occurrence of the primary endpoint, the composite outcome of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or coronary revascularization (MACE-4), by 13% compared to placebo, with a hazard ratio (HR) of 0.87 (95% confidence interval [CI]: 0.79 to 0.96, p = 0.004). Of the component endpoints of MACE-4, risk reductions were noted for non-fatal myocardial infarction (HR of 0.73, 95% CI: 0.62 to 0.87) and coronary revascularization (HR of 0.81, 95% CI: 0.72 to 0.92), but not for non-fatal stroke (HR of 0.82, 95% CI: 0.64 to 1.05) nor for cardiovascular death (HR of 1.04, 95% CI: 0.88 to 1.24). A hierarchical statistical approach was also pre-specified to evaluate the key secondary endpoints following the evaluation of the primary endpoint. Accordingly, the secondary endpoints met statistical significance, which, compared to placebo, demonstrated a 15% reduction in the composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke (MACE-3) with an HR of 0.85 (95% CI: 0.76 to 0.96; p = 0.006); a 23% reduction in fatal or non-fatal myocardial infarction with an HR of 0.77 (95% CI: 0.66 to 0.91; p = 0.002); and a 19% reduction in coronary revascularization with an HR of 0.81 (95% CI: 0.72 to 0.92; p = 0.001). The composite endpoint of fatal or non-fatal stroke was not significant, nor was death from cardiovascular causes or any cause.

After evaluation in Study 1002-040, 1,462 eligible patients were enrolled in Study 1002-050, an open-label, long-term clinical extension study conducted over 78 weeks. Patients were taking background lipid-lowering therapy, including maximum tolerated doses of statin drugs, and were previously randomized to Nilemdo (970 patients) or placebo (492 patients) in Study 1002-040. At Week 12, a mean percent change from baseline in LDL-C of -14.5% was observed in patients previously randomized to placebo, a result that was similar to that observed in patients previously randomized to Nilemdo (‑15.2%). At Week 78, mean percent change from baseline in LDL-C was -14.2% and -15.0%, respectively, for those previously randomized to Nilemdo and placebo. Thus, taking into account the treatment duration of both studies, the effectiveness of Nilemdo in improving LDL-C levels was observed over a period up to 2.5 years.

Indication

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

Primary Hyperlipidemia

Nilemdo is indicated for the reduction of low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia (heterozygous familial and non-familial):

• as an adjunct to diet and statin therapy, with or without other lipid-lowering therapies;

• as an adjunct to diet, as monotherapy or in combination with other non-statin lipid-modifying therapies, in patients who are either statin intolerant, or for whom a statin is contraindicated.

Prevention of Cardiovascular Events

Nilemdo (bempedoic acid) is indicated with or without other lipid-lowering therapies to reduce the risk of myocardial infarction and coronary revascularization in adults with:

• established cardiovascular disease (CVD), or

• a high risk for a CVD event but without established CVD.

To support safe and effective use of the product, Health Canada approved the following indication:

Primary Hyperlipidemia

Nilemdo (bempedoic acid) is indicated for the reduction of low-density lipoprotein cholesterol (LDL-C) in adults with hyperlipidemia, i.e., heterozygous familial hypercholesterolemia (HeFH) and mixed dyslipidemias,

• as an adjunct to diet, in combination with statins, with or without ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, or

• as an adjunct to diet, as monotherapy in patients who cannot tolerate recommended statin therapy, with or without ezetimibe and PCSK9 inhibitors.

Prevention of Cardiovascular Events

Nilemdo is indicated to reduce the risk of adverse cardiovascular events, defined as cardiovascular death, myocardial infarction, stroke, or coronary revascularisation, in adults at increased risk for these events.

Nilemdo should be used with statin drug therapy, as tolerated, with or without ezetimibe and PCSK9 inhibitors. In patients unable to take statins at any dose, Nilemdo may be used as monotherapy, or combined with ezetimibe and/or PCSK9 inhibitors, as appropriate.

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

Clinical Safety

The clinical safety of Nilemdo 180 mg once daily in patients with hyperlipidemia was evaluated in a pool comprised of 3,621 patients from Studies 1002-040, 1002-047, 1002-046, and 1002-048 described in the Clinical Efficacy section, in which patients received Nilemdo (2,424 patients) or placebo (1,197 patients). Adverse reactions that occurred in 1% or more of patients and more frequently in the Nilemdo group than in the placebo group included hyperuricemia (3.8% vs. 1.1%), pain in extremities (3.1% vs. 1.8%), anemia (2.5% vs. 1.6%), gout (1.4% vs. 0.4%), and increased aspartate aminotransferase (1.2% vs. 0.3%) with no associated increases in total bilirubin. The incidence of myalgia or arthralgia was not increased in the Nilemdo group. Serious adverse events were reported in 14.1% of patients randomized to Nilemdo and in 13.3% in patients randomized to placebo. The serious adverse event that occurred more frequently in the Nilemdo group than in the placebo group was tendon rupture; all tendon rupture events occurred more frequently in the Nilemdo group than in the placebo group (0.5% vs. 0%). Adverse events leading to study drug discontinuation occurred in 11.3% of patients treated with Nilemdo compared with 7.8% of patients treated with placebo. Adverse events leading to the discontinuation of Nilemdo were related to gastrointestinal disorders (1.6% vs. 0.7%), including diarrhea (0.5% vs. less than 0.1%), and musculoskeletal disorders (3.4% vs. 2.5%), including muscle spasms (0.7% vs. 0.3%).

Fatalities occurred in 0.8% of patients randomized to Nilemdo compared with 0.3% of patients randomized to placebo, all of which occurred in long-term studies conducted in patients with a high cardiovascular risk who were already taking maximally tolerated statins. These cases were derived from Study 1002-040, in which the incidence of fatality was 0.9% in the Nilemdo group and 0.3% in the placebo group, and from Study 1002-047, in which the incidence of fatality was 1.1% in the Nilemdo group and 0.8% in the placebo group. All fatal adverse events in these studies were considered unrelated to study drug by the investigator. The difference in fatalities in Study 1002-040 was driven primarily by a low, but differing, incidence of death due to cardiac reasons (0.3% vs. 0%) and neoplasms, whether benign, malignant, or unspecified (0.3% vs. 0%).

Consistent with the study entry criteria and the overall population, the patients in Studies 1002-040 and 1002-047 had extensive histories of cardiovascular disease, along with significant medical histories of adverse cardiovascular events and other risk factor comorbidities, such as smoking, obesity, hypertension, and diabetes. For example, 96.7% of patients had a medical history of atherosclerotic cardiovascular disease, including significant cardiovascular-related medical or surgical histories such as (Nilemdo vs. placebo) coronary revascularization (53.6% vs. 53.0%), coronary artery disease (53.0% vs. 50.8%), and myocardial infarction (41.5% vs. 37.8%). In addition, most of these patients were hypertensive at baseline (80.8% vs. 80.2%), and approximately 30% had a diagnosis of diabetes (29.0% vs. 28.9%). All patients enrolled in the studies also had hyperlipidemia and required additional LDL-C lowering therapy despite the use of maximally tolerated lipid-lowering therapy.

The cardiovascular outcomes study (Study 1002-043) described in the Clinical Efficacy section was conducted in 13,970 statin-intolerant patients at a high risk for adverse cardiovascular events and had a median duration of follow-up was 3.4 years. The most commonly reported adverse reactions occurring in 3% or more of patients and more frequently in the Nilemdo group than in the placebo group were hyperuricemia (16 % vs. 8 %), renal impairment (11% vs. 9%), anemia (5%, vs. 4%), increased liver enzymes (4% vs. 3%), muscle spasms (4% vs. 3%), and gout (3% vs. 2%). Adjudicated tendon rupture was reported in 1.2% of patients in the Nilemdo group and in 0.9% of patients in the placebo group. All-cause fatalities occurred in 6.2% of patients in the Nilemdo group and in 6.0% of patients in the placebo group. Non-cardiovascular deaths occurred in 2.4% and 2.3% of patients, respectively. No imbalances in causes of non-cardiovascular deaths were noted, nor were there any imbalances noted in cardiovascular-attributed causes, i.e., sudden death, including sudden cardiac death and cardiac arrest (0.2% vs. 0.2%), myocardial infarction (0.2% vs. 0.2%), cerebrovascular accident (0.2% vs. 0.2%), and cardiac failure (0.2% vs. 0.2%).

Overall, hyperuricemia was noted consistently across the drug development program, with an associated 1% increase in the incidence of gout observed. Modest increases in serum transaminases were observed; however, no cases of increased bilirubin were seen and no cases of Hy’s Law criteria were met. No increases in serious adverse events or fatalities that were likely related to study drug were observed in the clinical development program for Nilemdo. Thus, the overall safety profile of Nilemdo was considered acceptable and manageable through product labelling and monitoring.

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

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

Bempedoic acid demonstrated pharmacological selectivity consistent with its intended mechanism of action. Safety pharmacology evaluations showed no adverse effects on cardiovascular, respiratory, or central nervous system function at exposures exceeding clinical levels.

The pharmacokinetic profile of bempedoic acid is favourable, characterized by rapid absorption, high plasma protein binding, and predictable elimination. Based on concordance with monkey data, renal excretion is considered to be the primary clearance pathway in humans. Transporter interaction studies suggest a low likelihood of clinically meaningful drug-drug interactions, with considerations limited to the potential effects on organic anion transporting polypeptide (OATP) 1B1, OATP1B3, and organic anion transporter 2 (OAT2). This suggests a low likelihood of dosage adjustment due to the co-administration of bempedoic acid with other drugs.

Repeated-dose toxicity studies identified hepatic changes in rats; however, the pattern of liver injury was determined to be rodent-specific and not expected to be clinically relevant. Monkeys did not exhibit comparable hepatotoxicity at similar or higher exposures, supporting low hepatic risk within the proposed clinical dosing range.

Reproductive toxicity studies demonstrated impaired fertility and embryo-fetal effects at exposures at, or below, expected clinical levels. These findings support a strict contraindication in pregnancy; therefore, bempedoic acid should not be used in pregnant individuals or those intending to become pregnant. Women of childbearing potential should use effective contraception, and treatment should only be initiated following confirmation of non-pregnant status. Due to the risk of serious adverse reactions in the fetus, and because it is currently unknown if bempedoic acid and its metabolites are excreted in human milk, the use of Nilemdo is contraindicated in breastfeeding women.

Carcinogenicity studies were limited by low systemic exposure in rodents. While hepatic and thyroid tumours were deemed species-specific and not relevant to humans, the translational relevance of pancreatic and brain tumours could not be definitively excluded, resulting in a residual but low level of uncertainty regarding the long-term carcinogenic potential of bempedoic acid.

Overall, the benefit-harm-uncertainty profile of bempedoic acid is considered favourable in the intended non-pregnant population, as no clinically relevant safety concerns were identified in non-rodent species and key risks can be managed through appropriate labelling. Uncertainties related to chronic use and carcinogenic potential were characterized through clinical data and will be further monitored through pharmacovigilance.

Appropriate warnings and precautionary measures are in place in the approved Product Monograph for Nilemdo to address the identified safety concerns.

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

The quality (chemistry and manufacturing) information submitted for Nilemdo has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper pharmaceutical development and supporting studies were conducted and an adequate control strategy is in place for the commercial processes. Changes to the manufacturing process and formulation (if any) made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 60 months is acceptable when the drug product is stored at 20 °C to 25 °C with excursions permitted between 15 °C and 30 °C.

The proposed drug-related impurity limits are considered adequately qualified (e.g., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [ICH] limits and/or qualified from toxicological studies, as needed).

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy).

All sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations.

Nilemdo was found to be compliant with the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products (EMEA/410/01, Revision 3). The lactose monohydrate used in the manufacture of Nilemdo was also produced in compliance with the above note.