Regulatory Decision Summary for Nilemdo

This submission was filed for Nilemdo (bempedoic acid) 180 mg tablets, given orally, for the treatment of hyperlipidemia and for the reduction of cardiovascular risk in those at high risk of atherothrombotic events.

Upon review of the submitted data package, Health Canada authorized Nilemdo for 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 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 revascularization, 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.

Cardiovascular disease remains the leading cause of death among most populations in the world. Elevation of serum low density lipoprotein cholesterol (LDL-C) is a validated, modifiable risk factor for the development of atherothrombotic events, including myocardial infarction and ischemic stroke. Lowering of serum LDL-C levels results in a lowering the risk of the occurrence of these adverse cardiovascular events.

The efficacy was assessed in four pivotal clinical trials demonstrating the ability of Nilemdo 180 milligram (mg), administered orally once daily, to lower LDL-C as add-on therapy to other lipid lowering medications. Studies 1002-040 and 1002-047 were Phase 3, double-blind trials randomizing 1,488 and 522 patients, respectively, in the Nilemdo treatment arm, and 742 and 257 patients, respectively, in the placebo-treatment arm with statins as background therapy. The primary efficacy endpoint of these studies demonstrated placebo-corrected LDL-C reductions of 18.1% (p < 0.001) and 17.4% (p < 0.001) from baseline at week 12 favouring Nilemdo, respectively. Studies 1002-046 and 1002-048 were Phase 3, double-blind trials randomizing 234 and 181 patients to the Nilemdo treatment arm, respectively, and 111 and 88 patients to the placebo treatment arm, respectively, in patients intolerant to statin therapy. The primary endpoints of these studies demonstrated placebo-corrected reductions of LDL-C of 21.4% (p < 0.001) and 28.5% (p < 0.001) from baseline favouring Nilemdo at week 12, respectively.

The cardiovascular outcome trial, CLEAR OUTCOMES, was a randomized, double-blind, placebo-controlled trial conducted in 13,970 patients, with 6,992 assigned to Nilemdo and 6,978 to placebo. Its objective was to assess the effects of Nilemdo when used as an add-on to other lipid-lowering therapies in statin intolerant patients with, or at high risk of, atherothrombotic cardiovascular events. Treatment with Nilemdo demonstrated a significant 13% reduction in the risk of the primary composite endpoint of major adverse cardiovascular adverse events, consisting of either cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or a coronary revascularization procedure, over a median follow-up period of 3.4 years (p = 0.004). Further evidence of this clinical outcome benefit was provided by the pre-specified hierarchical testing approach that evaluated key secondary outcomes, which demonstrated a significant 15% reduction in major adverse cardiovascular adverse events (p = 0.006), consisting of the time-to-first-event of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke; a 23% reduction in fatal or non-fatal myocardial infarction; and, a 19% reduction in coronary revascularization procedures. No effect on mortality was observed in this study.

The safety of Nilemdo was assessed in the pooled database of the four placebo-controlled clinical trials in the hyperlipidemia program. Studies 1002-040 and 1002-047 evaluated Nilemdo when used in statin treated patients, and Studies 1002-046 and 1002-048 evaluated the drug in statin-intolerant patients. In this pooled database, comprised of 3,621 patients, of which 2,424 patients received Nilemdo 180 mg once daily and 1,197 patients received placebo, the most common adverse reactions occurring in 1% or more of patients and more frequently in the Nilemdo group than in the placebo group included hyperuricemia (3.8% versus [vs.] 1.1%), anemia (2.5% vs. 1.6%), gout (1.4% vs. 0.4%), increased aspartate aminotransferase (1.2% vs. 0.3%), with no evidence of associated increases in total bilirubin and pain in extremities (3.1% vs. 1.8%). Serious adverse events (SAE) were reported in 14.1% of patients randomized to Nilemdo, and 13.3% of patients randomized to placebo. The SAE that occurred more frequently with Nilemdo compared to placebo was tendon rupture (0.2% vs. 0%). Tendon rupture events occurred in 0.5% in the Nilemdo treatment group and 0% in the placebo group. Adverse events leading to study drug discontinuation occurred in 11.3% of patients treated with Nilemdo and 7.8% of those treated with placebo. Adverse events (AE) leading to drug discontinuation in patients treated with Nilemdo compared to those treated with placebo were related to gastrointestinal disorders (1.6% vs. 0.7%), including diarrhea (0.5% vs. < 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 treatment and in 0.3% randomized to placebo, all of which occurred in the long-term studies conducted in patients at high cardiovascular risk. All fatal AEs in these studies were considered unrelated to study drug by the investigator.

The safety of the cardiovascular outcomes study, CLEAR OUTCOMES (N = 13,965), was assessed over a median follow up duration of 3.4 years. The most commonly reported adverse reactions with Nilemdo compared to placebo, that occurred at an incidence ≥ 3% and more frequently with Nilemdo than with placebo 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 treated with Nilemdo, and 0.9% of patients treated with placebo. In this study, all-cause fatalities occurred in 6.2% of patients treated with Nilemdo and 6.0% of those treated with placebo. No imbalance of non-cardiac or cardiac deaths in the Nilemdo vs placebo group were observed. The most common AEs were included in the Nilemdo Product Monograph. Monitoring of the potential of Nilemdo to cause gout-related AEs, as well as liver toxicity and anemia, will be conducted in the post-marketing setting. Overall, safety in terms of harms and uncertainties were considered manageable through product labelling, monitoring, and post-marketing surveillance.

Nilemdo can be commonly administered with statin drugs for the treatment of hyperlipidemia. A pharmacokinetic drug interaction has been identified, where concomitant use of these drugs leads to an increase of statin plasma levels of about 45% with most statin drugs, when administered with a supratherapeutic dose of bempedoic acid, while an approximately 2-fold increase of simvastatin plasma levels was noted, when administered as a single dose in patients taking bempedoic acid 180 mg daily at steady state. Except for simvastatin, in most cases such a pharmacokinetic interaction is unlikely to be clinically relevant and should not meaningfully increase the risk of SAEs with statin drug use. However, simvastatin should be used with caution with bempedoic acid, and as such combined use is contraindicated with a dose of simvastatin higher than 40 mg daily, due to the potential of development of rhabdomyolysis. Because animal studies with bempedoic acid have shown reproductive toxicity, use in pregnancy is contraindicated. Due to the risk of SAEs in the fetus, and because it is currently unknown if bempedoic acid and its metabolites are excreted in human milk, use of Nilemdo is contraindicated in the setting of breastfeeding.

The bioavailability data from Study 1002-016, from the analysis of the food effect component, shows that the rate and extent of absorption of Nilemdo from two different administrations (fasting and fed conditions), are considered to be comparable following single-dose administration (1 x 180 mg).

The 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.

A Risk Management Plan for Nilemdo was reviewed by Health Canada and considered acceptable.

The final labelling and Product Monograph were considered acceptable.

Overall, the benefit-harm-uncertainty profile was favourable for Nilemdo for the authorized indication when used under the conditions of use recommended in the approved Product Monograph. Therefore, a Notice of Compliance was recommended.

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