DAIICHI-SANKYO

Daiichi Sankyo Europe GmbH (hereafter, ‘Daiichi Sankyo’) today announced additional results from prespecified subgroup analyses of the Phase 3 CLEAR (Cholesterol Lowering via Bempedoic Acid, an ATP citrate lyase (ACL)-Inhibiting Regimen) Outcomes trial. The results, presented at the 92^nd European Atherosclerosis Society (EAS) Congress 2024, add to the growing understanding of the efficacy of NILEMDO^®▼ (bempedoic acid) for the reduction of cardiovascular (CV) risk among patients at high-risk of CV disease. Specifically, results were presented for the subgroups of patients with obesity*, with metabolic syndrome (MetS)**, and female patients.^1-6

LDL-C reduction in obese patients

Among patients with obesity in the CLEAR Outcomes trial, bempedoic acid reduced low-density lipoprotein cholesterol (LDL-C) levels by 22.5% and MACE-4 by 23% versus placebo, and was well-tolerated with a similar safety profile as reported in the overall CLEAR Outcomes population.¹ This increased efficacy regarding MACE-4 compared to the overall CLEAR Outcomes population is likely due to the higher underlying risk of CV events in this patient group.¹ This data was previously presented at the ACC conference in April 2024.

LDL-C reduction in patients with or without MetS

In the CLEAR Outcomes subgroup analysis of patients with or without MetS, treatment with bempedoic acid reduced the risk of MACE-4 to a similar extent. This demonstrates bempedoic acid’s suitability as an option for patients requiring lipid-lowering therapy irrespective of their MetS status.² Furthermore, results showed a small but significant reduction in body weight for patients with MetS.² Bempedoic acid did not lead to an increase in new-onset diabetes in patients with or without MetS.² The safety profile was generally comparable between MetS status and treatment group, however, higher rates of hyperuricemia were observed in patients with MetS randomised to bempedoic acid.²

Similar efficacy and safety profile across genders

CV outcomes data in women are scarce. In the CLEAR Outcomes trial, 48% of participants were female (6,740/13,970), achieving a near-equal gender balance.³ In this prespecified subgroup analysis, results showed that bempedoic acid demonstrated similar efficacy in CV risk reduction, versus placebo, in both male and female patients.³ Furthermore, the overall incidence of adverse events did not differ meaningfully between male and female patients.³ This data was previously presented at the ACC conference in April 2024.

Data from these subgroup analyses are consistent with results from the main CLEAR Outcomes analysis, which showed a 13% reduction in the relative risk of major adverse cardiovascular events defined as a four-component composite of death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke or coronary revascularisation (MACE-4).⁷ Furthermore, the safety profile in all patient subgroups was in line with that of the overall trial population.^1-6

“Both men and women with obesity and/or metabolic syndrome are at significant risk of future cardiovascular events. The results presented at the EAS Congress suggest that bempedoic acid is an effective treatment for a range of patient subgroups.” said Ioanna Gouni-Berthold, University of Cologne, Center for Endocrinology, Diabetes, and Preventive Medicine. “As clinicians, our priority is to reduce LDL-C levels to lower the risk of CV events. Combination therapy with bempedoic acid may be one way to address this issue.”

“Our goal at Daiichi Sankyo is to help protect people from cardiovascular disease. To achieve this, we are working to improve the understanding of CV risk among a range of patient subgroups – including female patients who have previously been underrepresented in clinical trials. The data presented today adds to the growing body of evidence that bempedoic acid can be used effectively to address and manage the CV risk of patients who typically present to doctors,” said Stefan Seyfried, Vice President Medical Affairs, Specialty Medicines, at Daiichi Sankyo Europe GmbH.

Results of the CLEAR Outcomes subgroup analyses were presented as two ePoster sessions and four posters at the EAS Congress 2024:

• ePoster session: Bempedoic acid for prevention of cardiovascular events in patients with obesity: A CLEAR Outcomes subset analysis, by S Nicholls, et al.¹
• ePoster session: Bempedoic acid efficacy and safety in 7,597 non-diabetic patients, with and without metabolic syndrome, from the randomized, placebo-controlled CLEAR Outcomes Trial, by P Taub, et al.²
• Poster: Characteristics and outcomes for statin-intolerant women receiving bempedoic acid in the CLEAR Outcomes trial, by L Cho, et al.³
• Poster: Identification and characterisation of patients with statin intolerance in France, by F Schiele, et al.⁴
• Poster: Lipid-lowering therapy use and LDL-C goal attainment in France: Results from 1-year follow-up of the European observational SANTORINI study, by R Allouche, et al.⁵
• Poster: Simulation of ezetimibe and bempedoic acid effect on LDL-C goal attainment in statin-intolerant patients across Europe: the 1-year follow-up SANTORINI observational study, by M Farnier, et al.⁶

*Obesity defined as BMI ≥30 kg/m²

**Metabolic syndrome defined as the presence of 1 or more of the following criteria: triglycerides ≥150mg/dL; HDL-C <40mg/dL for men or <50mg/dL for women; history of hypertension or blood pressure ≥130/85mmHG; fasting plasma glucose ≥100mg/dL; body mass index (used as a proxy for waist circumference) >25kg/m2 and >30kg/m2 for Asian and non-Asian patents, respectively.

About bempedoic acid and its fixed-dose combination with ezetimibe

Bempedoic acid is a first-in-class, oral, once-daily treatment to lower cholesterol, and which can be combined with other oral treatments to help lower cholesterol even further.^8,9 Bempedoic acid inhibits ATP citrate lyase (ACL), an enzyme which is involved in the production of cholesterol in the liver.¹⁰

Bempedoic acid acts on the well-known cholesterol synthesis pathway, upstream of the statin target in the liver, which allows additional LDL-C lowering when added to statin or other LDL-C-lowering therapies.¹¹ Bempedoic acid is not activated in skeletal muscle.¹⁰

Bempedoic acid is indicated in adults with established or at high risk for atherosclerotic CV disease to reduce CV risk by lowering LDL-C levels, as an adjunct to correction of other risk factors:^8,12

• in patients on a maximum tolerated dose of statin with or without ezetimibe or,^8,12
• alone or in combination with ezetimibe in patients who are statin-intolerant, or for whom a statin in contraindicated.^8,12

Bempedoic acid is indicated in adults with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet:^8,12

• in combination with a statin or statin with other lipid-lowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a or,^8,12
• alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated.^8,12

The fixed-dose combination NUSTENDI^®▼ combines two complementary ways of reducing cholesterol in a once-daily tablet. NUSTENDI^®▼ is a fixed-dose combination (FDC) tablet containing bempedoic acid (the active pharmaceutical ingredient in NILEMDO^®) and ezetimibe.

Bempedoic acid / ezetimibe FDC is indicated in adults with established or at high risk for atherosclerotic CV disease to reduce CV risk by lowering LDL-C levels, as an adjunct to correction of other risk factors:^12,13

• in patients on a maximum tolerated dose of statin and not adequately controlled with additional ezetimibe treatment or,^12,13
• in patients who are either statin-intolerant, or for whom a statin in contraindicated, and not adequately controlled with additional ezetimibe treatment or,^12,13
• in patients already being treated with the combination of bempedoic acid and ezetimibe as separate tablets^12,13

Bempedoic acid / ezetimibe FDC is indicated in adults with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet:^12,13

• in combination with a statin in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin in addition to ezetimibe,^12,13
• alone in patients who are either statin-intolerant or for whom a statin is contraindicated, and are unable to reach LDL-C goals with ezetimibe alone,^12,13
• in patients already being treated with the combination of bempedoic acid and ezetimibe as separate tablets with or without statin.^12,13

Daiichi Sankyo Europe has licensed exclusive commercialisation rights to bempedoic acid and its FDC with ezetimibe (marketed as NILEMDO^® and NUSTENDI^®) in the European Economic Area, UK, Turkey and Switzerland from Esperion and is the full Marketing Authorisation Holder in these territories.

About CLEAR Outcomes trial

The CLEAR Outcomes trial was a Phase 3, event-driven, randomised, multicentre, double-blind, placebo-controlled trial.¹⁴ It was designed to evaluate whether treatment with bempedoic acid, marketed as NILEMDO^®▼ in Europe, reduced the risk of cardiovascular events in a mixed population of patients who had or were at high-risk for CVD, and for whom primary or secondary CVD prevention was clinically indicated but who were unable or unwilling to receive statin treatment.¹⁴

The trial, which was fully enrolled in August 2019, randomised 13,970 patients, aged 18–85 years of age with an average age of 65.5 years at 1,250 sites in 32 countries across the world including 485 sites in Europe.¹⁴ Patients had a mean LDL-C at baseline of 3.59 mmol/L (139.0 mg per decilitre) and were randomised to either treatment with bempedoic acid 180 mg daily or matching placebo on a background of guideline-directed medical therapy in both the bempedoic acid and placebo groups.⁷ Patients were followed up for a median duration of 40.6 months.⁷

The primary endpoint of the CLEAR Outcomes trial was a four-component composite of major adverse CV events (MACE-4) defined as death from CV causes, non-fatal myocardial infarction, non-fatal stroke, or coronary revascularisation.¹⁴ Key secondary endpoints included: MACE-3, a composite of three major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke); fatal and nonfatal myocardial infarction; coronary revascularisation; fatal and non-fatal stroke; cardiovascular death; and all-cause mortality.¹⁴

About Daiichi Sankyo

Daiichi Sankyo is an innovative global healthcare company contributing to the sustainable development of society that discovers, develops, and delivers new standards of care to enrich the quality of life around the world. With more than 120 years of experience, Daiichi Sankyo leverages its world-class science and technology to create new modalities and innovative medicines for people with cancer, cardiovascular, and other diseases with high unmet medical need.

For more information, please visit www.daiichisankyo.com

▼ This medicinal product is subject to additional monitoring.

References

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¹ EAS 2024 ePoster. Bempedoic acid for prevention of cardiovascular events in patients with obesity: A CLEAR Outcomes subset analysis, by S Nicholls, et al.
² EAS 2024 ePoster. Bempedoic acid efficacy and safety in 7,597 non-diabetic patients, with and without metabolic syndrome, from the randomized, placebo-controlled CLEAR Outcomes Trial, by P Taub, et al.
³ EAS 2024 Poster. Characteristics and outcomes for statin-intolerant women receiving bempedoic acid in the CLEAR Outcomes trial, by L Cho, et al.
⁴ EAS 2024 Poster. Identification and characterisation of patients with statin intolerance in France, by F Schiele, et al.
⁵ EAS 2024 Poster. Lipid-lowering therapy use and LDL-C goal attainment in France: Results from 1-year follow-up of the European observational SANTORINI study, by R Allouche, et al.
⁶ EAS 2024 Poster. Simulation of ezetimibe and bempedoic acid effect on LDL-C goal attainment in statin-intolerant patients across Europe: the 1-year follow-up SANTORINI observational study, by M Farnier, et al.
⁷ Nissen, S.E., et al. Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients. N Engl J Med. 2023. 13;388;(15): 1353–1364.
⁸ European Medicines Agency. Nilemdo - opinion on variation to marketing authorisation. Available at: https://www.ema.europa.eu/en/medicines/human/variation/nilemdo. Last accessed May 2024.
⁹ The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020. 41;(1): 111–188.
¹⁰ European Medicines Agency. NilemdoSummary of Product Characteristics. May 2024. Available at: https://www.ema.europa.eu/en/documents/product-information/nilemdo-epar-product-information_en.pdf. Last accessed May 2024
¹¹ Pinkosky, S.L., et al. Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis. Nat Commun. 2016. 7: 13457.
¹² Daiichi Sankyo Europe GMBH. First-in-class cholesterol-lowering treatment NILEMDO®▼ and its combination with ezetimibe, NUSTENDI®▼, approved in Europe to lower LDL cholesterol and reduce cardiovascular risk. Available at: https://www.businesswire.com/news/home/20240514593487/en/First-in-class-cholesterol-lowering-treatment-NILEMDO%C2%AE%E2%96%BC-and-its-combination-with-ezetimibe-NUSTENDI%C2%AE%E2%96%BC-approved-in-Europe-to-lower-LDL-cholesterol-and-reduce-cardiovascular-risk. Last accessed May 2024
¹³ European Medicines Agency. Nustendi - opinion on variation to marketing authorisation. Available at: https://www.ema.europa.eu/en/medicines/human/variation/nustendi. Last accessed May 2024.
¹⁴ Nicholls, S.J., et.al. Rationale and design of the CLEAR-outcomes trial: Evaluating the effect of bempedoic acid on cardiovascular events in patients with statin intolerance. Am Heart J. 2021. 235: 104–112.

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