New secondary analysis of CLEAR Outcomes data for bempedoic acid show significant risk reduction of total cardiovascular events and no increase of new-onset diabetes in patients at high-risk of cardiovascular disease

Daiichi Sankyo Europe, (hereafter, Daiichi Sankyo) today announced results from two prespecified analyses from the Phase 3 CLEAR (Cholesterol Lowering via Bempedoic Acid, an ATP citrate lyase (ACL)-Inhibiting Regimen) Outcomes trial. The results, presented at the European Society of Cardiology (ESC) Congress 2023, further support the long-term use of bempedoic acid in patients at high-risk of cardiovascular (CV) events and demonstrate particular benefit in those with diabetes.

A prespecified CLEAR Outcomes trial data analysis of the impact of treatment with bempedoic acid on total – first and subsequent – CV events in high-risk patients shows a 20% (HR 0.80 [95% CI 0.72, 0.89] p=0.0001) relative risk reduction (RRR)* in the primary endpoint of a four-component composite of major CV adverse events (MACE-4), defined as death from CV causes, non-fatal myocardial infarction, non-fatal stroke or coronary revascularisation.¹ The CLEAR Outcomes trial previously reported that treatment with bempedoic acid reduced the risk of a first MACE-4 CV event by 13% among those at high-risk of cardiovascular disease and unable or unwilling to take statins.¹ This latest total events analysis, which followed-up patients for a median of 3.4 years, shows an increase in RRR of MACE-4 CV events when not only the first, but all events are considered.¹ It is well documented that those that have experienced an adverse CV event are at higher risk of experiencing subsequent events.⁴ This data establishes the ongoing risk reduction of both first and subsequent CV events with bempedoic acid.¹

Results from the total events analysis presented today also included a: 17% RRR for the three-component composite of major adverse cardiovascular events (MACE-3) defined as death from CV causes, non-fatal myocardial infarction or non-fatal stroke; 31% RRR for non-fatal myocardial infarction and 22% RRR for coronary revascularisation.¹ This new data establishes the benefits of long-term treatment with bempedoic acid in patients at high-CV risk.¹

An additional prespecified sub-analysis of the CLEAR Outcomes data focused specifically on the CV benefits by blood glucose status and risk of new-onset diabetes (NOD) when treated with bempedoic acid over a median 3.4 years follow-up.³ Those with diabetes are at greater risk of CVD and comprise a particularly high-risk group with an excess risk of CV events ranging from 25% for MACE-4 and 58% for MACE-3, compared to those whose blood glucose levels are within normal range.³ The sub-analysis results demonstrate that bempedoic acid both lowered LDL-C and reduced the risk of CV events with greater absolute benefit for those with diabetes.³ Furthermore, unlike statins, bempedoic acid did not increase HbA1c levels or the incidence of NOD (11.1% with bempedoic acid vs 11.5% with placebo) among those without diabetes.³

“We know that patients who have experienced an adverse CV event are at an increased risk of experiencing subsequent events. Today’s data support the benefits of long-term LDL-C lowering with bempedoic acid and its effectiveness at helping reduce patients’ risk of not just a first CV event but subsequent ones too,” said Professor Kausik Ray, Professor of Public Health and President of the European Atherosclerosis Society, Honorary Consultant Cardiologist, Director ICTU Global and Deputy Director of the Imperial Clinical Trials Unit at Imperial College London. “Furthermore, the data show that treatment with bempedoic acid does not impact HbA1c levels or the incidence of new-onset diabetes. This is particularly important given diabetes patients’ increased risk of a CV event regardless of the presence or not of CVD. These findings reinforce bempedoic acid as an effective treatment option for LDL-C lowering and CV risk reduction in Europe. In addition, bempedoic acid provides an effective treatment option for those unwilling or unable to take or increase their statin dose marking an exciting and pivotal step in addressing a high unmet clinical need.”

“Cardiovascular disease is the cause of 10,000 lives lost in Europe every day, making it an urgent priority for people and healthcare authorities alike,” said Dr. Stefan Seyfried, Vice President, Medical Affairs, Specialty Medicines, Daiichi Sankyo Europe GmbH. “We are pleased to be able to provide clinicians with new analyses of data to help inform their clinical practice and best manage their patients who are at high-risk of cardiovascular disease.”

* All RRR % and hazard ratios (HR) in publicly available sources have been rounded.

-ENDS-

About CLEAR Outcomes trial

The CLEAR Outcomes trial was a Phase 3, event-driven, randomised, multicenter, double-blind, placebo-controlled trial.⁵ It was designed to evaluate whether treatment with bempedoic acid, marketed as NILEMDO^®▼ in Europe, reduces 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.⁵

The study, which was fully enrolled in August 2019, included 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.⁵ 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.⁵ Patients were followed up for a median duration of 40.6 months.⁵

The primary endpoint of the CLEAR Outcomes study 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.⁵ 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.⁵

About bempedoic acid

Bempedoic acid (commercialised in the European Economic Area, Turkey and Switzerland as NILEMDO^®▼) is a first-in-class, oral treatment which lowers cholesterol, and which can be combined with other oral treatments to help lower cholesterol even further.² Bempedoic acid inhibits ATP citrate lyase (ACL), an enzyme which is involved in the production of cholesterol in the liver.²

Bempedoic acid has been approved for use in adults with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet:²

• 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 statin, or
• alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated.

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 lipid-lowering therapies.⁶ Due to its unique mechanism of action, bempedoic acid is not activated in skeletal muscle.²

Daiichi Sankyo Europe has licensed exclusive commercialisation rights to bempedoic acid in the European Economic Area, Turkey and Switzerland from Esperion and is the full Marketing Authorisation Holder in these territories.

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

¹ Nicholls SJ, et al. Impact of bempedoic acid on total cardiovascular events in high risk patients: analysis of the clear outcomes trial. Presented at ESC Congress 2023.

² European Medicines Agency. Nilemdo® Summary of Product Characteristics. March 2020. Available at: https://www.ema.europa.eu/en/documents/product-information/nilemdo-epar-product-information_en.pdf Last accessed August 2023.

³ Ray KK, et al. Cardiovascular Benefits and Risk of New Onset Diabetes by Glycaemic Status with Bempedoic Acid: Prespecified Analyses of the CLEAR OUTCOMES trial. Presented at ESC Congress 2023.

⁴ Escofet M, et al. Long-Term Morbidity and Mortality after First and Recurrent Cardiovascular Events in the ARTPER Cohort. J Clin Med. 2020; 16;9(12): 4064.

⁵ Nicholls SJ, 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.

⁶ Pinkosky SL, et al. Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis. Nat Commun. 2016; 7: 13457.

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Contact information

Dr. Wolfgang Schiessl
Daiichi Sankyo Europe GmbH
PR & Portfolio Communication Lead, Specialty Medicines
+49 151 1714 7317