Daiichi Sankyo Europe, (hereafter, Daiichi Sankyo) today announced the presentation of results from the Phase 3 cardiovascular CLEAR (Cholesterol Lowering via Bempedoic acid, an ATP citrate lyase (ACL)-Inhibiting Regimen) Outcomes Trial and the multinational observational SANTORINI (Lipid management in patients with high- and very-high CV risk; data from clinical practice in Europe) study. Both studies were presented in a late-breaker session at the 91st European Atherosclerosis Society congress.
Findings from the CLEAR Outcomes trial, led by US-based biotech company Esperion Therapeutics Inc., demonstrate a 13%* relative risk reduction (RRR) in the primary endpoint of a four-component composite of major adverse cardiovascular (CV) events (MACE-4) defined as death from CV causes, non-fatal myocardial infarction, non-fatal stroke or coronary revascularisation.1 Results from the CLEAR Outcomes trial also included statistically significant risk reduction rates for the key secondary endpoints of 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; a fatal or non-fatal myocardial infarction alone; and coronary revascularisation.1 These findings complement earlier evidence demonstrating that bempedoic acid reduces LDL-C levels by 17–28% and show that treatment with bempedoic acid among patients who were unable or unwilling to take statins was also associated with a lower risk of major adverse CV events.1 The new data firmly establish bempedoic acid as the first ACL inhibitor known to reduce both LDL-C and the risk of major CV events and marks a pivotal step in addressing the burden of CVD in Europe.1
SANTORINI is a multinational, prospective, observational, non-interventional study, primarily designed to document, in routine clinical practice, the effectiveness of current treatment options for managing LDL-C levels in patients.3 It is also the first study, since lower LDL-C goal recommendations were made in the 2019 ESC/EAS lipid guidelines, to investigate how lipid management has evolved in clinical practice.2 One-year follow up data from the SANTORINI study including 7,210 patients showed an improvement in average LDL-C levels by ~0.4mmol/L in both high- and very high-risk patients.2 At one-year follow-up, a higher proportion of patients reached goal versus baseline (31.2% vs. 21.2%).2 This could be partly driven by a shift in patients taking no lipid lowering therapies at baseline who had started any treatment at one-year follow-up.2 Additionally there was a greater use of combination therapies at one-year follow-up versus baseline (41.2% vs 27.5%).2 Combination therapy rather than monotherapy should be considered as standard of care for high-, and in particular for very high-risk, patients.2
“I am encouraged by the latest findings from SANTORINI that more people are reaching target LDL-C goals, but we still have a long way to go. Nearly 80% of patients who are at high- or very high-risk of CV events in Europe do not attain the guideline-recommended LDL-C goals, putting them at high risk of suffering an acute and often life-threatening cardiovascular event. It’s critical that healthcare professionals make full use of all the tools available to them to lower LDL-C and support patients in reducing their risk of heart attacks and ischemic strokes,” 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, and Principal Investigator of the SANTORINI trial. “The data presented today marks an exciting and pivotal step in equipping physicians with much needed treatment options to curb the impact of cardiovascular disease across Europe and clearly demonstrates the essential role that combination therapies play in achieving LDL-C goals.”
“Up until now, we’ve had evidence demonstrating that bempedoic acid, a first-in-class oral ACL inhibitor, effectively reduces LDL-C levels, but its impact on CVD morbidity and mortality had not been studied. The CLEAR Outcomes trial answers those remaining questions and shows that bempedoic acid reduces the risk of major cardiovascular events in patients at high- and very high-risk. We now know that, as an additional treatment option, bempedoic acid can not only help patients reach their guideline LDL-C recommendations but also lower their CV risk. Furthermore, this data shows that bempedoic acid can address a high unmet clinical need by providing a much needed and effective treatment option for patients who are unwilling or unable to take or increase the dosing of their statin therapy,” said Professor Stephen Nicholls, Program Director of Monash Heart, Director Monash Victorian Heart Institute, Professor of Cardiology, Monash University Australia.
Treatment with bempedoic acid in the CLEAR Outcomes trial appeared to lead to few adverse events and the overall incidence of adverse events leading to discontinuation of the trial regimen did not differ meaningfully between the bempedoic acid and placebo groups.1 Furthermore, bempedoic acid as compared with placebo did not increase blood glucose levels or the incidence of new-onset diabetes.1
“Cardiovascular disease remains Europe’s number one cause of death, responsible for more than 10,000 lives lost every day,” said Dr Stefan Seyfried, Vice President Medical Affairs Specialty Medicines, Daiichi Sankyo Europe GmbH.“At Daiichi Sankyo, we continue to invest to improve CVD outcomes for patients in Europe and reduce the impact of this immense and persistent health burden. We are committed to providing evidence-based effective and innovative medicines as well as bringing relevant scientific information to the medical community to help inform clinical decision-making and improve patients’ lives.”
* Percentages in publicly available sources have been rounded to the nearest whole number.
About CLEAR Outcomes trial
The CLEAR Outcomes Trial is a Phase 3, event-driven, randomised, multicenter, double-blind, placebo-controlled trial.4 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.4
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.1 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 bempeodic acid and placebo groups.1 Patients were followed up for a median duration of 40.6 months.1
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.1 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 non-fatal myocardial infarction; coronary revascularisation; fatal and non-fatal stroke; cardiovascular death; and all-cause mortality.1
The SANTORINI study is a multinational, prospective, observational study that enrolled 9,602 patients from over 800 sites in 14 countries across Europe, conducted between March 2020 and February 2021 with a follow-up until 31 May 2022.3 The primary objective was to document, in the real-world setting, the effectiveness of current LDL-C management approaches in high- and very high-cardiovascular-risk patients requiring lipid-lowering therapies over a 1-year period.3 The study included both previously diagnosed and treated patients and those newly diagnosed and requiring treatment.3
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.5 Bempedoic acid inhibits ATP citrate lyase (ACL), an enzyme which is involved in the production of cholesterol in the liver.5
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:5
- 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.6
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 dedicated to creating new modalities and innovative medicines by leveraging our world-class science and technology for our purpose “to contribute to the enrichment of quality of life around the world.” In addition to our current portfolio of medicines for cancer and cardiovascular disease, Daiichi Sankyo is primarily focused on developing novel therapies for people with cancer as well as other diseases with high unmet medical needs. With more than 100 years of scientific expertise and a presence in more than 20 countries, Daiichi Sankyo and its 16,000 employees around the world draw upon a rich legacy of innovation to realise our 2030 Vision to become an “Innovative Global Healthcare Company Contributing to the Sustainable Development of Society.”
For more information, please visit www.daiichisankyo.com
▼ This medicinal product is subject to additional monitoring.
1 Nissen SE, et al. Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients. N Engl J Med. 2023. 13;388(15):1353–1364.
2 Ray KK, et al. Lipid management in patients with high and very high cardiovascular risk: Data from routine clinical practice in Europe (SANTORINI Study) data presented at EAS Congress 2023.
3 Ray KK, et al. Treatment gaps in the implementation of LDL cholesterol control among high- and very high-risk patients in Europe between 2020 and 2021: the multinational observational SANTORINI study. Lancet. 2023;29:100624.
4 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.
5 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 May 2023.
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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