Bempedoic Acid and Its Fixed-dose Association With Ezetimibe Also Approved in Europe to Lower Cholesterol and Reduce Cardiovascular Risk
Thursday, May 23, 2024
The European Commission (EC) has approved the extension of the indications of both bempedoic acid ▼ and the fixed-dose combination of bempedoic acid and ezetimibe ▼ from Daiichi Sankyo and Esperion Therapeutics, as treatments for hypercholesterolemia and to reduce the risk of adverse cardiovascular events. 1,2 The EC decision is based on the positive results of the phase III CLEAR Outcomes study and makes bempedoic acid the first and only non-statin lipid-lowering treatment indicated for the primary and secondary prevention of cardiovascular events.
The EC decisions follow previous CHMP opinions received last March and approve bempedoic acid and the fixed combination of bempedoic acid/ezetimibe for use in adults with established atherosclerotic cardiovascular disease or at high risk of cardiovascular disease atherosclerotic disease, to reduce cardiovascular risk by reducing LDL-C levels, in addition to correcting other risk factors. 1,2
In Europe, around one in seven people have high LDL-C levels and cardiovascular disease is the main cause of death; they are in fact responsible for over 10,000 lives lost every day 3,7 However, 80% of patients do not reach the LDL-C targets recommended by the guidelines, despite taking therapies such as statins, and are therefore exposed to a greater risk of heart attack or stroke. 3,4,5,6
Bempedoic acid is a first-in-class oral treatment that lowers cholesterol and can be combined with other oral treatments to further lower cholesterol. Bempedoic acid, in addition to statin therapy, provides an additional reduction in cholesterol of up to 28% compared to placebo. 8 The fixed-dose combination of bempedoic acid and ezetimibe combines two complementary modalities of cholesterol reduction in a once-daily tablet, reducing LDL-C by 38% compared to placebo, in high-risk patients already taking therapy with statins at the maximum tolerated dose. 9
"The positive decision to update the therapeutic indications reconfirms the effectiveness of these two treatments in reducing LDL cholesterol levels and, ultimately, in reducing the risk of serious cardiovascular events", declared Professor Alberico Catapano of the University of Milan. “The announcement will give doctors across Europe further confidence in prescribing bempedoic acid, alone or in fixed-dose combination with ezetimibe, to best manage their patients' needs.”
The European Commission's approval is based on results from the phase 3 CLEAR Outcomes study ( Cholesterol Lowering via Bempedoic Acid, an ATP citrate lyase (ACL)-Inhibiting Regimen ). 10 The study enrolled a total of 13,970 patients aged between 18 and 85 and took place in 1,250 centers in 32 countries, including 485 centers in Europe. 10 CLEAR Outcomes results demonstrated a 13% reduction in the relative risk of major adverse cardiovascular events, defined as a 4-component composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization (MACE-4 ).10 Results of key secondary endpoints and subgroup analysis were also published. 10
“Today's announcement marks a pivotal moment in our ongoing efforts to reduce cardiovascular risk. With this new indication, which covers both primary and secondary prevention, we can help healthcare professionals better meet therapeutic needs in their daily practice - said Oliver Appelhans , Head of the Specialty Division of Daiichi Sankyo Europe – "At the same time we are certain that it will reassure patients that the drug really reduces their cardiovascular risk. All this once again affirms our commitment to be a trusted ally in improving cardiovascular care across Europe.”
“We are thrilled with the European Commission's approval, which reflects the significant cardiovascular risk-reducing benefits that the global bempedoic acid franchise offers to patients around the world,” said Sheldon Koenig, President and CEO of Esperion, “This milestone further strengthens our efforts to offer innovative therapeutic options for the management of cardiovascular risk in patients with elevated LDL-C.”
Bempedoic acid and its fixed-dose association with ezetimibe
Bempedoic acid is a first-in-class oral molecule that reduces LDL cholesterol and can be combined with other oral treatments to further lower levels. 1,3 Bempedoic acid inhibits ATP citrate lyase (ACL), an enzyme involved in the synthesis of cholesterol in the liver. 11
Bempedoic acid acts on the well-known process of cholesterol synthesis, upstream of the statin target in the liver, allowing a further lowering of LDL-C if added to statins or other lipid-lowering therapies. 12 Bempedoic acid is not activated in skeletal muscle. 11
The fixed-dose combination of bempedoic acid (180mg) and ezetimibe (10mg) combines two complementary ways of reducing cholesterol in a single tablet to be taken once a day.
Daiichi Sankyo Europe has obtained from Esperion the exclusive license to market bempedoic acid in the European Economic Area, Turkey and Switzerland and holds the marketing authorization in these territories.
The CLEAR Outcomes study
The Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen ( CLEAR ) Outcomes study was a phase 3, randomized, event-driven , multicenter, double-blind, placebo-controlled study. 13 It was designed to evaluate whether treatment with bempedoic acid reduced the risk of cardiovascular events in patients who had or were at high risk of cardiovascular disease (CVD) and for whom primary or secondary prevention of CVD was clinically indicated , but who nevertheless could not or did not want to take statin treatment. 12
The study, which completed enrollment in August 2019, included 13,970 patients aged 18 to 85, with an average age of 65.5 years, at 1,250 centers in 32 countries around the world, including including 485 centers in Europe. 10 Patients had mean baseline LDL-C levels of 139 mg/dL (3.59 mmol/L) and were assigned to treatment with bempedoic acid, 180 mg daily, or matching placebo, in the context of medical treatment addressed by the guidelines in both the bempedoic acid group and the placebo group. 12 Patients were followed for a median follow-up duration of 40.6 months. 12
The primary endpoint of the CLEAR outcomes trial was a four-component composite of major adverse cardiovascular events (MACE-4) defined as cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization. 12 Secondary endpoints included MACE-3, a composite of three major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke); fatal and nonfatal myocardial infarction; coronary revascularization; fatal and non-fatal stroke; cardiovascular death and all-cause mortality. 12
Daiichi Sankyo
Daiichi Sankyo is an innovative global pharmaceutical company that contributes to the sustainable development of society by discovering, developing and providing new standards of care to enrich the quality of life around the world. With more than 120 years of experience, Daiichi Sankyo uses its world-class science and technology to create new treatment modalities and innovative medicines for people with cancer, cardiovascular disease and other conditions with a high unmet need for treatment. For more information visit the website www.daiichi-sankyo.it
▼ This drug is subject to additional monitoring. Healthcare professionals are asked to report any suspected adverse reactions.
1 European Medicines Agency. Nilemdo - opinion on variation to marketing authorisation. https://www.ema.europa.eu/en/medicines/human/variation/nilemdo . Last accessed May 2024.
2 European Medicines Agency. Nustendi - opinion on variation to marketing authorisation. https://www.ema.europa.eu/en/medicines/human/variation/nustendi . Last accessed May 2024.
3 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.
4 Bandyopadhyay D., et al . Safety and efficacy of extremely low LDL-cholesterol levels and its prospects in hyperlipidemia management. Journal of Lipids . 2018.
5 Fox, K.M., et al . Treatment patterns and low-density lipoprotein cholesterol (LDL-C) goal attainment among patients receiving high-or moderate-intensity statins. Clin Res Cardiol . 2018. 107;(5): 380–388.
6 Kotseva, K., et al . Lifestyle and impact on cardiovascular risk factor control in coronary patients across 27 countries: Results from the European Society of Cardiology ESC-EORP EUROASPIRE V registry. Eur J Prev Cardio . 2019. 26;(8): 824–835.
7 Timmis, A., et al . European Society of Cardiology: Cardiovascular Disease Statistics 2019. European Heart Journal . 2020. 41;(1) 12–85
8 Ballantyne, C.M., et al . Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: A randomized, placebo-controlled study. Atherosclerosis . 2018. 277: 195–203.
9 Ballantyne, C.M., et al . Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy. Eur J Prev Cardiol . 2019. 27;(6): 593–603.
10 Nissen, S.E., et al . Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients. N Engl J Med . 2023. 13;388;(15): 1353–1364.
11 European Medicines Agency. Summary of product characteristics: https://www.ema.europa.eu/it/documents/product-information/nustendi-epar-product-information_it.pdf Last access: May 2024
12 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.
13 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.
Contacts
Daiichi Sankyo
Elisa Porchetti
Tel.+39 0685255-202
elisa.porchetti@daiichi-sankyo.it
Valeria Carbone Basile
Tel: +39 339 1704748
valeria.carbonebasile@gmail.com
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