In which countries is Bempedoic acid approved?

Introduction to Bempedoic Acid
Bempedoic acid is a first‐in‐class, orally administered lipid‐lowering agent that works by inhibiting adenosine triphosphate citrate lyase (ACL), an enzyme critical to the cholesterol biosynthesis pathway. This inhibition leads to lower concentrations of low‐density lipoprotein cholesterol (LDL‐C) and results in a concomitant upregulation of LDL receptors on hepatocytes. The drug’s molecular design not only offers a novel approach for patients who are unable to tolerate statins but also opens a new therapeutic avenue in reducing cardiovascular risk. The vast array of preclinical investigations, clinical trials, and regulatory submissions has contributed significantly to our current understanding of bempedoic acid’s mechanism of action, its safety profile, and its efficacy in different patient populations.

Chemical and Pharmacological Profile
Bempedoic acid is a small‐molecule prodrug. It is inactive until it is converted in the liver by very long‐chain acyl‐CoA synthetase 1 (ACSVL1) into its active coenzyme A (CoA) thioester form. This selective activation in hepatic cells is crucial because it minimizes its activity in peripheral tissues, thereby reducing the risk for muscle-related side effects—a known adverse event associated with statins. The drug’s pharmacokinetic parameters have been extensively characterized. Steady-state conditions are typically reached within seven days of once-daily oral administration, and its linear pharmacokinetics over a dosing range have been rigorously demonstrated in multiple studies. Furthermore, the active metabolite, ESP15228, contributes modestly to the overall therapeutic efficacy, underscoring a well-balanced drug profile that maximizes cholesterol lowering while minimizing systemic adverse effects.

Therapeutic Uses
Bempedoic acid is principally used for reducing LDL cholesterol in patients with hypercholesterolemia, particularly in those who are statin intolerant or who do not achieve LDL-C targets with existing statin therapy. As an add-on therapy, it is indicated for adult patients with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD) who require further lowering of LDL-C. In clinical trials such as the CLEAR series, bempedoic acid was not only shown to reduce LDL cholesterol by approximately 18–21% on top of background lipid‐lowering therapy, but it was also demonstrated to lower inflammatory markers like high-sensitivity C-reactive protein (hsCRP). This dual mechanism of action, involving lipid modulation and inflammation reduction, supports its emerging role in comprehensive cardiovascular risk management.

Regulatory Approval Process
The regulatory approval process for drugs like bempedoic acid involves multiple layers of scrutiny, from initial preclinical studies to postmarketing surveillance, ensuring that the therapeutic benefits outweigh any risks for patients.

General Drug Approval Process
In most major regulatory jurisdictions such as the United States and the European Union, the approval of a novel drug follows a well-established, multistep process. The process begins with an Investigational New Drug (IND) application where preclinical data are submitted to demonstrate the drug’s safety. Following IND clearance, the clinical trial process is organized into several phases (Phase I through Phase III) that test for safety, dosage, efficacy, side effects, and overall benefit–risk profiles in progressively larger patient populations. Once the clinical trials have produced data that confirm the safety and efficacy of the molecule, a New Drug Application (NDA) in the United States or a Marketing Authorization Application (MAA) in the European Union is filed. This submission comprises all preclinical, clinical, manufacturing, and stability data. Regulatory authorities in regions including the United States, the European Economic Area (EEA), and Switzerland undertake comprehensive reviews often involving advisory committees before granting marketing authorization.

Specific Requirements for Cardiovascular Drugs
Cardiovascular agents, given their widespread use and the critical nature of their indication, are held to stringent standards. Regulatory submissions for such drugs must include robust data on both the lipid-lowering efficacy and the long-term impacts on major cardiovascular events. For bempedoic acid specifically, pivotal phase III trials such as CLEAR Harmony and CLEAR Wisdom provided substantial evidence of its efficacy in lowering LDL-C levels, its tolerability, and its potential clinical benefits beyond lipid modification. In addition, regulatory documents often include detailed analyses of subpopulations, such as those with renal impairment, and comparisons with standard-of-care therapies to directly address safety concerns and comparative efficacy. The FDA and EMA also require postmarketing studies, such as the cardiovascular outcomes trial (CLEAR Outcomes), which further support the product’s risk–benefit profile and help validate its role in the broader cardiovascular treatment landscape.

Approval Status of Bempedoic Acid
The approval status of bempedoic acid is a culmination of extensive global regulatory reviews. Current approvals reflect positive reviews by leading regulatory authorities in territories where the evidence for its safety and efficacy has been deemed strong.

Approved Countries
Bempedoic acid is approved primarily in the following regions and countries:

• United States: Bempedoic acid was approved by the U.S. Food and Drug Administration (FDA) based on comprehensive clinical trials that demonstrated its safety and efficacy in lowering LDL-C. The approved brand in the United States is Nexletol, which received market authorization in February 2020. The approval was granted specifically as an adjunct to diet and maximally tolerated statin therapy for adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease requiring additional LDL-C lowering.

• European Economic Area (EU/EEA): In the European Union, bempedoic acid is marketed under the brand name Nilemdo. The European Medicines Agency (EMA) granted approval in April 2020 following rigorous review of the CLEAR trial program and supportive clinical data. This approval covers adults with primary hypercholesterolemia (both familial and non-familial) and mixed dyslipidemia who need additional LDL-C lowering, either in combination with statins or as a monotherapy in statin-intolerant patients. The approval in the EU jurisdiction is particularly noteworthy because it involved coordinated efforts among multiple European regulatory agencies, ensuring harmonized safety standards across the member states.

• Switzerland: Swissmedic, the Swiss regulatory authority, has approved bempedoic acid. This approval confirms that the drug meets the strict guidelines for efficacy, safety, and pharmaceutical quality required by Swiss regulatory standards. The Swiss approval plays a crucial role in providing access in a market noted for its high standards in clinical care and precision medicine.

• Additional European Regions: Although approval in the EU/EEA primarily covers the European Union member states, there are indications that other European markets, such as Turkey, have embraced bempedoic acid as part of their therapeutic armamentarium. Market dynamics in Turkey have often aligned with the broader EU standards following positive CHMP opinions and subsequent national licensing, thus expanding the geographic reach of bempedoic acid within Europe.

Pending Approvals
While bempedoic acid is approved in major jurisdictions, there are ongoing regulatory reviews and potential label expansions in several regions that might further broaden the market landscape for the drug:

• United States Label Expansion: There are ongoing supplemental applications for extended indications such as cardiovascular risk reduction beyond the current labeling. The recent submissions and positive analyses from the CLEAR Outcomes trial indicate that further approval for expanded cardiovascular indications may be forthcoming in the first quarter of 2024.

• European Supplement Submissions: In Europe, additional applications seeking an update of the product label to expand its indication for cardiovascular risk reduction have been submitted. The Committee for Medicinal Products for Human Use (CHMP) of the EMA has recently issued positive opinions recommending such updates, with an expected decision from the European Commission in the first half of 2024.

• Other Countries/Regions: Although the primary approvals are in the United States, EU/EEA, and Switzerland, other countries are monitoring the evolving data on bempedoic acid. For example, countries in Asia (such as India) are potential future markets since there is currently no valid product patent in India for bempedoic acid, which might allow local pharmaceutical companies to launch generic versions once the data and market potential become unequivocal. However, to date, such approvals are awaited and should be considered for future market assessments.

Implications of Approval
The approval of bempedoic acid in major jurisdictions has far‐reaching implications across several dimensions, encompassing market dynamics, healthcare delivery, and future clinical research.

Market Impact
• Competitive Position: With its approval in both the United States and Europe, bempedoic acid has emerged as a reliable alternative for patients who are statin intolerant or those not achieving optimal LDL cholesterol reduction with conventional therapies. This development adds a significant competitor to the global lipid-lowering market, which has been traditionally dominated by statins and, more recently, PCSK9 inhibitors.
• Market Expansion: The simultaneous approval across key regions such as the USA, EU/EEA, and Switzerland has enabled the drug to carve out a substantial share in the cardiovascular medications market. Furthermore, ongoing label expansion applications (as indicated by recent CHMP opinions and supplementary FDA applications) are poised to further reinforce its market potential by broadening the eligible patient population.
• Economic Considerations: Companies like Esperion Therapeutics, Inc. and Daiichi Sankyo Europe GmbH have demonstrated significant investment and strategic partnerships aimed at optimizing commercial potential. Licensing deals, such as the one with Neopharma LLC in Israel, illustrate efforts to penetrate additional markets and enhance revenue streams through region-specific commercialization strategies.
• Future Prospects: Pending approvals and label expansions in the United States and Europe will likely contribute to increased market uptake and may encourage similar regulatory agencies in other regions (such as Asia or Latin America) to consider bempedoic acid for local approvals, thereby further stimulating global market growth.

Healthcare and Clinical Implications
• Improved Patient Options: For patients with heterozygous familial hypercholesterolemia or established ASCVD, the availability of bempedoic acid offers an alternative for those who do not tolerate standard statin therapy due to muscle-related side effects or other adverse reactions. This is particularly pertinent in clinical populations where maximally tolerated statin doses fail to produce sufficient LDL-C reduction.
• Enhanced Cardiovascular Risk Management: The anti-inflammatory effects of bempedoic acid, evidenced by reductions in hsCRP levels, suggest that its clinical benefits may extend beyond mere lipid lowering. The ongoing and upcoming cardiovascular outcomes trials, such as CLEAR Outcomes, are instrumental in validating these additional benefits, which could translate into reductions in major adverse cardiovascular events (MACE) such as myocardial infarction and stroke.
• Tailored Therapeutic Strategies: Given its distinct mechanism of activation in the liver and minimal peripheral effects, bempedoic acid may be incorporated into personalized treatment regimens for patients at high cardiovascular risk. This tailored approach can maximize therapeutic efficacy while minimizing adverse effects, especially in populations with comorbid conditions like renal impairment or diabetes, where treatment customization is crucial.
• Regulatory Benchmarking: The successful regulatory reviews of bempedoic acid set a precedent for the expeditious yet safe approval of similar novel agents. They highlight the importance of contemporary clinical trial designs, robust pharmacokinetic/pharmacodynamic modeling, and the integration of real-world data in supporting regulatory submissions. This progress may encourage the broader adoption of streamlined regulatory processes globally.

Conclusion
In summary, bempedoic acid is currently approved in major jurisdictions including the United States (marketed as Nexletol) and the European Economic Area (marketed as Nilemdo), with additional approvals in Switzerland through Swissmedic. European markets, encompassing EU member states and additional territories such as Turkey, have embraced its use after rigorous reviews by the EMA and CHMP, with further label expansion applications under review that may broaden the approved indications to include more explicit cardiovascular risk reduction benefits in the near future. Moreover, the consolidated efforts by regulatory authorities reflect a harmonized approach to ensuring safety and efficacy, thereby bolstering the drug’s credibility and market penetration potential. Pending approvals, particularly label expansions in the United States and Europe, indicate that bempedoic acid’s clinical utility and market uptake are anticipated to grow further, which in turn can lead to enhanced patient care through improved management of hypercholesterolemia and cardiovascular risks.

From a general perspective, the drug meets an unmet clinical need by offering a viable alternative to patients who struggle with statin intolerance. In a more specific context, its approval in critical markets such as the US, EU/EEA, and Switzerland demonstrates its established efficacy and safety profile, backed by robust clinical data. Finally, on a global scale, the regulatory success of bempedoic acid not only expands therapeutic options but also serves as a model for the expedited review and approval of innovative cardiovascular drugs.

Conclusively, the approval of bempedoic acid represents a significant milestone in lipid management and cardiovascular risk reduction. Its regulatory journey—from extensive clinical trials to multi-regional approvals—exemplifies the rigorous standards and collaborative efforts required in modern drug development. The convergence of favorable clinical outcomes, strategic regulatory submissions, and impending label expansions underscores its importance as a transformative therapeutic option in the battle against hyperlipidemia and cardiovascular disease.