Cardiovascular disease (CVD) is the most prevalent of all diseases and the leading cause of mortality, resulting in over $17mn deaths each year worldwide, and about 33% of all deaths in the US. Aside from following a careful diet and exercising regularly, lowering cholesterol is a key factor to decreasing the risk of developing coronary artery disease.
A stagnant cholesterol industry
For the longest time statins were the medical solution to lowering the ‘bad’ cholesterol, known as low-density lipoprotein cholesterol (LDL-C), as reflected by the success stories of Pfizer’s Lipitor and AstraZeneca’s Crestor that reeled in billions of dollars blockbuster sales annually. Statins, which are now generic and inexpensive, are still used as first-line therapy however ~5-20% patients are unable to tolerate them due to muscle aching side effects. Zetia (ezetimibe), which works by preventing cholesterol absorption from the intestine, and bile acid sequestrants are alternatives for statin intolerant patients but are generally used as later line treatments in all other patients due to modest benefits and limited clinical utility.
The market entry of Amgen’s Repatha and Sanofi Regeneron’s Praluent – injectable inhibitors that lower high cholesterol by blocking the PCSK9 enzyme – held a lot of promise for the treatment of statin-intolerant patients. However, they have struggled with uptake due to payer restrictions. These drugs were originally listed at $14,000 per year leading health insurers to reject coverage. Both companies subsequently entered a downward-spiraling pricing competition to make inroads with insurers, but despite shaving price tags by 60%, Repatha and Praluent uptake has been underwhelming.
Nearly 15 million patients (~1 in 4 patients) in the US cannot achieve guideline recommended LDL-C levels despite the available standard of care treatments.
Nexletol & Nexlizet: game changing approvals?
Fast forward to two decades later, in late February 2020, the FDA approved Esperion’s Nexletol (bempedoic acid) and Nexlizet (bempedoic acid + ezetimibe fixed dose combination) as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults that are genetically predisposed to having high cholesterol (heterozygous familial hypercholesterolemia) and patients who have heart disease (atherosclerotic cardiovascular disease) that require additional LDL-C lowering. Nexletol is an ATP Citrate Lysase (ACL) that lowers LDL-C by inhibition of cholesterol synthesis in the liver; it does not target the muscle and therefore may not cause the same side effects as statins.
Nexletol is the first oral non-statin LDL-C lowering medicine approved in the US in nearly 20 years, and Nexlizet is the first non-statin LDL-C lowering combination medicine ever to be approved. Approval of Esperion’s first-in-class tablets has broken the clinical innovation inertia in this field, which had led to a dearth of solutions to address the huge gap in targeting patients that do not achieve their LDL-C goals with existing therapy, and in patients that are statin-intolerant. Healthcare providers will finally have new alternative therapies for the millions of patients that struggle to meet their cholesterol goals.
Perhaps the most refreshing news – at least within a space that has been battling pricing scrutiny – is that Esperion has learnt from the roadblocks its predecessors faced and is pricing Nexletol and Nexlizet at ~$10 per fill, up to a 90 day supply in the US for eligible patients. Whether this price-point leads to a treatment-paradigm shift remains to be seen. Even though Esperion will likely be able to leverage this favorable price point and dosing convenience over its competitors, unlike Repatha and Praluent it will not be able to boast a cardio-benefit for its pills until 2022 when its cardiovascular risk reduction outcomes trial is expected to read-out.
The pivotal Phase 3 CLEAR program supporting the approvals demonstrated Nexletol lowered LDL-C levels by ~18% when used with moderate or high intensity statins, and Nexlizet resulted in 38% LDL-C lowering when added on to maximally tolerated statins. Nexletol will be available to patients in the US end of March 2020, followed by Nexlizet availability beginning of July 2020. Esperion is currently awaiting European Commission approval decision in April 2020 after a positive CHMP opinion was issued end of January 2020.
A disruptive future
The future is looking bright – at least for patients, maybe less so for the existing players – with Novartis recently joining the space by acquiring The Medicines Company and its RNA-targeting therapy inclisiran for nearly US$10 billion. Positioned as a “cholesterol-lowering vaccine” and touted to “transform population health” by Novartis, inclisiran is expected to have disruptive blockbuster potential due to its 6-monthly, patient-friendly dosing that is timed with routine HCP visits and clean safety profile. Global approvals are expected by early 2021, thereby adding further energy into a field that was dormant until just earlier this year.