2020-02-25| Trials & Approvals

FDA Approval of Cholesterol Lowering Drug, NEXLETOL, A Value-Add to Existing Treatments

by Ruchi Jhonsa
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By Ruchi Jhonsa, Ph.D.

Low-density lipoprotein cholesterol (LDL-C) or just bad cholesterol in lay terms is a well-established risk factor for cardiovascular diseases. LDL-C, when present within limits, helps in cell repair but excessive amounts could lead to arterial wall deposits causing plaques and blocks. Despite the standard care of treatment like statin therapy, nearly 15 million people in the U.S. are estimated to have not achieved the guideline-recommended LDL-C levels. Moreover, muscle-related side effects and other problems such as elevated liver enzymes might limit the use of statins. Other cholesterol-lowering drugs like PCSK9 inhibitors, Praulent and Repatha also have their limitations such as being invasive and costing up to $6000 or more a year.

Nearly two decades after the first approval of statin, Esperion, a lipid management company has announced the FDA approval of its first-in-class cholesterol-lowering medicine, NEXLETOL. This oral, once-daily, non-statin LDL-C lowering drug is indicated for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD). FDA recommends that the drug be taken with a normal diet and the highest level of statin dose the patient can tolerate.


NEXLETOLTM – Mode of Action

Unlike drugs that target the β-Hydroxy β-methylglutaryl-CoA (HMG-CoA) for treating high cholesterol, NEXLETOL works by inhibiting ATP Citrate Lyase. The active compound bempedoic acid is a prodrug that is converted to its active moiety primarily in the liver by very-long chain acyl-CoA synthetase-1. ATP citrate lyase is an enzyme two steps upstream of HMG-CoA reductase, a target of statins. NEXLETOL on its own can reduce the LDL-C levels by 25% and an additional 18% when taken together with statins, making it a valuable add on to the existing treatment.

Phase III Trial and Safety Data

The approval was supported by data from Phase III efficacy studies. In the global, randomized, double-blind, placebo-controlled clinical trial, a total of 3000 patients were enrolled who either had atherosclerotic cardiovascular disease or heterozygous familial hypercholesterolemia or both and met randomization criteria, which included LDL-C level 70mg/dl or greater while receiving maximally tolerated lipid-lowering therapy. Patients were randomized 2:1 to treatment with bempedoic acid or placebo once daily for 52 weeks. The primary endpoint of change in LDL-C level from baseline at week 12 was met. Bempedoic acid managed to reduce LDL-C levels by 18% when used with moderate or high-intensity statins. A significant reduction was also observed for secondary endpoints that included change in levels of total cholesterol, lipoproteins, and other biomarkers.

NEXLETOL was mostly well tolerated with some patients experiencing hyperuricemia with the development of gout, as well as increased risk of tendon rupture or injury. Common adverse events included upper respiratory tract infection, muscle spasms, back pain, abdominal pain, bronchitis, anemia, and elevated liver enzymes.


Ensuring Accessibility to Patients

With plans of reaching the U.S. market by 30th March, the company is discussing with insurance providers to provide the best deal for patients. It is estimated that eligible patients with commercial drug insurance coverage may pay as little as $10 per fill, up to a 3 month supply. Moreover, Esperion will provide resources like educational material, a dedicated call center as well as a co-pay program to patients. Esperion also plans to test NEXLETOL in combination with a cholesterol absorption inhibitor Ezetimibe, the FDA review of which is expected to be out in a few days.

“NEXLETOL delivers upon a commitment we’ve made to millions of patients for a new treatment alternative if they struggle with bad cholesterol and have ASCVD or HeFH. Even with maximally tolerated statins, which may mean no statin at all, some of these patients can’t achieve their LDL-C goals. Today’s approval provides them with a new medicine to go along with a healthy diet. We express our sincere gratitude to all of the patients and physicians who put their confidence in Esperion’s team of lipid experts” said president and CEO, Tim Mayleben.

Related Article: NHS Strikes Inclisiran Deal with Novartis

  1. Goldberg et al., 2019, JAMA
  2. Ray et al., 2019, NEJM


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