New Drug
Cara Aldridge Young
FDA recently approved bempedoic acid (Nexletol), the first once-daily, oral nonstatin drug to lower LDL-C in nearly 20 years, as well as bempedoic acid and ezetimibe (Nexlizet), the first nonstatin combination drug ever approved. Both drugs are manufactured by Esperion.
As an adjunct to diet and maximally tolerated statin therapy, the medications provide an important new option for the nearly 15 million U.S. adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who cannot achieve guideline-recommended LDL-C levels despite standard-of-care treatments, including statin therapy, according to Esperion.
Nexletol
Nexletol is a first-in-class adenosine triphosphate (ATP)-citrate lyase (ACL) inhibitor that lowers LDL-C by reducing cholesterol biosynthesis and up-regulating LDL receptors. The recommended dosage is 180 mg orally once daily, with or without food.
Pivotal clinical trial. In a global Phase III LDL-C lowering program, more than 2,000 patients on moderate or high-intensity statins who were treated with the drug had an average 18% reduction in their LDL-C compared with placebo.
Warnings and precautions. Hyperuricemia, including elevations in serum uric acids, may occur. The label recommends assessing uric acid levels periodically as clinically indicated, monitoring for signs and symptoms of hyperuricemia, and initiating treatment with urate-lowering drugs as appropriate.
In the clinical trial, the risk for gout events was higher in patients with a prior history of gout, although gout also occurred more frequently than placebo in patients who had no prior history.
Tendon rupture also has occurred. Patients who have a history of tendon disorders or rupture should not use the drug and other patients should discontinue use at the first sign of tendon rupture.
The label includes cautions on use in pregnant and breastfeeding women. The drug may cause fetal harm because of its mechanism of action. Breastfeeding is not recommended.
Adverse reactions and drug interactions. The most common adverse reactions are upper respiratory tract infection, muscle spasms, hyperuricemia, back pain, abdominal pain or discomfort, bronchitis, pain in extremity, anemia, and elevated liver enzymes.
Drug interactions can occur with simvastatin and pravastatin. Avoid concomitant use with simvastatin greater than 20 mg and pravastatin greater than 40 mg.
CVOT. A global cardiovascular outcomes trial (CVOT)—known as the CLEAR Cardiovascular Outcomes Trial—is assessing Nexletol’s effects on major cardiovascular events in patients with or at high risk for cardiovascular disease (CVD) who are only able to tolerate less than the lowest-approved daily starting dose of a statin and are considered statin averse. The randomized, double-blind, placebo-controlled study has enrolled more than 14,000 patients with hypercholesterolemia and high CVD risk at more than 1,400 sites in 32 countries. Nexletol’s effect on cardiovascular morbidity and mortality has not been determined.
Nexlizet
Nexlizet contains bempedoic acid, an ACL inhibitor; and ezetimibe, a cholesterol absorption inhibitor. The drug lowers elevated LDL-C through complementary mechanisms of action by inhibiting cholesterol synthesis in the liver and absorption in the intestine.
The recommended dosage is one tablet (180 mg bempedoic acid and 10 mg ezetimibe) orally once daily, with or without food. If coadministered with bile acid sequestrants, Nexlizet should be taken at least 2 hours beforehand or at least 4 hours afterward.
Phase III clinical trial. Nexlizet’s approval was based on the Phase III fixed combination drug product LDL-C lowering program, as well as safety data from the Nexletol Phase III LDL-C lowering program and the existing ezetimibe safety profile. Compared with placebo, Nexlizet lowered LDL-C by 38% when added on to maximally tolerated statins.
Warnings and precautions. Nexlizet is generally well tolerated. Hyperuricemia has occurred, along with the development of gout in a small percentage of patients. There is also an increased risk of tendon rupture or injury.
Adverse events. The most common adverse events are upper respiratory tract infection, muscle spasms, hyperuricemia, back pain, abdominal pain or discomfort, bronchitis, pain in extremity, anemia, elevated liver enzymes, diarrhea, arthralgia, sinusitis, fatigue, and influenza. The majority are mild to moderate in severity.
Availability and cost
Nexletol became available in U.S. pharmacies on March 30, and Nexlizet will be available in July 2020. For eligible patients with commercial drug insurance, each drug will cost approximately $10 per fill for up to a 3-month supply. Esperion also said it is “committed to achieving the lowest branded tier coverage for Medicare patients.”