The once-daily oral medication is meant to be taken as an add-on to a heart-healthy diet and the maximum dose of statins a patient tolerates. “This is an exciting new class of drug and a new option for an oral medication that we can use for patients who are at high risk of atherosclerotic vascular disease like heart attacks or stroke,” says Alec J. Moorman, MD, an associate professor of cardiology and medicine at the University of Washington School of Medicine in Seattle. “Nexletol will be useful as an add-on therapy to statins for patients who aren’t at their treatment goals or for patients who are unable to tolerate statins, which is most commonly due to muscle-related side effects,” he says. Statins are considered first-line therapy for treating LDL cholesterol, but sometimes people can’t tolerate a dose high enough to get to their goal LDL, and in some cases, they can’t take a statin at all, according to Dr. Moorman. Nexletol blocks an enzyme involved in cholesterol synthesis that actually works upstream of the enzyme that statins block, according to Moorman. “Nexletol works on the same pathway but at a different location, and because it works only in the liver and on this different enzyme, it seems to greatly reduce or eliminate those muscle-related effects,” he says. “Muscle-related side effects are definitely the number one reason why patients are unable to take a statin or the recommended dose of a statin medication,” he says. HeFH is an inherited genetic disorder that causes a person to have dangerously high LDL cholesterol levels of above 190 for adults. Compared with people who have an average LDL, people with this condition have a five times higher risk for coronary heart disease over a 30-year span, according to the American Heart Association (AHA). High LDL cholesterol can increase the risk of atherosclerotic cardiovascular disease (ASCVD), which includes coronary artery disease, peripheral artery disease, and transient ischemic attack (TIA) or stroke, according to guidelines from the American College of Cardiology (ACC) and the American Heart Association (AHA).
Trials Show Nexletol Is Effective in Lowering LDL
The approval was based on several phase 3 pivotal trials that looked at the safety and efficacy of Nexletol.
A randomized placebo-controlled trial published in March 2019 in the New England Journal of Medicine studied people with an LDL of at least 70 who were on the maximum dose of a statin that they could tolerate as determined by the researchers. After 12 weeks, the average LDL of the group taking Nexletol went from 103 to 84, a drop of 16.5 percent from baseline.A total of 779 people with existing atherosclerotic cardiovascular disease (ASCVD), heterozygous familial hypercholesterolemia (HeFH) or both were randomized to receive Nexletol or placebo in addition to the maximum dose of a statin they could tolerate.
At the completion of the 12-week trial, published in the Journal of the American Medical Association in November 2019, people taking Nexletol showed a 17 percent reduction in their LDL cholesterol compared with the group taking just the statin plus placebo.
Does Lowering Cholesterol Equal Fewer Heart Attacks and Deaths?
LDL cholesterol is one component of overall cholesterol, and “LDL” stands for low-density lipoproteins; the name is based on its physical characteristics, according to Moorman. “The LDL penetrates the arterial wall and forms plaques and promotes inflammation. These cholesterol plaques can grow and restrict blood flow to the heart muscle. If a plaque ruptures it can cause a heart attack.” Whether lowering LDL cholesterol in this population with Nexletol will translate into fewer major heart events or fewer deaths due to heart disease remains unknown. A phase 3 trial is currently underway to determine if the drug reduces cardiovascular risk, and it’s likely that the data won’t be presented until 2022. “I expect that we’ll see some benefit in event reduction, but I will say that this drug’s effect on LDL lowering is modest compared with some other types of drugs that we have,” says Moorman. He notes that PCSK9 inhibitors have shown greater reduction in LDL than Nexletol, but the vascular event reduction in that class of medications was smaller than anticipated. Studies have shown PCSK9 inhibitors can lower LDL by about 48 percent. Two published trials involving PCSK9 inhibitors both reported a 15 percent reduction in all-cause deaths. PCSK9 inhibitors are a class of drug that help preserve the number of liver cell receptors whose job it is to get rid of excess cholesterol, which in turn lowers the amount of cholesterol in the blood. These biologic drugs are available only as a shot. “We know that cholesterol is causal in contributing to heart attack and strokes; this is why the FDA accepted that cholesterol lowering alone is a sufficient outcome to approve the drug,” says Moorman. “I do think there’s reason to be cautious and take a ‘wait and see’ approach. I think that I, along with many of my colleagues, will hold off on prescribing this drug until the event studies are completed; we may reserve the drug for a very small segment of our patient population, whereas there might be more broad use if we see event reduction proven in these later trials,” he says.
Is Nexletol Safe?
From what we’ve seen in the trials, Nexletol looks like a relatively safe drug overall, says Moorman. “The one concerning thing that was shown in both the large trials was an increased incidence of gout,” says Moorman. Gout can be a painful disorder for patients, and uncontrolled gout can lead to important adverse clinical complications, he adds. The most common adverse reactions of Nexletol were upper respiratory tract infections, muscle spasms, increased uric acid levels (hyperuricemia), back pain, abdominal pain or discomfort, bronchitis, pain in the extremities, anemia, and elevated liver enzymes. Although the studies looked at the LDL lowering benefits with what investigators determined was the highest statin dose tolerated, the new drug shouldn’t be used with a dose of simvastatin (Zocor) higher than 20 milligrams (mg) or pravastatin (Pravachol) 40 mg. According to a release from Esperion, Nexletol will be available by prescription beginning on March 30, 2020.
