Bempedoic acid, the first agent in a new class of drugs that reduce LDL cholesterol, received Food and Drug Administration approval on Feb. 21 for treating selected hypercholesterolemic patients and is a welcome addition to the medicine cabinet, say lipid experts.
However, it is a tertiary option at least until results from a 14,000 patient clinical-outcome trial of bempedoic acid come out, likely in 2022, they agreed.
“I’m excited to have a new tool in the toolkit for treating high-risk patients, but I will always reach first for the drugs proven to reduce clinical outcomes,” said Erin D. Michos, MD, director of Women’s Cardiovascular Health and associate director of Preventive Cardiology at Johns Hopkins Medicine in Baltimore. That sentiment, shared by other experts, should for the time being relegate bempedoic acid (Nexletol) to a backup role behind statins, ezetimibe, and the PCSK9 inhibitor antibodies that are all now on the U.S. market and all buttressed with evidence of their ability to cut cardiovascular disease death and other CVD outcomes from large outcome studies.
The existing evidence base for bempedoic acid rests primarily two multicenter, randomized, placebo-controlled clinical trials of bempedoic acid in patients with LDL levels above 70 mg/dL while on maximally tolerated lipid-lowering therapy. In CLEAR Harmony, results showed that treatment with bempedoic acid cut LDL-cholesterol levels by an average of 18% more compared with placebo (N Engl J Med 2019;380:1022-32). In CLEAR Wisdom, bempedoic acid reduced LDL cholesterol levels by 17% (JAMA. 2019;322:1780-8).
While those two trials proved the drug’s ability to lower levels of LDL cholesterol, they lacked the power to address whether this effect cut the incidence of CVD events, a question that the CLEAR Outcomes trial aims to answer.
“I believe in the lipid hypothesis, but the main thing we need to see is whether bempedoic acid leads to a meaningful reduction in CVD events. The window for bempedoic acid will remain narrow until we see the outcomes results,” Dr. Michos said in an interview.
Bempedoic acid is a prodrug that’s activated in liver and targets the same cholesterol synthesis pathway as statins by inhibition of ATP-citrate lyase, an enzyme that’s upstream of HMG-CoA reductase, thereby enhancing LDL cholesterol clearance via up-regulation of LDL receptors
“Jennifer G. Robinson, MD, professor of epidemiology and medicine and director of the Prevention Intervention Center of the University of Iowa in Iowa City. That would be just a portion of the newly labeled target population. The FDA’s approved label for bempedoic acid cites the drug as an “adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD) who require additional lowering of LDL-C.”,” said
The current lack of outcomes evidence for bempedoic acid was not an issue for Robert H. Eckel, MD, an endocrinologist and lipid management specialist at the University of Colorado at Denver in Aurora. Having results from CLEAR Outcomes “may be helpful, but LDL cholesterol lowering in the range where the FDA has indicated using bempedoic acid seems all we need for now,” he said in an interview. Viewing bempedoic acid as potentially useful for both HeFH and ASCVD patients, Dr. Eckel particularly cited the possibility of using the new drug in combination with ezetimibe, another oral, once-daily agent with a moderate but additive effect for cutting LDL cholesterol.
Combined treatment with bempedoic acid and ezetimibe “may be successful in avoiding [using] a PCSK9 inhibitor in some patients, and in particular patients with HeFH or those who are statin intolerant.” But like his colleagues, Dr. Eckel agreed that, for the moment, ezetimibe has an edge over bempedoic acid because of its more extensive evidence base. “If the combination of bempedoic acid and ezetimibe is not needed, the decision [of which one of these to use] needs to depend on the outcome trial results for ezetimibe,” he said. Other factors clinicians could apply if faced with choosing between these two agents include the significant reduction in high-sensitivity C-reactive protein that bempedoic acid produces; the downside that bempedoic acid can cause in some patients an early and persistent rise in serum uric acid levels that can trigger gout flares in patients with a history of gout or at risk for gout; and cost, he said.
Cost is the room-dwelling elephant that colors many decisions about which lipid-lowering drug to use for patients, with options running the price gamut from the generic and uniformly affordable statins and ezetimibe, to the notoriously pricey PCSK9 inhibitors that remain for many patients either prohibitively expensive or hard to get covered by some insurers. Bempedoic acid seems on track to fall somewhere between these two poles, although staff members from Esperion, the company that developed and will market bempedoic acid as Nexletol starting on March 30, declared in a conference call on Feb. 24 that “cost will not be an issue,” for indicated patients prescribed the drug. Company representatives cited a program of coupons, discounts, and rebates they have planned that they anticipate will allow patients who meet the labeled indications to have an out-of-pocket cost for bempedoic acid of “as low as” $10 for a 90-pill supply. They also noted their goal of getting bempedoic acid onto the lowest tier of the Medicare formulary.
How these steps actually play out in the fun house of U.S. prescription drug pricing and preauthorizations remains to be seen. “Out-of-pocket costs are not the real drivers” of drug access, noted Dr. Robinson. “Insurers will likely start with restricted access and prior authorization requirements, just as they did with ezetimibe when it was on patent and prior to having the results from a CVD outcomes trial.” For the time being, bempedoic acid can generally be seen as “expensive ezetimibe,” summed up Dr. Robinson.
Despite that somewhat dismissive characterization, experts are intrigued by the possibility of combining two moderately potent, oral, and safe lipid-lowering drugs in selected patients as a potential alternative to the still financially challenging PCSK9 inhibitors. Combining bempedoic acid and ezetimibe “has a lot of appeal,” said Dr. Michos. “Even though preauthorization has gotten better, it’s still a challenge to get a PCSK9 inhibitor approved.”
Much of her enthusiasm stems from a study reported last year that randomized 301 patients to treatment with bempedoic acid, ezetimibe, or both. The results showed that combined treatment has a similar safety profile to treatment with either drug alone, and produced a cut in LDL cholesterol that was roughly additive for the reductions produced by each drug by itself: Ezetimibe alone cut LDL by about 23%, bempedoic acid alone by about 17%, and the two dosed together once daily resulted in an average 36% drop (Eur J Prev Cardiol. 2019 Jul 29. doi: 10.1177/2047487319864671). The results showed that, “in patients requiring intensive LDL cholesterol lowering, who cannot afford PCSK9 inhibitors, or have statin intolerance, bempedoic acid and ezetimibe are stronger together and can serve as an alternative approach for lipid management in ASCVD prevention,” wrote Dr. Michos and a coauthor in a commentary that appeared with the study results (Eur J Prev Cardiol. 2019 Jul 29. doi: 10.1177/2047487319864672).
The concept of combined bempedoic acid and ezetimibe treatment is so appealing that the bempedoic acid manufacturer, Esperion, has already developed a single-pill formulation of the two drugs that received FDA marketing approval on February 26. A company statement said that marketing of this combined formulation, Nexlizet, will start in July 2020.
Although interest in bempedoic acid seems running high for patients included in the new FDA indication, Dr. Michos and others see possibly greater potential for what would now be off-label use for primary prevention in high-risk patients without HeFH, patients who generally don’t qualify for insurance coverage of a PCSK9 inhibitor.
“Use in primary prevention in [non-HeFH] patients with insufficient lowering of LDL cholesterol wouldn’t surprise me,” but a big concern will be out-of-pocket cost when off-label use precludes insurance coverage or discount eligibility, noted Dr. Eckel. An Esperion spokesperson said that the undiscounted, wholesale acquisition cost for bempedoic acid is expected to be roughly $10/pill, or about $300 for a 30-day supply, positioning it more or less midway between generic statins and ezetimibe and the list price for a PCSk9 inhibitor of roughly $500/month.
“I’m most excited about bempedoic acid in the off-label space, for patients who can’t get approved for a PCSK9 inhibitor, for treating patients with subclinical ASCVD, or really high-risk patients with multiple risk factors including diabetes,” especially when these patients are intolerant of a high-intensity statin regimen, said Dr. Michos. “I have a clinic full of patients” who can’t take their full, indicated dosage of a high-intensity statin, and when those patients also can’t get on treatment with a PCSK9 inhibitor then bempedoic acid will be an important part of their alternative regimen, she explained.
Dr. Michos had no disclosures. Dr. Robinson has received research funding from Esperion and from several other companies, and she has been a consultant to Amgen, Merck, Novartis, Novo Nordisk, Pfizer, Regeneron, and Sanofi. Dr. Eckel has received honoraria from Kowa, Merck, Novo Nordisk, and Sanofi/Regeneron.
This article was updated 2/27/20.