Approval of the first oral PCSK9 inhibitor could be a boon for some clinical scenarios, although questions remain about real-world impact on prescribing and adherence.

FDA approval of the once-daily tablet, enlicitide, comes after years of speculation about whether an oral PCSK9 inhibitor would ever be developed to treat the tens of millions of patients eligible for them in the US.

“It’s a nice addition to therapeutic armamentarium,” said Steven Nissen, MD, chief academic officer of the Heart, Vascular & Thoracic Institute at the Cleveland Clinic, Cleveland. “There’s a convenience factor, and there are patients, some still, that are needle shy even though the injectable agents are very well tolerated.”

Ann Marie Navar, MD, PhD, preventive cardiologist at the UT Southwestern Medical Center in Dallas who led clinical trials with enlicitide, was more enthusiastic.

“Since statins, we have not had an oral pill that lowers LDL [low-density lipoprotein] cholesterol nearly this much. This blows out of the water the degree of LDL lowering that we have with ezetimibe or bempedoic acid,” she said.

Efficacy Results

The FDA gave the green light for patients with hypercholesterolemia, including heterozygous familial hypercholesterolemia, following a pair of clinical trials:

• CORALreef Lipids, which showed a 56% relative reduction in LDL cholesterol with enlicitide over placebo at 24 weeks in a population of patients with an LDL cholesterol of at least 55 mg/dL if they had a history of major adverse cardiovascular events and at least 70 mg/dL in primary prevention.
• CORALreef HeFH, which showed a 59% relative reduction in LDL cholesterol over placebo with enlicitide at 24 weeks in adults with heterozygous familial hypercholesterolemia and an average baseline LDL cholesterol of 119 mg/dL.

That efficacy puts enlicitide on par with the PCSK9 monoclonal antibodies and the small interfering RNA injectable inclisiran, Nissen said. While enlicitide is not more efficacious than the injectables, Nissen said that he’s already had a number of patients on PCSK9 monoclonal antibodies — who inject every 2 weeks — ask to be switched to the oral drug. 

“This is yet another option for lowering LDL cholesterol that may be desirable for some patients who don’t want to use the injectable,” he said. For example, maintaining temperature controls and taking along the injectors can be cumbersome for someone who travels a lot.

Potential for Primary Care

More critically, an oral medication could find a bigger role than injectables in primary care prescribing, Navar predicted. She cited her team’s prior research showing that more than 95% of primary care physicians and almost 40% of cardiologists hadn’t prescribed a PCSK9 inhibitor as of 2022.

“If this drug is able to actually unlock the sort of the biggest barrier we’ve had, which is getting people to use more than just statins to get patients to goals, then I actually think it does have the potential to be groundbreaking,” she said. “If it truly does become part of primary care doctors’ armamentarium and cardiologists start prescribing this widely to their patients, then I think it will move the needle on population health and lipid control.”

The lower price point — $315 for a 30-day supply ($10.50 per day) — compared with the injectables could also help, she noted.

Prescribing information instructs patients to take their tablet each morning on an empty stomach and then wait at least 30 minutes before eating or drinking anything aside from their other medications.

While patients took the drug as directed in the clinical trials to achieve the reported effect, this food interaction requires patient education in the clinic. 

And clinicians will need to keep an eye on adherence, Nissen added, pointing to the substantial drop-off in oral statin use at 1 year even among people taking it after a serious cardiovascular event such as myocardial infarction.

“So you always worry with a pill, you know. Are they going to take it? Are they going to take it every single day?” he said. With injectable agents — and that includes the GLP-1 agonists and PCSK9 inhibitors — “people, if they have an injector, they’re going to use it. If they have a pill, they might forget. And so we’ve got to see what happens in the long run outside of the clinical trial sphere to make sure that people are, in fact, adherent.”

What’s on the Horizon

Another question revolves around impact on hard clinical events, as trials have only been powered to show a reduction in cholesterol as a surrogate for heart attacks and other major risks. While large outcome trials with placebo control are underway, now that there are several PCSK9 agents with proven benefit, Nissen suggested he’s satisfied that the effect likely extends to enlicitide.

Cholesterol- and apolipoprotein B-lowering efficacy is so similar to the monoclonal antibodies and to inclisiran that there’s no reason to expect that enlicitide won’t have the same cardiovascular outcome benefit, he said. “So it’s good for patients to have options.”

And those options might continue to expand. Other oral PCSK9 inhibitors, such as laroprovstat, are in development and do not have a food effect, Nissen said.

“We’ll have to see what happens with these drugs that don’t have a food effect,” he said. “Sometimes the first drug in a class doesn’t turn out to be the very best drug.”

Navar said she’s looking forward to fixed-dose PCSK9 combinations with a statin, which are in the works for enlicitide and rosuvastatin.

“It’s one thing to tell a patient they need another pill; it’s another to just switch from the statin they’re already taking to the statin plus something else,” she said. “The potential here, if this works out, is to be able to have a single pill that gets patients’ LDL all the way down to the goal below 55.”

PCSK9 first rose to attention in 2003 when researchers in France identified a gain-of-function genetic mutation that caused familial hypercholesterolemia. A few years later, distinct loss-of-function variants in the same gene were linked to lowered LDL cholesterol. Drugs to lower PCSK9 levels soon followed, with the first positive phase 1 clinical trial results in 2012 and first FDA approvals in 2015.

Injectable monoclonal antibodies led the way, followed by the small interfering RNA injectable inclisiran in 2021, with years of speculation about whether an oral agent might be possible.

The surface where PCSK9 binds to its LDL receptor is “relatively flat, featureless, and undruggable,” as one review notes, lacking the deep, well-defined pockets that small molecules typically need to bind and exert a strong inhibitory effect.

“I was really surprised when they were able to figure out a way to do this,” Nissen said. “But they managed to do it.”

Navar reported having a financial relationship with Merck Sharp & Dohme, Amgen, Arrowhead, Bayer, Esperion, Janssen, Eli Lilly and Company, New Amsterdam, Novartis, Novo Nordisk, Pfizer, Roche, and Silence Therapeutics.

Nissen reported non-remunerative consulting for Amgen and Glenmark Pharmaceuticals, as well as research grants from AbbVie, Arrowhead Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, CRISPR Therapeutics, Eli Lilly and Company, Esperion Therapeutics, Mineralys, New Amsterdam Pharmaceuticals, Novartis, and Silence Therapeutics.

Crystal Phend is an award-winning medical journalist with decades of experience reporting on clinical research and healthcare developments across specialties. When not walking the halls at a medical conference, she can be found at a keyboard in upstate New York.