Long viewed as one of the biggest hype-to-disappointment stories in pharmaceutical history, the PCSK9 cholesterol drug class has struggled to live up to its commercial promise. Merck & Co. aims to flip that narrative with Lipfendra, betting the first-ever oral option can finally unlock the market’s full potential with support from regulators and doctors.
Lipfendra (enlicitide) earned an early approval in July following a rapid review by the FDA under the Commissioner’s National Priority Voucher (CNPV) program.
“In our conversations with this administration’s FDA, they wanted to use Lipfendra as a cornerstone way to demonstrate what they’re trying to do with” CNPV, Merck’s R&D chief, Dean Li, M.D., Ph.D., said Tuesday during the company’s second-quarter earnings call.
Announced in June 2025, the CNPV program significantly accelerates review timelines of products that align with five U.S. health priorities: addressing significant unmet medical needs, large population impact, innovative approach, manufacturing onshoring and affordability.
While other drugs included in the initiative may touch on some of the requirements, the FDA wanted Lipfendra to meet all of them, Li said.
Interest among doctors and patients is high, and pharmacies began placing orders last week, Merck CEO Rob Davis said on Tuesday’s call. Nevertheless, the chief executive suggested that access, particularly in terms of reimbursement, will take time to build.
“We are expecting to see the pace not be as fast out of the gate,” Davis said. He added that, over the longer term, Merck continues to view Lipfendra as “definitely a blockbuster opportunity.”
Reimbursement hurdles were the culprit behind the slow rollouts of all existing PCSK9 drugs, which are all injections, except for Lipfendra.
When Amgen’s Repatha and Regeneron and Sanofi’s Praluent first reached the U.S. market in 2015, their eye-popping list prices—compared with cheap generic medications like statins—received significant payer pushback, leading to onerous prior authorization requirements and heavy coverage rejections. The initial lack of evidence that these meds can reduce heart risks fueled reluctance among doctors for years.
At the end of 2021, Novartis’ siRNA therapy Leqvio arrived. But for cardiologists who were used to giving drugs for patients to take at home, Leqvio’s buy-and-bill reimbursement process proved to be a major drag on uptake. The drug finally reached blockbuster status last year, bringing in $1.2 billion in global sales.
This time around, analysts have again pinned megablockbuster hopes on Lipfendra, projecting the first oral PCSK9 med could reach $5 billion in annual peak sales.
On pricing, Merck has set Lipfendra’s list price at $315 per month, roughly half the cost of those injectable treatments. Merck has also committed to making the drug available at a discount through the Trump administration’s direct-to-patient platform, TrumpRx, as part of the company’s “most favored nation” deal with the White House. Davis said Merck is getting the initial launch moving before putting Lipfendra on TrumpRx.
Regarding the injectables, Davis stressed that Merck’s focus is not on taking shares from existing players, citing a mere 5% penetration rate so far in a population of 30 million people who are not at their recommended LDL cholesterol levels despite receiving lipid-lowering therapies.
“What we are about is market expansion and helping people understand that cardiovascular disease continues to be the No. 1 silent killer in the United States,” Davis said.
Again, Davis flagged that the process of expanding and educating the market “will all take time because there is inertia we’re working against.”
Similarly, aiming to drive category growth, Novartis CEO Vas Narasimhan recently dismissed Lipfendra as a threat to Leqvio.
“Even with orals launching, our opportunity remains for driving strong growth in the segment that wants infrequently administered, physician-administered medicines for lipid lowering in the United States,” he said on Novartis’ second-quarter earnings call on July 21.
Leqvio is on track to read out two cardiovascular outcomes trials next year, and Merck has its own Lipfendra outcomes study expected to report results in 2029.
Meanwhile, Merck is already thinking about bolstering Lipfendra through potential combinations, including one with rosuvastatin (Crestor) and another with MK-7262, Merck’s Lp(a) candidate.
Lipfendra on its own has demonstrated an ability to lower LDL-C by nearly 60% at Week 24. With rosuvastatin, Merck hopes to get that reduction to 80%, Li said. As for Lp(a), while the company is still waiting to see how MK-7262 stands on its own, Li said he hopes its Lipfendra combo could drive “unprecedented” cardiovascular outcomes in patients with high Lp(a).
The Merck R&D chief also confirmed the possibility of pairing Lipfendra with oral GLP-1s but cautioned that step-up dosing might be needed to reduce the side effects of nausea and vomiting.