New PCSK9s Nearing Market Will Help Meet Cholesterol Targets

The market for proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors to lower cholesterol is taking off with several new drugs being introduced or nearing the market, which will increase competition and enable more patients to reach low-density lipoprotein (LDL) goals, experts said.

One new anti-PCSK9 agent — lerodalcibep from LIB Therapeutics — is a small protein molecule, which is expected to reach the market by early 2026. It is being positioned as a step forward from the two monoclonal antibody products already available — evolocumab (Repatha; Amgen) and alirocumab (Praluent; Sanofi/Regeneron).

The new option can be given less frequently than the antibodies with a once-a-month injection instead of every 2 weeks. It also does not need to be kept refrigerated like the antibodies, Evan Stein, MD, chief scientific and operating officer of LIB Therapeutics, said in an interview.

Two phase 3 trials have recently been reported, showing impressive reductions in LDL in patients already taking statins.

The LIBerate Trials

The LIBerate-HR trial, published in JAMA Cardiology, involved 922 patients who still had LDL above target despite taking maximally tolerated statin therapy plus other lipid-lowering agents in some cases.

The trial found a time-averaged mean reduction in LDL cholesterol of 62%.

“This large reduction resulted in more than 90% of patients reaching the new lower LDL targets set in recent guidelines of less than 55 mg/dL for patients with cardiovascular disease or at very high risk, and less than 70 mg/dL in patients at risk,” said Stein.

Another phase 3 trial, LIBerate-CVD, has also shown reductions in LDL cholesterol levels of more than 60% in patients at high risk for cardiovascular disease on maximally tolerated statins.

LIB Therapeutics plans to file approval applications for lerodalcibep in the United States and Europe later this year.

A Crowded Field

Stein said PCSK9 inhibitors have been underused so far, but this is starting to change.

“The monoclonal antibodies were way overpriced costing around $14,000 per year when they were first introduced, which resulted in huge pushback from insurance companies,” Stein said, which made the drugs difficult to prescribe. “Then a few years ago, the price dropped a bit, and now they’re probably running at about $4000 per year, which made them more accessible.”

He said the market is now rapidly taking off. Lerodalcibep will compete in the anti-PCSK9 market with not only the two monoclonal antibodies but also with the new short-interfering RNA agent, inclisiran (Leqvio; Novartis) , a novel injectable agent that is given just twice a year but has to be administered at a medical facility.

Despite the crowded field, there appears to be plenty of room in the market. “Last year, growth was just under 40%. The first quarter of this year, it has increased by 44%. While the introduction of inclisiran has added to this growth, it hasn’t dented the sales of the existing monoclonal antibodies,” said Stein.

He estimates that the anti-PCSK9 market will reach $3 billion globally this year, and by the time lerodalcibep is launched, it could be worth $5 billion.

As well as inclisiran and lerodalcibep, there are other innovations in the anti-PCSK9 field in development, with oral drugs now also in the pipeline. The first one of these, in development by Merck, is in early phase 3 trials, and AstraZeneca has an oral agent in earlier development.

Enthusiastic Response

Other experts in the lipid field are also enthusiastic about new developments in the PCSK9s.

Jorge Plutzky, MD, director of preventive cardiology at Brigham and Women’s Hospital in Boston, said he welcomes the prospect of new approaches to PCSK9 inhibition.

“The increase in the number of safe, effective tools for LDL lowering, whether through PCSK9 or other targets, is inevitably beneficial for patients and the field,” he said during an interview.

Plutzky pointed out that although the current agents are effective, cost and coverage remain an issue despite some recent progress in these areas, and new agents will increase competition and should hopefully drive prices down. Having a variety of dosing methods and frequencies provides more options for patients to find the one that works best for them.

Lerodalcibep’s once-monthly dosing schedule and the lack of need for refrigeration may be appreciated by some patients, he said, particularly those who need to travel for long periods.

Connie Newman, MD, adjunct professor of medicine at NYU School of Medicine, New York City, said there is plenty of room in the market to accommodate patient’s needs and preferences.

“Despite the US FDA approval of three medications that target PCSK9, there is a need for more anti-PCSK9 agents that reduce LDL and cardiovascular events,” she said. “In the US alone, 25% of adults have LDL levels of 130 mg/dL and above. Of all the non-statin therapies, medications targeting PCSK9 produce the greatest reduction in LDL. However, some patients may not tolerate one or more of the medications available or may prefer a monthly injection of lower volume.”

Newman said she believes there will still be a market for injectable formulations of PCSK9 inhibitors in the future, even if oral formulations are approved.

“Oral formulations usually require more frequent administration. Some people prefer longer-acting medications that can be taken less often. This might lead to better adherence,” she said.

Stein said he agrees there will always be room for different options. “And you only have to look at what is happening with the weight loss drugs to see that there is a market for injectables.” The ability to get patients to the new, more aggressive LDL goals is what is important, he added. “These drugs do that, and offering patients a choice of agents and delivery mechanisms is helpful.”