By Bill Alpert

Forty years after the first statin drug started lowering levels of artery-choking cholesterol, heart attacks and strokes remain the world's biggest killers. This year will see test results on some drugs that cut cholesterol even more.

Statins are cheap and effective drugs for reducing blood levels of the "bad" cholesterol known as LDL, which gunks up arteries over time. A quarter of Americans have high LDL. But only about half of patients stay on their prescribed statins, and the drugs don't get LDL low enough in some 10% of patients.

A pack of new cardiovascular drugs are being tried as pills, biweekly or semiannual shots, and even as once-for-a-lifetime infusions. And their benefits all seem additive to those of statins and each other. Successful trial results in the next few years could save thousands of lives and generate billions in new annual revenue for drugmakers.

"Even with everything that we've done in the field, there is actually a fair amount of new things in the pipeline," said researcher Steve Nissen, a cardiologist at the Cleveland Clinic who conducts clinical trials on many of the new drugs.

Companies working on new cholesterol-lowering drugs range from pharmaceutical companies -- like Eli Lilly, Merck, and AstraZeneca -- to biotechs -- like Amgen, Regeneron Pharmaceuticals, and NewAmsterdam Pharma -- to gene-editing specialists -- like Crispr Therapeutics and Verve Therapeutics. As cash-consuming start-ups, the last three companies would benefit mightily from a successful cardio product.

LDL isn't the only fatty vandal in circulation. High levels of triglycerides and something called lipoprotein(a) are also associated with cardiovascular disease, and many of the same companies are targeting them.

"My hope is that if we hit all these targets then we can stop this disease before it causes all the trouble that requires stenting and bypasses," says Nissen.

Regeneron and Sanofi took the first big step beyond statins in 2015 with Praluent, a biweekly injection of antibodies that sop up the enzyme called PCSK9, which strongly affects blood levels of LDL. Amgen followed just weeks later, with the PCSK9 antibody Repatha. In 2021, Novartis launched Leqvio, which blocks the genetic instructions for making PCSK9 and can be injected just twice a year.

The PCSK9 drugs are lifesavers for families with genetically high LDL levels. But they require regular injections and can cost $30,000 a year for the rest of a patient's life.

The cost and hassle has led to sales that are good, but not as great as expected. Regeneron and Sanofi's Praluent sales were $585 million in 2024. For the same year, Amgen's Repatha pulled in $2.2 billion, up 15% year over year. Last year's sales of Leqvio for Novartis were $260 million, up 80%.

To address these drugs' cost and convenience issues, Merck is testing a pill treatment that it code-named MK-0616. The company is betting the drug will help replace some of the revenue it will lose after patents expire on its huge-selling cancer drug, Keytruda.

On April 7, Merck finished the once-daily pill's Phase 3 trial in about 300 people with inherited high-LDL cholesterol. In August, it expects to complete the broader study among some 2,800 patients with serious cardiovascular problems. Both studies measure reductions in LDL -- which regulators accept as good-enough proof that cardiovascular problems will also be prevented. Analysts hope the company will report results at the November 2025 meeting of the American Heart Association.

Merck aims for a bigger market than just high-LDL families, so a third Phase 3 for MK-0616 will use the gold-standard test of whether those on the pill actually have fewer heart attacks, strokes, or other cardiovascular calamities. That study, which is enrolling over 14,000 people, won't finish until 2029.

While Merck's pill could find its way to a larger population than today's PCSK9 injections, it still has some convenience issues. Patients have to take MK-0616 on an empty stomach and shouldn't be on certain other drugs.

That's why AstraZeneca is pushing ahead with its own PCSK9 pill, dubbed AZD0780, which requires no fasting. In March, the company said the pill achieved 50% reductions in LDL in a Phase 2 study on patients whose statin treatment wasn't doing the job. AstraZeneca has said the annual market for a PCSK9 pill could exceed $5 billion.

The size of the cardio market and the current PCSK9 drugs' issues have also caught the eye of the gene-editing industry. These companies' Crispr technology can zero in on a particular, troublesome stretch in the 3 billion links of our DNA, and then permanently inactivate it, or make a repair.

So far, genetic-medicine firms have struggled to convince investors that there's real money to be made from the Nobel Prize-winning technology. Companies like Crispr Therapeutics initially focused on dire, but somewhat uncommon diseases like sickle cell disorder. Revenue has been slow to come.

Verve Therapeutics, however, focused on cardiovascular disease from the start. It licensed a second-generation Crispr technology called base-editing, from the company Beam Therapeutics. Base-editing gently changes a single letter at a time in DNA genetic code. By permanently disrupting the code for PCSK9, Verve's one-time treatment could lower LDL for life.

The stock perked up in April when the company reported initial Phase 1 data that showed no serious side effects among 14 patients -- with LDL reductions of around 60% even two years after the one-time treatment. That reduction is comparable to today's PCSK9 injectables. Eli Lilly has an option to partner on Verve's cardio programs, and could opt in this year.

"Genetic therapy is frankly a game changer," said Nissen. Instead of a lifetime of statins and PCSK9 treatments for a young person with inherited high cholesterol, a one-and-done DNA edit could knock out the troublesome gene altogether. To make sure that long-term side effects don't turn up, the first gene-editing patients will be followed for 15 years.

Other genetic-medicine approaches to PCSK9 are exploring nonpermanent, but long-lasting fixes. The privately held Scribe Therapeutics has reported intriguing results in monkeys from "epigenetic" edits of the molecules that turn genes on and off.

And PCSK9 isn't the only strong lever on cholesterol levels. Another that our body uses to control blood levels of cholesterol is a protein called CETP. Early in May, NewAmsterdam Pharma reported on a couple of Phase 3 trials of obicetrapib, its antibody that blocks CETP. By itself, the antibody cut LDL levels by a third. Combined with a statin, LDL levels fell by half.

Another lever on LDL is ANGPTL3, a protein controlling blood levels of LDL and harmful triglycerides. Since 2021, Regeneron has marketed Evkeeza, an antibody that inhibits ANGPTL3. Sales of the drug to patients with inherited high cholesterol were $126 million in 2024.

Lilly, Arrowhead Pharmaceuticals, and Regeneron are all testing so-called siRNA drugs, which degrade the RNA messages that tell cells to make ANGPTL3. They are injections that work for as long as a year at a time.

Verve began Phase 1 trials in November 2024 on a base-editing treatment that permanently disrupts the genetic instructions for ANGPTL3. It hopes to report some data later this year.

Crispr Therapeutics, meanwhile, is further along in trials of a one-and-done edit that blocks ANGPTL3. In April, it reported that LDL dropped by two-thirds, among the first 10 patients treated. No serious side effects surfaced in the first months after infusion.

For rare but deadly disorders, gene-editing fixes are priced above $1 million. The Crispr crowd thinks it can find a price that is attractive to the healthcare payers that cover the expensive siRNA injections now given to patients with inherited high levels of cholesterol.

"If you're talking about siRNA, that is $30,000 a year for 50 years," said Crispr Therapeutics Chief Executive Samarth Kulkarni at an April conference. "We could spend one-tenth of that and charge $150,000 for a single-shot therapy. For the payer, the economic argument is very clear."

Besides LDL cholesterol, other fatty risk factors for heart attack and stroke are triglycerides and lipo(a).

The triglyceride inhibitor Tryngolza is one of its first wholly owned products for Ionis Pharmaceuticals, whose monthly injections bind to RNA messages that tell liver cells to make the fat. Tryngolza is approved for a rare inherited triglyceride disorder, but a recent Phase 3 trial showed 60% reductions in patients with the more common problem of moderately high triglycerides.

An even deeper reduction in triglycerides was achieved by Arrowhead's siRNA drug plozasiran in a Phase 3 trial reported in January. Injected every three months, it cut triglycerides 80%.

There is no approved drug treatment for the roughly 65 million Americans whose genes leave them with high blood levels of lipoprotein(a), and an estimated two-to-three times higher risk of cardiovascular disease.

Next year, Novartis and Ionis will report the first Phase 3 trial that tests whether cutting lipo(a) levels indeed reduces heart attacks and strokes. Their monthly injectable, pelacarsen, cut lipo(a) levels nearly 80% in earlier trials.

Using the longer-acting siRNA technology, a single shot of Lilly's lepodisiran cut lipo(a) by 94% for six months, in a recently reported Phase 2 trial. Amgen and Arrowhead achieved comparably deep drops with their siRNA olpasiran. These rival siRNA teams are now running Phase 3 studies to see if cardio outcomes benefit.

Drugs for lipo(a)'s inherited risks have been a long time coming, said Nissen. So he thinks the lipo(a) outcome studies under way hold out some of the most exciting prospects in heart medicine.

Write to Bill Alpert at william.alpert@barrons.com

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May 28, 2025 14:06 ET (18:06 GMT)

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