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Drug Discovery

The many ways to inhibit PCSK9

Companies are exploring multiple drug types to target the heart disease–linked protein

by Alla Katsnelson, special to C&EN
January 30, 2022 | A version of this story appeared in Volume 100, Issue 4

Two people at work in a gene therapy lab.
Credit: Verve Therapeutics
Verve Therapeutics hopes its gene therapy inhibiting the PCSK9 gene will be a one-and-done treatment for high cholesterol.

In 2015, when the first cholesterol-lowering drugs targeting a protein called PCSK9 were about to hit the market, anticipation in the cardiovascular community ran high. Elevated levels of low-density lipoprotein cholesterol, known as LDL, cause heart disease, which is the leading cause of death worldwide, responsible for one in three deaths each year. Low-cost LDL-lowering statins have not stemmed this tide, and the need for new therapeutics is huge.

Those first PCSK9 inhibitors, however—the monoclonal antibodies Repatha from Amgen and Praluent from Sanofi and Regeneron Pharmaceuticals—turned out to be a bit of a bust, in part because of their cost.

But boom times have returned to PCSK9-oriented drug discovery. Therapies based on almost every possible modality are at various stages of development by multiple companies.

On Dec. 22, the US Food and Drug Administration approved Novartis’s Leqvio, a first-in-class small interfering RNA therapy, after unexpectedly rejecting it in 2020. The pipeline also includes an antisense compound as well as a gene editing–based therapy that promises to confer cholesterol control in a single dose and that is set to begin human trials this year. And oral inhibitors—widely considered to be the holy grail in therapeutics for common diseases—are wending their way through preclinical testing and human trials.

This proliferation of possibilities is turning heads. “PCSK9 is going to be, I think, the poster child for what modern drug discovery looks like,” says Robert Garbaccio, head of discovery chemistry at Merck & Co., which has an oral peptide-based PCSK9 inhibitor in clinical trials. “Every modality under the sun is going to be applied to PCSK9.”

PCSK9 is going to be, I think, the poster child for what modern drug discovery looks like.
Robert Garbaccio, head of discovery chemistry, Merck & Co.

Drug discovery scientists have been pursuing PCSK9 inhibition for about 15 years. In 2003, researchers found that a mutation in the gene PCSK9 upregulates expression of the protein and ramps up LDL levels (Nat. Genet. 2003, DOI: 10.1038/ng1161), causing a condition called familial hypercholesterolemia (FH), which affects about 1 in 250 people.

Shortly thereafter, a different team reported that people with naturally occurring mutations that dampen PCSK9 expression have extremely low levels of LDL—and a correspondingly low incidence of heart disease—and no negative effects.

Several features make PCSK9 an especially attractive target. On top of the clear connection between PCSK9 and cholesterol, the protein is primarily expressed in the liver, where drugs tend to end up. “It just happens to be a highly validated target in the right tissue from a delivery standpoint,” Garbaccio says. “It opens up the door for really great innovation across the industry.”

Molecular diversity
The first PCSK9 inhibitors that the US Food and Drug Administration approved were monoclonal antibodies, but companies are developing many other modalities.
A table of companies developing therapies that lower PCSK9.
Source: Informa Pharma Intelligence. Note: List does not include all preclinical compounds in Informa's database or compounds in development outside the US.

Normally, the PCSK9 protein regulates the degradation of LDL receptors on cell surfaces. Inhibiting the protein leaves more receptors available to clear LDL from the blood, and doing so has no obvious negative consequences.

“Some genes are truly spare parts,” says Sekar Kathiresan, a cardiologist and CEO of Verve Therapeutics, which is developing a gene editing–based therapy targeting the gene for PCSK9. That uselessness may be because our environment today is so different from the one we evolved in, he says. For most of human history, the main selective pressure on the gene may have been lack of nutrition, whereas today it is excess nutrition. “In the current environment, this gene is just a bad actor.”

The antibody therapies from Amgen and Sanofi and Regeneron—which were approved for people with FH and other genetically caused cases of elevated cholesterol, as well as those with atherosclerotic cardiovascular disease—pack a great therapeutic punch, lowering cholesterol levels by about 60%. And without a doubt, experts say, they provided the biological proof of concept for the target.

Yet looking back, it’s no surprise that their popularity has been disappointing. Between their original outsize cost (about $14,000 per year before rebates) and the vast treatable population, insurance companies feared footing the bill for the drugs, so they required clinicians to acquire stringent prior authorizations to prescribe them, says Peter Chang, a principal analyst at Informa Pharma Intelligence, a data and market information firm. To boot, cardiologists weren’t always comfortable prescribing injectable drugs, and patients may have been put off by the need to inject themselves with the medicine every 2 weeks, Chang says.

The structure of a compound developed by Merck & Co. to inhibit PCSK9.
Merck & Co. has developed peptide molecules that inhibit the PCSK9 protein. One is this molecule, dubbed compound 44. The company has not said whether compound 44 is the same as its lead peptide-based PCSK9 inhibitor, MK-0616.

“The approval of PCSK9 antibodies in 2015 was a major revolution for FH patients,” says Joshua W. Knowles, a cardiologist at Stanford University and chief research advisor for the Family Heart Foundation, a group that advocates for people with hypercholesterolemia. But even among people with FH who have had a heart attack or stroke and are thus at extremely high risk of another cardiovascular event, “a pitiful proportion”—less than 5%—are on PCSK9 antibodies, he says.

Beyond FH, the numbers are equally stark. About 22 million people in the US have atherosclerotic heart disease and should be on LDL-lowering medication, according to a study funded by Sanofi and Regeneron. Yet even among people who have already had a heart attack and are at risk of another one, fewer than half are still taking their LDL-lowering medicines a year after the event, Kathiresan says.

Novartis hopes to start turning those statistics around with Leqvio. The drug was approved in the European Union in 2020 and in the UK in 2021, but approval was delayed in the US ­because of inspection issues at a contract research organization’s facility.

Leqvio’s adoption could be relatively slow because a major safety and efficacy trial reporting cardiovascular outcomes is still in process, Chang says. And just as reimbursement issues muted uptake of the antibody therapies, pricing concerns exist with Novartis’s drug.

On the other hand, one of the drug’s key selling points is that it requires just two injections per year. “LDL lowering works best when it is consistent,” explains David Soergel, global head of cardiovascular drug development at Novartis. That’s easier to achieve with semiannual dosing than with daily pills or biweekly injections.

What’s more, Novartis’s promotion of Leqvio will spur broader physician education about PCSK9 inhibition, which may boost interest in Repatha and Praluent as well, says R. Scott Wright, a cardiologist at the Mayo Clinic who was involved in clinical trials for Leqvio.

The mechanism by which Leqvio ­operates differs from that of antibodies or small molecules, Soergel says. Rather than knocking out PCSK9 protein in the blood, Leqvio inhibits the translation of the PCSK9 gene using a double-stranded RNA molecule. The molecule also carries an N-acetylgalactosamine residue that targets it specifically to the liver. It reduces LDL cholesterol by about 52%—only slightly less than the antibodies.

Meanwhile, excitement around oral small-molecule and peptide-based PCSK9 inhibitors is especially high. “We worked for years, as did the industry, to try to find traditional small-molecule disruptors of this protein-protein interaction,” Merck’s Garbaccio says. “The access of an oral pill—we think that could make a huge difference.”

One reason development of small-molecule drugs is taking so long is that the interface between the LDL receptor and the PCSK9 protein is unusually large, making it difficult to interrupt the binding of the two molecules. Merck accomplished the feat with the help of messenger RNA display, a technique that allows directed protein evolution toward a binding target. Using the technique, the firm’s scientists obtained multiple cyclic peptides in the 1,000–2,000 molecular weight range that bind strongly to PCSK9.

Unfortunately, they showed poor permeability across the cell membrane. To get over that hurdle, the scientists turned to a relatively new family of lipid-based molecules called permeation enhancers, which help compounds pass paracellularly from the gut to the bloodstream.

What we are looking to do is ultimately solve atherosclerotic cardiovascular disease.
Sekar Kathiresan, CEO, Verve Therapeutics

Rounding it all out was a significant medicinal chemistry effort that used structure-based design to build cross-links into the molecule to stabilize it. “Conformational restraint was the real secret in getting from 500 nanomolar to 5 picomolar,” Garbaccio says, referring to the dosing concentration (J. Med. Chem. 2021, 10.1021/acs.jmedchem.1c01599).

Merck’s data so far show that its lead PCSK9 inhibitor compound, MK-0616, lowers LDL by 65%—about the same as antibodies and with a similarly clean side-effect profile. The one drawback reported to date is that a person’s absorption of the molecule is halved if they consume food within 30 min of taking the pill.

The win-big-or-go-home approach to PCSK9 inhibition is a gene-editing drug in development by Verve that would be administered just once. Kathiresan, the CEO, doesn’t mince words about his vision. “What we are looking to do is ultimately solve atherosclerotic cardiovascular disease,” he says.

Kathiresan started working on a gene therapy inhibiting the PCSK9 gene back in 2016. Two years later he started Verve to develop the therapy. The main challenges, he says, were identifying how to deliver the therapy to the liver and which editing technique to pursue. The team considered the standard CRISPR-Cas9 approach, often described as molecular scissors, but settled on base editing, which is “more like a pencil and eraser,” he says.

Last year, the company reported that a dose of the therapy reduces LDL levels in cynomolgus monkeys by 60% for at least 8 months (Nature 2021, DOI: 10.1038/s41586-021-03534-y). At 15 months, Kathiresan says, the treatment is still working. This year, the company plans to begin testing the therapy in humans.

And Kathiresan vows that if the product reaches the finish line, he won’t make the same pricing mistakes that plagued Repatha and Praluent. “For gene editing or gene therapy, people are typically thinking millions of dollars per dose,” he says. “That’s not going to be us.”

Assuming the drug succeeds, Verve plans to roll it out in phases—first seeking approval for people with FH, then for people with established atherosclerotic cardiovascular disease, and finally for all adults in the general population at risk of atherosclerotic cardiovascular disease. Kathiresan contends that if Verve’s gene therapy proves itself within the expanding pools of people his company has defined, other options—be they small molecules or monoclonal antibodies—will simply fall away.

“We are going to be the ultimate destination here—one and done,” he says.

Others are more circumspect—not least because gene editing is still an unproven modality. “I’m not worried about the LDL lowering; it’s the gene therapy part we don’t have a lot of experience with,” says Marc Sabatine, a cardiologist at Brigham and Women’s Hospital who has conducted clinical trials of both Repatha and Leqvio.

Also, Katherine Wilemon, the Family Heart Foundation’s CEO, says that people tend to underestimate the threat of heart disease and atherosclerosis. “We all have a strong image in our minds that heart disease is affiliated with old age,” she says. “I think there’s going to have to be some work done to get the population to say, ‘I’m willing to go in and do something as dramatic as gene editing to circumvent [it].’ ”

More likely, experts say, the therapies that manage to win regulatory approval will all find their place. And of course, much will depend on the messy details of pricing and reimbursement. But the multitude of approaches for inhibiting PCSK9 demonstrate that the right target can bring out the pharmaceutical industry’s complete box of drug discovery tools.

Alla Katsnelson is a freelance writer who covers biology and biomedical research.


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