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For those who play the high-stakes game of drug discovery, cholesterol-lowering PCSK9 inhibitors don’t seem anything like a sure bet. Patients will need to inject the drugs. They’re likely to be expensive. There are already inexpensive statins on the market to treat patients with high cholesterol. And yet these biologics, the first two of which are likely to receive approval from the Food & Drug Administration this summer, are probably the most anticipated drugs of the year.

These drug candidates block the cholesterol regulator proprotein convertase subtilisin/kex­in type 9, or PCSK9, thereby reducing levels of low-density lipoprotein cholesterol, also known as LDL or “bad” cholesterol. And they do so dramatically, slashing cholesterol counts by about 60%, even in patients who are already taking statins.

Perhaps even more encouraging, preliminary results presented at the American College of Cardiology meeting earlier this month indicate that two of these drug candidates—evolo­cumab, developed by Amgen, and alirocumab, developed jointly by Sanofi and Regeneron—could cut in half the risk of major cardiovascular events, such as heart attacks or strokes. Considering the large number of people who could benefit from such cardiovascular risk reductions, analysts say PCSK9 inhibitors could bring drugmakers billions of dollars.

A billion-dollar payday is a fine prize, to be sure, but PCSK9 inhibitors could give patients such as Robert Guesno something even bigger: a new life. Every two weeks, doctors remove all the blood from Guesno’s body. They stick two 16-gauge needles in his arm, drain the blood pint by pint, strip it of LDL cholesterol, and return the filtered blood to his body. The whole process, known as lipoprotein apheresis, takes about four hours.

Guesno endures the ordeal because seven years ago he had two heart attacks in one week. He was 36. Guesno wasn’t overweight. He exercised regularly. There was nothing to suggest that he should have two such dramatic cardiovascular events—until doctors tested his lipid levels.

LDL cholesterol is the main source of cholesterol buildup and blockage in the arteries. A healthy LDL cholesterol level tops out at 100 mg/dL. Guesno’s level was around 500 mg/dL.

Some genetic sleuthing led doctors to diagnose Guesno with familial hypercholesterolemia (FH), a genetic disorder that affects the liver’s ability to clear LDL cholesterol from the blood. Between 600,000 and 1.2 million people in the U.S. have FH, although only about 10% of FH patients are ever diagnosed. “You don’t have symptoms if you have very high cholesterol,” explains Joshua W. Knowles, a physician at the Stanford Center for Inherited Cardiovascular Disease and chief medical adviser for the FH Foundation. “There are a lot of ticking time bombs out there.”

Two of Guesno’s three children also have FH. At ages 12 and 16, they’ve both been on statins for a year. But many patients with FH can’t get their LDL cholesterol levels down to a healthy range, even with high-dose statins, Knowles says. And, of the tens of millions of people who are prescribed statins, about 10% can’t tolerate the drugs, which can cause unbearable muscle pain.

That’s what happened to Guesno. Statins made his muscles atrophy, which is why he’s had to resort to the invasive LDL apheresis regimen. His doctors recommended undergoing the treatment every week, but Guesno says the procedure is so draining that he’s opted to do it every other week instead. “Within a week after it’s done, my cholesterol is right back up to the high level that’s normal for me,” he says.

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With PCSK9 inhibitors poised for approval, Guesno and patients like him might have a much better option to keep their LDL cholesterol in check. Patients will have to inject these biologics, but the pain from the pinch will likely be salved by the fact that they’ll only have do so once or twice a month.

The discovery of PCSK9 and the development of PCSK9 inhibitors “is really a major triumph of the modern genetic revolution,” Knowles points out.

PCSK9’s story begins a dozen years ago when researchers led by Nabil G. Seidah of the Clinical Research Institute of Montreal discovered an unusual protein (Proc. Natl. Acad. Sci. USA 2003, DOI: 10.1073/pnas.0335507100). Seidah and coworkers weren’t certain what the protein was doing, but they knew it had activity in the liver, kidneys, intestines, and the developing brain. They called it NARC-1, short for neural apoptosis-regulated convertase 1.

The researchers also knew that the gene for this protein was on the short arm of chromosome 1, which prompted them to reach out to Catherine Boileau, of Paris’s Necker Hospital. Boileau’s group had spent years searching the short arm of chromosome 1 for a gene that could be linked to a group of families with extremely high levels of LDL cholesterol.

Seidah told Boileau that he thought the gene that made NARC-1 might be what she was looking for. Later that year, their research groups published a paper suggesting that a mutation in this gene shared by the families with high cholesterol might ramp up activity of the protein. Editors at the journal renamed NARC-1 “PCSK9” to conform with standard nomenclature (Nat. Genet. 2003, DOI: 10.1038/ng1161).

Scientists have learned that PCSK9’s principal job is to control LDL receptors on the surface of liver cells. These receptors bind to cholesterol-carrying LDL particles, remove them from the bloodstream, and shuttle them to lysosomes, cellular compartments where biomolecules are broken down. The receptors get recycled back to the cell surface. The more LDL receptors available on cells, the more efficiently cholesterol is removed from the bloodstream.

To control this process, cells secrete PCSK9, which binds with LDL receptors on the cell surface. When PCSK9 binds to an LDL receptor, the receptor doesn’t get recycled back to the cell surface but is broken down in the lysosome instead. That’s how PCSK9 reduces the overall number of LDL receptors available to clear cholesterol. In the families Boileau was studying, this process was kicked into a higher gear than it is for most people.

The report caught the attention of University of Texas Southwestern Medical Center researchers Helen H. Hobbs and Jonathan C. Cohen. They reasoned that if a gain-of-function mutation, such as the one Boileau and Seidah observed, resulted in high LDL cholesterol, a loss-of-function mutation should have the opposite effect: extremely low LDL cholesterol.

Hobbs and Cohen had been involved in the Dallas Heart Study, in which researchers put together detailed physiological profiles of 3,500 Dallas residents, each of whom had given a sample of blood for testing. Searching for mutations in the PCSK9 gene, Hobbs and Cohen examined the blood samples of patients who had extreme levels of LDL cholesterol. In those with very low levels, they found that the gene was mutated in such a way that it basically didn’t make functioning PCSK9 (Nat. Genet. 2005, DOI: 10.1038/ng1509).

Shortly thereafter, Hobbs and Cohen identified a woman who had inherited bad copies of the PCSK9 gene from both parents. Her LDL cholesterol was a stunningly low 14 mg/dL (Am. J. Hum. Genet. 2006, DOI: 10.1086/507488). What’s more, she was healthy. The lack of PCSK9 appeared to have no impact on her well-being whatsoever.

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Drugmakers realized if they could somehow block or eliminate PCSK9, they’d have a powerful tool for lowering LDL cholesterol. The competition to find such a drug was on.

Although a number of companies are pursuing PCSK9 as a target, three therapies appear closest to reaching FDA approval. Alirocumab, the PCSK9 inhibitor developed jointly by Sanofi and Regeneron, has an expected approval date of July 24. Amgen’s PCSK9 inhibitor, evolocumab, has an estimated approval date just a little over a month later, on Aug. 27. Pfizer also has a PCSK9 inhibitor, bococizumab, in Phase III clinical trials.

All three of these therapies’ names have the telltale -mab ending, indicating they’re monoclonal antibodies. Antibodies are Y-shaped proteins produced by the immune system that latch onto antigens—such as foreign substances or proteins—and neutralize them. Monoclonal antibodies are produced by cloned cell lines with identical cells, so the resulting proteins are all the same.

“The challenge with PCSK9 is that it’s a secreted protein that does its work outside the cell while it’s in circulation and on the cell surface,” explains Scott M. Wasserman, Amgen’s vice president of global development. “You’re trying to block a protein-protein interaction and because of the size of the proteins and their interactions, we felt that the best way to do that was with a monoclonal antibody,” rather than with a small molecule, for example.

“It’s easier to target PCSK9 with a monoclonal antibody, which is why I think you’re seeing all the initial development programs going in that direction,” adds William J. Sasiela, vice president of program direction at Regeneron.

The other advantage of using monoclonal antibodies, Wasserman and Sasiela say, is that they’re highly specific for their targets. Therefore, there’s little risk of off-target toxicity or unwanted interactions with other drugs, which are common problems with small molecules.

“The only safety issues that you would anticipate from a monoclonal antibody are ones that are on-target,” Wasserman adds. Because people who produce inactive PCSK9 or no PCSK9 at all, such as the 14-mg/dL woman, are healthy, on-target effects don’t seem likely.

“This is a rare example where human genetics told us at the beginning of the program that interfering with the action of this protein would be absolutely safe as well as effective,” explains Morris J. Birnbaum, chief scientific officer of Pfizer’s Cardiovascular & Metabolic Disease Research Unit.

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Clinical trial results for the monoclonal antibody therapies show they’re effective and well tolerated, although FDA has raised concerns over possible adverse neurocognitive effects of PCSK9 inhibitors. As reported in the biologics license applications filed with FDA for the drug candidates, evolocu­mab and alirocumab each lowered LDL cholesterol levels in thousands of patients by around 60% compared with placebo and other cholesterol-reducing therapies. Pfizer’s bococizumab showed similar reductions in smaller Phase IIb trials.

Whether these drug candidates will translate to fewer heart attacks and strokes is still an open question. “It’s one thing to understand the mechanism—the immediate effect on LDL—but it’s another to demonstrate the value of that in a large population,” says Steve Romano, head of global medicines development at Pfizer.

To that end, ongoing trials are under way for all three monoclonal antibodies to test their ultimate impact on cardiovascular health. For each drug candidate, the respective pharmaceutical companies are following tens of thousands of patients to see if the antibodies’ LDL-lowering powers do in fact lead to better heart health.

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Results from studies of cardiovascular health were presented this month at the American College of Cardiology meeting in San Diego and also published in the (2015, DOI: 10.1056/nejmoa1500858 and 10.1056/nejmoa1501031). Patients taking evolocumab and alirocumab were half as likely to have a cardiovascular event compared with those taking nothing or taking other cholesterol-reducing therapies alone. The evolocumab study followed patients for a year, and the alirocumab study followed patients for 18 months. Although physicians were excited about the results, they cautioned that longer-term studies, the results of which are expected in 2018, are needed before drawing any definitive conclusions.


Many have described the competition to get a PCSK9 inhibitor on the market as a race. When Amgen filed its biologics license application for evolocumab last August, it looked like it would be the first to receive approval. But last summer, Sanofi and Regeneron announced that they had bought a priority review voucher from BioMarin Pharmaceutical for $67.5 million and that they planned to use it to speed up approval for alirocumab. The voucher cuts alirocumab’s review time to six months from the standard 10 months and will push the drug candidate across the approval finish line first.

In October, an obstacle popped up for Sanofi and Regeneron when Amgen filed a patent infringement lawsuit against the pharmaceutical companies for developing alirocumab. The lawsuit, however, is still in its infancy and could take years to resolve.

“The benefits of lowering LDL cholesterol are so impactful,” Regeneron’s Sasiela points out. “Given the efficacy that we’re seeing for alirocumab, being able to bring those reductions to the patients who need them is really what this race is about.”

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Amgen’s Wasserman echoes that statement. “I’m less concerned about the competition and more concerned about the patients,” he says. “What we’re trying to do is to get this potentially valuable therapy to patients as quickly as possible, and how that plays out in the marketplace will be how it plays out in the marketplace.”

Any edge in the competition could be worthwhile, says Victoria Hudson, a senior analyst at Datamonitor Healthcare. Because alirocumab and evolocumab are so similar, she points out, “it’s very difficult to find something clinically to differentiate them.”

Hudson says the combined annual sales of PCSK9 inhibitors in the U.S., Japan, and five major European markets are projected to be $11.5 billion by 2021.

“Treating a cardiovascular event, such as a heart attack or a stroke, is very expensive, so you want to try as best you can to reduce the risk of having an event,” Hudson says. The efficacy and safety data for PCSK9 inhibitors have been really impressive so far, she says, and there are potentially a lot of patients who could take these therapies.

Determining what insurance companies are willing to pay for PCSK9 inhibitors is where Hudson sees the biggest challenge. Currently, a lot of patients are taking inexpensive statins. Because making a biologic is technologically taxing and therefore much more expensive than making a small molecule, she notes, the entire investment structure for these patients is going to change.

Expensive biologics certainly aren’t new, Hudson says, “but I don’t think there’s ever been a market where there’s such high potential for their usage.” Hudson estimates that PCSK9 inhibitors could cost as much as $8,500 per patient annually. That high price tag combined with the large potential market for drugs that will be used to treat a chronic illness could add up to unprecedented costs.

Writing for Health Affairs Blog last month, officials from the pharmacy giant CVS Health noted that PCSK9 inhibitors may challenge the health care system’s ability to absorb costs in ways that have never been seen before. They estimated that the cost to treat FH patients like Robert Guesno with PCSK9 inhibitors will be about $16 billion annually. Treating statin-intolerant patients would add another $20 billion. And using PCSK9 inhibitors to treat those with a history of coronary artery disease could add a whopping $150 billion.

Even in the U.S. health care system, which costs $4 trillion per year, “a single therapy adding $100 billion to $200 billion in costs annually is extraordinary,” they write.

So, what may ultimately determine the market leader in PCSK9 therapies is how much the drugs wind up costing. “I wouldn’t be surprised if price is the distinguishing factor over which one gets prescribed over the other,” Hudson says.