PCSK9 Inhibitors: Good Early Responses With Pricey Drugs, but Doctors Still Waiting on Real Data
Seductive early trial results showed massive reductions in LDL cholesterol among patients who took PCSK9 inhibitors—the new injectable cholesterol-lowering medications—including those already taking high-intensity statin therapy. Now that they are on the market, physicians are coming to terms with how to best use the costly drugs in selective patients.
Late summer 2015, the US Food and Drug Administration approved alirocumab (Praluent; Sanofi/Regeneron), the first proprotein convertase subtilisin kexin 9 (PCSK9) inhibitor, for the US market. A second PCSK9 inhibitor, evolocumab (Repatha; Amgen), gained approval shortly thereafter.
The indications for the agents are similar, with alirocumab approved for patients who fail to achieve sufficient LDL cholesterol lowering through diet and maximally-tolerated statin therapy, including patients with heterozygous or homozygous familial hypercholesterolemia (FH). The FDA approved evolocumab for use in addition to diet and maximally tolerated statin therapy in adults with heterozygous and homozygous FH or clinical evidence of atherosclerotic cardiovascular disease who require further LDL-cholesterol lowering.
Alirocumab and evolocumab, which are both monoclonal antibodies delivered via subcutaneous injection, are also available in Europe. The European Commission granted marketing authorization for both drugs in the second half of 2015.
Big excitement preceded and followed the FDA approval. But in the days and weeks that followed that milestone, the drugs started to raise some eyebrows among physicians and patients, not to mention insurance companies, when the price tag was listed: a year-long supply of evolocumab costs $14,100 while alirocumab goes for $14,600. Prices have been reported to be cheaper in Europe, with the drug costing approximately $6,800 USD per year in the United Kingdom, for example. Every statin, bar rosuvastatin (Crestor; AstraZeneca), is available as a generic medication at a fraction of that cost.
So far, despite the sticker shock, the PCSK9 inhibitors are starting to enter clinical practice, with lipid specialists, those on the front lines in treating patients with genetic abnormalities such as FH or those who manage high-risk patients with cardiovascular disease, saying they are having good success with the drugs.
“We’re using it very selectively, such as in people with familial hypercholesterolemia, or patients with high-risk coronary artery disease,” Seth Martin, MD, of Johns Hopkins Hospital (Baltimore, MD), told TCTMD. “We see a lot of patients with various degrees of intolerance to statin therapy, and in those patients we are talking to them about PCSK9 inhibitors.”
To give an example of the type of patient who might be a good candidate for alirocumab or evolocumab, Martin highlighted a man who had been followed in their lipid clinic for multiple decades. The patient, who had heterozygous FH, had known coronary artery disease and an extensive family history, with 2 brothers dying from cardiovascular causes in their 20s. “He was a highly motivated patient, doing everything he could to lower LDL cholesterol levels, including wearing a Fitbit, getting lots of exercise, trying to eat the right foods, and was taking 4 lipid-lowering medications,” said Martin. “He still had an LDL cholesterol level of 150 mg/dL.”
Aware that the PCSK9 inhibitors were now available—the patient had been following their progress through the trials and approval process—Martin discussed the risks and benefits, including the lack of long-term outcomes data, and put the patient on alirocumab. His LDL cholesterol level dropped from 150 mg/dL to 24 mg/dL. Martin points out they used the Friedewald equation to measure LDL cholesterol, which is known to underestimate LDL levels, especially in patients with elevated triglycerides. “His LDL cholesterol was probably closer to 50 [mg/dL],” said Martin. “He’s had a very nice response to alirocumab.”
FH Patients Waiting on PCSK9 Inhibitors for Years
Characterized by high LDL cholesterol levels (≥ 190 mg/dL), heterozygous FH is believed to be more common than previous estimates. In the past, the accepted wisdom was that approximately 1 in 500 individuals had the genetic mutation—FH is primarily caused by mutations in LDLR, the LDL receptor gene, as well as by mutations in the APOB or PCSK9 genes—that lead to significantly elevated LDL cholesterol levels and a premature death from coronary heart disease. Now, however, heterozygous FH is believed to occur in closer to one in every 200 individuals. In 2015, Sekar Kathiresan, MD, of Massachusetts General Hospital (Boston, MA), and colleagues published a genetic study in Nature showing that one in every 217 individuals had the pathologic LDL receptor mutation. 
Homozygous FH, in which individuals have mutations in both alleles of the gene encoding the LDL receptor, is extremely rare, occurring in approximately one in 160,000 to 1,000,000 individuals. Patients with homozygous FH have LDL cholesterol levels exceeding 500 mg/dL, multiple xanthomas, and experience rapid onset of coronary heart disease, often in their teens and early 20s.
“Many FH patients have been waiting for these medications for years,” Joshua Knowles, MD, of the Stanford University Medical Center in California, told TCTMD. “These folks have mutations that cause them to have extremely high cholesterol levels from birth. That high cholesterol poisons the blood vessels and leads to a 10- to 20-fold lifetime increased risk of heart attack. One remarkable statistic is that if you’re a man with [heterozygous] FH and you don’t get treated, there’s a 50% chance you’ll have a heart attack by age 50. If you’re a woman, there’s a 30% chance by age 60.”
For interventional cardiologists who treat patients, there is a 1 in 5 chance that the young MI patient in the cath lab (younger than 45 years old) has FH, said Knowles. If the MI patient is younger than 60 years old, there’s a 3% to 5% chance the event was caused by FH. The average age of diagnosis tends to occur late in life, he added, noting that a “sizeable minority” of heterozygous FH patients have already had an event by the time they’re identified.
Stanley Hazen, MD, of the Cleveland Clinic in Ohio, said interventional cardiologists are likely familiar with patients who might be good candidates for PCSK9 inhibition, and more than likely have seen them in their clinical practice. These are patients currently on maximum statin therapy, as well as other LDL-lowering medications, yet the disease progresses and they are having recurrent events.
“All interventional cardiologists know this type of patient, the patient who receives stent after stent,” Hazen told TCTMD. “What we try to do is lower their LDL cholesterol and pacify what is going on in the artery wall. Oftentimes we see elevations in lipoprotein(a) in these patients, too. I think these are the types of patients who are going to do very well on a PCSK9 inhibitor, because not only do the drugs lower LDL cholesterol but they also lower Lp(a). I think this is the patient that often has recurrent restenosis going on. I look at these issues as grease on the fire—if you lower LDL cholesterol and Lp(a), you take the grease off the fire.”
Knowles is on the scientific advisory board and board of directors of the FH Foundation, a patient-led, nonprofit advocacy group with funding from several drug companies, including the makers of PCSK9 inhibitors. He estimates that approximately 20% of FH patients are able to achieve optimal LDL cholesterol levels with existing therapies, such as statins, ezetimibe (Zetia; Sanofi-Aventis), bile-acid binding resins, and niacin. A national registry, known as CASCADE-FH, tracks the treatment and care of FH patients and includes roughly 20 lipid clinics in the United States. Based on data from CASCADE, Knowles said the average LDL cholesterol level remains too high in FH patients.
“The average LDL cholesterol achieved [pre-PCSK9 inhibitor] was way higher than it should have been, higher than 130 mg/dL, despite the majority of them being on more than 1 lipid-lowering medication,” said Knowles. “Those data have been consistently replicated in other places, such as the Netherlands and England.”
To TCTMD, Kathiresan said it remains an open question about just how low to go in terms of LDL cholesterol reduction with these FH patients.
“I think the lower the better,” he said. “Many of them can get down to 130, 140, or 150 mg/dL [with statins and ezetimibe], but some of them can’t. These patients are high risk and they definitely need to be treated. I think this is a pretty good patient population to go after. They present with high LDL cholesterol, they have family history of heart disease, and you give them a statin and ezetimibe but their LDL cholesterol is still 150 mg/dL, for example. That’s a patient in whom we’d want to strongly consider these medicines.”
So What Exactly Is ‘High’ Cholesterol After Statin Therapy?
In addition to the FH patient, said Hazen, there are patients with cardiovascular disease who are unable to get their LDL cholesterol levels down low enough, such as those who missed thresholds established by previous clinical guidelines (less than 100 mg/dL in high-risk patients or less than 70 mg/dL in very high-risk patients, for example). In these high-risk secondary-prevention patients, they are using PCSK9 inhibitors “aggressively,” he said, and these patients constitute the majority they see in practice.
Hazen stressed that PCSK9 inhibitors are not for patients simply reluctant to take a statin.
To TCTMD, Kathiresan said that at their prevention clinic, PCSK9 inhibitors are reserved for patients with “high” LDL cholesterol levels despite maximal therapy with statins and ezetimibe. In the Partners Healthcare system, the hospital network that includes the Brigham and Women’s Hospital and Massachusetts General Hospital, high cholesterol in secondary prevention is defined as 130 mg/dL or greater despite maximally tolerated treatment. “There aren’t that many patients like that, per se,” he said, noting that most patients who can take a statin are able to “get into the 100s, or even much lower than that.”
Where there is some ambiguity, continued Kathiresan, would be the patient with coronary artery disease who lands around 110 mg/dL after maximally-tolerated treatment. In the absence of evidence that alirocumab or evolocumab reduce hard clinical outcomes, such as mortality, MI, stroke, or the need for coronary revascularization, physicians might be “on the fence” about starting one of the PCSK9 inhibitors. With the heterozygous FH patient, if the LDL cholesterol level remains higher than 160 mg/dL despite treatment, then physicians can consider a PCSK9 inhibitor. “Most patients can get to below those numbers with statins plus ezetimibe,” said Kathiresan. “The challenge is with patients who can’t take statins.”
He noted that physicians, in general, are going to need to be more rigorous about labeling patients as statin intolerant before turning to a drug that costs $15,000 per year. Typically, if a patient is statin intolerant, physicians can be uncertain if the drug is the reason for the muscle aches, a commonly reported side effect from the drug class. Kathiresan said they will stop the medication, re-challenge the patient with the same drug, and then if the symptoms persist, switch to another statin. They will try 2 or 3 statins before labeling a patient statin intolerant.
Martin agreed that statin intolerance can be tough to evaluate because once a patient has made the connection the statin is the culprit, that can be difficult to break. “But we do find, more often than not, patients are open to trying multiple statin regimens,” said Martin. “Oftentimes, they might have tried rosuvastatin, atorvastatin, or simvastatin, but maybe not fluvastatin, which tends to be one of the more tolerated statins.”
Price Remains the Elephant in the Room
As of December 2015, Kathiresan said their prevention clinic had used the PCSK9 inhibitors in a “handful of patients,” while Martin said approximately 20 patients at their lipid clinic at Johns Hopkins had been prescribed either alirocumab or evolocumab. So far, neither has encountered any difficulties in terms of patient access. In October, Express Scripts, which is the largest pharmacy benefit company in the United States, placed both PCSK9 inhibitors on the national formulary. CVS, however, only went with evolocumab, making it the sole PCSK9 inhibitor on their list of covered drugs for private insurance plans.
Cost remains an issue, as expected. In fact, an evaluation from the Institute for Clinical Economic Review (ICER), an independent, nonprofit research group, concluded the drugs aren’t cost-effective for patients, providers, or payers at their current price.  To be cost-effective in FH patients, the price of treatment would need to come down to $2100 per year, according to ICER, and to approximately $2,500 per year in the secondary-prevention setting.
In October, Kevin Schulman, MD, from the Duke Clinical Research Institute (Durham, NC), and colleagues reiterated concerns about cost in a perspective in the New England Journal of Medicine, arguing that the broad indications for alirocumab and evolocumab had set cardiology “on a collision course with specialty pharmaceutical pricing models that were previously reserved for drugs that benefited relatively limited patient populations.” 
“At this point, it’s all about economics and practicalities,” said Hazen. “It’s going to be an issue that’s grappled with initially. The patients who are going to have the highest benefit are those with the highest risk—those are patients who will be the first to use the agents, but I predict over time this will just keep expanding. And that’s the biggest issue right now. Who do we treat? At least in terms of the patients we see in our prevention program, we’re prescribing them quite often.”
‘Bated Breath’ While Waiting for Major Outcome Trials
To date, alirocumab and evolocumab have only definitively shown they can significantly lower LDL cholesterol levels, and they were approved by the FDA on this basis. The big question is whether or not they can reduce the risk of clinical events.
The first of the clinical outcomes studies to make data available will likely be the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) study, a 27,500-patient trial testing evolocumab against statin therapy for the reduction of the primary composite end point of cardiovascular death, MI, hospitalization for unstable angina, stroke, or coronary revascularization. Amgen, the makers of evolocumab, say topline results are expected in the second half of 2016. The ODYSSEY-Outcomes study will include 18,000 ACS patients randomized to alirocumab or placebo on top of optimal medical therapy, with results expected in early 2018.
“We’re all waiting with bated breath for the longer-term outcomes studies,” said Knowles, noting he is optimistic given early data showing endpoints all moving in the right direction. In a study published last year in the New England Journal of Medicine, the OSLER investigators combined data from 2 open-label randomized trials and reported that treatment with evolocumab reduced the risk of cardiovascular events by 53% at 1 year when compared with patients who received standard therapy alone.
Like Knowles, Martin said he expects the data from FOURIER and ODYSSEY-Outcomes to be positive. “I will personally be blown away and shocked if the hard events trial is negative,” said Martin. “The reason is because all the other lines of evidence line up so nicely, including the genetic studies. I personally feel really good about those studies. Of course, you don’t know until you do them.”
Kathiresan also expects the results to be “strongly positive,” and says if and when that occurs, things become even trickier. In the outcome studies, he expects the achieved LDL cholesterol level to be approximately 80 mg/dL in patients treated with optimal lipid-lowering therapy plus diet and 40 mg/dL in patients who receive PCSK9 inhibition on top. If the 2 studies show a significant reduction in clinical events, “then the implication would be that everybody with coronary disease should be on these medications, which would be 10% of the US population,” said Kathiresan.
“Cost is always the elephant in the room,” said Knowles, “but the lifetime cost of an MI is also high.”
Pfizer is also currently testing a PCSK9 inhibitor, known as bococizumab, but it’s much further behind in development. The drug is currently being studied in the SPIRE-LDL study, which will assess its ability to lower LDL cholesterol levels in patients with hyperlipidemia, as well as in SPIRE-2, a large cardiovascular-event reduction study in high-risk patients.
1. Do R, Stitziel NO, Won HH, et al. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature. 2015;518:102-106.
2. Institute for Clinical and Economic Review. PCSK9 inhibitors for treatment of high cholesterol: effectiveness, value, and value-based price benchmarks draft report. Published September 8, 2015. Available here.
3. Schulman KA, Balu S, Reed SD. Specialty pharmaceuticals for hyperlipidemia—impact on insurance premiums. N Engl J Med. 2015;373:1591-1593.
4. Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1500-1509.
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- Martin reports receiving grants from the Aetna Foundation, American Heart Association, Google, and PJ Schafer Cardiovascular Research Fund. He has received honoraria from the American College of Cardiology for dyslipidemia-related educational activities and is listed as a co-inventor on a pending patent filed by Johns Hopkins University for a novel method of LDL-C estimation.
- Kathiresan reports serving on the scientific advisory board of the Regeneron Genetics Center.
- Knowles reports receiving research grants from the American Heart Association and research support from Amgen.
- Hazen reports no conflicts of interests related to the PCSK9 inhibitor field. He is a co-inventor on patents held by the Cleveland Clinic related to cardiovascular diagnostics and/or therapeutics and reports rights for royalty payments for inventions or discoveries related to cardiovascular diagnostics and/or therapeutics from the Cleveland Heart Laboratory. He reports rights for royalty payments stemming from cardiovascular diagnostics/therapeutics from Siemens, Esperion, and Frantz Biomarkers. He is a paid consultant Esperion and Procter & Gamble and has received support from AstraZeneca, Pfizer, Procter & Gamble, Roche, and Takeda.