Enthusiasm for PCSK9 Inhibitors Remains High but Guarded Before FDA Advisory Panels

June 05, 2015

GAITHERSBURG, MD — Over 2 days next week the US Food and Drug Administration (FDA) will hear from a panel of experts and advisors about the safety and efficacy of a new cardiovascular drug class that has the attention of everyone from physicians to payers to Wall Street.

On June 9, 2015, the FDA Endocrinologic and Metabolic Drugs Advisory Committee will debate the effectiveness of alirocumab (Praluent, Sanofi/Regeneron) and discuss its potential role in cardiovascular care. The following day, it will do the same with evolocumab (Repatha, Amgen).

The two new drugs, both of which are proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors, effectively lower LDL-cholesterol levels. The drugs differ from statins—the traditional means of lowering LDL-cholesterol levels to reduce cardiovascular risk—in their mechanism and mode of delivery. And if the drugs are approved later this summer, it's all but certain they will differ in how much they cost payers and patients themselves.

For physicians who treat patients with hypercholesterolemia and dyslipidemia, there is a sense of cautious excitement. Even with that caution, though, it's hard not to feel alirocumab and evolocumab will change the way doctors treat and manage a wide range of patients with elevated LDL-cholesterol levels.

Dr Amit Khera

"If you're a cardiologist, you must not have a pulse if you're not excited" about the potential availability of the two new agents, Dr Amit Khera (University of Texas Southwestern Medical Center, Dallas) told heartwire from Medscape.

"For those of us who take care of patients with familial hypercholesterolemia [FH], this is just an amazing option," he said. "I know this seems like a small group of patients—one in 500—but it's really not all that small. There's also the advanced coronary artery disease patient who still has high lipids. It almost seems arcane in this modern era that we're just watching patients who have recurrent events and our hands are tied. I think this offers an incredible option for those people."

Physicians Enthusiastic But Still Want Outcomes Data

Such excitement is shared by others.

"This is a really fun time to be a physician who focuses on the prevention of cardiovascular disease," Dr Jeffrey Berger (New York University Langone Medical Center, NY) told heartwire . "We are all waiting to see what happens with the FDA and, more important, waiting to see the results of the hard-outcomes trials. All the preliminary data suggest this group of compounds will change the paradigm of both how we treat and prevent cardiovascular disease."

Dr Seth Martin (Johns Hopkins University School of Medicine, Baltimore, MD) said physicians, including himself, are upbeat about the drug class for a number of different reasons.

"The excitement stems from the trial data looking so good," said Martin, referring to the significant reductions in LDL cholesterol. "The other thing, and this has been noted by others, including the OSLER investigators, is that the trial data line up with the pretrial data, including Mendelian randomization studies, the genetic studies showing that people with loss-of-function mutations in PCSK9 have lower lifetime LDL-cholesterol levels and a lower risk of events."

While physicians are enthusiastic about the promise, they did express some concerns. Berger, for one, pointed out the medical and cardiovascular community has been surprised in the past with other promising drugs that failed to reduce MI, stroke, and cardiovascular death despite significant improvements in surrogate end points. Various cholesteryl ester transfer protein (CETP) inhibitors, drugs that significantly raised HDL-cholesterol levels, have not borne out in large outcomes trials, for example. Niacin, another HDL-raising agent, failed in the same setting.

Dr Jeffrey Berger

"When we did the large outcome-based trials, the results were not consistent and in certain cases even caused more harm," said Berger. "The preliminary data with the PCSK9 inhibitors suggest that is not going to be the case, and there is a lot of optimism—I am personally optimistic—but I think a sense of cautious optimism is warranted."

Dr Stephen Kopecky (Mayo Clinic, Rochester, MN), the immediate past president of the American Society of Preventive Cardiology, said the drugs "look great, with all of them lowering LDL cholesterol a lot more than we've been able to do in the past." The efficacy of the drug class is particularly promising for FH patients or those who can't take statins for one reason or another, he added. Like Berger, Kopecky said physicians are guarded—the caution derived from "having been burned before" with other once-promising agents.

Excitement in Advance on FDA Advisory Committee

The buzz with the monoclonal antibodies, which target and inactivate hepatic PCSK9, has been building since the phase 2 and 3 studies showed the agents are very effective in lowering LDL-cholesterol levels in a wide range of patients, most notably difficult-to-treat FH patients. PCSK9 is a key player in cholesterol metabolism and is specifically involved in the degradation of LDL receptors in the liver. By blocking PCSK9, the monoclonal antibodies make LDL receptors in the liver more available and increase cholesterol-rich LDL clearance from the bloodstream, thereby lowering LDL-cholesterol levels.

In the past couple of years, there have been a growing number of reports showing that alirocumab and evolocumab, as well as bococizumab (Pfizer), which is further behind in development relative to the other agents, reduce LDL-cholesterol levels in a veritable smorgasbord of patients. These patients include those with homozygous and heterozygous FH, as well as those intolerant to statins, those with mixed dyslipidemia, and those patients treated with a variety of background lipid therapies, including high-dose statins and ezetimibe (Zetia, Merck/Schering Plough).

Only 2 weeks ago, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended approving evolocumab, taking that agent one step closer toward being available in Europe. For the FDA, the proposed indications for the two drugs before the advisory panel are similar.

Alirocumab is being proposed as an adjunct to diet for adults with primary hypercholesterolemia or mixed dyslipidemia, including those with type 2 diabetes, to reduce LDL cholesterol, total cholesterol, non-HDL cholesterol, apolipoprotein B (apoB), triglycerides, and lipoprotein A and to increase HDL cholesterol and apolipoprotein A1 (apoA1). Sanofi is seeking an indication for alirocumab for use with a statin or as monotherapy in patients with statin intolerance.

Amgen, the maker of evolocumab, is also seeking a similar indication and is looking for approval in combination with a statin, a statin plus other lipid-lowering agents, such as ezetimibe, or in statin-intolerant patients.

After the conclusion of next week's FDA advisory panel, the agency will make a decision about Amgen's application for evolocumab by August 27, 2015. A decision on alirocumab is expected earlier, in this case by July 24, 2015, as Sanofi/Regeneron purchased a priority-review voucher for $67.5 million from BioMarin. The priority-review voucher, originally intended to provide incentive for companies to develop drugs for neglected/rare diseases, shortens the FDA review process from the standard 10 months to 6.

Treating to Reduce Events, Not LDL Cholesterol

An FDA approval of alirocumab and evolocumab can feel like a done deal. Wall Street analysts have already predicted sales of more than $2 billion annually by 2020, in fact. Other drugs, including statins and ezetimibe, were approved on the basis of their ability to safely lower LDL-cholesterol levels. So far, the PCSK9-inhibitor trial data have not suggested any detrimental adverse effects that might doom the drug class (there were early questions raised about possible neurocognitive side effects, but so far nothing has emerged).

Still, approval is not a foregone conclusion. The FDA caught a lot of grief over ezetimibe, given that it took more than 9 years between the FDA approval and the conclusion of a large clinical-outcomes trial showing the drug also reduced cardiovascular events. In that interim, ezetimibe was dogged by cancer concerns and data from imaging studies showing a null effect on surrogate markers of subclinical atherosclerosis such as carotid intima-media thickness.

I do not tell a patient to take a drug because it lowers their cholesterol. I tell them to take a drug because it lowers their risk of having a heart attack, a stroke, or dying.

When IMPROVE-IT was finally presented—the manuscript was only just published this week—researchers showed the addition of ezetimibe to simvastatin in acute coronary syndrome patients modestly reduced cardiovascular outcomes compared with patients who received simvastatin alone.

"At the end of the day, I personally do not tell a patient to take a drug because it lowers their cholesterol," said Berger. "I tell them to take a drug because it lowers their risk of having a heart attack, a stroke, or their risk of dying. So while I'm extremely impressed with the LDL lowering [with the PCSK9 inhibitors], when I treat a patient I want to tell them I know this drug will lower your risk of having an event. I do not know that today."

To heartwire , Berger noted that with the now-available IMPROVE-IT data, there is evidence that adding ezetimibe on top of statin therapy can reduce cardiovascular events in ACS patients.

"In certain patients, I would prefer to use a drug that lowers cardiovascular events," said Berger. "I like to practice evidence-based medicine. In the modern era, we have two drugs that target lipids known to lower cardiovascular events. What is encouraging with PCSK9 inhibitors, though, is that they affect other types of lipoproteins. I see many patients in my practice with a dyslipidemia that might not be corrected by statins. I'm excited about how this class might work in those types of patients."

Dr Scott Wright (Mayo Clinic, Rochester, MN) said he too will start first with proven therapies. For at-risk patients, he will start with a statin. If the patient still does not have their cholesterol level controlled, he will add ezetimibe to the maximally tolerated statin dose. And if the patient still has abnormally high LDL-cholesterol levels, then a PCSK9 inhibitor would be the next step.

Wright noted the debate over whether to prescribe a drug in the absence of clinical-outcomes data is not a new debate. In the 1990s, there was excellent evidence that pravastatin and simvastatin reduced cardiovascular events, but atorvastatin was also on the market without such supportive evidence.

Dr Scott Wright

"The question was whether it was a class effect or an individual drug effect, but we all sort of learned that it really was about LDL lowering," said Wright. Given the lessons from the statin era, as well as with ezetimibe, Wright said he is "reasonably confident" that lowering LDL cholesterol with a PCSK9 inhibitor will confer a clinical benefit to patients.

Unlike ezetimibe, physicians won't have to wait a decade to see the results of the large outcome-based trials with alirocumab and evolocumab.

The Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) study is 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. Full results are expected in 2017. With alirocumab, the ODYSSEY-Outcomes study is similar in design and duration and will include 18,000 ACS patients randomized to PCSK9 inhibition or placebo on top of optimal medical therapy. Full results of the ODYSSEY trial will be available in early 2018.

What Will the FDA Decide?

Given that hard clinical-outcomes data is still 2 years away, one option for the FDA advisory committee would be to recommend a limited approval of the PCSK9 inhibitors. Such a limited approval might restrict use to FH patients or to FH patients and statin-intolerant patients only. Approval for use on top of statin therapy for patients with still-elevated cholesterol levels could wait until after the results of FOURIER and ODYSSEY are known.

Dr Seth Martin

To heartwire , Martin said the preliminary data suggest the PCSK9 inhibitors do confer a benefit on hard clinical outcomes. In a paper published in the Annals of Internal Medicine, researchers combined phase 2 and 3 studies with 10,159 patients randomized to treatment with or without a PCSK9 inhibitor and showed a statistically significant 55% reduction in mortality with the drugs[1]. There was also a statistically significant 51% reduction in MI.

"We have a preliminary look at the outcomes data, and while we don't definitively know, at least the initial look in the Annals paper, as well as the longer-term data from OSLER and ODYSSEY, suggest the events are lining up [with the reduction in LDL cholesterol]," said Martin. "It's generally expected the definitive outcomes studies will be positive."

Martin said that while the evidence supporting statins for the reduction of hard clinical outcomes is strong and these drugs will remain the cornerstone of cardiovascular risk reduction in patients with elevated cholesterol, he treats patients with severe dyslipidemia and others at high cardiovascular risk. As such, there is a need for another option.

"These patients really need something else," he said. "In some cases, I do think we have patients where we'd discuss a PCSK9 inhibitor. We're not going to automatically start there, but it might make sense to use for some patients in our clinic, even before those long-term outcomes studies are completed."

Khera said if the drugs are approved, he'd be willing to use them in selected patients, most notably FH patients or secondary-prevention patients who are unable to achieve a sufficiently low enough LDL-cholesterol level despite attempts at treatment with a statin and ezetimibe. "In those patients, they're risk is so high that an acceptable risk with this therapy is worth it, in my opinion," said Khera. "In the primary-prevention patient at lower risk, it might not be worth using them."

How Real Is Statin Intolerance?

Studies to date investigating the safety and efficacy of the PCSK9 inhibitors have highlighted a segment of patients that can't, for one reason or another, take a statin. While the statin-intolerant patient might represent a market for use if approved by the FDA, statin intolerance is a subjective measure not easily defined.

In fact, the true prevalence of statin intolerance varies across clinical trials and observational studies. As one expert recently pointed out, in a study of "statin-intolerant" patients in the ODYSSEY ALTERNATIVE trial with alirocumab, a trial that used low-dose atorvastatin arm as a comparator, more than 75% of patients were able to tolerate atorvastatin 20 mg, suggesting they weren't exactly intolerant to the drugs.

To heartwire , Khera estimates 10% to 15% of patients can't take the high-intensity statin therapy because of side effects, typically muscle-related symptoms. He added that while nearly every physician who treats patients with high-dose statin therapy encounters a patient who develops myalgia while on treatment, identifying true statin-related muscle pain is challenging.

"Statin intolerance is a real problem," said Khera. "One area of concern would be if we're too quick to label aches and pains, which everybody gets, as myalgia and then say they can't take a statin. If you treat a lot of these patients, you have to have a lot of patience, no pun intended."

Martin agreed, noting there is "always a little bit of concern when the statin gets blamed" by the patient for muscle pain.

In March 2015, the European Atherosclerosis Society published a consensus statement for dealing with patients who develop muscle pain while being treated with statins. The European experts said that before abandoning a statin because of muscle symptoms, physicians need to be absolutely certain the muscle-related events are attributable to the drug.

I don't think anybody wants to see us start prescribing these quite-expensive drugs early on when lifestyle changes and generic statins, with a proven track record, can do just as much.

In recent years, studies from clinical centers have shown the importance of such patience, with researchers from the Cleveland Clinic reporting that more than 70% of patients who stopped their statin because of side effects could be successfully restarted with a different statin. A Boston-based study showed that 92% of patients who stopped their statin were successfully rechallenged with statin therapy and were still taking the drug 12 months later.

To heartwire , Kopecky, who runs a statin-intolerance clinic at the Mayo Clinic, said intolerance isn't truly appreciated because the early clinical trials testing statins screened out these patients during the roll-in period. "Then they came out with the studies and said the intolerance rate is only 1% or 2%," he said. "What we've done is repeat that to patients who come see us with these aches and pains and we tell them it's not real."

Dr Stephen Kopecky

"There are patients who are truly statin intolerant, and I think it's our goal in the medical community to address this very important issue," added Berger. "Price and cost-effectiveness of the PCSK9 inhibitors will have to play an important role. Statins are not going to be thrown out the window. We have many statins that are generic and have been shown to lower cardiovascular risk. I think we need to do a better job to figure out who is and who isn't statin intolerant."

Right now, Amgen and Sanofi/Regeneron have not said how much the drugs will cost, but they won't be cheap. Financial analysts speculate that depending on the dose—evolocumab is expected to be available as a 140-mg biweekly injection and a monthly 420-mg injection while alirocumab will be available in biweekly injections of 75 mg and 150 mg—the costs could range from $5000 to $12,000 per year.

Berger told heartwire that getting patients to take their medication, particularly pills, is difficult, but physicians need to do a better job. Kopecky said the cost alone of the PCSK9 inhibitors might spur more patients to stick with the statins.

"It's one thing when that pill costs 25 cents, but when those 'pills' cost maybe a $1000 per month, that's a huge difference," said Kopecky. "We also really need to impress on patients the importance of lifestyle change—physical activity, eating right, reducing stress, and taking care of other risk factors—because that's what's going to help them the most. I don't think anybody wants to see us start prescribing these quite-expensive drugs early on when lifestyle changes and generic statins, with a proven track record, can do just as much."

Martin, Khera, and Berger have no relevant financial relationships. Wright reports consulting for Pfizer, the Medicines Company, Eli Lilly, Boehringer Ingelheim and AstraZeneca. Kopecky reports consulting for Applied Clinical Intelligence, Esperion Therapeutics, Merck, Fusion Conferences, and Prime Therapeutics; honoraria from the Atherosclerosis Advisory Board, Merck; and research grants from Genzyme, Amgen, and Regeneron. He is the immediate past president of American Society for Preventive Cardiology, a member of Mayo Clinic Support Services, and a steering committee member of the Familial Hypercholesterolemia Foundation.


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