For many patients with dyslipidemia, low-density lipoprotein cholesterol (LDL-C) levels remain above current guideline recommendation even after treatment with maximally tolerated statins. In fact, estimates suggest that between 10% and 20% of this patient population cannot tolerate statins at all or at a dose high enough to achieve these goals.¹

“We know that LDL-C plays the primary role in the development and complications of atherosclerosis … and some of the complications are sudden and severe,” Norman E. Lepor, MD, clinical professor of medicine at the David Geffen School of Medicine at UCLA in Los Angeles, told Cardiology Advisor. “There are patients, especially those with familial hyperlipidemia, who have LDLs of 200, 300, or 400 [mg/dL] and don’t really have any good therapeutic options to get to goal.”

Enter the first-in-class compound known as proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors. By blocking the ability of PCSK9 to function, these compounds increase the availability of liver receptors that eliminate LDL-C from the blood.² PCSK9 inhibitors, when combined with maximally tolerated statins, have been shown in several randomized controlled trials to lower LDL-C compared with placebo plus maximally tolerated statins without increasing the frequency of serious adverse events.³

“When the drug went neck and neck with placebo, it reduced LDL-C by 60%, which is unbelievable,” said Dean J. Kereiakes, MD, medical director at The Christ Hospital Heart and Vascular Center in Cincinnati and principal investigator of the ODYSSEY COMBO I trial that evaluated the PCSK9 inhibitor alirocumab (Praluent, Sanofi/Regeneron). “It’s hard to find medicines that are that effective and well tolerated.”⁴

Although the data show great promise for PCSK9 inhibitors in a population of patients who do not have other options, concerns have been raised centering on the appropriateness of approval and the considerable costs associated with the therapies.

FDA Approvals Based on Biomarker Reduction

In July 2015, the US Food and Drug Administration (FDA) approved alirocumab, followed 1 month later by the agency’s approval of a second PCSK9 inhibitor evolocumab (Repatha, Amgen). The drugs were approved for use in addition to diet and maximally tolerated statin therapy in adult patients with heterozygous familial hypercholesterolemia or those with clinical atherosclerotic cardiovascular (CV) disease requiring additional LDL-C lowering.^2,5

In addition, a third PCSK9 inhibitor, bococizumab (Pfizer), is far along in development but is not currently FDA approved.

As the discussion of whether to approve alirocumab and evolocumab intensified, some questioned the appropriateness of approving the compounds based on LDL-C reduction, a surrogate end point, and not on a reduction in CV events. Currently, data from large, long-term randomized controlled outcomes trials—ODYSSEY Outcomes (alirocumab), FOURIER (evolocumab), and SPIRE (bococizumab)—are anticipated to provide clear answers as to the drugs’ impact on CV events and safety profiles; however, these findings are not expected until 2017 or 2018.

As a result, alirocumab and evolocumab are not currently indicated in the United States for reducing CV events.

“We know from trials involving different approaches to LDL reduction—whether by a drug such as a statin, bariatric surgery, or dietary manipulation—that lowering LDL seems to have a common response, which is called the ‘LDL theory,’” Dr Lepor said. “Personally, I do believe in the LDL theory and that compounds such as PCSK9 inhibitors, which reduce cholesterol by up to 60%, will have a significant ability to reduce CV events; but, at present, this is only a hypothesis. This theory will be put to the test when we get [the outcomes trials] results.”

In the meantime, recent data from a meta-analysis do suggest there may be a CV event benefit with PCSK9 inhibitors. In a study published in the Annals of Internal Medicine in 2015, Eliano Pio Navarese, MD, PhD, Dr Kereiakes, and colleagues performed an analysis of phase 2 and 3 randomized controlled trials (n=24) that compared PCSK9 antibodies with no anti-PCSK9 therapy in adults with hypercholesterolemia (n=10,159).

Results revealed that for those who received PCSK9 antibodies, there was a significant reduction in all-cause mortality (odds ratio [OR]=0.45; 95% confidence interval [CI], 0.23-0.86; P=.015) and myocardial infarction (OR=0.49; 95% CI, 0.26-0.93; P=.03), and a signal for a reduction in CV mortality (OR=0.50; 95% CI, 0.23-1.10; P=.084), without increasing the risk for serious adverse events.³

“The curves … are going in the right direction, meaning that lower is better and that reduction in LDL is associated with a reduction in adverse CV events,” Dr Kereiakes said in an interview.

A Costly Proposition

With the rollout of these new drugs, the issue of cost was raised. In a report published by the Institute for Clinical and Economic Review (ICER) in October 2015, the wholesale cost of alirocumab and evolocumab was estimated at more than $14,000 per patient per year.⁶

One of the reasons for this price is the complex process of manufacturing the drugs. Dr Lepor, who has witnessed this process, said it is significantly more expensive than putting compounds into a tablet form.

“For instance, now generic atorvastatin is about $10 a month. You are never going to achieve [costs] like that [with PCSK9 inhibitors],” Dr Lepor said. “There is this rather incredible process that takes place because you are raising these antibodies in animals, and then there is a purification process. It’s rather complicated and costly, and that doesn’t include the cost of clinical trials and education about appropriate use.”

Yet, according to the ICER report, for the drugs to be considered cost effective, the price must be substantially reduced. ICER stated that to achieve cost effectiveness at a threshold of $100,000 per quality-adjusted life year, a 60% to 63% reduction from the current price would be necessary.⁶

Furthermore, to avoid excessive cost burdens to the healthcare system, an additional reduction is required. According to the report, the value-based price benchmark for each PCSK9 inhibitor is $2,177 annually, representing an 85% reduction from the list price of $14,350.⁵

The Promise of PCSK9 Inhibitors

Despite the concerns over cost and lack of outcomes data, many clinicians and their patients have been won over by the life-changing potential of these new compounds.

“I have a couple dozen patients with familial hypercholesterolemia on [PCSK9 inhibitors] who I’ve been following for years. I can say that clinically they have done incredibly well,” Dr Kereiakes said. “These patients are running LDLs of well under 50 [mg/dL], and they have never done this in their entire lives.”

As a practicing interventional cardiologist, Dr Kereiakes understands firsthand the consequences of high LDL-C and said that PCSK9 inhibitors could substantially reduce the number of interventional and surgical procedures performed.

“[Atherosclerosis] is systemic. If you put a 15-mm long stent into somebody, you haven’t treated the whole arterial system, only a focal blockage,” he said. “Miles and miles of arteries are diseased or developing plaque. What you need is to buy the time for lipid-lowering medicines to work. If you go low enough, long enough with LDL-C, you get that kind of benefit.”

The Role of Statins

As clinicians await the outcomes data, which will likely shed light on the lingering questions with PCSK9 inhibitors, Dr Lepor said that regardless of the findings, statins are poised to remain the primary therapy for dyslipidemia, at least for the time being.

“With probably 50% to 60% of this population, high-dose statins will allow us to achieve goal in terms of lipid modification. But at present levels, about 40% of patients need more,” Dr Lepor said. “With that being said, we may find from the results of the outcomes trials that our goal therapy may have to be modified from current conventional thinking. So if we are going to aim for goals much lower, then we are going to need stronger medicines—such as the PCSK9 inhibitors—to achieve those goals.”

Disclosures: Dr Kereiakes is a consultant for Amgen and Sanofi/Regeneron and has received research grants from Sanofi, Amgen, and Pfizer. Dr Lepor serves on the advisory board for Sanofi/Regeneron and is on the speakers’ bureau for Sanofi/Regeneron and Amgen.

References

Lepor NE, Contrearas L, Desai C, et al. The potential role of anti-PCSK9 monoclonal antibodies in the management of hypercholesterolemia. Rev Cardiovasc Med. 2014;15:290-309.
FDA approves Praluent to treat certain patients with high cholesterol. US Food and Drug Administration website. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm455883.htm. Updated July 24, 2015. Accessed November 6, 2015.
Navarese EP, Kolodziejczak M, Schulze V, et al. Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia. Ann Intern Med. 2015;163:40-51. Doi: 10.7326/M14-2957.
Kereiakes DJ, Robinson JG, Cannon CP, et al. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: The ODYSSEY COMBO I study. Am Heart J. 2015;169:906-915.
FDA approves Repatha to treat certain patients with high cholesterol. US Food and Drug Administration website. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm460082.htm. Updated August 28, 2015. Accessed November 6, 2015.
Institute for Clinical and Economic Review. PCSK9 inhibitors for treatment of high cholesterol: effectiveness, value, and value-based price benchmarks draft report. Revised: Oct. 8, 2015. http://cepac.icer-review.org/wp-content/uploads/2011/04/PCSK9_REVISED_Draft_Report_1008152.pdf. Accessed November 6, 2015.

PCSK9 Inhibitors: Breakthrough in LDL-C Reduction, But Comes at a Cost