By Debra L. Beck

Although it hasn't gotten its big break yet, a brash new star may be climbing the cholesterol charts soon, ready to take the spotlight from the reigning diva of diminished lipids. In a gaggle of studies presented at ACC.14, the PCSK9 inhibitor class of lipid-lowering drugs took an important step in establishing themselves as the latest, greatest thing in cardiovascular risk lowering.

If the last 25 years of cardiovascular preventive therapy were ruled by statins, the proprotein convertase subtilisin/kexin type 9 inhibitors (catchy!) hope to be center stage soon, perhaps nudging some of the older stars from their headliner's spot into more supporting roles. As a protein that targets low-density lipoprotein (LDL) receptors for degradation, PCSK9 reduces the liver's ability to remove LDL cholesterol. At the recent ACC Scientific Sessions, inhibition of this protein was shown in the first available phase III trial data to markedly lower LDL cholesterol, offering an opportunity for a potentially wide spectrum of patients to reduce their cardiovascular risk.

"I think these are the next most likely blockbusters in cardiovascular medicine," said Robert Giugliano, MD, in an interview with CardioSource WorldNews. Dr. Giugliano, assistant professor at Harvard Medical School, was the principal investigator for the phase II LAPLACE-TIMI 57 study. That may be, but the first question on everyone's mind is whether these drugs improve hard clinical outcomes. The answer to that question remains a few years away.

"We're very interested in following these short-term biomarker studies, but ultimately the proof in the pudding is in the long-term outcome studies to show efficacy and to show safety," said Peter Libby, MD, chief of the division of cardiovascular medicine at Harvard Medical School and Brigham and Women's Hospital, Boston, during an ACC press conference.

"While the human mutations that have loss-offunction of PCSK9 provide us with a great deal of assurance that we're going to have safety, the monoclonal antibody strategy is a new one, and we really require the outcome studies to show us long-term safety signals."

LDL in a Target-less World
Some may wonder where these novel agents fit with the new guidelines that de-emphasize treating LDL cholesterol to specific target levels.

"I don't see the guidelines as a major factor," said Dr. Giugliano. "Whereas the guidelines have in some ways moved away from LDL targets, it's really in the sense of selecting your statin dose and how far you push the statin based on LDL. But if you look at what the guidelines say about who should be on a statin, four of the five criteria mention LDL... and it's explicit in the guidelines that you still want to aim for an LDL of 40 to 70 [mm/dL] in high-risk patients, so LDL is still most definitely in the guidelines. What's a bit different is the detailed, algorithmically-driven use of drugs to treat to a specific target."

At an ACC.14 press conference, Dr. Libby, the invited discussant on the two PCSK9 late-breaking trials presented during the Scientific Sessions, noted that "guidelines are not static." Rather than serve as an impediment to PCSK9 inhibitor use, he expects the guidelines will readily adjust to the new situation, assuming the drugs are shown to be clinically effective and approved.

"The latest [cholesterol] guidelines that were issued by the ACC/AHA have made a great advance... and I expect those guidelines to evolve as we gain more trial evidence," Dr. Libby said. "So, when we get these big trials with the PCSK9s, I expect the guidelines to take into account what we've learned from those trials as well."

PSCK9 at ACC.14
Evolocumab (formerly called AMG 145; Amgen) garnered the most attention at ACC.14 with five phase III studies presented—including two Late- Breaking Clinical Trials. Also attracting eyes to the stage were a phase III trial using the Sanofi/ Regeneron candidate drug, alirocumab (formerly SAR236553/REGN727), and a phase IIb trial of the Pfizer agent, bococizumab (formerly called RN316). All are monoclonal antibodies with a subcutaneous or intravenous administration. Several other companies, including Roche, BMS, and Alnylam, have candidate PCSK9 inhibitors, but have released little information on their drugs.

Evolocumab
MENDEL, GAUSS, DESCARTES, OSLER, LAPLACE, RUTHERFORD, GLAGOV, TAUSSIG, FOURIER... seeing a pattern here? In naming its study series, Amgen paid homage to medical figures of yore. Well, a couple are less yore than the others. Remember Helen Taussig, MD, the mother of pediatric cardiology? Or Seymour Glagov, MD, the American physician who first described the process of vessel remodeling in response to atherosclerotic plaque build-up? Dr. Taussig died in 1986 and Dr. Glagov in 2008, and both are memorialized with phase III evolocumab studies.

Five phase III evolocumab studies were presented at ACC.14: MENDEL-2,¹ DESCARTES,² RUTHERFORD- 2, GAUSS-2,³ and LAPLACE-2.⁴ (DESCARTES ran 52 weeks, while the remainder were 12-week trials.) Together they enrolled more than 4,000 patients to test the agent in different hyperlipidemic populations, such as statin-intolerant patients and those with heterozygous familial hypercholesterolemia (HeFH). Evolocumab (or evo in the TABLE) was tested as monotherapy, in combination with statins, and against ezetimibe as a comparator and showed good ability to lower LDL cholesterol. The 140 mg Q2W and 420 mg monthly dosing regimens appeared to be clinically equivalent.

Importantly, the drug was well tolerated across the board, including by the statin-intolerant group (GAUSS-2), a highly-selected patient population who could not tolerate effective doses of at least two different statins due to muscle-related side effects. Myalgia was seen in 8% of the evolocumab arm in GAUSS-2 and 18% of the ezetimibe arm.

"Tolerability was unexpectedly good," said GAUSS-2 lead author Eric Stroes, MD, Academic Medical Center, Amsterdam, during a press conference. "These patients call you up every other week because they have side effects. Well, in this case, if you look at the side effects, there was no signal noise comparing evolocumab to ezetimibe."

The evolocumab phase III trial program named PROFICIO (not the name of a distinguished scientist) will ultimately evaluate the agent in 20 clinical trials, with a combined planned enrollment of about 30,000 patients. Five of these studies will provide long-term safety and efficacy data, including the currently-recruiting FOURIER trial (as in Joseph Fourier, whose name is inscribed on the Eiffel Tower, as is the name of Pierre-Simon Laplace). The FOURIER trial will involve 22,500 patients with hypercholesterolemia and a history of clinically evident cardiovascular disease and compare evolocumab in combination with moderate- or highintensity statin therapy to statin therapy alone. The primary endpoint is time to cardiovascular death, MI, hospitalization for unstable angina, stroke, or coronary revascularization, whichever occurs first.

Alirocumab
The 24-week ODYSSEY MONO trial presented at ACC.14 showed that in patients not taking statins and receiving a 75 mg Q2W dose of alirocumab, LDL cholesterol was reduced by 48.1% at 12 weeks, versus a 19.6% reduction for ezetimibe 10 mg daily. Treatment-emergent adverse event rates did not differ between groups. The study included 103 patients with hypercholesterolemia and moderate cardiovascular risk.

Perhaps emblematic of new paths being traveled, Sanofi/Regeneron calls its phase III program for alirocumab ODYSSEY and it will ultimately include more than 23,500 patients across more than 2,000 study centers, with 14 trials testing alirocumab either as monotherapy or in combination with other lipid-lowering agents.

One major component, ODYSSEY OUTCOMES, launched in December 2013 and will enroll about 18,000 patients to evaluate the effect of alirocumab on the composite occurrence of coronary heart disease (CHD) death, nonfatal MI, fatal and nonfatal ischemic stroke, and unstable angina requiring hospitalization.

In December, Sanofi and Regeneron Pharmaceuticals, Inc., announced a collaboration with the ACC to utilize the National Cardiovascular Data Registry (NCDRR)—specifically the ambulatory office-based PINNACLE Registry®—to help recruit eligible patients for the trial. Termed the Data Driven Trial Recruitment Program (D-TRP), the PINNACLE-ODYSSEY venture represents the inaugural effort at harnessing the power of clinical registries to identify and recruit patients for trials.

Bococizumab
Pfizer got a smaller piece of the ACC action with positive findings from a 24-week phase IIb doseranging study in 354 statin-treated patients with mean baseline LDL cholesterol of 109 mg/dL. Twicemonthly bococizumab (50 mg, 100 mg, or 150 mg) and once-monthly (200 mg or 300 mg) were tested, but the dose was lowered if LDL cholestrol was reduced to ≤25 mg/dL.

At week 12, the greatest LDL cholesterol reductions were seen with 150 mg for the twice-monthly regimen (–53.4 mg/dL mean change from baseline, placebo-adjusted) and 300 mg for the once-monthly regimen (–44.9 mg/dL). Even greater mean reductions in LDL cholesterol were seen prior to dose reductions made due to an LDL cholesterol ≤25 mg/dL.

The Pfizer phase III PCSK9 program, SPIRE, entered the ring a bit later than the other trials, tipping off in October 2013 and consisting of two cardiovascular outcome trials, as well as several lipid-lowering studies that will altogether include more than 22,000 patients across the spectrum of dyslipidemia. The SPIRE-1 trial will assess whether lowering LDL cholesterol to levels well below current European guideline-recommended targets will lead to further reduction in cardiovascular events. This study includes a high-risk patient population with baseline levels of LDL cholestrol ranging from 70 to <100 mg/dL. SPIRE-2 will evaluate the efficacy and safety of bococizumab in a range of high-risk patients who have not achieved LDL cholesterol levels lower than 100 mg/dL despite the use of high-dose statins.

Juggling Tolerability and Adherence
Across all the studies, the new agents demonstrated good tolerability, with similar percentages of patients across treatment groups reporting any adverse events. The most common adverse events: headache, nausea, diarrhea, influenza, urinary tract infection, upper respiratory tract infection, nasopharyngitis, and back pain.

"Statins can do a whole lot of things, but PCSK9 is an inert thing," said Dr. Stroes. "It doesn't do anything itself, all it can do is bind LDL to the receptor. It doesn't do anything in the muscle or elsewhere."

Regarding the issue of oral drugs versus these strictly subcutaneous agents, there were varying opinions at the meeting: John J.P. Kastelein, MD, PhD, University of Amsterdam, the Netherlands, suggested the subcutaneous administration might sway physicians and patients towards other novel agents, but Dr. Libby thought otherwise, noting that parenteral administration helps ensure adherence and maintain appropriate levels whereas on-board medication dissipates when patients forget to take pills.

Dr. Giugliano said that about one-third of the patients in his study were diabetics and were used to injecting themselves, but that some of the older patients found the auto-injector a bit daunting.

"I would say that overall, people are surprisingly willing to learn how to do the injections if they know they're getting a large reduction in cholesterol and they don't have to worry about taking a pill every day to do that," he added.

Spotlight on Lp(a)
One tantalizing aspect of these agents is that they cause significant reductions in lipoprotein(a) (Lp[a]), which has recently garnered great interest as a cardiovascular risk factor. Lp(a) appears to be primarily genetically determined and relatively refractory to both lifestyle and drug intervention, with the exception of niacin, which is not well tolerated. Just as an example, Lp(a) was reduced 32% versus placebo in the 140 mg Q2W arm of the RUTHERFORD-2 trial and 28% in the 420 mg QM arm.

Frederick Raal, MD, PhD, from University of Witwatersrand, Johannesburg, South Africa, and colleagues recently published a meta-analysis of four phase II trials including 1,359 patients treated with evolocumab or placebo.⁵ Treatment with evolocumab resulted in significant dose-treated reductions in Lp(a) that were reversible upon discontinuation of the drug and sustained during continued treatment. Greater absolute reductions were seen in those considered at higher risk, with baseline Lp(a) >125 nmol/L.

"We think that Lp(a) is probably the second most important advantage of these drugs," said Dr. Giugliano, the second author on the paper by Dr. Raal. "It's a distant second, because, of course, the real benefit is that with an injection once a month we can lower LDL cholesterol by 50% of more, but the Lp(a) story, in my mind, is a home run."

Delta Dawn of a "New Era of Biologics in Cardiology"
"It's really a remarkable story about how fundamental investigation of an esoteric and rare genetic disease—that is autosomal dominant hypercholesterolemia— led to the identification of a new target for therapy that would never have been suspected based on first principles," said Dr. Libby.

"And it led also to incredibly rapid, warp-speed development of therapeutics that may address some very important unmet medical needs."

The general consensus seems to be that PCSK9 inhibitors will be FDA-approved, perhaps even in 2014. The only question is for whom.

"I'm not going to second-guess a regulatory agency, but traditionally an agent that can lower LDL cholestrol by 15% or more is accepted as a therapeutic," said Dr. Libby. "We've learned painfully over the last several years, that the change in biomarker induced by therapy doesn't always confer clinical benefit, but if I was advising the agency, if there is a commitment to a large-scale hard outcomes study, I would consider some use for certain indications of an agent."

He added: "We have genetic confidence—patients with certain mutations give us confidence that lifelong lowering of PCSK is very safe. We don't have that certitude with therapeutic antibodies, but I think that we will know that answer. I think it would be very appropriate for them to grant access to the medication for certain specific patient populations."

Dr. Giugliano agrees that the drugs will likely be granted at least limited approval even before the outcomes trials are completed, particularly "for certain patients for whom we really don't have good treatment options such as those with homozygous familial hypercholesterolemia, and heterozygous familial hypercholesterolemia, and, perhaps, statin-intolerant patients."

Before we continue to sing the praises of PCSK9 inhibitors, one off-key element may make acceptance more difficult: cost. "A large consideration here, particularly the way we practice in the United States, is what the major payers are going to say. A lot of that is cost, which is as-yet unknown," Dr. Giugliano added. "I imagine these drugs are going to cost in the thousands of dollars a year, hopefully less than $5,000, but that's going to be a lot for many people."

References
1. Koren MJ, Lundqvist P, Bolognese M, et al. J Am Coll Cardiol. 2014 March 25. [Epub ahead of print]
2. Blom DJ, Hala T, Bolognese M, et al. N Engl J Med. 2014 March 29. [Epub ahead of print]
3. Stroes E, Colquhoun D, Sullivan D, et al. J Am Coll Cardiol. 2014 March 25. [Epub ahead of print]
4. Robinson JG, Nedergaard BS, Rogers WJ, et al. JAMA. 2014;311:1870-82.
5. Raal FJ, Giugliano RP, Sabatine MS, et al. J Am Coll Cardiol. 2014;63:1278-88.