PCSK9 Inhibitors: The Next Big Thing in Lipidology

What's the next incremental step in lipidology, where the last biggest thing was a monster, blockbuster class that included the best-selling drug in the world? It is certainly not an area anyone would consider "maxed out" in terms of treatment or "licked" since there is substantial residual CV risk even after "successful" therapy.

Many had presumed that the next great thing would be a drug targeting high-density lipoprotein cholesterol. But after this year's AHA meeting (not to mention the AIM-HIGH results), it would be surprising if anyone still thinks the next big thing will be in that direction.

Instead, it appears the PCSK9 inhibitors have officially come to town. At AHA.12, three out of four of the lipidology Late-Breaking Clinical Trials (LBCTs) were phase 2 trials of PCSK9 inhibitors. Similarly, three of four of the Clinical Science Special Reports that dealt with lipid disorders were phase 2 PCSK9 trials. Several of these studies published simultaneously and, in case you missed the meeting, there was yet another phase 2 trial reported in The New England Journal of Medicine the day before the meeting.

What Is a PCSK9 Inhibitor?
The abbreviation stands for "proprotein convertase subtilisin/kexin type 9." (And you thought "HMG Co-A reductase inhibitors" was a mouthful.) This serine protease was first described in 2003.1 PCSK9 binds to low-density lipoprotein (LDL) receptors and promotes their degradation, reducing the removal rate of LDL-C from the circulation. Blocking this interaction with the use of a PCSK9 inhibitor has been shown to lower LDL-C in animal and human phase 1 studies.

The evolution of PCSK9 as a therapeutic target for hyperlipidemia began with the observation that gain-of-function mutations of PCSK9 resulted in hypercholesterolemia,2 while loss-of-function mutations are linked to low LDL-C.3 Carrying this further, in 2006, researchers showed that individuals who carried a loss-of-function mutation actually had an 88% reduction in the risk of coronary heart disease.4

"So, in essence, the first outcome trial—albeit a genetic trial—was completed in 2006 and showed us that inhibiting the action of this protein would be beneficial," said Jay D. Horton, MD, of the University of Texas Southwestern Medical Center, Dallas, in an introduction to PCSK9 presented at an AHA LBCT session.

Several companies have PCSK9 candidate drugs, including Amgen (AMG 145), Sanofi/Regeneron (REGN727/SAR236553, thankfully called alirocumab), Pfizer (RN316), Novartis (LGT209), and Roche/Genentech (RG7652). All are monoclonal antibodies. To date, Roche/Genentech and Novartis have released very little information on their candidate drugs.

The Drugs and Their Trials
Four phase 2 trials of AMG 145 were presented at AHA.12. These trials all met their primary endpoints, with few or no safety signals.

Table 1
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The four trials covered patients with familial hypercholesterolemia (RUTHERFORD), statin intolerant individuals (GAUSS), individuals with elevated LDL-C but for whom treatment was not mandated (MENDEL), and hypercholesterolemic subjects not optimally managed on statin therapy with or without ezetimibe (LAPLACE-TIMI 57). The Amgen product is a subcutaneous injection that was tested in multiple doses on either an every-other-week schedule (Q2W) or a once-monthly schedule (Q4W; Table 1).

In general, the most commonly noted adverse effects seen with AMG 145 were nasopharyngitis, headache, injection-site reactions, cough, and nausea, Amgen plans to start phase 3 studies in early 2013.

RN316 is the Pfizer PCSK9 candidate. Unlike the other two subcutaneous agents, RN316 is administered intravenously. Its efficacy and safety were tested in two 12-week trials in patients with primary hypercholesterolemia on high- and maximal-dose statins. Despite aggressive treatment, mean baseline LDL-C in the two studies was 123 mg/dL. Pooled results were presented by Barry M. Gumbiner, PhD, executive director, Biotherapeutics Research and Development at Pfizer (Table 2).

Table 2
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As per protocol, dosing was interrupted when LDL-C was ≤25 mg/dL and resumed when LDL-C returned to ≥40 mg/dL. Interrupting dosing attenuated the mean LDL-C lowering by about 15-20%.

"Over half of the subjects in the top two dose groups had at least one of their doses interrupted because their LDL reached the 25 mg/dL threshold," said Dr. Gumbiner. There were few adverse events in these studies and none were considered related to the study drug.

Although not prominently displayed during the main AHA trial events, REGN727/SAR236553 is the most clinically advanced of the PCSK9 inhibitors, already in phase 3 study. At the 2012 ACC annual meeting, James McKenney, PharmD, presented a phase 2 trial of SAR2356553 in patients with primary hypercholesterolemia.9 Participants (n = 183) on stable-dose atorvastatin 10, 20, or 40 mg for at least 6 weeks were randomly assigned to matching placebo or SAR236553 50, 100, or 150 mg Q2W or 200 or 300 mg Q4W, alternating with placebo for a total treatment period of 12 weeks.

Clear dose-dependent responses in lowering LDL-C were seen for both dosings, ranging from 14% to 72% for Q2W and 43% and 48% for the two Q4W doses.

The phase 1 results of this study were published just before AHA in The New England Journal of Medicine.10 In this study, Roth et al. compared SAR236553 coadministered with high-dose (80 mg) or low-dose (10 mg) atorvastatin to high-dose atorvastatin alone in patients with primary hypercholesterolemia and LDL-C levels above 100 mg/dL.

After 8 weeks of treatment, LDL-C was reduced 73% with high-dose atorvastatin plus SAR236553, compared to 17% for atorvastatin 80 mg alone, and 66.2% for atorvastatin 10 mg plus SAR 2356553. All patients who received the PCSK9 inhibitor reached a target LDL-C level of <100 mg/dl="" and="" 90%="" reached="" ldl-c="" levels="" of=""><70>

Commenting on the RUTHERFORD, GAUSS, and RN316 trials, Peter W. F. Wilson, MD, from Emory University in Atlanta, noted that the trials demonstrated efficacy and offered "a fair amount of information about quite good safety." He noted: "We're doing pretty well! We have biologics now for lipid lowering. The PCSK9 approach is extremely promising." He added that there seems to be some myalgia risk and that CK elevations may occur and need to be watched carefully.

One important issue may be cost. Biologics, and in particular monoclonal antibodies, are the fastestgrowing segment of the branded prescription drug market, but they can be a bitter pill to swallow with costs that are up to 22 times more than traditional medication. Because these PCSK9 inhibitors are biologics, the annual cost of such drugs could be $10,000 a year or more. In a recent piece for Forbes, John L. LaMattina, PhD, former president of Pfizer Research and Development and senior partner at PureTech Ventures, noted that the phase 3 ODYSSEY OUTCOMES trial will likely cost Sanofi-Regeneron about half a billion dollars, although he said it "will provide excellent evidence as to the value of PCSK9 inhibition in people with serious CV disease."—Debra L. Beck

1. Seidah NG, Benjannet D, Wickham L, et al. Proc Natl Acad Sci USA. 2003;100:928-33.
2. Abifadel M, Carret M, Rabes JP, et al. Nat Genet. 2003;34:154-6.
3. Cohen J, Pertsemlidis A, Kotowski IK, et al. Nat Genet. 2005;37:161-5.
4. Cohen JC, Boerwinkle E, Mosley TH Jr., et al. N Engl J Med. 2006;354:1264-72.
5. Sullivan D. Olsson AG, Scott R, et al. JAMA. 2012 November 5. [Epub ahead of print]
6. Raal R, Scott R, Somaratne R, et al. Circulation. 2012;126:2408-17.
7. Koren MJ, Scott R, Kim JB, et al. Lancet. 2012 November 6. [Epub ahead of print]
8. Giugliano RP, Desai NR, Kohli P, et al. Lancet. 2012 November 6. [Epub ahead of print]
9. McKenney JM, Koren MJ, Kereiakes DJ, et al. J Am Coll Cardiol. 2012;59:2344-53.
10. Roth EM, McKenney JM, Hanotin C, et al. N Engl J Med. 2012 October 31. [Epub ahead of print]

Keywords: Nausea, Hyperlipoproteinemia Type II, Coronary Disease, Serine Proteases, Receptors, LDL, Heptanoic Acids, Hypercholesterolemia, Subtilisin, Headache, Mutation, Proprotein Convertases, Pyrroles, Drug Delivery Systems, Cholesterol, Oxidoreductases, Azetidines, Injections, Subcutaneous, Biological Products, Nasopharyngitis, Cough, Myalgia

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