PCK9 Inhibitors: Blockbusters or Bust?

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Written By

Dawn Fuke, PharmD, BCPS
Abby Frye, PharmD, BCACP

Reviewed By

Evan Sisson, PharmD, MSHA, CDE
Robert Talbert, PharmD

Citation

Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015; 372: 1489-1499. AND 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.

Monoclonal antibodies (mAb) are used to treat many disorders — from cancer to age related macular degeneration. These agents consistently come with a very high price tag often costing more than $200,000 per patient per year in the United States.1 Two new mAbs, alirocumab (Praluent®) and evolocumab (Repatha®), have been approved to treat elevated cholesterol when added to maximally tolerated statin therapy in patients with familial hypercholesterolemia or history of atherosclerotic cardiovascular disease (ASCVD). This new class of drugs, the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, is considered to be the biggest breakthrough in cholesterol treatment since statins were approved 3 decades ago. But are they worth it?

 

ASCVD continues to be the leading cause of death and disability in the United States; contributing to over 740,000 deaths in 2013.2 Both primary and secondary prevention trials demonstrated that statin therapy reduces major cardiovascular (CV) events by a third when compared to placebo.3 Some secondary prevention studies demonstrated that maximizing statin dose can reduce CV events even more.4,5 Despite these benefits, a large percentage of patients continue to experience CV events. PCSK9 is a protein that binds to the low density lipoprotein cholesterol (LDL-C) receptor, thereby reducing the LDL-C receptor density on the hepatocellular surface membrane and increasing circulating LDL-C levels.6 Alirocumab and evolocumab inhibit PCSK9; in doing so, they increase available hepatocyte LDL-C receptors and subsequently decrease circulating LDL-C levels. The beneficial effects of statins are believed to be due their ability to reduce LDL-C. However, is lowering LDL-C enough? Statins may also have pleiotropic effects that may contribute to fewer CV events.7 Two studies published simultaneously in the New England Journal of Medicine examined the effects of PCSK9 inhibitors — often combined with statins — on LDL-C lowering, safety, and CV events (See Tables 1 & 2).8,9

 

Table 1: Study Characteristics

 

Alirocumab (ODYSSEY LONG TERM)

Evolocumab (OSLER-1 & OSLER-2)

Design

A randomized, double-blind, placebo-controlled study

Two randomized, open-label, controlled studies

Population

Adults at a high risk of CV events due to heterozygous familial hypercholesterolemia, established coronary heart disease (CHD), or a CHD risk equivalent, who were already taking a statin at the max-tolerated dose with an LDL-C ≥ 70 mg/dL

Adults who had successfully completed one of the parent trials (12 Phase 2 or Phase 3 trials) and who had not experienced an adverse event leading to study drug discontinuation

Patients

n=2341
(1553 assigned to alirocumab)

n=4465
(2976 assigned to evolocumab)

Intervention

Alirocumab 150 mg SQ every 2 weeks v. placebo; all subjects were also instructed to follow a TLC diet

Evolucomab 420 mg SQ monthly or 140 mg SQ every 2 weeks plus standard therapy v. standard therapy alone

Duration

78 weeks

mean study-drug exposure: 70 weeks

56 weeks (OSLER-1),
48 weeks (OSLER-2)
median follow-up: 44 weeks

Baseline characteristics

Age (mean)

60 years

58 years

Sex

63% male

50% male

Risk

18% heterozygous familial hypercholesterolemia

69% CHD

41% CHD risk equivalent

35% diabetes

21% current smokers

80% had at least one CV* risk factor

20% coronary artery disease

9% cerebrovascular or peripheral artery disease

13% diabetes

15% current smokers

LDL

mean 122 mg/dL

median 120 mg/dL
(mean not reported)

Medication Use

>99.9% on statin therapy

47% on high-intensity statin¥

28% on other lipid lowering therapy, including 14% on ezetimibe

70.1% on statin therapy

27% on high intensity statin¥

13% on ezetimibe

CHD risk equivalent: peripheral arterial disease, ischemic stroke, moderate chronic kidney disease (eGFR 30 to <60), or T2DM plus 2 additional risk factors

* CV risk factors: hypertension, diabetes mellitus, metabolic syndrome, current cigarette use, family history of premature coronary artery disease, known familial hypercholesterolemia

¥ High intensity statin therapy defined as atorvastatin 40-80 mg/day, rosuvastatin 20-40 mg/day, or simvastatin 80 mg/day

 

There are several fundamental differences between these trials, but perhaps the most notable is the composition of the patient populations. A major strength of the alirocumab data is that the study population in the ODYSSEY LONG TERM trial was limited to truly high-risk patients. Although it was a mixed population [some with familial hypercholesterolemia, coronary heart disease (CHD) or a CHD risk equivalent] the patient selection seems to be more appropriate to those that could be considered for treatment in practice. It was comprised of individuals who were already on a high-intensity or max-tolerated statin therapy with an LDL-C greater than 70 mg/dL. This is a suitable patient population for these high-cost injections. Conversely, in the OSLER (evolocumab) trials, 20% of patients did not have an ASCVD risk factor and 30% were not on a statin. Thus a significant proportion of patients in this study would be considered low-risk of ASCVD and, based on the current guidelines, may not have an indication for a statin.

 

Another prominent difference between the two study populations is that the evolocumab trials only included patients who had successfully completed one of the drug’s parent trials, meaning that they had tolerated and been adherent to the injections (either study drug or placebo). Given the potential selection bias along with the open label nature of the OSLER trials, the results should be interpreted cautiously.

 

Despite these methodological differences, the results are similar (see Table 2). Both PCSK9 inhibitors reduced LDL-C by approximately 60% to a median / mean LDL-C of 48 mg/dL after 12-24 weeks. In the alirocumab study, the percentage change in LDL-C was reasonably similar regardless of age, sex, or baseline LDL. Patients with heterozygous familial hypercholesterolemia also experienced similarly large reductions in LDL-C. With regard to safety, the OSLER and ODYSSEY studies were powered for safety and there was no appreciable difference in the incidence of abnormal liver function test or elevated creatine kinase levels, or new onset diabetes. Both agents were well-tolerated with an overall adverse event rate similar to placebo or standard therapy. However, both studies did report a higher incidence of neurocognitive events compared to placebo that was not statistically significant (0.9-1.2% vs 0.3-0.5%), a finding that certainly deserves more exploration. These studies provide some reassurance that “extreme” LDL-C lowering is safe. In the ODYSSEY study, 37.1% of patients receiving alirocumab had at least 2 consecutive LDL-C values below 25 mg/dL, and there was no significant difference in adverse event rates including neurocognitive events in this subgroup. Similarly, in the OSLER trial there was no signal of increased adverse events in patients whose LDL-C was less than 25 mg/dL. Finally, but most intriguingly, both studies found that treatment with the PCSK9 inhibitor significantly lowered the rate of composite CV-related outcomes. This is understandably exciting news.

 

Table 2: Study Results

 

Alirocumab (ODYSSEY LONG TERM)

Evolocumab (OSLER-1 & OSLER-2)

Efficacy Outcomes (study drug v. placebo or standard therapy for all comparisons)

Percentage change in calculated LDL-C cholesterol from baseline

At week 24:
difference v. placebo: -61.9%
(95% CI -64.3 to -59.4); p<0.001

At week 12:
difference v. standard therapy: -60.9%
(95% CI -63 to -59); p<0.001

Absolute LDL-C

At week 24 (mean):

48mg/dL v. 119 mg/dL

At week 12 (median):

48 mg/dL v. 121 mg/dL

At Goal LDL-C < 70mg/dL

At week 24:

79.3% v. 8.0%

At week 12:

73.6% v. 3.8%

Safety Outcomes (study drug v. placebo or standard therapy for all comparisons)

Any adverse event

81.0% v. 82.5%

69.2% v. 64.8%

Specific adverse events

injection site reactions: 5.9% v. 4.2%

myalgia: 5.4% v. 2.9% (p=0.006)

ophthalmologic events: 2.9% v. 1.9%

new cases of diabetes: 1.8% v. 2.0%

injection site reactions: 4.3% v. n/a

arthralgia: 4.6% v. 3.2%

headache: 3.6% v. 2.1%

limb pain: 3.3% v. 2.1%

fatigue: 2.8% v. 1.0%

Neurocognitive events

1.2% v. 0.5%

0.9% v. 0.3%

Serious adverse events

18.7% v. 19.5%

7.5% v. 7.5%

Adverse event leading to d/c of study drug

7.2% v. 5.8%

2.4% v. n/a

Cardiovascular Events (study drug v. placebo or standard therapy)

Composite of cardiovascular events¶ ¥

27 (1.7%) v. 26 (3.3%);
HR 0.52; 95% CI 0.31-0.90; p=0.02
(NNT = 63)

29 (0.95%) v. 31 (2.18%);
HR 0.47; 95% CI 0.28-0.78; p=0.003
(NNT = 81)

The ODYSSEY LONG TERM composite (post-hoc) included death from CHD or death from unknown cause, nonfatal MI, fatal or nonfatal ischemic stroke, unstable angina requiring hospitalization

¥The OSLER composite included death, coronary events (MI, unstable angina requiring hospitalization, or coronary revascularization), cerebrovascular events (stroke or tia), and heart failure requiring hospitalization

 

Since the introduction of statins, only one other class of lipid lowering drugs (the selective cholesterol absorption inhibitor, ezetimibe) has been approved. The recent results from the IMPROVE-IT study reinforce the argument that lowering LDL-C improves outcomes.10 In the IMPROVE-IT trial, the addition of ezetimibe 10 mg to simvastatin 40 mg in patients with acute coronary syndrome significantly reduced the composite endpoint of CV death, nonfatal MI, unstable angina requiring re-hospitalization, coronary revascularization or nonfatal stroke when compared to simvastatin 40 mg alone (p=0.016, NNT 50 over 7 years).

 

Given that PCSK9 inhibitors also and quite dramatically reduce LDL-C (alone or in combination with statins), many believed they would reduce CV risk. This hypothesis is substantiated by data that shows that people with genetic variants where PCSK9 activity has been lost have significantly lower rates of CV events.11 The PCSK9 inhibitors clearly possess potent LDL-C lowering capability (as much as a high intensity statin) with a 50-65% reduction achieved within 3-6 months of treatment initiation and sustained with continued therapy.6 The agents’ effects on other lipid variables also appears favorable — reductions in total cholesterol, triglycerides, non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B, lipoprotein(a), with modest increases in HDL-C and apolipoproteinA1. However, as we have learned from other clinical trials, improvements in the lipid profile aren’t always enough. (See AIM-HIGH Misses the Target, But Who Was in the Center of the Bull’s Eye and Potential Uses of Niacin: Flushing Out The Results of HPS2-THRIVE).

 

Health professionals and Wall Street are buzzing about the PCSK9 inhibitors. Five years ago, it was the cholesterylester transfer protein (CETP) inhibitors that generated excitement based on their ability to substantially increase HDL-C. However, results of eight clinical trials with more than 36,000 patients were underwhelming: three of the eight CETP trials were stopped early due to either adverse events or futility. In the end, the CETP inhibitors were found to have no significant effect on mortality, non-fatal MI, or stroke.

 

History often repeats itself and only time will tell if the PCSK9 inhibitors are blockbusters (like statins) or a bust (like CETPs). Once again we have a new class of drugs delivering promising results. Long term CV trials (FOURIER, ODYSSEY OUTCOMES) are ongoing and will hopefully affirm the reductions in CV events seen in these two studies. Like the newest drugs for hepatitis-C, the PCSK9 inhibitors may be lifesavers and millions of patients may be eligible for treatment, but can we afford to treat everyone who might benefit? To what extent should we enthusiastically endorse the use of PCSK9 inhibitors before clear improvements in morbidity and mortality have been demonstrated? Tell us what you think!

Comments

1

Just a quick practical point that was shown to me by someone who works with spreadsheets more than I do.....if you use the q2wk dose, you will go through 26 syringes in a year. If you use the monthly dose (3x140mg), you will go through 36 syringes in a year.