Lowering cholesterol with statins leads to a dose-dependent decrease in cardiovascular (CV) mortality and major adverse cardiac events (MACE).¹ However, residual risk on statins still remains.^2,3 Individuals especially at risk for CV-related morbidity and mortality include those with elevated atherogenic cholesterol levels and CV disease risk factors, those with familial hypercholesterolemia, and those who are unable to tolerate at least daily doses of moderate-intensity statin therapy.⁴

One promising target in treatment of these populations involves inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9), which leads to decreased degradation of low-density lipoprotein (LDL-C) receptors and, thus, decreased levels of circulating LDL-C. Combining PCSK9 inhibitors with a statin may also lead to increased statin efficacy, as PCSK9 levels are increased with statin therapy through negative feedback.^5,6 The primary agent studied in the ODYSSEY trials, alirocumab, is an injectable monoclonal antibody that inhibits PCSK9. Phase II trials showed a significant reduction in LDL-C levels with a 73% reduction in LDL-C levels at week eight using 150 mg every other week with statin use and favorable side effect profile.⁷

Current Update on the ODYSSEY Trials

Currently, there are 14 phase III ODYSSEY trials enrolling individuals for a total of over 23,500 patients, including studies examining the efficacy of alirocumab. These include:

1) Lipid Lowering

1. LDL-C lowering efficacy and safety profiles of patients on high-intensity statin with heterozygous familial hypercholesterolemia (HeFH), include ODYSSEY FHI/FHII and ODYSSEY HIGH FH (safety and efficacy of alirocumab as add-on therapy to statin versus placebo).
2. ODYSSEY trials exploring the lipid lowering efficacy and safety of alirocumab in individuals with high CV risk include ODYSSEY COMBO I/II (alirocumab on statin versus ezetimibe) CHOICE I/CHOICE II (alirocumab in those with primary hypercholesterolemia not treated with a statin) and OPTIONS I and II (alirocumab versus up-titration of atorvastatin or rosuvastatin dose).
3. Statin intolerance - ODYSSEY ALTERNATIVE (alirocumab in comparison with ezetimibe and low-dose atorvastatin in those intolerant to statins)
4. Monotherapy – ODYSSEY MONO (alirocumab with ezetimibe monotherapy for 24 weeks in patients with hypercholesterolemia)

2) Safety – ODYSSEY LONG TERM (safety of alirocumab vs. placebo in high CV risk patients with hypercholesterolemia), ODYSSEY OLE (safety of alirocumab added to lipid lowering therapy in individuals with HeFH)

3) Major Adverse Cardiac Events – ODYSSEY OUTCOMES (incidence of CV events on alirocumab vs. placebo including death, non-fatal myocardial infarction [MI], fatal and non-fatal ischemic stroke, and unstable angina requiring hospitalization in those who have experienced an acute coronary syndrome four to 52 weeks prior to randomization)

ODYSSEY MONO, the first completed phase III alirocumab trial comparing alirocumab vs. placebo in those with moderate CV risk and hypercholesterolemia, revealed significantly greater reductions in LDL-C levels in the alirocumab group versus ezetimibe (47.2% reduction in LDL-C versus 15.6% reduction respectively, P <0.0001). Treatment-emergent adverse events (TEAE) in each group were similar.⁸

The promising results of this trial were supported by four trials that were presented at the European Society of Cardiology Congress (ESC) 2014: ODYSSEY FH I and FH II, ODYSSEY COMBO II, and ODYSSEY LONG TERM. The studies used 75 mg of alirocumab injected every two weeks, with the ability to increase the dose to 150 mg at week 12 if subjects were not at goal by week eight. ODYSSEY FH I and FH II demonstrated significant reductions in LDL-C versus placebo in patients with HeFH (reduction of 49% vs. 9% respectively, P <0.0001), with FH II showing similar results (reductions of 49% vs. 3%, P <0.0001).

ODYSSEY COMBO II demonstrated significant reduction in LDL-C versus ezetimibe (reductions of 51% vs. 21%, respectively) in individuals with high CV risk. ODYSSEY LONG TERM demonstrated significant reductions in LDL-C vs. placebo (reductions of 61% vs. 10%) with similar TEAE leading to drug discontinuation (6.2% vs. 5.5% respectively), and adverse CV events between both groups (1.4% in alirocumab vs. 3% in placebo).

Results of ODYSSEY ALTERNATIVE, ODYSSEY COMBO I, ODYSSEY HIGH FH, and ODYSSEY OPTIONS I and II were presented at the 2014 AHA conference. ODYSSEY ALTERNATIVE, designed to evaluate alirocumab in individuals intolerant to statins, showed increased reduction in LDL-C versus placebo (reductions of 45% vs. 15%, P <0.0001) and importantly, similar dropout rates between all arms (alirocumab, 20 mg of atorvastatin, and ezetimibe). COMBO I/II found that alirocumab significantly reduced LDL-C versus placebo (reductions of 48% vs. 2% respectively, P <0.0001) with similar TEAE. Similarly to ODYSSEY FHI/FHII, ODYSSEY HIGH FH also found that alirocumab significantly reduced LDL-C at 24 weeks compared with placebo in individuals with HeFH and LDL-C over 160 mg/dL (reductions of 46% vs. 7% respectively, P <0.0001).

ODYSSEY OPTIONS I/II, designed to evaluate alirocumab vs. ezetimibe vs. doubled dose of atorvastatin or rosuvastatin showed significant reductions in LDL-C at 24 weeks in OPTIONS I (reductions of 44% in individuals taking atorvastatin 20 mg and 54% in atorvastatin 40 mg), as well as in OPTIONS II (reductions of 51% in individuals taking rosuvastatin 10 mg and 36% in individuals taking rosuvastatin 20 mg).

Perspective/Commentary

The results of these phase III trials suggest that alirocumab is effective at lowering LDL-C levels in individuals: 1) at increased risk of CV events who are not at LDL-C goal; 2) are intolerant of statins; 3) who have HeFH not at treatment goal or with LDL-C >160 mg/dL; and 4) those with moderate or high CV risk on maximally tolerated doses of statins with elevated LDL-C level.

Questions that remain and what studies have demonstrated thus far include:

1) PCSK9 inhibitors have successfully demonstrated impressive lowering of LDL-C levels. Will this translate into improved outcomes?

This is the central question remaining to be answered within ODYSSEY OUTCOMES. Prior studies have demonstrated that individuals with genetic variants of PCSK9 resulting in decreased LDL-C had a 28% reduction in mean LDL-C cholesterol and 88% reduction in CHD risk.⁹ Post hoc pooling from the major placebo trials at the 2014 American Heart Association (AHA) Annual Scientific Sessions including 3,459 individuals showed a hazard ratio of 0.65 (95% CI 0.40-1.08; P = 0.0985) for those on alirocumab in Kaplan-Meier estimates for time to first adjudicated major CV event (defined as coronary heart disease death, non-fatal MI, fatal and non-fatal ischemic stroke, and angina requiring hospitalization); however, this was not statistically significant.

The mean change in LDL-C by week 24 was a decrease of 48-60% (placebo 4.3%-0.5%). Although suggestive that alirocumab may lead to decreased CV events, caution must be used when interpreting these results, as the analysis was post-hoc. The incidence of CV events on alirocumab vs. placebo including coronary heart disease death, non-fatal MI, fatal or non-fatal ischemic stroke, and unstable angina requiring hospitalization in those who experienced an acute coronary syndrome four to 52 weeks prior to randomization after approximately 5.6 years of follow-up will be presented in ODYSSEY OUTCOMES.

2) What is the long-term tolerability and safety of PCSK9 inhibitors?

Data presented at the ESC Congress and AHA Annual Scientific Sessions have shown nearly identical safety profiles between PCSK9 inhibitors, and those in control groups generally taking doses of maximally tolerated statins. Some studies have demonstrated a slight increase in injection site reactions (ODYSSEY LONG TERM, COMBO I, and HIGH FH), but these trials have demonstrated similar rates of drug discontinuation in each arm. Follow-up has only extended to roughly 52 weeks, and long-term safety and tolerability remains to be seen in ODYSSEY OUTCOMES.

3) Given that PCSK9 inhibitors result in markedly decreased levels of LDL-C, with approximately 36% of patients treated with alirocumab and low-dose statin achieving two consecutive LDL-C levels of <25 mg/dL in ODYSSEY LONG TERM, is there an LDL-C level considered "too low?"

Prior studies have suggested that very low levels of LDL-C on treatment did not have adverse safety outcomes and had improved efficacy.¹⁰ ODYSSEY LONG TERM did not demonstrate any increase in TEAE compared to those on placebo and maximum dose statin; however, the long-term effects of very low levels of LDL-C remain to be seen in addition to other safety data.

Taken together, these studies have demonstrated excellent LDL-C lowering in individuals taking PCSK9 inhibitors, with good safety and tolerability compared to statins and ezetimibe; however, long term outcomes and safety profiles remain to be examined.

References:

1. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495-1504.
2. Boekholdt SM, Arsenault BJ, Mora S, et al. Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis. JAMA 2012;307:1302-9.
3. Mora S, Wenger NK, Demicco DA, et al. Determinants of residual risk in secondary prevention patients treated with high- versus low-dose statin therapy: the Treating to New Targets (TNT) study. Circulation 2012;125:1979-87.
4. Dadu RT, Ballantyne CM. Lipid lowering with PCSK9 inhibitors. Nat Rev Cardiol 2014;11:563-75.
5. Careskey HE, Davis RA, Alborn WE, Troutt JS, Cao G, Konrad RJ. Atorvastatin increases human serum levels of proprotein convertase subtilisin/kexin type 9. J Lipid Res 2008;49:394-8.
6. Welder G, Zineh I, Pacanowski MA, Troutt JS, Cao G, Konrad RJ. High-dose atorvastatin causes a rapid sustained increase in human serum PCSK9 and disrupts its correlation with LDL cholesterol. J Lipid Res 2010;51:2714-21.
7. Roth EM, McKenney JM, Hanotin C, Asset G, Stein EA. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med 2012;367:1891-1900.
8. Roth EM TM, Ginsberg HKJ, Colhoun HM, Merlet L, Pordy R, Baccara-Dinet MT. A 24-week study of Alirocumab as monotherapy versus Ezetimibe: The first phase 3 data of a proprotein convertase sutilisin/kexin type 9 inhibitor. J Am Coll Cardiol 2014;63.12_S.
9. Cohen JC, Boerwinkle E, Mosley TH, Jr., Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006;354:1264-72.
10. Wiviott SD, Cannon CP, Morrow DA, Ray KK, Pfeffer MA, Braunwald E. Can low-density lipoprotein be too low? The safety and efficacy of achieving very low low-density lipoprotein with intensive statin therapy: a PROVE IT-TIMI 22 substudy. J Am Coll Cardiol 2005;46:1411-16.

Keywords: Acute Coronary Syndrome, American Heart Association, Angina, Unstable, Azetidines, Cholesterol, Cholesterol, LDL, Control Groups, Coronary Disease, Fluorobenzenes, Heptanoic Acids, Hospitalization, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Hyperlipoproteinemia Type II, Kaplan-Meier Estimate, Lipoproteins, LDL, Maximum Tolerated Dose, Myocardial Infarction, Patient Dropouts, Proprotein Convertases, Pyrimidines, Pyrroles, Risk Factors, Stroke, Subtilisins, Sulfonamides, United States

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