FenofibrateFenofibrate EzetimibeEzetimibe SurrogateSurrogate TrialsTrials

ThomasThomas Dayspring,Dayspring, MD,MD, FACPFACP Clinical Assistant Professor of Medicine University of Medicine and Dentistry of New Jersey Attending in Medicine: St Joseph’s Hospital, Paterson, NJ

Certified Menopause Practitioner: North American Menopause Society North Jersey Institute of Menopausal Lipidology PharmacokineticPharmacokinetic DataData FenofibrateFenofibrate –– EzetimibeEzetimibe PharmacodynamicPharmacodynamic andand PharmacokineticPharmacokinetic InteractionInteraction StudyStudy

Placebo (n = 8) Ezetimibe 10 mg (n = 8) Patients have no physical 30 activity and are on a high Fenofibrate 200 mg (n = 8) carbohydrate low fat diet which lowers HDL-C 20 Fenofibrate 200mg + 10 Ezetimibe 10 mg (n = 8)

0

-10

-20

-30

Change from Baseline (%) -40

-50 TC LDL-C HDL-C TG Mean (SE) percentage change from baseline in serum lipids on day 14 following oral administration of fenofibrate monotherapy, ezetimibe monotherapy, fenofibrate-ezetimibe co- administration therapy or placebo once daily to 14 healthy subjects with hypercholesterolemia

Kosoglou T et al. Curr Med Res & Opin 2004;20:1185-1195 FenofibrateFenofibrate –– EzetimibeEzetimibe PharmacodynamicPharmacodynamic andand PharmacokineticPharmacokinetic InteractionInteraction StudyStudy

Placebo (n = 8) 30 Ezetimibe 10 mg (n = 8) Fenofibrate 200 mg (n = 8) Combination therapy 20 produced significantly Fenofibrate 200mg + 10 Ezetimibe 10 mg (n = 8) greater reductions in 0 LDL-C and in small LDL-III -10 Levels of apoCIII were -20 also reduced greater -30 than monotherapy with

Change from Baseline (%) Change from Baseline either drug -40

-50 LDL-C LDL-1 LDL-II LDL-III Large Intermed Small

Kosoglou T et al. Curr Med Res & Opin 2004;20:1185-1195 FenofibrateFenofibrate –– EzetimibeEzetimibe PharmacodynamicPharmacodynamic andand PharmacokineticPharmacokinetic InteractionInteraction StudyStudy

8.0 180 Ezetimibe 10 mg (n = 8) 7.0 160 Fenofibrate 200mg + Ezetimibe 10 mg (n = 8) Ezetimibe 10 mg (n = 8) 6.0 140 Fenofibrate 200mg + 120 5.0 Ezetimibe 10 mg (n = 8)

100 4.0 80 3.0 60 1.0 40 Ezetimibe Conc (ng/ml) 20 1.0 Total Ezetimibe Conc (ng/ml) Total Ezetimibe Conc 0 0 0 4812 16 20 24 0 4 81216 20 24 Time (hr) Time (hr) Mean (+SD) plasma concentration-time profiles of total ezetimibe (ezetimibe + ezetimibe glucuronide) and ezetimibe on day 14 following multiple dose, once-daily oral administration of either ezetimibe alone or co-administered with fenofibrate

Concomitant fenofibrate administered as a 200 mg micronized capsule formulation resulted in a significant (~50%) increase in the steady state total ezetimibe exposure. However, this exposure is probably not clinically important. The increased plasma total ezetimibe appear to be due to an increase in ezetimibe bioavailability rather than inhibition of clearance

Kosoglou T et al. Curr Med Res & Opin 2004;20:1185-1195 EzetimibeEzetimibe -- FenofibrateFenofibrate PharmacokineticPharmacokinetic StudyStudy

) EzetimibeEzetimibe hadhad nono clinicallyclinically significantsignificant effecteffect onon thethe pharmacokineticspharmacokinetics (e.g.(e.g. absorbtionabsorbtion,, metabolismmetabolism andand excretion)excretion) oror pharmacodynamicspharmacodynamics (e.g.(e.g. bindingbinding actionaction ofof thethe drugdrug toto certaincertain receptorsreceptors andand consequentconsequent effectseffects onon CNS,CNS, GIGI tracttract andand otherother CVCV parameters)parameters) ofof fenofibratefenofibrate oror vicevice versaversa..

www.sch-plough.com/news/2001/research/20010521.html EzetimibeEzetimibe -- FenofibrateFenofibrate PharmacokineticPharmacokinetic StudyStudy 32 patients with hypercholesterolemia for 14 days: on strict diet

LDL-C TG (median) HDL-C

0% Mean % Change From Baseline -20%

-30% -32% Placebo Zetia -36%* TriCor *P≤0.03 vs placebo or either drug. Combo ZaijkaZaijka StudyStudy FenofibrateFenofibrate –– EzetimibeEzetimibe CombinationCombination TherapyTherapy

50 Mixed dyslipidemia patients who cannot tolerate a statin

Baseline Fenofibrate 160 mg Fenofibrate + Ezetimibe 10 mg

280 500 46 12.5%* * 45 437 44 200 31%* 43 * 375 42 * 41 312 32%* 40 39 250 100 187 * Concentration in mg/dL Concentration Concentration in mg/dL Concentration 69%* 125 20 TC LDL-C HDL-C TG * p<0.01 compared to baseline Zaijka, P. Poster Presentation NLA Annual Meeting Orlando, Fl Aug 2004 FarnierFarnier StudyStudy (Abstract(Abstract && Publication)Publication) EzetimibeEzetimibe –– FenofibrateFenofibrate StudyStudy

After a six- to eight-week washout period, patients with mixed hyperlipidemia LDL cholesterol between 130 and 220 mg/dL (between 100 and 180 mg/dL for type 2 diabetics) and triglycerides between 200 and 500 mg/dL were randomized in a 1:3:3:3 ratio to one of four daily treatments:

Placebo (n=64). After the completion of Ezetimibe 10 mg (n=187). this double-blind, placebo-controlled Fenofibrate 160 mg (n=189). study, the trial is to be Ezetimibe 10 mg and fenofibrate 160 mg (n=185). extended for an additional 48 weeks

The primary end point of the study compared the LDL-cholesterol reduction efficacy of fenofibrate plus ezetimibe vs fenofibrate alone at 12 weeks.

Farnier M et al. Drugs Affecting Lipid Metabolism 2004 meeting, October 24-27, 2004; Venice, Italy. EzetimibeEzetimibe –– FenofibrateFenofibrate StudyStudy End point Placebo Ezetimibe Fenofibrate Ezetimibe 10 mg + (n=64) 10 mg 160 mg fenofibrate 160 (n=187) (n=189) mg (n=185) LDL cholesterol 0.2 -13.4 -5.5 -20.4 (% change)* HDL cholesterol 3.2 3.9 18.8 19.0 (% change) Triglycerides -9.2 -11.1 -43.2 -44.0 (% change) Non-HDL -0.2 -14.7 -16.2 -30.4 cholesterol (% change) ApoB (% change) -1.2 -11.3 -15.2 -26.1 High-sensitivity 9.1 -6.1 -28.0 -27.3 CRP (% change) Fibrinogen -0.3 -0.3 -10.1 -11.5 (% change)

Percent change in study end points *Indicates primary end point

Farnier M et al. Drugs Affecting Lipid Metabolism 2004 meeting, October 24-27, 2004; Venice, Italy. EzetimibeEzetimibe –– FenofibrateFenofibrate StudyStudy

Placebo Ezetimibe Fenofibrate Combination

20 18.8 19.0 10 9.1 3.2 3.9 0.2 0 0.2 1.2 .3 .3 5.5 6.1 9.2 -10 11.3 10.1 11.1 11.5 13 14.7 15.2 16.2 -20 20 26.1 -30 28 27.3 30.4 -40 43.2 42 -50 LDL-C HDL-C TG Non HDL-C ApoB hs-CRP Fibrinogen

Farnier M et al. Drugs Affecting Lipid Metabolism 2004 meeting, October 24-27, 2004; Venice, Italy. EzetimibeEzetimibe –– FenofibrateFenofibrate StudyStudy

) Fenofibrate and Ezetimibe administered together produced significant, positive benefits on the atherogenic lipid profiles and the inflammation biomarker, hs-CRP, in patients with mixed hyperlipidemia. ) Depending on the study variable, the effects of coadministration of Fenofibrate and Ezetimibe were either additive (LDL-C, TC, non-HDL-C, and apo B) or Fenofibrate-dependent (TG, HDL-C, apo A-I, hs-CRP, fibrinogen, and LDL size pattern shift). ) Moreover, co-administered Fenofibrate and Ezetimibe demonstrated a good safety profile that was comparable to Fenofibrate alone.

Farnier M, et al. Eur Heart J. 2005;26:897-905. EzetimibeEzetimibe –– FenofibrateFenofibrate StudyStudy

) Per cent reduction in LDL-C was greater with EZE treatment compared with FENO alone, but LDL-C reduction was additive when both FENO and EZE were used together. ) However, the change in LDL-C was influenced by baseline TG levels in patients with mixed hyperlipidemia in the present study. ) Greater LDL-C lowering was noted with all active treatments in patients with baseline < TG 250 mg/dL. • In contrast, in the high TG subgroup, FENO treatment produced virtually no change in LDL-C, whereas the effect of EZE was maintained.

Farnier M, et al. Eur Heart J. 2005;26:897-905. EzetimibeEzetimibe –– FenofibrateFenofibrate StudyStudy % Achieving NCEP ATP III Goals 70 Placebo Ezetimibe Fenofibrate Combination 60 More than 62% of patients shifted to 50 the larger, more buoyant LDL 40 pattern from the smaller, more 30 dense pattern with 20 coadministration, and FENO alone 10 treatments. Proportion attaining target (%) Proportion attaining Proportion attaining target (%) Proportion attaining 0 LDL-C Non HDL-C

Baseline: LDL-C ~ 140 HDL-C ~ 40 TG ~ 240240 The Non HDL-C goal attainment was comparable across baseline TG values

Farnier M, et al. Eur Heart J. 2005;26:897-905. FenofibrateFenofibrate andand EzetimibeEzetimibe CombinationCombination EffectsEffects

Ezetimibe Fenofibrate Combination 20

10

0 -<1 -10 -6 -10 -11 -20 † †

-30 -28 -27

† † Change From Baseline, % -40

-50 hsCRP Fibrinogen

†P<.05 versus ezetimibe

Farnier M, et al. Eur Heart J. 2005;26:897-905 EzetimibeEzetimibe –– FenofibrateFenofibrate StudyStudy

TheThe coadministrationcoadministration ofof EzetimibeEzetimibe withwith FenofibrateFenofibrate offersoffers aa wellwell--toleratedtolerated newnew lipidlipid managementmanagement strategystrategy forfor patientspatients withwith mixedmixed hyperlipidemiahyperlipidemia inin thisthis study.study. TheThe combinedcombined useuse ofof thesethese agentsagents providesprovides aa therapytherapy withwith complementarycomplementary effectseffects toto improveimprove thethe atherogenicatherogenic lipidlipid profileprofile observedobserved forfor thesethese patients.patients.

Farnier M, et al. Eur Heart J. 2005;26:897-905. DIACORDIACOR TheThe DIACORDIACOR StudyStudy TripleTriple TherapyTherapy withwith aa Statin,Statin, FibrateFibrate andand EzetimibeEzetimibe

) Methods:Methods: 3737 T2DMT2DM patientspatients (35%(35% female),female), mixedmixed dyslipidemiadyslipidemia withwith nono CVD.CVD. (~age(~age 59)59) ) AfterAfter 1212 weeksweeks ofof fenofibratefenofibrate 160160 mg,mg, simvastatinsimvastatin 20m20m mgmg oror theirtheir combination,combination, patientspatients withwith anan LDLLDL--CC >> 100100 mg/dLmg/dL oror TGTG >> 150150 mg/dLmg/dL werewere randomizedrandomized toto simva/fenosimva/feno plusplus placeboplacebo oror ezetimibeezetimibe 1010 mgmg.. ) FollowedFollowed forfor 66 weeksweeks

Pearson RR et al. JACC 2006;47(Suppl) 316A Abstract 808-6 TheThe DIACORDIACOR StudyStudy TripleTriple TherapyTherapy withwith aa Statin,Statin, FibrateFibrate andand EzetimibeEzetimibe

) ForFor combocombo ++ EzetimibeEzetimibe • 23.5% vs 0% (placebo) met all 3 NCEP goals ) TheThe likelihoodlikelihood ofof meetingmeeting allall threethree goalsgoals waswas significantlysignificantly increasedincreased inin thethe combocombo ++ ezetimibeezetimibe groupgroup (p=0.006)(p=0.006) • There was an incremental reduction in TC (16%), LDL-C (25.2%) and VLDL-C (14%) ) NoNo seriousserious adversityadversity seenseen

Pearson RR et al. JACC 2006;47(Suppl) 316A Abstract 808-6 McKennyMcKenny StudyStudy SafetySafety andand EfficacyEfficacy ofof LongLong--TermTerm CoCo--AdministrationAdministration ofof FenofibrateFenofibrate andand EzetimibeEzetimibe inin PatientsPatients WithWith MixedMixed HyperlipidemiaHyperlipidemia

James McKenney, PharmD; Michel Farnier, MD, PhD; Kwok-Wing Lo, MD; Harold Bays, MD; Inna Perevozkaya, PhD; Gary Carlson, BS; Michael Davies, PhD; Yale Mitchel, MD; Barry Gumbiner, MD FenofibrateFenofibrate andand EzetimibeEzetimibe CombinationCombination LongLong TermTerm EffectsEffects onon LipidLipid ProfileProfile

P<.02 Fenofibrate Fenofibrate with Ezetimibe +22 20 +17.8 P=.12 +10.1 10 Non +7.8 LDL-C HDL-C Apo B TG CRP 0 HDL-C Apo A-I -10 -8.6 Baseline -16.2 -20 -19.4 LDL-C ~ 160 † -21.1 -22.0 -25.3 HDL-C ~ 42 -30 -25.2 † TG ~ 276 Non -31.6 † HDL-C ~ 220 -40 apoB ~ 169

Change From Baseline, % Change From apoA-I ~ 150 †P<.0001 versus fenofibrate -41.8 -45 -50 CRP ~ 2.8 P=.002 60 weeks in patients with mixed Percent change from baseline values to endpoint values: dyslipidemia Values expressed as least squares mean % change McKenny J et al. JACC 2006; 47:1584-87 MOAMOA EzetimibeEzetimibe && FenofibrateFenofibrate DecreaseDecrease BetaBetaBeta-lipoprotein--lipoproteinlipoprotein SynthesisSynthesis Hepatocyte Endoplasmic Reticulum

Degradation mRNA

Me mbra ne Ribosome

Cytosol + MTP/Lipid VLDL Precursor Nascent apoB interacts with apoB lipid free MTP and is ubiquinated EZEZ Golgi Reduced Production of Beta-lipoproteins FENOFENO VLDL Reduced Apo B, Non Triglycerides HDL-C, LDL-C IndirectIndirect RCTRCT atat thethe HepatocyteHepatocyte

Hepatocyte LDL receptors Larger LDL Small LDL

Cholesteryl ester

Ezetimibe upregulates LDL receptors which are more efficacious removing larger rather than small LDL ABCA1 Fenofibrate shifts LDL particle size

ABCG4 ABCG5/8 ABCB11 Increased apoB, Non HDL-C reduction BileBile DuctDuct EzetimibeEzetimibe andand FenofibrateFenofibrate IncreaseIncrease StoolStool CholesterolCholesterol ExcretionExcretion

Micelles Ezetimibe upregulates Plasma Hepatocyte LDL receptors Large EZEZ LDL NPC1L1 Protein Cholesterol

Enterocyte Fenofibrate upregulates SR-B1 CE which delipidates the HDL Large Small Increased biliary excretion of ABCG5/G8 cholesterol via ABCG5, G8 HDL HDL

Increased biliary excretion of sterols Micelles and micelle formation. Ezetimibe ABCG4 ABCG5/8 ABCB11 decreases absorption of sterols from micelles at the NPC1L1 protein BBileile DuctuleDuctule

Adapted from Kidambi S et al. Future Lipidology. 2006;1:357-368