Figure 3: Statistical Analysis Strategy for IGA Study

Statistical Analysis Strategy for IGA Study

TAAL (Efficacy)

PK

PD

Binned Group {CYP2C9

E~~,~~ CYP2CI9

CYP2C9

CYP2CI9

CYP3A5

CYP2B6

Linear Mixed-effects Models

The primary clinical endpoint was a composite of CV death, nonfatal MI, or nonfatal stroke asadjudicated by CEC with reaching any component; patients received aspirin and wererandomized to receive either a 300 mg LOnS mg MD of Clopidogrel or a 60 mg LD/10 mg MO ofPrasugrel. Endpoints from randomization through a patient's termination visit or 464 dayswhichever was earlier. The primary genetic endpoints were the combined CYP2C19 and CYP2C9functional group: EMfg and RMfg. Variations in CYP2C19 and CYP2C9 were associated withlower exposure to active metabolite and decreased inhibition of platelet aggregation followingadministration of Clopidogrel. The effect of CYP genetic variations on cardiac event rate wascompleted in all patients with ACS and also in the subgroup of patients with UAINSTEMI.

TABR

The genomic data analysis strategy for the TABR study was analogous to that for IGA, but itinclUded results for measurement of platelet aggregation by several methods, and selectiveapplication of linear regression and logistic regression models.

304

Figure 4: Statistical Analysis Strategy for TABR Study

Statistical Analysis Strategy for TABR Study

CYP1A2

CYP2B6

CYP2C9

CYP2C19

CYP3A4

CYP3A5

DMPA (784 patient

PRU (490 patientsF----,'+---_

VASP (578 patients

AUC (293 patients) -------o: Binned Group { CYP2C9EMfg• PMfgIM2C19 CYP2C19

fg

Linear Regression Models

Logistic Regression Models + x2 test

4.5 Confirmation of Analysis and Results

We were able to confirm the analysis and results submitted by the sponsor after modifying thecomputational code submitted by the sponsor. Important results reproduced by this work areshown below:

Figure 5: IGA Study. Analyses with Pharmacokinetic Measurements

BasoUno CharactoJlsUcsIPA 67. TB 8.101

PharmacoklneUc Pa...meters CONFIRMATION: Effects botwoen AllCO·tllasl)and CYP GonoUc Classlflcatlons

6powI._Adw......llIUC04Jao.,'...lIlmInlI11>-. aoo- II' ............_ ..~. '".... I lUhlU&

Mo.t.sD

Wr""" ! 1HOIIUJo.......<A '"..JJ n'........ '"..... ........ II J

~'ull..

'",....II>W

"' ..

........ 21' ....... 1M1..'.L-.g 2" SIlo.' D).lI

111_........1 JI.... n. U2.' -U4.'

;::-;; :::~: ::::~

.....J.:n... J"7;), "1••...... '.10.11U ......SI.J: :l'J•••

Gene iPr>tugrel :"",ougrel !Clopidogtol :Clopl~..1!wleth :WfOeu"l lwfeth ;w{o~h

.._-_. ~j _ _- ._._~,. __ -!- _ - t -3A5 :0.947 :0.398 !0.502 ;0.651-·-;·--····-----··7"--·----4----· . - ---·f·-----·--286 jO.542 !O.413 ;0.02'9 10.040

iCi-··!o.i44····--·:O:;'8i·----iii586····--·-1G.""6if"-- -'-"___I·..·~_· _I.. l ..._'--.--...2C19 ~O.OOO8 10.311 jO.CXXXlOll jO.OOX034

1(0.062)'1(0.679)' i i2C19 ;O.oooa3 10.0277 ,0.00002 jO.OOOO33+2C9 I ! ; :

Conclusion: no correlation of genotype with Prasugrel pharmacokinetics if ethnicity effects areexcluded.

305

Figure 6: IGA Study. Analyses with Pharmacodynamic Measurements

.........'"

....­........

......................

Basollno Charaetorlsllcs(Pg 44, TB 8.4)

,)JJIJJ)4'!

I~ •..11 of

'"..SllU".oht.~

nKlfJIU'

,II"~ .~.. ,..~11

l't~'lLlI

Pharmac:odynamle Paramoto. (IIMPA)

Ch>"S"tom 90..11"" In Ma.....,P_Agg~llonm R.,SXX'" to 20 ~M AOP.by TreatrMnland line~ 0-,.. ,Lao- • 1I_....cl... 5\ ,,\............ <II... . W Iii d.e,. h h

2tJo9w ;In n •• 4' .' ..'.... ...,.. 'oU ".J n " It)'lloV n. 'lo'''' J( II

n ..""t"l H'" •~ I" n.. Jr.. 0.' n ..lU_l HI .... n.1 .;1 t&

Cl..........t ..... '_t- .. n .• '" II J&II., "'" ".;1 ..." n ..,n..l.,..l"" .,""u I" n.'.' :n fII'''''''' ..) 'Ii•• U • 1.

CONFIRMATION: Effeets between IIMPA andCYP Gonolle Ciaosllleatlons

GC!IMI ~ Prawgrel wi ; Prasugrel :CIopidogrei !CIopidogtel

leth ;W/ooth !w/elh lw/oeth

3A5j"o.43i---To.rn---kOO8-- '10:463-'-'

286 iO~__ io.88ll 1° 019 !~__:2C9 10.7515 :0.:;118 -~!0.696

2C19 '0.724 :0.887 10.00032 !0.005

Conclusion: no correlation of genotype with Prasugrel pharmacodynamics independently ofethnicity.

Figure 7: TAAL Study. PK and Clinical Endpoint AnalysesPK Madel for Pras"gre' AUC Expoaura

Gene P·ValueCYP2C19 0.235

100'9<...,.. ..-

CYP2C9 0.311/IYIoO.._ .."""

"':::::~:",0.182

CVP3A5 0.402~ ..-.c.CYP2Cl9+2 0.369C9Pfl..,..

Number and Percentage of SUbjects Having GeneUcInformaUon Reaching Compo_lie Endpoint

Number 8nd Percentage of SubJeetl Reaching Number and Percentage of Subjects ReachingCompoelle Endpoint P....ugreI2C19+2C9 EMfgs Composite Endpoint: Clapldogrel2C19+2C9 EMfDI. VfIrsua RMfgs. verwu. RUfgs

Tct.I Cox Gelwl· =. PIN. Pra&.. Tetal Col GeNiD- ~.. ' Q» I Clop 'I ToteI: CCAlI IGeI>an.~~Jonal WI:lO:lOn. 2C1111"2l::tDol 2C1lW2CtAM ~ Wfoln'on :::",,*' .:!Ct$Io'X:lOl'Ui X' trX:91tW l~portional VIb:noo

f--t.,...-r,,,,;;+'~;-r;..-J"'r.-T,.,1I;...£<,,,,---+=-+-+..r.-r....;;+'.;-r..,,,....-+.....,;-t..-+~.--b=----1f--I-::··:-'I""~ I~, t l' i~' I" I" j'''' i"'''<:1 ,.-..

Conclusion: no significant correlation of genotype with Prasugrel pharmacokinetics or with clinicalendpoints.

Figure 8: TABR Study. Relationship between PO Responses and Individual Cytochrome Genes

VASP AlIIrA.

.- .,...,"" - '"

,.. ..... "- ,. "" "'" ,.. ... - ..... ,. '" ... - ... ".CYP2CI Cl.E>I-<UN ~.'" O~12 ... .....

cmc» O.E»-a.... ...." ."" .- ."'" ...", ClII»-<DW .- ..... ..... ..- U'" ..I>• --..-....... ...,., ..",. ...,., ..", .............. .... .."" .- "'101 ...... ....... ............~-..". -- .",. ..,." ."" --CU>I-<1Jt>I ~l96I .... -- ..". <U......... .,710) ...", O.lm oms ..,.. ClII»-<DW .... urn .,'" .- .,.., ...., .....CYI1" CYP286 <mooPr.na.".RW. .m. 0.,'" 0.6Sl1 ..... .............. o..,m ~.... 0,9911 o.<US ...... ............. ..... .- .." .- .- .".., .-

cyp.wal)fodRW 0.1611 ,J... ..... U .. w,,,·<:,,,,, e,'", ...,., 0212A .".. O.6m ".......... -- ...., .- .- .- ." ..""Pr.nt--fr.RW un .J'" ..,., 0.00)7 c-m.u ........,.... .,." ....., .m, 0JlU O.oltS

mw...ElHo.... .- ..... .- UI)I •,'* .... 1I.10JZ

Conclusion: no consistent correlation of genotype for individual cytochrome genes with Prasugrelpharmacodynamics measured by three different methods.

306

4.6 Conclusions

No correlation of genotype with Prasugrel pharmacokinetics if ethnicity effects are excluded. (IGAstudy) No correlation of genotype with Prasugrel pharmacodynamics independently of ethnicity.(IGA study) No significant correlation of genotype with Prasugrel pharmacokinetics or with clinicalendpoints. (TAAL study) No consistent correlation of genotype for individual cytochrome geneswith Prasugrel pharmacodynamics measured by three different methods.

5 Labeling

Label section 12.3: "'n healthy subjects, patients with stable atherosclerosis, and patients withACS receiving EFFIENT, there was no relevant effect of genetic variation in CYP3A5. CYP2B6,CYP2C9, or CYP2C19 on the pharmacokinetics of EFFIENT or its inhibition of plateletaggregation."

307

This is a representation of an electronic record that was signed electronically andthis page is the manifestation of the electronic signature.

lsi

Elena Mishina6/20/2008 06:27:46 PMBIoPHARMACEUTI CS

Rajnikanth Madabushi6/21/2008 07:51:22 PMBIOPHARMACEUTICS

Sripal R Mada6/23/2008 01:25:09 PMBIOPHARMACEUTICS

Frederico Goodsaid6/23/2008 01:30:08 PMBIOPHARMACEUTICS

Yaning Wang6/23/2008 02:08:02 PMBIOPHARMACEUTICS

Patrick Marroum6/27/2008 04:31:19 PMBIOPHARMACEUTICS

Clinical Pharmacology Review, IND 63.449& NDA 22-307

CLINICAL PHARMACOLOGY REVIEW

6/10/08

Prasugrel10 mgtabletEli Lilly, me.Responses to FDA General Comment and Major Concerns in FDACMC Discipline Review Letter

NDA 22-307 (0032)

Drug Name:Formulation:Applicant:Submission:

Submission Date:Received:

April 30, 2008June 2, 2008

Reviewer:

Background:

Elena V. Mishina, Ph.D.

On April 30, the sponsor sent a CMC amendment in response to the FDA requests forinformation.

The chemistry reviewer requested a consult from the clinical pharmacology point ofview,to the Specific Concerns #1 on page 7. The question was, whether the clinicalpharmacology reviewer agrees with Lilly's conclusion that the Cmax difference observedfor the current formulation with PPI is ofno clillical significance.

Response:The Clinical Pharmacology review of the "Study of the Effects of a Proton Pumpfuhibitor (Lansoprazole) on the Single Loading Dose Pharmacokinetics andPharmacodynamics of CS-747.HCl and Clopidogrel in Healthy Subjects (TAAI)"contains the following Reviewer's Comments:

1. The exposures to the active metabolite (R138727) of prasugrel with and withoutlansoprazole passed the bioequivalence criteria with respect to AUC(0-8) and AUC(O­tlast). However, its rate of absorption (Cmax) was reduced by about 30%. The inactiveprasugrel metabolites demonstrated a similar trend for Cmax, AUC(0-8) and AUC(O­tlast) when the treatments with and without lansoprazole were compared.

2. Co-administration of lansoprazole with prasugrel did not affect the pharmacodynamicresponse to prasugrel, the changes in mean IPA were <10% at each time point.

3. The PK of the inactive metabolite of clopidogrel was not affected by coadministrationof lansoprazole.

4: Since the 30% differences in Cmax values for the active metabolite ofprasugrel did notchange the PD response, this differences probably would not be of clinical significance,and a dose adjustment ofprasugrel when administered with lansoprazole is not required.

Clinical Pharmacology Review. lND 63.449& NDA 22-307

Recommendation:

6110108

The Office of Clinical Pharmacology reviewed the CMC amendment in response to theFDA requests. The clinical phannacology reviewer agrees with Lilly's conclusion that theCmax difference observed for the current formulation with PPI is probably of no clinical .significance.

Date-------Elena Mishina, Ph. D.Clinical Pharmacology Reviewer

Patrick Marroum, Ph. D.Cardio-Renal Team Leader

cc list: NDA 63,449, MehuIM, UppoorR, MarroumP, MishinaE, SrinivasacharK, Ge,Zhengfang HFD 110 BIOPHARM

2

Clinical Pharmacology Review. IND 63,449& NDA 22-307

APPEARS THIS WAY ON ORlGINAl

6/10/08

3

This is a representation of an electronic record that was signed electronically andthis page is the manifestation of the electronic signature.

/s/

Elena Mishina6/10/2008 10:40:37 AMBIOPHARMACEUTICS

Patrick Marroum6/11/2008 05:26:50 PMBIOPHARMACEUTICS