Eli Uily and Company
`
`Roc~vi|Ie. Maryi~n~t 20552
`301.770.078B
`F~u~ 30~.°~1.6,317 .
`
`Feb~ary 16,2000
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`DMsion of Oncology Drug Products, HFDo~50
`Attn: Mr. Alvis Dunson, Project Manager
`"[45~t Rockville Pike
`Rockville, Maryland 20852-1448
`
`Briefing Document
`
`LY231514 (MTA, MultiTargeted Antffolate); IND # 40,061 Serial No.: 207
`Briefing Document for March 1 Meeting to Discuss Vitamin
`Supplementation in the Ongoing Mesoit3elioma Registration Trial
`
`Reference is made to Eli Lilly and Company’s submission to th~ LY231514 IND
`(#40,061) on January 25., 2000 (serial no. 203).
`
`We thank the FDA for granting the meeting on March 1, 2000 from 10:30 &M.
`until noon to discuss the implications of adding vitamins to the ongoing
`mesothelioma registration trial (H3E-MC~IMCH). The bdei~ng document is
`enclosed. The major points for discussion at this meeting are as follows:
`¯ The rationale for the intervention of adding folic acid for patient safety
`¯ The implications of adding folic aci6 to the ongoing mesothelioma
`registration tda! (H3E-MC-JMBQ)
`o Lifly’s proposal for changes in the second-line NSCLC registration trial
`(H3E-MC-JMBQ).
`
`,As related to the third point above, Lilly proposed changes to the current NSCLC
`registration trial (H3E-MC-JMBQ) on October 14, 1999 (sedal no. 186). On
`December 1, 1999 the Medical Reviewer, Dr. White, sent to Lilly several
`questions regarding the October 14 Lilly proposal. Lilly has not previously
`provided answers to Dr. White’s questions due to the fact that we were focusing
`on the folio acid supplementztion issue and also we were awaiting the resutts of
`the Oncology Drug Advisory Committee meeting in December where docetaxel
`for second-line NSCLC was discussed.
`
`FEB 16 281~t 16-’09
`
`PAGE.
`
`CONFIDENTIAL
`ELAP00013758
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1076-0001
`
`

`
`Lilly now is again proposing changes to this NSCLC regi~bation trial in today’s
`briefing document, and to aid the FDA in preparing to answer our questions
`regarding this trial, we have provided answers to Dr. White’s December 1
`questions (see Attachment 2 to the Briefing Document for these answers).
`
`We again thank the Division of Ontology Drug Products for its assistance in the
`deve~opmer~, of LY231514. P~ease cart Mr. John Worza|ta at (317) 276-5052 or
`me at (317) 277-3799 if there are any questions. Thank you for your continued
`cooperation and assistance.
`
`Sincerely,
`
`ELI LILLY AND COMPANY
`
`Gregory T. Bropfiy, Ph.D.
`Director
`U.S. Regulatory Affairs
`
`Enclosure
`Briefing Document
`
`P~GE. ~3
`
`CONFIDENTIAL
`
`~--I
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1076-0002
`
`

`
`DEPARTMENT OF HF.ALTH AND HUMAN SEP~V1CES
`PUBLIC HF.ALTH SERVICE
`FOOD AND DRUG ADMINfSTRA’RON
`INVEST~GATIONAL NEW DRUG APPLICATION (IND)
`~tTt~ 2f, CODE OF FEDERAL REGUL~ON_S ~’CR_R R~ 312)
`
`NAME OF ;SPONSOR
`
`ELI LILLY AND COMPANY
`ADDRESS (N~Jer. S~.~ C~. ~
`
`Lilly Corpor~t~ Csnter
`Indianapolis, IN 462B5
`
`Compound LY231514 Disodium (MTA)
`
`I ~. D AT~ OF SUSM]SS=¢N
`
`Februa~ 16. 2000
`
`4. TI:-’I.EPHONE NUMB~N
`
`(317) Z7~2000
`
`[ND 40,051
`
`PHASE(S) OF CUh[ICAL [N’,,’F...~’IGAT1oN TO e£ CON~JCTI~O: O Pl.t,~£ I L3 PHASE Z O PHAS~ 3 Q OTHER
`
`LIST NUMBE~RS OF ALL INVESTIGATIONAL N~gV ORU(3 APPMCAT|ON~ (2~ CFR P,~ 312~, N~.N’ DRUG OR ANTI~IO’1’~C AF’i:’LtCA’T1oNS
`~ CFR Part 314), DRUG MA~’~R RLES (21 GFR P-~1314.4Z0)o ~ PRODUCT LIC~.NSf~ APPLICATION~ ~21 C,~R PPJt 607~ RF_FERRED
`TO IN ~15
`
`NA
`
`IND submLss~on should be consecutJve]y numbered. The ir~tfai IND should be numbered
`*SePal number:. 000." The nP.x~ (cid:128)4tbrai~ion (p_g. amendmen~ ~’epo~, or correspondence)
`shoufd be numbered "Serial Numbe~. 001." Subse~Jen= submissiot~ shouid be
`numbered consecul~el¥ in the order in wlde.h they are Submffted.
`
`THIS SUBMZS.~ON CONTAINS THE FOLLC~G: (Che¢~ a/l ~aza,o,o/j9
`O IN~ tNVEb"r’[GATIONAL N~ 0RUG~PPUCATiON {INO)
`
`PROTOCOL
`~ NEW PROTOCOL
`1~ ClI~NG~ IN PROTC~:OL
`I~ NE1N INV~rlGA’rOR
`
`INFORMATION
`I~ CHEMt,~£RY/MICRO 810f..OGY
`1~) PHARM~C~LOGWTOX ZCQLOGY
`~ CLINICAL
`
`I~ P~S~:~3NSE TO CUN!CAL HOLD
`
`~I~D SAFETt" REPORT, S|:
`
`O INtT~L WRrI,~_N REPORT
`C~. FOLLOW .AJP TO A WR~Ft"~N R~PORT
`
`CI f~SPON3E TO FDA REQUF.~’r FOR IMFOR~’nc~I
`C~ REQU£ST !=OR RE1N..~’AT=_.MENT OF INO THAT LR VO"I’HORAV~I.
`INACTWATED, "~’RMINAT~O OR OISCON’r[NUL~D
`
`Q/q~UAL REPORT
`Q OTHER.
`
`¯ GENI~RAL CORRI~SPONO~NCE
`
`CHECK ONLY
`
`FEB 16 2~88 16:~9
`
`CONFIDENTIAL
`ELAP00013760
`
`Sandoz hie. 1PR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1076-0003
`
`

`
`1. Fom~ FDA 157~ ~21 CFR
`2. Ta~Ie of Contents ~I CFR
`
`Q a. S~ pro~(s)
`
`B. P~~ and ~gy
`9. ~e~i~ human exped~
`10. ~5on~ in~6on ~1 C~ 312.23(a)(10)]
`
`i~. ~ISANYPARTOFTHECLIN[CALSTUOYTOBICCONOUCTEDBY’A.C~’~TRACTF~$F.ARCHORGAN~O~ QYE,.~ QNO
`
`IF YES. WILL ANY SPONSOR (~ELIGATIONS BE TRANSFERRED TO THE C0~’r’RACT RESEARCH ORGANIZATI.0N? Q YES Q NO
`
`tF YES. ATTACH A ~’rA~F.,MENT CONTAINING; 1"H~ NAME AND ADDRE3$ OF THI~ coNTRACT RES,~A.RCH ORGANIZA’t3ON.
`tDENTIFICA’RON OF THE CUNICAL STUDY, AND A LISTING. OF "rH~ O~LIGA3IOhLS TRANSFIERRJE).
`
`I~’VSST~GAT] 0 ~.3
`
`James Rust~toven, M.D.
`
`~ OF ~E ORU~
`
`Same as "#14 Above
`
`in
`
`~ccordacFe" -~h ,~J. {,t~e~’ apDtica~e regu~at0rf r~q,.dremen~,
`’~S, NAME OF SPONSOR OR SPONSORS AUTHORIZED
`REPR~SENTATIV~
`
`Gregow T. Btophy, Ph.D., DirecIor
`U:S. Regu~a~on]
`
`EI~ Lilly and Company
`LSy Corpora~ Cerder
`Indianapolis, IN 46285
`
`(317) 277-3799
`
`Title I~ S~ 100%)
`~e 100 ~ ~r ~, ~g ~ dine ~ ~ng ~o~ ~
`
`FORM FDA 1S’1I
`
`PAGE2 OF 2
`
`FEB 16 2000 16:10
`
`381881631?
`
`PAGE.
`
`CONFIDENTIAL
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1076-0004
`
`

`
`TH IS DOCUMENT CONTAINS. T’RAD E. SECRETS,
`OR COMMERCIAL OR FINANCIAL INFORMATION,
`PRIVILEGED OR CONFID ENTIALDELIVERED
`IN CONFIDENCE AND RELIANCE THAT SUCH
`INFORMATIONWiLL NOT BE MADE AVAILABLE
`TO THE PUBLIC WITHOUT EXPRESS WRITI’EN
`CONSENT OF ELI LILLY AND COMPANY
`
`CONFIDENTIAL
`ELAP00013762
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1076-0005
`
`

`
`Briefing Document
`16 February 2000
`
`Confident|!!
`
`Page I
`
`W16~000
`
`CONFIDENTIAL
`ELAP00013763
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1076-0006
`
`

`
`PURPOSE OF THE MEETING
`
`RATIONALE FOR PROGRAMMATIC INTERVENTION
`
`5
`
`Folin~c A~d versus
`
`Summary of Data on the Relatiomldp Between Folle Acid and the Toxidty or Activity of Anfifolates~
`
`Cancer ~ Pre~|ini~ Dant
`
`C~r - Clin~cal Da~x
`
`Rheur~toid Arthri~
`
`Relevance of Homocysteh~e to Folate Metabolism
`
`.(cid:128)~d’ety Analysis and ~a~onsOe for Pr~granm~ffc Intervention
`Synopsis of Safety Analys~s Findings
`Clinical Retevan~ of Hom~ysteine to LY231S 14
`
`IM~-I Mortality a.qd Safety Interv¢~lions
`
`6
`
`7
`
`9
`
`10
`
`10
`
`10
`
`1!
`
`11
`
`impw~e ~ff~ s~e~ in ~31514 ~ri~ ~ ~a~ ~ai~ ~w ~ follc a~d s~ptement~on approp~ate~
`
`se~es th~ pu~os¢?
`
`RECENT CONCERNS THAT A RANDOMIZED TRIAL OF LY231514 WITH
`FOI3C ACID VS LY231514 WITHOUT FOMC ACID IS NO LONGER FEASIBLE
`13
`
`Ethic! Comlderatlom
`
`Legbtical Considerations
`
`13
`
`I3
`
`Question lb Does t~e FDA agree thor a randomized trial ~a~g ~tien~ receiv~8 L~315!4 with a~
`
`without vitam~s ~ no longcr~le or advbable 8iven the ~n~trated toxic~ ~ to ~51514
`
`~tients?
`
`I4
`
`STATIS’I~CAL IMPUCATIONS FOR PROPOSED ANALYSIS OF JMCH DATA
`15
`
`£~¢a~" Analysis
`
`S~ety Analy~b
`
`i5
`
`16
`
`Confidential
`
`Page 2
`
`2/16/2000
`
`CONFIDENTIAL
`ELAP00013764
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1076-0007
`
`

`
`a~r~ ~ ~pact of th~ foli¢ acM xupplem~ation ~e~enn~n
`tria! will s~ll q~h~ ~ a ro~mized, ~lf-cont~lled t~al for ~e meso~elio~
`
`PROPOSED CHANGES TO THE SECOND-LINE NSCLC STUDY JMBQ
`
`18
`
`Question 3a Does the agency suppor~ th~ replacement of vinore/bin~ with doeetaxel as th# comFarator in
`
`the JMBQ ~atdy? I$
`
`the role of a randomized, well-~onzrol!td ~rial in support of the mesorhelioma and second-line
`
`indications, a~ prevloasly dtscusxed in th~ End.of Pha.~e !i meeting in Jun~ of 19997
`
`REFERENCES
`
`19
`
`20
`
`ATgACHMENT 1 LIST OF COMMUNICATIONS BETWEEN THE FDA AND
`LILLY CONCERNING LY231514 FOR MESOTHELIOMAAHD NON-SMALL
`CELL LUNG CANCER
`
`22
`
`ATTACHMENT 2 LILLY’S RESPONSE TO FDA GOMMUNICATION OF I4
`OCTOBER 1999 :30
`
`Confidential
`
`Pa~e 3
`
`2/16/2000
`
`CONFIDENTIAL
`ELAP00013765
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1076-0008
`
`

`
`Purpose of the Meeting
`
`The ongoing registration ~al, 1-13E-MC-~MCH (3~CH for brevity), has been modified
`through addition of folic acid for the purpose of promoting patient safety. The Medical
`Review Officer has stated that he does not support the.addition of vitamins to an ongoing
`registration trial (FDA communieatious to Liay on December 2I, 1999 and January
`2000). Th~ sponsor has sought a face-to-face me~ting to come to agreement as to
`implications of the aetioa of adding relic acid t~ the pivotal registration trial a~d for
`supporting trials.
`
`In addition, Lilly would llke to discuss proposed modifications to our second-line NS(7~C
`trial supporting the mesoth¢lioma registration trial. This document includes the issues
`that w~ ar~ s~Idug guidane~ on and background irtfonna~on r~latex[ to daes¢ issR~.
`
`Confidential
`
`Pa~e 4
`
`2/16/2000
`
`CONFIDENTIAL
`ELAP00013766
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1076-0009
`
`

`
`Rationale for Programmatic Inten, ention
`
`Compound Overview and Link to Fotate Metabolism
`
`The antitumor activity of LY231514, a mulfit~rgeted antifolat¢, is derived from
`simultaneous and multiple inhibition of s~vend key relate-requiring enzymes of
`thymidine and purine biosynthetic pathways. LY231514 bus been found to inhibit cell
`
`.growth by interfering with the action of the emymes thymidylate syachase (TS),
`~ihydrofolatg rcduct~s¢ (DHPR), and giyc~de ribonucleotid¢ formylt~ar, sferase
`(GARYT) by competing with the reduced re]ales 5,10-m.e~ylene [¢Ira~ydrofolate,
`dihydrofo]ate, and I0~forrayl tetrahydrofolate for binding rites on the r~pectiv¢ enzymes
`(S]fi~ ct al. 1997). Thus, the mechanism of action of Lg2~1514 and ot~¢r folio acid
`analogues such as msthottexat= and Iometrexd is crJticaJJy Iirtl~ to intracellular relate
`metabolism. The ~ffects of antifolates axe also sigrfificandy modulated by ~e re.aden
`of intracdlul~ po]yglutamates. Polygluta~ates axe rc~aincd wiflfin the cell for long
`periods t~us increasing the po~ncy of the mtifolat¢. ~ ~didon the polyglumma~¢
`derivatives of LY23LS14 are significantly mo~e potem irflfibitors of TS and GARFT than
`the parent compound and may thus serve to er~anc~ the action of the drag on
`targets.
`
`Preclinical and clinical smdie, s evaluating the impa~ of di¢ta~ folio acid on the toxicity
`or effica~ of andfolate~ such as LY231514 a~d lometrexol have been reported. Because
`tumor tissue and normal tissue, such as bone marrow, presumably have different relate
`req~fircments, it is possible to decrease the toxicity to heald;y tissu~ while maint~nlng
`anti,rimer effect through careful adjustment of relic acid iat~e. This has be~n shown in
`experimentaI systems for LY231514 and ano~er antifola~(cid:128), lometmxol (Womatla et al.
`1998; Alafi et al. 1996) and in clinlcal trials with lometrexol (Young et zl. !992;
`Laohavin~j et~. 1996). !a addition, it has be.~a ciinicallyobserved that the efficacy of Iow
`dose rn~otrexat~ used in ~h= treatment of rheumatoid arthritis is not negadwly affected
`by folio acid supplementation, while an improvement in t0XiCityis $~n (Morgan et al.
`1998).
`
`Folinic Acid versus Folio ~tcid
`
`If a padem receiving an antifolate experiences ~evet¢, life-threatening toxicity, standard
`medical treatment inCiudes rescue with high do~es of th~ reduced relate leucovod~
`(folinic acid). Because relates are not efficiently stored in the body, depletion and
`repletion can occur relatively qttickly with suppten~ntatio~ For example, megaloblastic
`hematopoeisis reverts to normal hematopoeisis witlfin 12 to 48 hem’s of folinic add
`supplementation (Antony 199t). Reversal of z~ethotrexat~ toxicity by folinic acid is due
`
`Confidential
`
`Page 5
`
`2/16/2000
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`ELAP00013767
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1076-0010
`
`

`
`to rcp]euishment of the tetrahydrofohte pool by folinic a~id and is therefor¢ non-
`competitive with respect to methotrexate. In the case of LY231514, reversal may be
`achieved by (i) competition of foliui¢ acid fo~ enzymatic binding sites and (ii)
`competition for the formation of the more potent polygiutamate forms of the drag.
`
`There are a number of re,sons why leucovorin is used as a rescue agent and folio ~cid is
`not, Folio acid is not used by the body as is, b~t must undergo a wansformation to its fully
`
`reduced form before it can be utilized as a cofactor in the one-carbon transfer r~actions
`critical in gne synthesis of thymidine and puriaes. Folb: acid is also a very poor substrate
`for an enzyme that catalyzes this reduction, dihydrofolate xeductas¢, which is why this
`reduction is probably the ram-limlting step for folio acid utilization in mammalian
`sysmrns. Folinic acid, on the other hand, is already fully reduced and is available for use
`as a cofactor in thymidine and put-ins synthesis as quickly as it can b~ Wansported into the
`
`In biological systems, the reduced folat~ carrier (RFC) is the predominant mechanism of
`relate transport imo cells. Whim folirdc acid is very efficiently transported by RFC, relic
`acid is aot. This limits Ih(cid:128) amount of folio aci~£ ta~mt can ~uter the cell via this mechanism.
`
`Folinic acid is preferred ovex folic acid as a resc~ agent when cells at risk for toxicity
`require reduced relates quickly. By conwast,.folic acid is a normal dietary supplement and
`can replenish relate pools efficiently, albeit n~or¢ slowly, at low oral doses. Thus dietary
`folio acid may be useful in modulating the toxicity of antifolat¢ chemotherapy agents.
`
`Summary of Data on the Relationship Between Follc Acid and
`the Toxicity or Activity of Antifolates
`
`Cancer - Pre¢ilnical Dsta
`
`Worzalla and coworkers have studied the eff¢cts of relic acid on the toxicity and
`mtitumor activity of LY231514 in [he in vitro and in rive settings. In a number of
`human tumor cell lines, folio acid protected teals from ~cytotoxicity at concentrations 100-
`to 1000-fold higher than those required for folinic acid protection, indicating that the
`action ofLY231514 is less sensitive in vitro to relic acid than it is to i~olinic acid. They
`also found that in mice fed a low relate diet (LFD), tumor growth inhibition was complete
`a~ LY231514 doses of 0.9 to 3.0 rag/m2, with 100% lethality occurring st LY231514
`dosts of 9.0 rag/m2 or higher. ~ receiving tim Smzx¢ IJFD who were supplemented
`with high dosss of relic a~id at 15 mg/kg/day (a dos~ approximat¢ly lO-fold greater than
`that in the normal diet) experienced complete tumor growth inhibiti0n at LY231514 doses
`
`of 90 to 3000 rag/m2 without any l¢thality. Mice on the standard di,t (approximamIy one
`tenth of the folic acid given to the supplenmnted mice) saw a virtually identicaldose
`
`Confidential
`
`Page 6
`
`2/16/2000
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`ELAP00013768
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1076-0011
`
`

`
`t
`
`f
`
`response, but grea~er lethality, with I00~ lethality occurring a~ 2400 mgim: (WorzaLla et
`aL 1998).
`
`Doses of LY231514 for Maximum Antitumor Aotivity and Lethalit
`
`’in Mice
`
`Diet
`
`Doses" of
`LY231514 Where
`
`Antitumor Activity
`is Observed
`From 90 io 1200
`
`From 90 to 3000
`
`Dose~ of
`LY231514 Wher~
`Lethality is
`Obse~ed
`2400 (100%
`
`(No lethality se~n up
`to3000)
`
`These dam show that aatitomor activity is vin~zally identical in mice r~ceivi~g a standard
`diet to that in mice receiving a 10-fold increase in daily folio acid. Mice ~ceiving h’~
`extra folic acid also showed a decreased lethality at h~ghvr doses of LY231514, Th~se
`data support the hypothe.sis that relic acid supplera~tation can protect healthy tissue
`from ths toxic effects of LY231514 with retention ot’ antitumor activity.
`
`The effect of fola~ stares on the efficacy a~d toxicity of chemotherapy was also
`investigated in we~,~l;ng FLscher 344 rats m~irttained on diets of varying relate content or
`supplemented with daily inj~ctiov.s of relic acid, 50 mg/kg, for 6 to 7 weeks. R~ul~s
`showed that corre~ort of relate deficier~y approxirn~ely d~bled ~l~ efficacy of
`cyclophosphamide in rats with much l~s host toxicity, and folam repletion improved
`survivM ~n 5-FU-trea~i :~r~Is. This indicates that nutritional folat¢ status has an
`important influence on the efficacy and toxiciw of som~ commonly used
`chemotherapeutic drugs (Branda et al. 1998).
`
`Cancer - Clinical Data
`
`A study ofLY2315.!4 ]n gas~c cancer began Mlate 1996. After3 o~the first 6 patiems
`treated died, enrollment into this study was suspended. At that time, the protocol was
`modified to include folio a~id supplementation at 5 mg peX day 2 days before, tke d~ty of,
`and 2 days a~ex the administration of 500 rag/m2 LY231514. This level of folio acid
`supplementation has been show~ to be effecti-ce in lowcri~g homoc3tste~e levels in a
`phase I study of LY231514 and relic acid. In the 7 patients treated since the _~tudy
`started, there have b~en no drug-r~lated deah’as, and responses have been reported in three
`patients (2 CR, I PR).
`
`Confidential
`
`Page 7
`
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`CONFIDENTIAL
`ELAP00013769
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`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1076-0012
`
`

`
`LY231514 lrl Gasldc Cancer -Tdel Resulm
`
`Patient
`Number
`
`l.,Y231514/f0iic acid # Cycles O~tcome
`received
`
`Patients without Folle Acid Supplementation
`~00 mg/m2/none
`6
`$~able
`2
`500 m~m2/none
`Discontinued due ~o neutropenia,
`death 3 weeks later
`Di~onfinu~ due ~o an adverse event
`Death from dru~-rdated anemia
`~o~ne~ive diaease
`Death from drug-relal~d toxicity
`(vomiting and diarrke~ leading
`renal failure)
`
`500 mg/m2 [none
`
`500 m~m2/none.
`500 rag/m2
`500 rag/m2/none
`
`1
`1
`4
`2
`
`1
`2
`
`62
`186
`
`4
`
`6
`7
`8
`9
`~0
`
`Patients with Folk Acid Sup
`’ 500 mg/ra2/5 mg x 5
`6
`500 mg/m215 rag x 5
`6
`6
`
`,lementation
`Stable disease,
`I~trt~ response--confirmed
`Stable dL~ea,~
`
`500 mffm2/5 m~ x 5
`500 m~!m2/5 mg × 5
`~00m~/m2/5 m~ × 5
`
`5
`2
`
`Complete ~- confirmed
`Pro~zes$1ve disease
`Complete response- po~-ba~eEne
`meeaurement by vchocardiogra~hy
`
`Although these data are preliminary, they point out that folic acid supplv~ntation of
`patient s receiving LY231514 as tre.al~nt for cancer may:
`
`I) Lead to s rezluctioa in severe ~oxidty and drug-related death
`
`2) Allow patients to ~ceive thexapy for more cycles, resulting in
`
`3) Retention of antimmor activity (ttkn~ responses in seven patients).
`
`In a dose-finding phase I study of lometrexol, a GARFT inhibitor, 53 patients were
`entered and received Iome~vxol, with 19 also rvce, iving oral folio acid at 1 mg/m~ datty.
`In patients who did not ~eceive folio acid, the maximally tolerated dose was 2.7 mg/m2
`twice weekly, a~d cmmuIafive toxicity was ob~e~rve.d, In pafi~n~ ~c¢iving fo}~c add, the
`maximally tolerated dose Was 4 to 5 mg/m2 twice weeldy, with no cmnulative toxicity
`observed- In 9 of these patients, mr/tumor effects were observed, with one patient
`experiencing a complete response of 18 months in oxophafyngeal cancer (Young e~ al.
`1992).
`
`Confidential
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`Page 8
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`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1076-0013
`
`

`
`Rheumatoid Arthritis
`
`Several trials have heron conducted to evaluate the ~ffects of oral relic acid on the toxicity
`associated with long-term, low-dose methotrexate in the treatment of rheumatoid arthritis.
`Two of note are summarized here.
`
`To determine the effect of either 5 mg or 27.5 mg of relic acid weekly on the toxicity aud
`efficacy of low dose oral methotrexate therapy for lheumatoid arthritis, a randomized,
`double blind, placebo-controLled study was .condu,~ted in 79 patients (Morgan ¢r al. I994).
`Folio acid supplementation at either dose did not affect th~ ~ffi .c~y of m~thotmxate
`therapy. Patients given folic acid supplements had lower toxicity scores than did the
`placebo group. Low blood relate levels and ima’eased mean corpuscular volumes were
`asseciated with substantial methOLmXam toxicity. It was concludvd that fell(cid:128) acid is safe
`in a broad range of doses and protects patients with rheumatoid art~tis from
`methotr~xate toxicity while preseawing efficacy.
`
`Thirty-two patients with rheumatoid m-thdtis completed a 24-we~k, placebo-controlled,
`double-blind ~al of relic mid (FA) supplementation during low-dose methotrexate
`(MTX) therapy (Morgan et al. t990). Administration of the daily FA supplement
`significantly lowered toxicity scores without affecting efficacy, as measured by joint
`counts, joint indices, and physician evaluation of diseas¢ activity. Fifteen patients
`experiential some sort of toxicity; 67% in the placebo group, and 33% in the PA
`supplement group. Four patients in the placebo group had toxicity levels serious enougtz
`to require discontinoation of the MTX, while no patients in the FA supplement gzoup
`discontinued MTX because of toxicity. It was concluded that a daily supplement of I mg
`of FA during low-dose MTX therapy is useful in lessening toxicity without altezing
`efficacy during th~ first 6 month.s of treatment.
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`Biochemical Relevance of Homocysteine to Folate Metabolism
`
`One of the principal routes o~ hoznocysmine metabolism is the f.olate-d~pend~nt
`mechm~ism. Through this route, homocysteine is corwerted to methionine by the enzyme
`metMoni~ae synd~ase, which is dependant on vitami~ B12 and incorporates amethyl group
`from 5-methylmtrahydrofol~ itxto homocyst~i~e, giviag methiot~a¢. Th~refor¢, ~ relate
`deficiency will result in lowered tnethioni~¢ synthase activity and lead to a.a elevation of
`plasma homocysteine levels. Indeed, homocysteine has tmen fouad to be a semidve
`m~rlcer for folio acid as well as B 12 deficiency (Morgan et al. 1991; Selhub aad Miller
`1991).
`
`Recent studies in cardiovascular patients have suggest,d that relate supplementation with
`or without supplementation with BI2 ~md B6 can signifiea~dy reduce homocysteine
`levels (Homocysteine Lowering Trialists’ Collabozation 1998; Malinow et el. 1998).
`Follc acid supplementation of 400 Fg daily i~ eld¢rly patients.with elevated homocysteine
`has been shown to substantially reduce plasma homocysteine within 2 weeks. The lev¢!
`continues to drop slightly for another 2 wee~. and then plateaus (Bronstrup et aL 1999).
`Brouwm- and coworkvr$ showed that low dose relic acid (250 pg - 500 ~g) intervention
`significantly deceases homocyst¢ine levels. An g-week washout period was not sufficient
`for blood relate a~d plasm~ homocysteine levels to return to baseline (Brouwer et el.
`I999). Ni~kiza e~ al have shown ~at in pati~ts who a~o not s-opplemented,
`homocysteine levels do not change over the corn-(cid:128)(cid:128) of treatraent with LY231514 (Niyikiza
`et el. 1998).
`
`Additionally it has been sho~m that mic~ on tow relate diet also have high plasma
`homocysteine levels (Worzalla et ld. 1996) ami that supplementation with dietary folio
`acid reduced the plasma homocystei~e level~ to near norxnal levets.
`
`On the oth~ hand, TS, DHFR and GAI~T m¢ not lmowa to have any binding sitt~ for
`Bi2 or B6 and arc not known in any way to be affected by thes¢ two vitamins. Thereffore,
`increasing the c¢tlular concentratio~ orb 12 a~d B6 is not exlmct~d to have an impact on
`the growth inhibitory effects of LY231514-.
`
`Safety Analysis anti Rationale for Programmatic Intervention
`
`Synopsis of Safety Analysis Findings
`
`Multivariate and multiple logistic regression analy~e, carried out by Niyikiza and
`coworl~rs have shown that a patient’s pre-tr~atm~nt serum homocysteine is a statistically
`significant lm~dietor for his or her risk of developing s~rious toxicity (Grade 4
`neutrolxmia + Grade 314 i~fection, Grade 4 thlombocytopenia, or Cwade 314 diarrhea,
`p <0. 00001) during the com-se of treatment with LY231514. This analysis w~s FaTormed
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`on patients from several trials in multiple tumor types. (Safety analysis communicated to
`F’DA on 03 D~cember 1999.) Specifically. a homocysteine level above 12 pznol/L puts a
`patient at a much greater risk of developing s,vere toxicity than a homocysteine level
`below this thmsh01d level. Mul~ivaz-iate modeling also showed that toxicity such as Grade
`4 neutropenia coupled with Grade 3/4 infection is sig-aificantly correlated with death (p
`<0. 0O001). Although the sample size of patients who died from drug-related death and
`who also had homocyst¢ins levels measured istoo small (n = ! 1) to provide any direct
`correlation between elevated homocysteine le~ls &nd death, this relationship may be
`inferred.
`
`Clinical Relevance of Homocystelne to LY231514 Studies
`
`These data clearly point out the clinical relevance of homocysteine to LY231514 studies.
`While hematologic toxicity does not always remlt in clinical symptoms, we have found
`that patients who experience Grade 4 neutropoaia coupled with Grad, 3 or4 infection am
`at a higher risk of death. Because a patient’s pie-treatment homocysteine level is an
`extmrn~ly sensitive predictor for severe hematologic toxicity, we are collecting this
`information on each patient.
`
`JMCH Mortality and Safety Interventions
`
`In the ongoing mesotholioma registration trim ~n which nearly 40% of patients have
`elevated (defined as greater than 12 tLrnol/L) homocysrelne, 3 treatment related deaths
`occurred in th, first 42 patients on.rolled into the CXl:ma-hnental arm (LY231514 and
`cisplatin). This infotrnation, coupled with the results of the multivariate analyses of
`safety, led Lilly to explore intervention options, as well as to seek guidance from external
`experts. The consensus re.suiting flom this series of disenssions was ~bat a 7% rate of
`death in a registration trial is unacceptable and that an intervention shouId be taken
`immediately. LiLly decided to give folio acid and BI2 to all patients for the following
`
`_r@aSOn~S:
`
`Given the strong body of d0t:~ discussed above, we feel that daily supplementation of
`all LY231514 patients with a daily low-dose of relic acid and periodic BI2 injections
`
`will aLlow the great~st number of patients with mesothefioma to benefit from
`t~eatment with this novel arttifolate while also providing for greater patient safety in
`atI LY231514 trials.
`
`Patients whose homocysteiae is less than 12 p~nol/L may also experience a benefit
`from low dose folic acid supplementation. That is, a reduction in homocystein, may
`be seen even itx patients with homocysteine lower nan 12 pmol/L, and thus, these
`patients may also benefit from supplementation.
`
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`In our database, 15% of patients have elevated methyl maloni¢ acid, a marker for
`vitm-dn B12 deficiency, and there is a risk that some of these patients may not scv a
`decrease in homocysteine with relic acid suppIementation alone. Therefore, we are
`also recommending B 12 injeclions a~ regular intervals for a!l patients.
`
`The level of supplementation that we have in]plemented (--450 ~tg/day) is noz high, ~nd in
`fact is similar to the US recommended di~tav/allowance and the amount r~¢omm~nded to
`pregnant women to reduce the risk of neural tube defects, and also to coronary he.ar~
`patiems to reduce the risk of cardiovascular events (Berry et a1.I999; Czeizel I993~
`Rimm e[ al. 1998; Graham 1999; Bmnstmp et al. I999; Brouw~r et al. 1999). We
`strongly f~i tha~ the balance between thv risk of sevvre toxicity to patlcnts and the
`concern of a detrirnentaleffe~t on ma~itumor ~ctiviry is now weighing in favor of zeducing
`Loxi¢ity.
`
`Question la ..
`Does the FDA agree that toxicity and mortality data support a
`programmatic intervention to improve patient safety in L Y231514
`t~a/s and that daily low dose folic acid supplementation appropriately
`serves this purpose?
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`Recent Concerns that a Randomized Trial of LY231514 with Folic
`Acid vs LY231514 without Follc Acid is no Longer Feasible
`
`Ethical Considerations
`
`Given the strong body of data discussed ah0ve~ Lilly now feels that conducting a
`clinical trial in which patients would be randomized to receive or not receive
`vitamin supplements while receiving LY231514 weald be ill-advised. Exposing
`patients in the control arm to L’£23 I514, pa~iculady those with eIevated homocystcine
`levels, without the potential benefit of-~itamin supplemem su1~t would be ill-advis~d,
`particularly when all other patients in LY2315 [4 u~als arc receiving the supplements. For
`similar reasons, Lilly feels that investigators would be reiuctanu to era-oil patients to such
`
`a study and patients would be reluctant to con~ent to risk not receiving vitamin
`supplements, making the u-ial no longer feasible. Also, external consultants have said
`Ethical Review Beau:is would be relucUmt to ~ppro’~e a t~ial such as this.
`
`Logistical Considerations
`
`We have concer~s about the ability of patients to remain compliant on both arms of
`such a trial and also that the difficalty in.controlllng for dietary habits in the ]patient
`population is a significant confounding factor. The amount of folio acid that will be
`used to supplement LY231514 patients is extremely small (-450 p~/.day). For those who
`a~(cid:128) assigned to ~ceiv¢ vit~n supplements, ~ aro co~:emod thee, give~ the easy
`accessibility of muldvitandn and heal~ food store pret~rations, patients n~y knowh~gly
`or inadvertently rake additional relic acid supp]ements wh~le on the trial. Similarly,
`on the con~ol arm not receiving vitamin supp]esn~ts ~ a risk of taking folic acid in
`some o~¢r preparation while on study. Again, ~he e~ss by wl~ch such relic acid could be
`taken wi~ou~ knowing about it is subsU~ndal. Furthermore, it wo~d be very di~cult to
`control dietary 1make such that patients on the control arm would not be taking ~mounts
`of folic acid d~ough cormnercial cereal product supplementation or other dietaxy sources
`of follc acid and ~sk confom~ding ~(cid:128)
`results of the triM.
`
`While choosing a population a~ particular risk for nntddonal deficiency might b¢ best m
`answer d~e question most clearly, this population also ~kes nuL~fional supplements (eg,
`En~ure) ~eg~l~rly ~.d again th~s may confound d~e results. Choosing a more genexal
`population would potentially make the re.s~t r~ore generalizable but it wo~]d be very
`difficult to estimate ~e sampl~ size if efficacyis a primary ouu:ome, since effics_.’y data
`varies by tumor type. It will also be difficult to get investigators to agr~ to treat patients
`m the front line setting with single agent MTA where the response rates are high enough
`to cortsider a feasible sample size for a randomized vitamin versus no vitamin trial. If we
`
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`Question lb
`Does the FDA agree that a randomized trial comparing patients
`receiving L Y231514 with and without vitamins is no longer feasible or
`advisable given the demonstrated toxicity risks to L Y231514
`patients?
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`Statistical Implications for Proposed Analysis of JMCH Data
`
`Efficacy Analysis
`
`Lilly believes, as previoasly stated, that the addition of low amounts of folic acid will
`not adversely affect the prinmry endpoint of survival in the ongoing mesothelioma
`registration trial, JMC]]. The san~ intervea~tion of vitamin supplementation is applied
`at the same time to both arms for the purpose of maintaining the integrity of the bl~ding,
`and r~erefore, no systematic bias is JnU’oduced. Since the trial was sized based on
`surviva~ endpoint and since the initial