LY231514 (ALIMTA): Impact of Folic Acid and Vitar~
`B12 Supplementation on Safety
`
`04 June 2001
`
`Eli I~lly
`
`06/04/01
`L¥~3151~
`
`TRIAL EXHIBIT
`
`TX 379
`
`CONFIDENTIAL
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1088-0001
`
`

`
`Table of Contents
`
`LY231514 (ALIMTA): Impact of Folio Acid and Vitamin B 12
`Supplementation on Safety .................................................................... 1
`
`Introduction ............................................................................................. 3
`1.
`1.1. Background Information .................................................................... 3
`1.2. Supplementation with Folie Acid and Vitamin B 12 .......................... 5
`
`2. Objectives ............................................................................................... 6
`
`3,
`
`Impact of Folie Acid and Vitamin B12 Supplementation
`on Safety ................................................................................................. 7
`3.1. Definition of Patient Population and Statistical
`Methods ............................................................................................. 7
`3.2. Results ................................................................................................ 8
`Impact of Supplementation of Folie Acid and
`3.2.1
`Vitamin B12 on the Time Course of Plasma
`Homocysteine Concentrations ................................................... 8
`Impact of ¥itamin Supplementation of Folic Acid
`and Vitamin B 12 on Drug-related Death .................................. 9
`3.2.3. Impact of Vitamin Supplementation on Incidence
`of Severn Toxieities ................................................................. I0
`Effect of Folio Acid and Vitamin B 12
`Supplementation on the Antitumor Activity of
`LY231514 ......................................... : ...................................... 12
`
`3.2.2.
`
`3.2.4
`
`4. Conclusions ........................................................................................... 13
`
`5. References ............................................................................................. 14
`
`Appendix 1 ........................................................................................................
`
`Appendix 2 ........................................................................................................
`
`Case I-Iistodes for on-study Deaths or Deaths within 30
`days of Discontinuation from Study Related to LY231514
`Therapy for Patients Fully Supplemented with Folic Acid
`and Vitamin B12
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`1. Introduction
`
`1.1. Background Information
`Consistent with the toxicity profile of other antifolates, studies of LY231514 (without
`the supplementation of folic acid and vitamin B 12) identified myelosuppression as the
`principal dose-limiting toxicity, although nonhematologic toxicities of mucositis,
`diarrhea, vomiting and infection were also significant. The incidence of CTC Grade
`3/4 neutropenia observed for LY23 I514 was approximately 50% [ I], with the rate of
`possibly or probably drug-related death approximately 4%.
`
`Given the relevance of folic acid to the pharmacology of antifolates, it is reasonable to
`postulate that functional folate status could be an important predictor of toxicity.
`Studies have suggested that plasma homoeyste~ne is a much more sensifiv~ meas~e
`of functional folate status than is serum folate or red blood cell foIate [2, 3].
`Methionine synthase is a highly folate-dependent enzyme that converts homocysteine
`to methionine. Thus, under conditions of folate deprivation, levels of plasma
`homocysteine increase. Elevated serum homoeysteine can also result from vitamin
`B 12 deficiency. The methylated form of vitamin B I2 is a cofactor for methionine
`synthase. Under conditions of vitamin B 12 deficiency, the homocysteine levels will
`increase because of inactiviation of the e~yme.
`
`In 1998, a multivariate analysis was conducted to assess the relationship of vitamin
`deficiency markers, LY231514 exposure, and pre-specified baseline patient
`characteristics to toxicity following therapy with LY231514 [4]. Data were exanained
`from 139 Phase 2 patients with tumors of the colon, breast, pancreas, and esophagus
`who had been treated with s~gle agent LY2315 I4 at 600 rag/m2 IV ove~ 10 minutes
`once every 21 days. These patients had vitamin-deficiency markers of homoeysteine
`.(Hcys), cystathionine, and methylmalonic acid levels measured in plasma at b~seline
`and once each cycle thereafter. Stepwise regression modeling, multivariate analysis of
`variance, and discriminant analysis were implemented to determine which predictors
`might correlate with severe toxicity, and to predict which patients might be at high
`risk of experiencing such toxicity. Prognostic factors considered were age, gender,
`prior therapy, baseline albumin, liver enzymes, ANC, platdets, vitamin deficiency
`markers, and AUC.
`
`In the analysis above, the B12 deficiency marker, methylmalonic acid, was highly
`correlated with homocysteine and was therefore removed from the initial multivariate
`analysis conducted in 1998 to eliminate issues of eolineadty.
`
`The initial analysis conducted in 1998 led to the following conclusions:
`
`The frequency of severe toxicities resulting from therapy with
`LY231514 is highly statistically linked with baseline plasma
`homoeysteine levels and appears to be higher in patients with elevated
`pretherapy homocysteine levels.
`
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`Elevated baseline homocysteine plasma concentrations (210 ~M, for
`the 139 patients included in this analysis) highly correlate witfi the
`frequency of severe hematological (Grade 4 neutropenia and
`thrombocytopenia) and nonhematologie (Grade 3/4,mucositis,
`diarrhea, rash, or fatigue) toxieities following therapy with LY231514.
`
`Treatment with LY231514 had no effect over time on plasma
`concentrations of homocysteine.
`
`Due in part to an increased incidence of drug-related deaths (8.3%; 3 of 36 patients)
`observed early in the Phase 3 pleural mesothelioma registration trial (JMCH), a
`second and more comprehensive multivariate analysis based on 880 patients without
`folio acid and vitamin B 12 supplementation was performed in 1999 in order to
`determine which predictors might correlate with drag-related death (see pages 1-5 of
`LY231514 Annual Report submitted as Serial Number I94 to IND #40,061 on
`November 8, 1999; see also Appendix 1, LY231514 (MTA) Safety Analysis, 03
`December 1999; submitted as Serial Number 195 to l!qD #40,06I on December 3,
`1999). Because the decision to measure markers of relic acid and vitamins B6 and
`B12 metabolism in LY231514-treated patients was made during the Phase 2
`development of the agent, these marker levels were available in only 11 of the 43
`patients whose deaths were reported as possibly or probably related to LY231514.
`Stepwise regression modeling, multivariate analysis of variance, and discriminate
`analysis were implemented. Prognostic factors considered for LY231514-related
`deaths were age, gender, baseline serum albumin, liver enzymes (alkaline
`phosphatase, alanine transaminase, aspartate transarninase), ANC, platelets, AUC,
`pre-treatment weight, prior chemotherapy, tumor type, grade 4 neutropenia in
`conjunction with grade 3 or 4 infection (a surrogate indicator of febrile neutropenia),
`post baseline minimum platelet count, grade 3 or 4 diarrhea, and grade 3 or 4
`mueositis.
`
`This analysis led to the following conclusion:
`
`Grade 4 neutropenia accompanied by Grade 3/4 infection, Grade 3/4
`diarrhea, and tumor type were all significarttly associated with drug-
`related death.
`
`A total of 305 of the 880 patients had baseline vitamin markers measured and
`recorded. To eliminate the complicating factors of the effect of folio acid
`supplementation on toxicity or, for Phase t studies, those LY231514 doses not being
`pursued, any patient who received relic acid supplementation at any point during
`therapy or who received any dosing regimen other than LY231514 500-600 rag/m2
`was removed from the analysis, leaving a final sample size of 246 patients. Data from
`this subset of patients were analyzed to determine which predictors might correlate
`with severe toxicity and to predict which patients are at high risk of experiencing such
`toxicity, especially those implicated in drug-related deaths. Stepwise regression
`modeling, multivariate analysis of variance, and discriminate analysis were
`implemented. Prognostic factors considered were age, gender, baseline serum
`albumin, liver enzymes (alkaline phosphatase, alanine transaminase, aspartate
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`transaminase), ANC, platelets, vitamin deficiency markers, pre-treatment weight, and
`AUC, tumor type, and prior t~eatrnent.
`
`This analysis led to the following conclusions:
`
`Baseline homoeysteine plasma concentration was a statistically
`significant predictor for febrile n~uttopenia, Grade 4 neutropenia,
`Grade 4 thrombocytopenia, and Grade 3 or 4 diarrhea.
`
`The results confirmed the findings of the original multivariate analysis
`that homocysteine plasma concentrations may be an important
`prognostic variable for predicting toxicity during LY231514 therapy.
`
`.The data showed a trend of decreasing toxicity with decreasing
`baseline homocysteine level.
`
`The specific toxicities (Grade 4 neutropenia, febrile neutropenia, and
`Grade 3/4 diarrhea) associated with high-level baseline homocysteine
`were those toxieities associated with drug-related death.
`
`In contingency analyses designed to compare the rate of death in
`patients receiving a starting dose of 500 rag/m2 versus 600 mg/m2, it
`was found that there was no difference in the relationship between the
`incidence of drug-related deaths and starting dose.
`
`1.2. Supplementation with Folic Acid and Vitamin B12
`As a result of these analyses, it was postulated that reducing plasma homoeyst~ine
`concentrations in parents given L¥231514 would result in a reduction in the
`frequency of severe toxicity associated with this agent and consequently a reduction
`in deaths attributable to. study drug. In addition, because the predictive nature of
`baseline homecysteine level behaved as a continuous risk factor for toxicity, the
`decision was made to supplement LY231514 study patients. Beginning in 2000,
`patients on all new and most on-going trials with LY231514 were supplemented with
`daily folic acid 350-1000 pg throughout the entire treatment and vitamin
`B 12 1000 ~g IM every 9 weeks and this was communicated to the FDA in
`communications to the FDA (Serial number 195 to IND #40,061 on December 3,
`1999; 196 on December I0, 1999; 199 on December 21, 1999; 200 on December 22,
`1999; 201 on December 22, 1999; 207 on February 16, 2000; and during a meeting
`between Lilly and the Division of Ontology Drug Products on March 1, 2000).
`
`Most patients had a blood sampIe drawn for the measurement of baseline vitamin
`deficiency markers before supplementation began. A second blood sample for the
`purposes of measuring changes in vitamin deficiency markers following initial
`supplementation was drawn just prior to the first treatment with LY231514 and on a
`per cycle basis thereafter as long as the patient remained on study.
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`2. Objectives
`
`The overaII objectives of this report are to assess the impact of folic acid and vitamin
`B 12 supplementation on homocysteine levels over time and to compare the incidence
`of severe toxicities and drag-related deaths associated with LY231514 therapy
`b~tween patients with and without folic acid and vitamin B 12 supplementation. A
`patient was considered fully compliant if at least five doses of folie acid were taken in
`the 7 days immediately preceding the first dose of LY231514 and if at least 14 doses
`of folic acid were taken in the 21 days prior to Day 1 of the next scheduled cycle
`while on study. Compliance for vitamin B 12 was ensur~-d as this agent was given as
`an intramuscular injection at the investigational sites. This report will address the
`question of whether supplementation with folio acid and vitamin B 12 as described
`above improves the safety profile of LY231514.
`
`The specific objectives of this analysis are to:
`
`Assess the impact of folic acid and vitamin B 12 supplementation on
`the incidence of LY231514-relate~l deaths.
`
`Compare the incidences of severe toxicities associated with LY231514
`therapy that occurred through the f’wst 2 cyetes and that occurred
`through the first 7 cycles of therapy in patients who received
`LY231514, folio acid, and vitamin B[2 to th~se patients who were not
`supplemented.
`
`Compare total plasma homocysteine concentrations in patients with
`and without folio acid and vitamin B 12 supp!ementation in order to
`determine whether or not homocysteine leveIs decrease and remain
`stable over time when folio acid and vitamin B I2 are given.
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`3. Impact of Folic Acid and Vitamin B12
`Supplementation on Safety
`
`3.1. Definition of Patient Population and Statistical Methods
`Two groups of patients with solid trxno~s treated with LY231514 for at least 2 cycles
`of therapy were selected for this analysis and had a baseline homocysteine
`concentration obtair~ed. The first group includes 394 patients who wer~ never
`supplemented with folic acid and vitamin B 12 at any time during their therapy with
`LY231514 500-600 mg/m2. The second group includes 196 patients supplemented
`with daily folio acid and vitamin B12 from study entry. Table 3.1 shows the
`distribution of patients by trials included in this analysis for both patient populations.
`Patient populations were chosen to include both single agent and combination trials.
`
`All toxicities reported were based on the CTC grading scale. A comparison of the
`incidence of severe toxicities and LY231514-related deaths between these 2 groups of
`patients was performed using the Chi-square Test. Additionally, mean homocysteine
`plasma concentrations between the groups were compared over dine using the normal
`Z-test.
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`Table 3.1. Distribution of Patient Populations by Trial
`
`Without relic acid and vitamin B12 supplementation (n=394 patients)
`No. of Treatment Tumor type
`patients,
`34
`~4
`34
`17
`30
`5
`12
`24
`25
`t 2
`
`Si~g]e agcm LY23 | 51 (cid:128)
`Single agent LY2315 ! 4
`Single agent LY231514
`Single agent LY231514
`Single agent LY231514
`Single agent LY231514
`Single agent LY231514
`Single agent LY231514
`Single agent LY231514
`Single agent LY231514
`
`~
`
`Colorectum
`Pancreas
`Breast
`Esophagus
`Renally impaired
`Lung
`Lung
`Breast
`Breast
`Mesothetioma
`
`Study code
`
`HS~MC-JMAC
`H3E-MC-JMAD
`H3E-MC-JMAG
`H3E-MC-J’MAH
`H3E-MC-JMAW
`H3E-MC-YMBQa
`H3E-MC-JMBR
`H3E-MC-JMBT
`H3E-MC-TMDM
`H3E-MC-JMDR
`
`H3E-MC-J’MAQ
`H3E-MC-JMAR
`H3E-MC-J’MAT~
`
`40
`16
`5
`
`LY23151a plus gemeitabine
`LY231514 plus 5-fluorouracil
`LY2315|4 plus navelbine
`
`Any advanced cancer
`Coloreetum
`Any advanced cancer or
`lung
`Any advanced cancer
`LY23 t514 plus carboplatin
`26
`H3E-MCJMAU
`LY231514 plus CPT-I 1
`Any advanced cancer
`H3E-MC-JMAX
`1
`Any advanced cancer
`H3E-MC-YMBU
`LY231514 plus taxotere
`13
`Coloreetum
`H3E-MC-YMBV
`LY231514 plus oxaliplatin
`33
`Lung
`LY231514 plus gemcitabine
`H3E-MC-JMCD
`5
`Pancreas
`LY231514 plus gemcitabine
`H3E-MC-JMDL
`1
`
`H3E-MC-JMCHb ..... Memthelioma
`27
`L..y.,2.31514/cisplatin _
`With folk acid and vitamin BI2 supplementation (n=196 patient~)
`Treatment
`No. of
`patients
`38
`10
`21
`36
`
`H31~’-MC-JMAW
`H3E-MC-J/VlBT
`H3E-MCJMDM
`H3E-MC-JMDR
`
`Single agent LY231514
`Single agent LY23 l~ 14
`Single agent LY23 I514
`Single agent LY231514
`
`Tumor type
`
`Renally impaired
`Breast
`Breast
`Mesothelioma
`
`Lung
`18
`H3E-MC-JMCD
`LY231514 plus gemcitabine
`Pancreas
`2
`LY231514 plus geracitabine
`H3E-MC-JMDL
`LY23 !514/cisplatin.
`Mesothetioma
`7 l
`H3E-MC-JMCHb
`a A discontinued Phase trial comparing LY231514 to vinorelbine. Only data for the LY2315 I4 arm
`is presented here.
`b Ongoing mesothelioma Pha~e 3 trial comparing LY231514 plus cisplatin to eisplatin alone. Data for
`the LY2315141cisplatin arm is presented here.
`
`3.2. Results
`
`3.2.1
`
`Impact of Supplementation of Folic Acid and Vitamin
`B12 on the Time Course of Plasma Homocysteine
`Concentrations
`Results from an analysis of plasma homocysteine levels over time are depicted in
`(Figure 3.1). Mean baseline homoeysteine concentration was 9.4 laM (range, 3.6-29.0
`~tM) for the supplemented group and 9.7 ttM (range, 3.6-132.4 laM) for the
`nonsupplemented group. Thirty-four of the 196 supplemented patients (I7%) had
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`baseline plasma homocysteine concentrations greater than or equal to 12 pM.
`Likewise, 69 of the 394 uonsupplemented patients (18%) had baseline plasma
`homocysteine concentrations greater than or equal to 12 laM. The data show that folic
`acid and vitamin B 12 supplementation caused a statistically significant reduction in
`plasraa homocysteine concentrations over time. This reduction was observed after I
`cycle of therapy and was maintained throughout the study.
`
`Without supplementation (n=394) With supplementation (n=196)
`
`Baseline 21
`
`63
`42
`Time (days)
`
`84
`
`105
`
`Figure 3.1, Mean Homocysteine Levels over Time
`
`&~.2. Impact of Vitamin Supplementation .of Folic Acid and
`Vitamin B12 on Drug-related Death
`The data shown in this and subsequent sections were drawn from the clinical trials
`database for LY2315 I4 for those patients as defined above who were reported as of
`June 2001. In this analysis, the incidence of drug-related death was calculated based
`on all patients who were exposed to LY23 I514 either with or without vitamin
`supplementation from the beginning of therapy. Seven of 504 patients (1.4%; see
`Appendix 2 for case histories) supplemented with folio acid and vitamin B 12 died as a
`result of toxicities possibly or probably related to LY231514 therapy compared to 49
`of 1169 patients (4.2%) not supplemented with folio acid and vitamin B 12 (Table
`3.3). These results indicate that folio acid and vitamin B12 supplementation results in
`a marked improvement in the incidence of LY231514-related death.
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`e
`
`Table 3.2. LY231514-related Deaths
`
`Without folic acid and
`vitamin B12
`supplementation
`All studies JMCIta
`
`49 (4.2%)
`
`3 (8.3%)b
`
`1169
`
`36°
`
`With folic acid and
`vitamin B12
`supplementation
`JMCHa
`All
`studies
`7 (1.4%)
`
`2 (1.4%)
`
`5O4
`
`148
`
`Number of drug-
`related deaths (%)
`Number of total
`patients
`alMCH is an on-going mesothelioma Phase 3 trial comparing LY231514 plus eisplatin to ¢isplatin
`alone. Data pr¢sented here is for the LY231514/cisplatin arm only as of June 2001.
`All 3 deaths occurred in patients who never received vitamin supplementation.
`This number represents patients who never received vitamin supplementation. If those patients given
`supplementation after r~ei,4ng one cycle (24 patients) are included, the ~otal patient population
`becomes 60 patients and the incidence of d~ath is 5.0%.
`
`3.2.3. Impact of Vitamin Supplementation on Incidence of
`Severe Toxicities
`Parents included in this analysis must have had at least 2 cycles of treatment. The
`analysis was performed looking at maximum toxicides within the first 2 cycles of
`therapy and within the first 7 cycles of therapy. The analysis within the first 2 cycles
`of therapy is intended to assess the acute toxieities related to LY231514 therapy. The
`analysis within the first 7 cycles of therapy is intended to assess cumulative toxicities
`related to LY231514 therapy. The two groups were balanced with regards to number
`of cycles administered. The analysis focused on those severe hematologic (Grade 4
`neutropenia and thrombocytopenia) and nonhematologie (Grade 314 infection,
`allan-hen, and mucositis) toxicities associated with LY231514 therapy that occurred
`Within the first 2 and 7 cycles. In is important to note that many supplemented padents
`were still receiving therapy at the time of this analysis.
`
`3.2.3.1. Impact of Vitamin Supplementation on incidence of Severe
`ToxicRies Occurring During the First 2 cycles of LY231514
`Therapy
`The majority of severe toxicities observed in nonsupplemented patients treated with
`LY231514 occurred during the first 2 cycles of therapy, while the majority of drug-
`related deaths occur immediately after the first 2 cycles of therapy. The incidence of
`severe toxicides, both hematologic and n0nhematologic, was profoundly reduced
`when folic acid and vitamin B 12 were added to study therapy. The incidence of Grade
`4 hematologic and Grade 3/4 nonbematologie toxicity decreased from 22% in the
`nonsupplemented group to 11% in the supplemented gloup (Table 3.4).
`
`It can be concluded from these data that supplementation with folic acid and vitamin
`B12 results in a clinically meaningful reduction within the first 2 cycles of therapy in
`the number of episodes of severe toxicity associated with LY231514.
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`Table 3.3. Incidence of Severe Toxicities Related to LY231514 Therapy in
`Patients with and without Folic Acid and Vitamin B12
`Supplementation During the First 2 Cycles
`
`Without
`supplementation
`
`with
`supplementation
`
`P value*
`
`(n=394)
`
`(n=196)
`
`Grade 4 hematologic and Grade 3/4
`nonhematologic toxicitiesa
`
`Grade 4 neutropenia
`
`Grade 4 thrombocytopeaia
`
`Grade 3/4 mucositis
`
`Grade 3/4 diarrhea
`
`Grdae 3/4 infection
`
`Grade 4 neutropenia + Grade 314
`mucositis
`
`Grade 4 neutropenia + Grade 314
`diarrhea
`
`Grade 4 neutropenia +Grade 3/4
`in~ecfion
`
`*O~termine~l by Cki-Sqx~e test.
`**NS=Not sta~sfic~ly si~ific~t.
`
`22%
`
`18%
`
`3%
`
`3%
`
`3%
`
`1%
`
`2%
`
`1%
`
`0.5%
`
`I1%
`
`0.0008
`
`8%
`
`0.5%
`
`0.5
`
`3%
`
`1%
`
`0%
`
`0.5%
`
`1%
`
`0.0007
`
`0,04
`
`0,03
`
`NS
`
`0.01
`
`Ns
`
`NS
`
`a Toxicities include Grade 4 neatropcnia, Grade 4 thrombocytopenia, G~I¢ 3/4 mucositis, Grade 3/4
`diarrhea, and Grade 314 infection.
`
`3.2.3.2. Effect ot Vitamin Supplementation on Incidence of Severe
`Toxicities Occurring During the First 7 Cycles of LY231514
`Therapy
`The incidence of se,~ere toxicities associated with LY231514 thorapy between
`padents with and without supplementation within the fLrst 7 cycles of therapy is
`shown in Table 3.5. The incidence of both Grade 4 hematologic and Grade 3/4
`non!aematologic toxicities decreased markedly in daose patients supplemented with
`vitamins. These data indicate a marked improvement in the incidence of severe
`toxicities associated with LY231514 therapy when patients are supplemented with
`folie acid artd vitamin B12.
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`Table 3.4. Incidence of Severe Toxicities Related to LY231514 Therapy in
`Patients with and without Folic Acid and Vitamin B12
`Supplementation Occurring within the First 7 Cycles
`
`Without
`supplementation
`
`With
`supplementation
`
`(n=394)
`
`33%
`
`(n=196)
`
`12%
`
`9%
`
`1%
`
`0.5%
`
`4%
`
`1%
`
`0%
`
`1%
`
`1%
`
`5%
`
`3%
`
`3%
`
`1%
`
`P value*
`
`<0.0001
`
`<0.0o0 !
`
`0.001
`
`0.OO2
`
`NS**
`
`NS
`
`0.002
`
`NS
`
`NS
`
`Grade 4 hematologic and
`Grade 3/4 nonhematologic
`toxicitiesa
`
`Grade 4 neutropenia
`
`Grade 4 thrembocytopenia
`
`Grade 3/4 mucesitis
`
`Grade 3/4 diarrhea
`
`Grade 3/4 infection
`
`Grade 4 ne~tropenia + Grade
`3/4 mucositis
`
`Grade 4 neutropenia + Grade
`3/4 diarrhea
`
`Grade 4 neutropenia +G3/4
`infection
`
`*Determined by Chi-Square test.
`**Not statistically significant.
`
`a Toxicides include Grade 4 neutropenia, Grade 4 thrombocytopenia, Grade 314 mucositis, Grade 3/4
`diarrhea, and Grade 314 infection.
`
`3.2.4 Effect of Folic Acid and Vitamin B12 Supplementation
`on the Antitumor Activity of LY231514
`In the Phase 2 clinical trial JMDR in which single agent LY23 I514 was administered
`ir~ patients with previously untreated mesothelioma, 5 of 40 vitamin-supplemented
`patients achieved a contrh--med partial response compared to 1 of 17 nonvitamin-
`supplemented patients.
`
`These results, when combined with those results from above, suggest that low-dose
`folio acid and vitamin B 12 supplementation markedly reduces the incidence of the
`severe toxicities associated with LY231514 therapy and LY231514-related deaths
`while maintain’.mg antitumor efficacy. The ongoing randomized Phase 3 trial in
`mesothelioma (JMCH) in which approximately one-third of patients have undergone
`therapy with LY231514/cisplatin before the requirement of vitamin supplementation
`will address this research question more thoroughly.
`
`Eli Lilly and Co~l~ny
`Paoe 12
`
`0~/04/01
`LY231514
`
`CONFIDENTIAL
`ELAP00019639
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1088-0012
`
`

`
`4. Conclusions
`
`This an~dysis confirms the hypothesis that the adminis=ation of d~dly folic zcid and
`vitaro.Jn B 12 reduces homocysteine and in turn results in a significant reduclion of
`death and loxiciry associated with LY231514. The results from tiffs analysis suppo~
`the following conclusions:
`
`¯ Supplementation with folic acid and vitamin B 12 causes a statistically significant
`reduction in homocysteine levels and these levels are maintained while on study
`as long as the patient continues to take the vitamins.
`
`Folio acid and vitamin B 12 supplementation results in a profound reduction of
`LY2131514-related deaths.
`
`Folic acid and vitamin B 12 supplementation significantly reduces the number of
`episodes of Grade 4 hematologic and Grade 3/4 nonhematologie toxieities
`associated with LY231514 therapy.
`
`Folic acid and vitamin B 12 supplementation acts quickly to protect the patient
`from the increased risk of developing severe toxicides and from drug related
`death, This protection continues throughout study therapy with LY23 ~ 514.
`
`¯ Preliminary results indicate that antitumor activity is retained in mesothelioma
`patients when fotic acid and vitamin B 12 supplementation is combined with
`LY231514 therapy.
`
`¯ Further analyses are underway to better characterize the safety profile of
`LY231514 when combined with other anticancer agents.
`
`Eli L~lly ann Company
`Paoe 13
`
`06~04/01
`LY231514
`
`CONFIDENTIAL
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1088-0013
`
`

`
`5, References
`
`Shih C, Thornton D: Preclirtical pharmacology studies and the clinical development of
`a novel multitargeted antifolate, MTA (LY231514). In: Jack.man AL (ed) Anti
`Cancer Drug Development Guide: Andfolate Drugs in Cancer Therapy. Humana
`Press, t999, pp 183-201.
`
`Vu T, Amin iI, Ramos M, Vanyo L, Tisman G: Cancer patients are frequently in
`negative vitamin B12 balance and exhibit homocysteinemia. Clin Res 39: Abstract
`667, 1991
`
`Allen R.H, Stabler SP, Savage DG, Lindenbaum J: Metabolic abnormalities in
`cobalamirt (vitamin B i2) and folate deficiency. The FASEB Journal Reviews
`7:1344-1353, 1993
`
`Niyikiza C, Baker S, Johnson R, Walling J, Seitz D, Allen R. 1998. MTA
`(LY231514): Relationship of vitamin metabolite profile, drug exposure, and other
`patient characteristics to toxicity. Annals of Ontology Supplement 4 to Vol 9,
`Abstract 609.
`
`Eli Lil~,y and Company
`Paae 14
`
`06/04/01
`LY231514
`
`CONFIDENTIAL
`ELAP00019641
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1088-0014
`
`

`
`|,nqpuaddv
`
`CONFIDENTIAL
`CONFIDENTIAL
`|:|
`l\Dfiflfi-1C]£l/I")
`
`Sandoz Inc. IPR2016-00318
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1088-0015
`Sandoz V. Eli Lilly, Exhibit 1088-0015
`
`

`
`Appendix I
`
`LY231514 (MTA) Safety Analysis, 03 December 1999
`
`Eli Utly and Company
`
`06/04/01
`II Y2"31514
`
`CONFIDENTIAL
`ELAP00019643
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1088-0016
`
`

`
`Lilly Research Laboratories
`A Division ol Eli Ully and Company
`
`December 3, 1999
`
`IND Safety Report Follow-Up and
`Request for FDA Input
`
`Food and Drug Administration
`Center for Drug Evaluation and Resea~.J-~
`Division of Oncoiogic Drug Products, HFD-150
`Attn: Mr. Aivis Dunson
`1451 Rockviile Pike
`Rode,,il]e, MD 20852-1448
`
`Subject: IND 40,061, MTA (LY231514) -Sedal no. 195
`Supplementation with Foti© Acid and Vitamin Bt2 To Reduce
`Toxicity in Patients Receiving LY231514 ’
`
`Recently, Lilly sent a letter to investigators irfforming them to exclude patients
`with high baseline homocysteine levels from participation in LY231514 c~inical
`trials (see submission sedal number 194 to IND # 40,061 dined November 24,
`1999). This letter was sent to all LY231514 investigators except for investigators
`in two studies (H3E-MC-JMAF and H3E-MC-JMAS) where patients are cun’ently
`receiving fblic acid supplementation. |n the illterest of patient safety, this action
`was taken preceeding formal protocol amendments.
`
`In the cover letter to t~e FDA accompanying the November 24 letter Lilly stated
`that the exclusion of patients w~h high baseline homocysteine levels was a
`weliminaw action, Lilly also indicated that a further communic~ion would be
`sent to the FDA with details of the updated s~f~tf analysis together with a plan
`for an inteP,,er~on to lessen serious toxic effects in patients wfth high baseline
`homocysteine levels. The updated safety analysis (see attachment) again
`rei~orces the relationship between high baseline homocyste’me levels and the
`potential for sedous toxicity after treatment with LY231514 as shown by the
`follo~ng:
`
`CONFIDENTIAL
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1088-0017
`
`

`
`Food and Drug Admin;~-~iion
`December 3, 1999
`
`..P~e2
`
`Elevated homocysteine level at baseline is highly correlated wflh severe
`toxicity (e.g. neutropenia, neutropenia accompanied by infection,
`diarrhea).
`
`¯ Drug-related death is highly correlated with severe toxicity.
`
`Preliminary data from an ongoing study in gastric cancer (H3E-MC-
`JMAF) in a, small number of patients has shown that at standard doses
`(500 mg/m’), LY231514 has demonstrated activity in the presence of folic
`acid supplementation.
`
`LY231514 may be escalated as high as 925 rng/mz when accompanied
`by folic acid supplementation at a schedule of 5 mg orally daily for two
`days before, the day of, and two days after LY231514 administration
`(Study H3E-MC-JMAS). Data from this study shows that in patients with
`elevated homocysteine levels, this amount of supplementation causes
`homocysteine levels to drop below 10 pM and causes no change in
`patients that do not exhibit an elevabad baseline homocysteine level.
`
`It is well known that elevated homocysteine levels are an indicator of
`poor nutritional status, and recently, elevated hornocysteine levels have.
`also been shown to be a predictor of mortality in cardiovascular disease.
`A study of homocysteine levels in 1788 middle-aged and eldedy
`volunteers has shown that an elevated homocysteine level of 14 ldVl or
`greater puts a patient at increased risk for death caused by.
`cardiovascular disease [Annals Internal Medicine 131:321-330, 1999].
`
`Folio acid supplementation of 400 pg daily !n eldedy patients with
`elevated homocysteine levels has been shown to substantially reduce
`plasma hornocysteine levels within two v.~--c_P.s. The level continues to
`drop stightly for another two weeks, and then plateaus [international
`Journal for Vitamin and Nu’xition Research 69:.187-93, 1999]. Brouwer
`and coworkers shov,~ that low dose ~tic acid (250 pg - 500 tug)
`intervention significantly decreases homocysteine ievels. An eight week
`washout pedod was not sufficient for blood folate and plasma
`homocysteine levels to return to baseline. [American JoumaJ of Ctinical
`Nutrition 69:9