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`BRISTOL-NIYERS SQUIBB COMPANY
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`SAXAGLIPTIN(BMS-477118)
`MODULE 2.5
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`CLINICAL OVERVIEW’
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`lnllicalion:
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`Type 2 Diabetes Mclli‘L'L1s
`
`Document Date:
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`30-May-2008
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`Bristol~Mycrs Squibb Research and Dcvclop1ncnt
`Bristol-Myers Squibb C.u;>mpany
`PI'il]CCtDl‘1, NJ 08543
`USA
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`
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`This dnculnmll is ;1 c0nIidL:11Iial L?(JI11]1‘]Ul‘Ji(2&|li[)[1 of B:'i.»‘10|—.\«Iycr.~' Squibb C(m1p2111y. Accr:pl;1r1(:c i)rl|‘1i:~.
`documem constitutes an agrc<:mv::nL by the recipient that no u11puhli.~;hcd infm‘m;1tinn co:1Lained hcrcin wit]
`bu pllblialnml or disclosud withuul Rl'i:;IL1I-\'[}’t.'FS .‘SL[uibb Comp:my's prior wrillen ':Ippru\-':1|.
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`
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`."-;f.‘J_r.-1.'r,‘..v-.=.--‘L1.r_'*?.I.'J
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`21300274-:7 1.0
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`I
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`Hylan v. !stra!eneca
`
`IPR2015-01340
`
`AstraZeneca Exhibit 2198
`Mylan v. AstraZeneca
`IPR2015-01340
`
`Page 1 of 64
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`

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`Saxttgliptin
`FEMS--I-TTI I3
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`2.5
`(_'_lirliL§ l §_)\-‘I.;L'_v'u,;}g_
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`TABLE OF CONTENTS
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`TITLE PAGE .
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`1
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`LIST OF TABLES .
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`LIST OF FIGURES .
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`LIST OF ABBREVIATIONS .
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`1 PRODUCT DEVELOPMENT RATIONALE .
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`1.1 Introduction .
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`1.2 Overview of Clinical Development Program .
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`1.2.1 Overview .
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`1.2.2 Phase 3 Dose Evaluation .
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`1.2.3 Phase 2b and 3 Clinical Development Program .
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`1.2.4 Ongoing Studies .
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`1.3 Overview of Health Authority Interactions .
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`2 OVERVIEW OF BIOPHARMACEUTICS .
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`3 OVERVIEW OF CLINICAL PHARMACOLOGY .
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`3.1 Pharmacokinetics .
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`3.1.2 Special Populations .
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`3.2 Pharmacodynamics .
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`4 OVERVIEW OF EFFICACY .
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`4.1 Methodology .
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`.i;p_r.-1.’-.“,‘..r-.=_--". V3.0
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`5330027/:-27 1.0
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`Page 2 of 64
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`Page 2 of 64
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`

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`Smcttgliptiit
`BM:-43?: I3
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`4.2 Results .
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`4.2.1 Short-term Efficacy .
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`2.5
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`4.2.3 Relevance and Applicability of Efficacy Data for Dosing .
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`5 OVERVIEW OF SAFETY .
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`5.1 Safety Background .
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`5.2 Safety Results .
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`5. 2. 4.1 Hypoglycemia .
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`5.2.6 Laboratory Findings .
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`5.2. 6.1 Lymphopenia .
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`Smcitglintin
`FEMS--I-77E I3
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`2.5
`(_'_]_irliL§ l §,_)\-‘I.;L'_\vig,;}g_
`
`5.2.? Relevance and Appiioabiiity of Safety Data for Dosing. .
`
`.
`
`. 48
`
`5.3 Limitations of the Saxagliptin Safety Database .
`
`6 BENEFITS AND RISKS CONCLUSIONS .
`
`6.1 Summary of Benefits .
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`. 51
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`. 52
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`6.2 Summary of Risks .
`
`6.3 Conclusions .
`
`7 REFERENCES .
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`25
`Saxugflpfin
`
`
`LIST OF TABLES
`
`Table 1.2.3: Summary of Controlled Pllase 2b-3 Clinical Trials .
`
`.
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`Table l.2.4: Sumrnaly 0['()ng0ing Clitiical Trials in Type 2 Diabetes .
`
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`Table 4.2: AIC, Fasting Plasma Glucose. and Postprandial Plasma Glucose.
`Difference [95%CI] froni Placebo in Adjtlstcd M6111] C.l1aI1_gt: frmn Bascline .
`
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`25
`Saxaghpfin
`
`
`LIST OF FIGURES
`
`Figure 3.2: Insulin Secretion Rate During I-Lyperglyeelnie Clamp in Conditions of
`
`Fasting ((}—| 80 minutes) and Post-OGTT ( I 80-480 minutes) at Baseline and
`
`Week 12 (LOCF) .
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`Figure 4.24%: A [C Adjusted Mean Changes from Baseline (95"/fiCI'_| at Vlfeek I2
`
`[L()CF) - Phase 2 Monotherapy Study CV1 81008 .
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`Figure 4.21%: A1 C Adjusted Mean Changes from Baseline £95‘?/{JCT} at ‘Week 24
`
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`. 26
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`(LOCF) - Phase 3 Mt.u1utl1erapy Studies .
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`Figure 4.2C: A I C Adjusted Mean Changes from Baseline [950/1C1) at Week 24
`
`(LOCI?) - Phase 3 Add-on Combination '|"h(.‘.ra]:I}* Studies .
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`Figure 4.2D: A [C Adjusted Mean Changes from Baseline (95"/ECI) at 'Week 24
`
`{I.(J(_TF) - Phase 3 Initial (.Iombi11ati0.n Study (IVIKIOS9 .
`
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`Saxagliptin
`BMS—4”/7l I8
`
`2.5
`Clinical ilvcrvicw
`
`LIST OF ABBREVIATIONS
`
`AlJlJr::\'iatiun Definition
`
`A [C
`AT,
`
`ALT
`
`AUG‘
`AZ
`
`Hl\.-TS
`
`BCS
`
`BNU
`CIIMP
`
`CK
`
`[.'n1:1x
`
`CrCl
`
`CR1‘
`
`glyutlsylzitual l1u.:mug_lul)in
`atl\'::n'sc I;:\'f:I"IL
`
`ulmline uminolmns fcrusc
`
`arc.-1 undcrp|:L~;1na L:onccn1'r:1Lim1—t1'mc curve from zero L0 infinity [amnuru-timcfxvnlumc]
`Astrazcncca
`
`Bristnl-Mycr.»'. Squibb
`
`Bi0ph211'n12tccu1ic.~3 Clz|s.siIicaLi0n Systcln
`
`I‘I1EL.‘-ES index
`lmd)-'
`CommiL1u:c For Medicinal Products for Human Use
`
`(:1'::'.1(lni.- kinust.‘
`
`maxirnum plas111:1 (peak) drug CDl1LII.':l'£l|'al.lI.’I11 aflcr single dose E|dT‘I‘|ll'|lfiI.'l'fll.lt')l‘|
`[:1I11uunlx'vulLI111c]
`c1'c'c1tini:1c ClCtl.T.'iJ.l'lL‘.C
`
`case rcr-orl form
`
`C'YP3A4.’5
`
`cytochrmnc P450 3A4»’5
`
`l‘)M(.‘
`
`DPP4
`
`FDA
`
`FPU
`GCP
`
`GIT’
`
`(}l'.l’~l
`LOCF
`
`.\'('J':__',L
`
`NYHA
`
`UGTT
`
`PPAR
`
`PPG
`
`PT
`
`QD
`
`Data Muniturillg C0r'nIT1iEIt:(-:
`
`dipcptidyl pcpIiLl‘cL.~;t- 4
`
`Fund and Drug /\d[nlJ1isl|':1liun
`
`fasnng plasma glucose
`Good CliI1icz1l Ir’1'aclict:
`
`glucose dcpcndcnl insulinolropic peptide
`
`glIII;:tg_nI1-llkc p¢:p1i(lu_'-I
`last 0bz‘.L:wa1lio11 calricd l'o1'wa11‘d
`
`1m—0h:=.t:rv:Lblevcl'fi:c‘L level
`
`New York Hceui A.~:s0ciati{1n
`
`oral glucose tolerance test
`
`pcmxismnc pm!if1:mmr—:n:Livat::d rcccpmr
`
`postprandial glucose
`
`prc ['1-.'|'1'cd term
`
`once daily
`
`.'3;p_nrD‘J:=.--‘L V3.0
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`

`

`3.5
`Clinical 0\«':::'vicw
`
`Saxagliplin
`BMS477118
`
`AIJbreviation Definition
`
`QTc
`
`SAWP
`
`SU
`
`SOC
`
`TZDM
`TZD
`
`UK PDS
`
`U-LN
`
`cnrrcclcd QT interval
`
`Scic:ntit'Ic Advice V\"nrkiII_s_:I’:1rty
`
`sulibnylurea
`
`system urgam clatss.
`
`type 3 clialbctcs mcllitus
`tl1iazolidinI:dim1c
`
`United King|:lnn1 Prospective Di:1l)ct::s Study
`
`upper !im1'L of normal
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`

`

`Saxagliptin
`B MS—477l I8
`
`2.5
`Clinical {)\-'erview
`
`1
`
`PRODUCT DEVELOPMENT RATIONALE
`
`1.1
`
`Introduction
`
`Sttxttgliplin is ti highly potent, s‘elet;tiv<:, re\«'ersiblt:, and competitive tlipeplidyl peptidase
`
`4 UJPP4] inhibitor. DPP4 is the enzyrne res]3onsil3le for the inactivation of the ineretin
`
`horrnones gltteagon-like
`
`peplide—l
`
`((iLP—l]
`
`and glueose-dependent
`
`insulinotropie
`
`polypeptide (Gll’)l. lneretin horrnoncs are gastrointestinal hormones that increase insulin
`
`secretion in response to enteral stimulation. These hormones contribute to the control of
`
`postprandial glucose excursions in 11 glucose dependent manner, which mitigates the risk
`
`of Iiypoglycemia.
`
`in addition to enltanced pestpra-tndial
`
`insulin release. GLP-l also
`
`reduces glueagtan release from the pancreatic tut-cells. thereby reducing hepatic glucose
`prc-dt1e[ion.3 This effect
`is also gluetJse—dependent, such that when plasma glucose is
`.
`.
`.
`3
`normal or low, the ct)1lI1it:r—t'egtll:;ttm‘_Vlesptittse of glueagon release is not !I't‘Ip'ct1rt:(_l.
`
`Type 2 diabetes mellitus ('l‘2DM] is a common chronic metabolic disorder that can lead
`
`to sttbstantial morbidity and increased mortality rates. Data from the Diabetes Control
`
`I diabetes) and the United Kingdom Prospective
`and (_.‘omplieatiot1s Trial; {in ‘type
`Diabetes Slutlys
`(in type 2 diabetes) compared intensive with standard glucose
`
`l1]al1E1gC111Cl1t and showed a reduced risk of complications with improved glucose control
`
`as measured by glycosylated hemoglobin (AICJ. These results have established tight
`
`glttcose control as a lttttdainetilal component in the management oidiabeles. In spite of
`
`the availability ol'tt number 0l'dilTere11t atntiliyperglyceniic classes ol'agenLs__ IdCl'Ii{:2VCT‘i1Ct‘Il
`
`of AIC targets remains .~¢.uboptim:-1|.{i Many available treatments are associated with
`
`undesirable side effects including increased risk ofhypoglyecmia, weight gain, or edema.
`
`wltieii present barriers to their use and acceptance. As a consequence, there rernains the
`
`need to identify additional effective, safe, and well-tolerated ttntihyperglyceniie agents [(3
`
`help patients achieve and sustain target giycemic levels.
`
`Saxagliptin is intended to improve glycemic control for patients with TEDM:
`
`I
`
`as menotherapy as an adjunct to diet and exercise:
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`Saxagliptin
`B M S-477 l I8
`
`2.5
`Clinical {)\-crvicw
`
`I
`
`I
`
`in combination with I1ict'lbt'|nin._ a thiazolidincdione {TZD), or a sulfonylurea (SU}
`when the single agent alone, with diet and It'.X(:'l‘L‘i5€ does not provide adequate
`glycemie control: and
`
`to diet and exercise, when
`as initial combination with mc[fo1'n1in._ as an adjunct
`treatment with dual saxagliptin and metformin therapy is appropriate.
`
`The proposed usual clinical dose is 5 nig once daily. The recommended dose is 2.5 mg
`
`once daily in subjects with moderate or severe renal
`
`impairment, and cnd—stagc renal
`
`disease requiring hemodialysis.
`
`1.2
`
`Overview of Clinical Development Program
`
`1.2.1
`
`Overview
`
`All studies described in this document were performed in accordance with the principles
`
`of Good Clinical Practice (GOP). The saxagliptin clinical program is considered
`concordant with EU and US guidelines on developing treatrrients for TZDM. Hi"
`
`The Clinical Pharmacology program consisted of 24 studies in 673 subjects, 620 of
`whom were dosed with saxagliptin (see Table l and Table 2 in Module 2.7'.2).g
`
`Ascending dose studies, hiopharmaccutical studies, a thorougli correctccl QT interval
`
`[QTc) study, and studies to investigate various clinical findings were conducted. Drug-
`
`drug, interactions with saxagliptin and other antihyperglycemie agents, drug inetabolizing
`
`enzyme inhibitors and probe drugs, as well as with other drugs commonly used in this
`
`patient population were evaluated. 'l‘he pharniacokinetics oi‘ saxagliptin was assessed in
`
`relation to age. gender, hepatic impairment, and renal
`
`impairrncnt, and severai studies
`
`have investigated the phannaeokineties of saxagliptin delivered in various fomiulations.
`
`In addition. a population pharmaeokinctic analysis was performed.
`
`1.2.2
`
`Phase 3 Dose Evaluation
`
`In the Phase 3 [}l'DgI"ctI‘l‘l, saxagliptin doses of 2.5, 5, and I0 mg administered once daily
`
`were evaluated to hilly characterize the efficacy, safety, and benefitrrisk profile of
`
`sax-agliptin within the dose-response range established in Phase 2.
`
`In addition,
`
`the
`
`potential 1lSCfillT1CS-S of titration of saxagliptin as monothcrapy, tising a starting dose of
`
`IO
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`

`

`Saxagliptin
`BMS—477l I8
`
`2.5
`Clinical Overview
`
`2.5 tng, was ex-a1'nincd.
`
`'l'he rationale for selectiiig the dose range and dosing interval for
`
`Phase 3 was based on an integrated assessrnent ofeffieacy, pharrnaeodynarnie. and safety
`
`data generated from subjects exposed to saxagliptin in Phase 1 and 2b studies. The main
`
`conclusions from t]1c i11Legratcd assessment were the following:
`
`I The largest effect on glyecmic control was generally seen at a tlosc of 5 or 10 mg.
`with no apparent increase in efficacy at doses higher than I0 mg.
`
`I The largest effect to inhibit plasma DPP4 at trough was seen at a dose of IO mg, with
`no apparent increase in inhibition at doses higher than 10 mg.
`
`I
`
`I
`
`I
`
`Significant inhibition of plasma DPP4 activity was seen at lhc [rough of the dosing
`interval, ie, 24 hours after dosing ofsaxagliplin 2.5, 5, and l{)n1g.
`
`Saxagliptin doses in the range of‘ 2.5 to 10 mg were associated with potentiation of
`postprandial GLP-l and reduction in excursion of postprandial glucagon.
`
`lJost:—relatt:tl reduction of absolute lymphocyte count was t)l.‘J£-{.(:1'\£Ef(l that was most
`apparent at doses of saxagliptin greater than or equal to 20 rng.
`
`The saxagliptin 5 mg dose was generally associated with maximal efficacy in the
`
`Phase 2h study, with no improvement in efficacy at [0 mg. Thus, saxagliptin 5 mg served
`
`as the anchor dose in the Phase 3 program. The saxagliptin 10 mg dose was studied to
`
`provide additional safety i|1’r'orn1:Ition at a higher dose and to assess whether incrernenial
`
`efficacy of a higher dose would be observed during long-term treatment beyond 12 weeks
`
`or in other settings besides monotherapy. The saxagliptin 2.5 mg dose was included to
`
`explore the lower end of the dose range. Strict rescue criteria were incorporated in the
`
`Core Phase 3 studies to permit additional glucose lowering treatment in the event that
`
`subjects experienced poor glycemie control as the clinical studies progressed.
`
`1.2.3
`
`Phase 2b and 3 Clinical Development Program
`
`The Phase 2b and Phase 3 worldwide clinical development program in TZDM included
`
`eight stticlios in which 4607 subjects were randomized and treated. 01' these, 3356
`
`subjects 1'eceivcd douhle-hlind saxagliptin [Table |.2.3); an additional 66 suhjeets
`
`received open-label saxagliptin [0 mg in Study CVIBIOI l. A total of [459 suhjeets
`
`received saxagliptin for more than 48 Weeks, including 344 who received saxagliptin 10
`
`mg. twice the recommended usual clinical dose [Table l.2.3A of Module 2.7.4_“).m The
`eight Phase 2b.r’3 studies included one 12-week Phase 2b dose-finding study“. one I2-
`
`ll
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`

`

`Saxagliptin
`BMS—477I I8
`
`2.5
`Clinical {)\«'e1'view
`
`week Phase 3 mechanism of action study”. and six Phase 3 studies with final data from
`
`the 24-week sho1't—lerm treatment period.
`
`In the six Phase 3 studies (1'efe:1'ed to as the
`
`Core Phase 3 studies). 4148 subjects with 'l'2F)M were randomized and received study
`
`dnlg. 302] efwhoin were treated with saxagliptin. All controlled studies in subjects with
`
`TZDM used a randomized, double-blind design.
`
`Interim leng—term data I‘rom the Phase 3 studies are also included in the submission,
`
`Table 1.2.3:
`
`Summary of Controlled Phase 2b-3 Clinical Trials
`
`Study No.
`
`Study objectives
`[Population]
`
`Ramlnmized
`and treated
`subjects
`All I Saxa
`
`Duration shm't-
`term
`(total)
`
`Saxagliptin (mg) dosage
`
`CV1 8 I 008
`
`CV/1810] I
`
`CV1 8 I 038
`
`CV1 8 I [J4-I
`
`CV1 8 I Ill 3
`
`CV1 8 I 0 I4
`
`C\/181040
`
`M onotherap)-' placebo-controlled
`
`Dose-ranging
`safety and efficacy
`[A] C 6.8%-9.7%)
`
`Saliety and eflicncy
`(A I C ?"/n— I 0%]
`
`Safety and efficacy
`(A I (1 7‘i/n- I 0%}
`
`Mechanism of
`action
`{AIC 6“/ .304)
`
`423 I 315
`
`401 I" 306*
`
`365 .5 2.9l
`
`36 I 20
`
`I2 weeks
`or
`6 weeks
`
`24 weeks
`[206 weeks)
`
`24 weeks
`(76 weeks)
`
`I2 weeks
`(I 16 weeks)
`
`2.5. 5.
`
`It}, 20. or -‘L0 QD
`or
`I00 QD
`
`2.5, 5, or 10 OD
`
`2.5. 5. or 2.535 QAM.
`or 5 Ql’.\d
`
`5 QD
`
`Add-cm eolnbinatium placebo-controlled
`
`Safety and efficacy
`(A I C 7':/..-10.5%)
`
`Safety and cliicalcy
`(A I C 7‘]/'o- I ll”/cl
`
`Safety and cflicacy
`(AIC 7.5‘?/o-l 0%)
`
`56:5 I 32%|
`
`743 .5 564
`
`768
`
`501
`
`24 weeks
`(76 weeks.)
`
`24 weeks
`(ZIIG weeks)
`
`24 weeks
`(76 weeks)
`
`Initial comhinatian active-eorltralled
`
`2.5 or 5 QT) I-I TZD]
`
`2.5, 5, or ID OD
`(‘I‘I'|l:[rl‘JI'IIlil1)
`
`2.5 or 5 QD I - glylrauridel
`
`CV1 8 I 039
`
`Safety and efficacy
`(A l C ?s"'/'o- l 3°/pl
`
`I306 » 973
`
`24 Weeks
`[76 weeks)
`
`5 or ID QD I-f-InctI"cn'min]
`or II] mg QT)
`
`"' an additional 66 subjects received open-label saxagliptin in Sttldy CVI 8101 I
`QD — once daily, QAM —- once daily ll'llI1C morning, QPM — once daily in the evening
`
`]'31..
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`Saxagliptin
`BMS-477118
`
`2.5
`Clinical Overview
`
`For the integrated analyses of safety, data from the Phase 3 mono therapy studies
`CV181011 and CV181038 were pooled. Data from the five placebo-controlled studies
`CV181011, CV181038, CV181013, CV181014, and CV181040 were also pooled
`(Pooled Safety Population) to facilitate the recognition of small safety signals, to better
`understand consistency across
`the database,
`to evaluate dose-relationship, and to
`potentially increase the precision of determining the frequency of adverse events. This
`analysis was complementary to the analysis of each individual study.
`
`Monotherapy studies CV181011 and CV181038 emolled drug naive subjects who were
`randon"lized to receive saxagliptin monotherapy 2.5 mg, 5 mg, 10 mg (CV181011 only)
`14 Study CV181038 also included a 5 mg
`or placebo once daily in the moming. 13
`'
`saxagliptin group with evening (PM) dosing as well as a saxagliptin titration group (2.5
`to 5 mg). Sixty-six subjects with screening AI C > 10% and ::::: 12% were enrolled into a
`saxagliptin 10 mg open-label cohort in Study CV181011 (not represented in Table 1.2.3).
`Subjects randomized to placebo who completed the short-term treatment period without
`requiring rescue therapy were given double-blind metformin in the long-term periods of
`both studies.
`
`The add-on combination studies were conducted in subjects who had inadequate
`glycemic control despite current therapy with SU, metformin, m TZD. In Study
`CV 181040, subjects who had inadequate glycemic control despite current therapy with a
`submaximal dose of SU were randomized to saxagliptin 2.5 mg or 5 mg or placebo in
`combination with an intermediate dose of glyburide.
`In this study, saxagliptin in
`combination with a fixed, intermediate dose of glyburide was compared with titration to a
`higher dose of glyburide plus placebo. 15 In all treatment groups, glyburide could be
`down-titrated once during the 24-week study period due to hypoglycemia as deemed
`necessary by the investigator. In Study CV181 014, subjects who had inadequate
`glycemic control despite current therapy with metformin were randomized to saxagliptin
`2.5, 5, or 10 mg, or placebo, in combination with metformin.16 In Study CV181013,
`subjects who had inadequate glycemic control despite current therapy with a TZD were
`randomized to saxagliptin 2.5 mg or 5 mg or placebo, in combination with a TZD. 17
`
`In Study CV181039, drug naive subjects who had inadequate glycemic control with AlC
`8%-12% were randomized to saxagliptin 5 or 10 mg in inital combination with
`
`13
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`Saxagliptin
`BMS-477118
`
`2.5
`Clinical Overview
`
`metformin 500 mg, to saxagliptin 10 mg monotherapy, or to metformin 500 mg
`monotherapy. 18 In the saxagliptin 5 mg and 10 mg plus metformin groups, and in the
`mettonnin alone group, mettormin could be titrated upward to a maximum of 2000 mg
`per day.
`
`These six studies in subjects with T2DM (Core Phase 3 studies) provide the primary data
`in support of the efficacy and safety of saxagliptin.
`
`The efficacy and safety of saxagliptin was established in a broad range of subjects with
`T2DM, including subjects who had inadequate glycemic control on diet and exercise
`alone, or who had inadequate glycemic control on a single oral antihyperglycemic agent
`(metformin, SU, or a TZD). The populations studied had inadequate glycemic control
`with mean baseline AlC values across studies ranging from 7.9%
`to 9.5%
`(Section 3.1.1.2 of Module 2. 7.3). 19 The geographic scope of the program resulted in a
`diverse population with subjects enrolled from the United States, Canada, Mexico,
`Europe, Latin America, and Asia. Several subpopulations classified by age, gender, race,
`and ethnicity were well represented in the clinical program. While only a small number
`of subjects:::>: 75 years of age at the time of randomization participated in the Core Phase
`3 program, amounting to 59 subjects ( 1.4%) overall, subjects :::>: 65 years of age were well
`represented in the clinical program, comprising 634 (15.3%) of subjects (see Appendix
`3.5 of the Integrated Summary of Efficacy). As the long-term extensions extend to 204
`weeks in two ongoing studies, additional experience in subjects :::>: 75 years will become
`available in the ongoing program. Saxagliptin has not been evaluated in subjects below
`18 years of age, in subjects treated with insulin, in immunocompromised individuals (eg,
`subjects who have undergone organ transplantation or were diagnosed with human
`immunodeficiency virus), in subjects with congestive heart failure defined as New York
`Heart Association (NYHA) stage Ill and IV and/or known left ventricular ejection
`fraction of ::5: 40%, or in pregnant or lactating women. Saxagliptin, in repeated dosing, has
`not been studied in subjects with clinical evidence of active liver disease or with alanine
`aminotransferase (ALT) > 2 times the upper limit of normal (ULN), in subjects with
`severe and end-stage renal disease, or in subjects receiving potent CYP3A4 inhibitor or
`inducer agents.
`
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`Saxagliptin
`BMS—477l I8
`
`2.5
`Clinical Overview
`
`The quality of data collected and analyzed was monitored according to the Sponsor’s
`
`Standard Operating Procedures. Issues that might have affected data quality or study
`
`conduct were dealt with appropriately. Two primary issues that potentially could have
`
`affected data quality are described below along with their resolution.
`
`ll
`
`2}
`
`Glucose in excess of the intended 75 g dose was ingested in :3. number of oral glucose
`tolerance tests [O(}TTs)
`in Studies CVl8l()38, C\/181039, and CVl8|(l4{). Data
`from these ()(i'l"l" procedures, affectittg a total of 382 subjects, were excluded from
`the efficacy analyses. This error primarily impacted the efficacy results in Study
`CVI 81038 by titrthcr reducing the sample size in this relatively small study.
`
`Because of a government—issued suspension on all export of biological samples from
`Russia over several weeks, a laboratory in Moscow was designated as an emergency
`central laboratory for all investigative sites in Russia. This situation affected Studies
`CV] 81038 and CVl8l039. For the laboratory parameters used in efficacy analyses.
`the samples were frozen during the export suspension and held for subsequent
`analysis at the central laboratory. Hence-._ any efficacy laboratory parameter anaiyzed
`at
`the emergency central
`laboratory was not utilized in the statistical efficacy
`analyses; only results from samples analyzed at
`the protocol specified central
`laboratory were utilized. Tlicreforc, this local suspension of lab shipments had no
`impact on the efficacy results of‘
`the studies. For hematology and urinalysis
`paramet.ers, the values obtained front the emergency central laboratory were used in
`analysis. The eentlitions for use of these values and the need for sensitivity analyses
`on these parameters based on the number of specimens analyzed at the emergency
`central laboratory were prc-specifier! in the study Statistical Analysis Plans.
`
`1.2.4
`
`Ongoing Studies
`
`Three Pliasc 3b studies ofsaxagliptitt in TZDM have recently been initiated (Table l.2.-4).
`No data are available for inclusion in the current submis.-;iot1_
`
`Table 1.2.4:
`
`Summary of Ongtiing Clinical Trials in Type 2 Diabetes
`
`Study No.
`
`Study objective (Population)
`
`CVLSI 054!
`D] 680C000{)l
`
`Safety and efficacy of saxagliptin in
`combination with melfonitin
`compzired with SU in combination
`with metlermin
`(AlC’ 6. “A;-I0"-’.3)
`
`Randomized
`and treated
`subjects
`(planned)
`All a‘ Sara
`
`83):‘ I 4| 9
`
`Duration
`sI1m't-term
`tlulal)
`
`S-axagliptin
`{mg} dosage
`
`52 weeks
`t [04
`weeks)
`
`(
`
`5 mg
`- Inetformin
`[R]
`
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`

`Saxagliptin
`Bi\1S—477lI8
`
`2.5
`Clinical Overview
`
`SIlIll_\-' No.
`
`Study ulnjcclivc (Population)
`
`CV1 8 I 056 i’
`l)lfiHlJC{l[)l)l)2
`
`(TVl8lI"D{12 i’
`D1 68C|C.00007
`
`Safety a.mle1‘ficaey of saxagliptin in
`combination with meltormin
`compared with sitagliptin in
`combination with metth rmi n
`(A1C' 6.5“/in-10%)
`
`l7.fiL::t (rl".sa¥ag.li['Itir1 t:um|‘iaI‘c:Ll with
`placebo i11 adult patients with
`TZDM and renal impairment
`(moderate. severe, and eml—st:tge}
`(Alt 7"/i.—lU"/1;)
`
`R-uulomizctl
`and tI'e-ated
`subjects
`(planned)
`All r’ Sax-.1
`
`Duration
`5Im|'t-term
`{total}
`
`Samgliplin
`{mg} dosage
`
`7| 0 I 355
`
`18 weeks
`
`(
`
`5 mg
`' meI.l'i)rrnin
`IR)
`
`l6R I’ 34
`
`i2 Weul-is
`(:12 weeks)
`
`2.5 mg
`{+ lJE.lL'l(gl‘4.'I‘l.1l1d
`medication)
`
`1.3
`
`Overview of Health Authority Interactions
`
`Key health authority interactions that
`
`impacted the saxagliptin clinical development
`
`program are summarized in this section.
`
`At the US Food and Drug Administration (FDA) End-of-Phase 2 meeting [July 2005].
`
`ag1'ee1ne11ts were. reached on the overall exposure in the elinixeal development prograrn, on
`
`the designs of the clinical
`trials to support
`pliarmaeology program, and on lhe nonelinieal
`
`intended indications, on the clinical
`toxicology p1‘ogram.w Corrmients were
`
`received on the design oi‘ the initial combination study (C'.VlXli)39'];
`
`:1 revised study
`
`design was approved by the US FDA in February 2006.
`
`In November 2005, the US FDA informed Spoiisors developing DPP4 inhibitors that as a
`
`class, administration of DPT‘-4 inliihitors to ntorikeys was associated with dose and
`
`duration—dependent neerotizing cutaneous lesions.
`
`3'
`
`In February 200?,
`
`the US FDA
`
`informed Sponsors developing D]’I’4 inhibitors that although the neerotizing cutaneous
`
`lesions had not been observed in liumans, symptomatic. edema oi‘ the l1and:-;;’l'eet and
`laboratory abnormalities had been observed in human subjects}: The US FDA advised
`
`all Sponsors that subjects should be closely lnonitored for similar, potentially drug
`
`related,
`
`findings. Bristo|«Myci's Squihh (EMS) and Astra7.eneea (A7) developed
`
`additional case report forms to monitor events of special interest (skin lesions, selected
`
`ll’)
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`Saxagliptin
`B M S-477 l
`
`I 8
`
`2.5
`Clinical tlvcrvicw
`
`infections,
`lymphopcnia, tliromboeytopcnia, and localized edema), that were submittetl
`and approt-‘ed by [he US FD/\.23’24
`
`The saxagliptin clinical prograrn was re\-'iewed by the Committee For Medicinal Products
`
`for lluman Use (CHM?) through the Scientific Advice Procedure. A Discussion Meeting
`
`was held on Fehrt1an_r 26, Ztltl? and Final Written Advice was received March 22, 2007.
`
`The CIIMI’ Seieittirie Advice Working Party LS/XWP] prmridccl feedback on the design
`
`of an add-on aetive—eontrol|.ed study. This study, Dl68t)COU[)0l /' CV] 8 I 054, is currently
`
`ongoing and is generally concordant with Cl-IMP SA\VP Advice.
`
`In addition, Cl-TMP
`
`SAWP commented on study designs For the ongoing studies CVIS I (J l 3, CVIS l 039. and
`
`C\/181040. Finally, CHMP SA'WP commented that
`
`the current safety—|1andling plan
`
`iinplcmciltcd in Phase 3 was thorough and adequate.
`
`The Format and content of the US NDA was agleetl at the US FDA pre-NDA meeting
`(November 2007). and the agreement on the exposure by indication was retiI1cti.25
`
`2
`
`OVERVIEW OF BIOPHARMACEUTICS
`
`Sax agliptin is a Hiopharmaeetltics tflassifiealioit System (HUS) (flass lll compound (high
`
`solubility,
`low permeability based on L‘.aeo—2 and Parallel Artificial Membrane
`2t3.'E7.7
`'8 but it is well absorbed in
`Perrneahilily Assay inLriI1sit': permeability assay data),
`
`humans {at
`
`least
`
`'?5%).Eq suggesting it
`
`is a borderline BCS Class I compound (high
`
`soltlbilityfhigh permeability). Biopharmaeetttics stttdies
`
`in the saxagliplin program
`
`examined the relative bioavailability of the capsule fo1'i11t1lations used until the end of
`
`Phase 2b l..'0l‘t‘lpE1I't'.‘.'£l to the Phase 3 tablet forniulations. In general, the tablet formulation
`
`had earlier and slightly higher maximum plasma concentration (Cmax) values for
`
`saxagliptilt cnmpared to the capsule tot't11ulatim1, but the overall absorptiolt was the same
`
`from both formulations and the degree of l)l‘l’4 inhibition prnvitled by each of the
`formulations was similar (sec Module 3.7.l for a suI111naI‘_v oi‘ the StL‘LlZllCS).3U There were
`
`no pivotal hioeqttivalenec studies in the hiopliarmaceutics clinical pliarrnaeology program
`
`since the Phase 3 tablet Formulation is very similar to the proposed marketed t"ormulation_.
`
`di'l"1"erint_1 only i11 color and ernbossing with the tablet strength and product code.
`
`I?
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`Saxagliptin
`B M S-4”/7i I 8
`
`2.5
`Clinical tlverview
`
`Atlrninistration of 10 mg saxagliptin in the clinical
`
`tablet forrnnlation with a high—fat.
`
`meal resulted in no change in saxagliptiri Crnax and a 27".: increase in area under the
`
`plas