CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`200678Orig1s000
`
`
`PHARMACOLOGY REVIEW(S)
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`
`
`Pharmacology/Toxicology
`Center for Drug Evaluation and Research
`Division of Metabolic & Endocrine Products
`
`Food and Drug Administration
`
`Memorandum
`
`
`
`NDA SECONDARY REVIEW MEMO
`
`Date: 30 September 2010
`NDA # 200678
`Sponsor: Bristol Myers Squibb
`Drug: Saxagliptin + metformin XR FDC
`Primary Reviewer: Lauren Murphree Mihalcik, Ph.D.
`Secondary Reviewer: Todd Bourcier, Ph.D.
`
`
`
`BMS is seeking marketing approval for a fixed-dose combination product of saxagliptin and
`metformin extended release as a treatment for type 2 diabetes. Both pharmaceutical components
`are currently approved for the chronic treatment of type 2 diabetes. Saxagliptin is a
`dipeptidylpeptidase-4 inhibitor approved in 2009 (Onglyza, NDA 22350), and metformin XR is
`an extended release biguanide (Glucophage XR, NDA 21202). BMS owns all data relevant to
`saxagliptin but is in part relying the FDA’s previous finding of safety and efficacy for
`metformin.
`
`Dr. Lauren Murphree Mihalcik, the primary pharm/tox reviewer, recommends approval of NDA
`200678. I concur with Dr. Mihalcik’s recommendation that the submitted nonclinical
`information supports approval of the saxa/met XR application. Our recommendation is based on
`the available information for saxagliptin and metformin as monotherapies, and on toxicology
`studies conducted with the drugs in combination to assess general toxicity and embryofetal
`development.
`
`The toxicology of saxagliptin and metformin in combination was evaluated in a 3-month study in
`dogs. Experimental groups assessed each drug separately and in combination for comparison.
`No toxicity unique to the drugs in combination was observed, and the toxicity of each drug
`separately was reasonably similar to the toxicology profile that supported approval of each drug
`component.
`
`The applicant also submitted embryofetal development studies in rats and rabbits in support of
`the saxa/met XR combination and in response to a post-marketing requirement for the
`saxagliptin monotherapy NDA 22350. During the review cycle for NDA 22350, an embryofetal
`study conducted in rats with the saxa/met combination yielded a weak signal for neural tube
`defects (NTD). A relationship specific to the combination could not be excluded due to a study
`design that lacked separate arms for saxagliptin and metformin. Therefore, the Division imposed
`a PMR for the saxagliptin monotherapy NDA to conduct embryofetal studies in rats and rabbits
`
`

`

`with the drugs alone and in combination. BMS conducted these studies, and as reviewed by Dr.
`Murphree Mihalcik, these studies did not identify a drug-related neural tube defect as was seen in
`the original rat study, despite using higher doses of metformin alone or in combination with
`saxagliptin. Moreover, the 4.5% incidence of NTD observed in the original rat study was shown
`to be consistent with updated historical control data from the study site for this finding.
`Therefore, I concur with Dr. Murphree Mihalcik’s conclusion that the saxa/met combination is
`not teratogenic in animals and that the original finding of NTD in rats was incidental to drug
`treatment. Pregnancy labeling for the saxa/met XR product and the saxagliptin monotherapy will
`be revised to reflect the most current embryofetal animal data.
`
`
`
`
`
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`TODD M BOURCIER
`10/01/2010
`Pharm/tox recommends AP
`
`Reference ID: 2844270
`
`

`

`
`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
`
`200678
`1
`29 December 2009
`29 December 2009
`saxagliptin + metformin extended release (FDC)
`Type 2 Diabetes Mellitus
`Bristol-Myers Squibb
`Division of Metabolism and Endocrinology Products
`Lauren Murphree Mihalcik, Ph.D.
`Todd Bourcier, Ph.D.
`Mary Parks, M.D.
`Mehreen Hai, Ph.D.
`
`Application number:
`Supporting document/s:
`Applicant’s letter date:
`CDER stamp date:
`Product:
`Indication:
`Applicant:
`Review Division:
`Reviewer:
`Supervisor/Team Leader:
`Division Director:
`Project Manager:
`Template Version: December 7, 2009
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and necessary for approval of
`NDA 200678 are owned by Bristol-Myers Squibb or are data for which Bristol-Myers Squibb has obtained
`a written right of reference.
`
`Any information or data necessary for approval of NDA 200678 that Bristol-Myers Squibb does not own or
`have a written right to reference constitutes one of the following: (1) published literature, or (2) a prior
`FDA finding of safety or effectiveness for a listed drug, as described in the drug’s approved labeling. Any
`data or information described or referenced below from a previously approved application that Bristol-
`Myers Squibb does not own (or from FDA reviews or summaries of a previously approved application) is
`for descriptive purposes only and is not relied upon for approval of NDA 200678.
`
`1
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`

`

`NDA 200678
`
`
`
`
`Reviewer: Lauren Murphree Mihalcik, Ph.D.
`
`TABLE OF CONTENTS
`
` 1
`
`
`
`2
`3
`4
`
`EXECUTIVE SUMMARY .....................................................................................................................5
`1.1
`RECOMMENDATIONS ......................................................................................................................5
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS................................................................................5
`DRUG INFORMATION.........................................................................................................................6
`STUDIES SUBMITTED........................................................................................................................9
`PHARMACOLOGY ............................................................................................................................10
`4.1
`PRIMARY PHARMACOLOGY ...........................................................................................................10
`4.2
`SECONDARY PHARMACOLOGY ......................................................................................................10
`4.3
`SAFETY PHARMACOLOGY .............................................................................................................11
`PHARMACOKINETICS/ADME/TOXICOKINETICS ..........................................................................11
`5.1
`PK/ADME...................................................................................................................................11
`5.2
`TOXICOKINETICS ..........................................................................................................................11
`GENERAL TOXICOLOGY.................................................................................................................12
`6.1
`SINGLE-DOSE TOXICITY ...............................................................................................................12
`6.2
`REPEAT-DOSE TOXICITY ..............................................................................................................13
`GENETIC TOXICOLOGY ..................................................................................................................22
`CARCINOGENICITY..........................................................................................................................23
`REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY............................................................23
`9.2
`EMBRYONIC FETAL DEVELOPMENT ...............................................................................................23
`11
`INTEGRATED SUMMARY AND SAFETY EVALUATION................................................................47
`
`
`5
`
`6
`
`7
`8
`9
`
`2
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`

`

`NDA 200678
`
`
`
`
`Reviewer: Lauren Murphree Mihalcik, Ph.D.
`
`Table of Tables
`Table 1. Drug formulation.............................................................................................................................8
`Table 2. In vitro Ki values for inhibition of DPP subtypes ..........................................................................11
`Table 3. Interspecies comparisons of multiples of human exposure for saxagliptin, BMS-510840, and
`metformin in pivotal studies.........................................................................................................................12
`Table 4. Single dose dog toxicity study: Toxicokinetics.............................................................................13
`Table 5. Two week dog study: Toxicokinetics............................................................................................14
`Table 6. Dog combination toxicity study: Body weight gain........................................................................17
`Table 7. Dog combination toxicity study: Respiration rate..........................................................................19
`Table 8. Dog combination toxicity study: Hematocrit..................................................................................20
`Table 9. Dog combination toxicity study: Microscopic findings..................................................................21
`Table 10. Dog combination toxicity study: Toxicokinetics...........................................................................22
`Table 11. Range-finding in pregnant rats: Toxicokinetics...........................................................................23
`Table 12. Rat combination EFD study (I): Toxicokinetics ...........................................................................26
`Table 13. Rat combination EFD study (I): Maternal performance ..............................................................27
`Table 14. Rat combination EFD study (I): Uterine and ovarian parameters...............................................27
`Table 15. Updated historical control incidence of craniorachischisis .........................................................29
`Table 16. Rat combination EFD study (I): Major malformations.................................................................30
`Table 17. Rat combination EFD study (I): Minor external and visceral anomalies .....................................31
`Table 18. Rat combination EFD study (I): Minor skeletal anomalies..........................................................31
`Table 19. Rat combination EFD study (I): Common skeletal variants ........................................................32
`Table 20. Rat combination EFD study (II): Maternal body weight ..............................................................34
`Table 21. Rat combination EFD study (II): Toxicokinetics ..........................................................................35
`Table 22. Rat combination EFD study (II): Maternal performance .............................................................36
`Table 23. Rat combination EFD study (II): Cesarean section data............................................................36
`Table 24. Rat combination EFD study (II): Fetal weights ...........................................................................38
`Table 25. Rat combination EFD study (II): Major malformations................................................................38
`Table 26. Rat combination EFD study (II): Minor alterations ......................................................................39
`Table 27. Metformin TK and tolerability study in pregnant rabbits: Toxicokinetics.....................................41
`Table 28. Rabbit combination EFD study: Mortality....................................................................................42
`Table 29. Rabbit combination EFD study: Maternal body weights .............................................................43
`Table 30. Rabbit combination EFD study: Toxicokinetics..........................................................................44
`Table 31. Rabbit combination EFD study: C-section data ..........................................................................45
`Table 32. Rabbit combination EFD study: Fetal parameters ......................................................................46
`Table 33. Rabbit combination EFD study: Fetal alterations........................................................................46
`Table 34.Rabbit combination EFD study: Incidence of NTD-like effects ....................................................47
`Table 35. Rabbit combination EFD study: Incidence of small/absent gallbladder......................................47
`Table 36. Rabbit combination EFD study: Skeletal variations ....................................................................47
`
`
`3
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`

`NDA 200678
`
`
`
`
`Reviewer: Lauren Murphree Mihalcik, Ph.D.
`
`Table of Figures
`Figure 1. Metformin HCl structure.................................................................................................................7
`Figure 2. Saxagliptin structure ......................................................................................................................7
`Figure 3. Dog combination toxicity study: Male body weight......................................................................17
`Figure 4. Dog combination toxicity study: Female body weight..................................................................17
`Figure 5. Dog combination toxicity study: Male food consumption.............................................................18
`Figure 6. Dog combination toxicity study: Female food consumption ........................................................18
`Figure 7. Rat combination EFD study (I): Maternal body weight ...............................................................25
`Figure 8. Rat combination EFD study (II): Maternal body weights .............................................................34
`
`
`4
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`

`NDA 200678
`
`
`
`
`Reviewer: Lauren Murphree Mihalcik, Ph.D.
`
`1
`
`Executive Summary
`
`1.1 Recommendations
`
`1.1.1 Approvability
`
`Pharmacology/Toxicology recommends approval of NDA 200678
`
`1.1.2 Additional Non Clinical Recommendations
`
`None
`
`1.1.3
`
`Labeling
`
`Reviewer’s note: Changes from the sponsor’s wording is underlined. Only new language regarding the
`combination is shown for section 8 below since wording under “saxagliptin” and “metformin” sections are
`identical to the approved monotherapy labeling and are considered acceptable. The wording in section
`13 is acceptable.
`
` USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`Pregnancy Category B
`There are no adequate and well-controlled studies in pregnant women with TRADENAME or its individual
`components. Because animal reproduction studies are not always predictive of human response,
`TRADENAME, like other antidiabetic medications, should be used during pregnancy only if clearly
`needed.
`
`Coadministration of saxagliptin and metformin, to pregnant rats and rabbits during the period of
`organogenesis, was neither embryolethal nor teratogenic in either species when tested at doses yielding
`systemic exposures (AUC) up to 100 and 10 times the maximum recommended human doses (MRHD;
`saxagliptin 5 mg and metformin 2000 mg), respectively, in rats; and 249 and 1.1 times the MRHDs in
`rabbits. In rats, minor developmental toxicity was limited to an increased incidence in wavy ribs;
`associated maternal toxicity was limited to weight decrements of 11-17% over the course of the study,
`and related reductions in maternal food consumption. In rabbits, coadministration was poorly tolerated in
`a subset of mothers (12 of 30), resulting in death, moribundity, or abortion. However, among surviving
`mothers with evaluable litters, maternal toxicity was limited to marginal reductions in body weight over the
`course of gestation days 21 to 29; and associated developmental toxicity in these litters was limited to
`fetal body weight decrements of 7% and a low incidence of delayed ossification of the fetal hyoid.
`
`
`Additional note: Existing pregnancy labeling language in the Onglyza monotherapy NDA will be revised to
`reflect the additional information on animal teratogenicity (NDA 22350, TSI 000758).
`
` 8
`
`1.2 Brief Discussion of Nonclinical Findings
`
`The sponsor has submitted studies using dosing with metformin and saxagliptin including a 3-month
`study in dogs for general toxicity and embryofetal development studies in rats and rabbits. None of the
`studies identified a unique or emergent toxicity as a result of co-administration of the two drugs.
`
`5
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`

`NDA 200678
`
`
`
`
`Reviewer: Lauren Murphree Mihalcik, Ph.D.
`
`
`Embryofetal development (EFD) studies using the combination were considered crucial for estimating the
`safety of combination dosing. The original combination study used saxagliptin/metformin doses of 0/0,
`5/200, and 25/200 mg/kg/day. In the 25/200 group, two fetuses (from the same litter) displayed
`craniorachischisis, a rare neural tube defect (NTD). At the time of the study, the litter and fetal incidence
`were outside the historical control range values for the laboratory. To address this issue, the sponsor
`used a two-pronged approach. They updated the historical control database, including dose range
`finding studies, and repeated the study using more animals (n=30) and higher doses of metformin (600
`mg/kg), along with appropriate controls (a vehicle control and groups with saxagliptin (25 mg/kg) or
`metformin alone). The new historical control data showed four instances of craniorachischisis in control
`animals, bringing the finding in the first EFD study to within the historical control range.
`
`The follow-up rat EFD study had verified exposures to saxagliptin of ~100X MRHD, to BMS-510849 of
`~7X MRHD, and to metformin of ~10X MRHD (AUC basis). There were additive decreases in weight gain
`observed in the drug-treated groups, but there were no malformations observed (other than in one control
`fetus). The only finding in this study that appeared to be related to treatment was a slight increase in
`wavy ribs observed in the combination group (a statistically significant increase in fetal incidence).
`Because wavy ribs are commonly observed in the offspring of dams with reduced body weight gain and
`because wavy ribs typically resolve during post-natal development in the rat, this finding was not
`considered an adverse effect. The reviewer does not consider the combination to be teratogenic in rats.
`
` A
`
` combination EFD study in rabbits was also requested by the Division as a follow-up to the original
`craniorachischisis finding in the rat. This study used doses providing ≥ 200X MRHD for saxagliptin and/or
`~1X MRHD (AUC basis) for metformin (due to mortality at 2X MRHD). There was high mortality (12/30
`dams) in the combination group. Satellite animals evaluated for toxicokinetics and clinical chemistry
`showed sporadic low levels for bicarbonate, suggesting lactic acidosis may have contributed to some of
`the deaths. There were no malformations in the nine early decedents with live litters at necropsy. One
`surviving dam in the combination dose group had a single fetus with malformations, including
`exencephaly, which is an NTD. This incidence was within the historical control range, however, and was
`considered incidental (not related to treatment) by both the sponsor and the reviewer. The saxagliptin-
`only group in this study had a significant increase offspring with small or absent gallbladder. Although
`this finding could reasonably be attributed to treatment (especially given a similar but not statistiscally
`significant finding in the monotherapy EFD study), any risk to a developing fetus is very low given the high
`multiples of exposure involved. This finding was not observed in the combination group.
`
`2 Drug Information
`
`2.1 Drug
`
`2.1.1 CAS Registry Number (Optional)
`
`945667-22-1
`
`2.1.2 Generic Name
`
`Saxagliptin/metformin HCL extended release
`
`2.1.3 Code Name
`
`BMS-477118-11 (saxagliptin)
`
`6
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`NDA 200678
`
`
`2.1.4 Chemical Name
`
`
`
`Reviewer: Lauren Murphree Mihalcik, Ph.D.
`
`Saxagliptin: (1S,3S,5S)-2-[(2S)-2-Amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)acetyl]-2-
`azabicyclo[3.1.0]hexane-3-carbonitrile, monohydrate
`
`Metformin: N,N-dimethylimidodicarbonimidic diamide hydrochloride
`
`2.1.5 Molecular Formula/Molecular Weight
`
`Saxagliptin: C18H25N3O2 • H2O / 333.43
`Metformin: C4H11N5 • HCl / 165.63
`
`2.1.6 Structure
`
`Figure 1. Metformin HCl structure
`
`Figure 2. Saxagliptin structure
`
`
`
`
`
`2.1.7 Pharmacologic class
`
`Saxagliptin: DPP-4 inhibitor
`Metformin: biguanide antihyperglycemic
`2.2 Relevant IND/s, NDA/s, and DMF/s
`
`
`Metformin: DMF
`Saxagliptin: IND 63634, NDA22350 (Onglyza®)
`Combination: IND 76500
`2.3 Clinical Formulation
`
`7
`
`(b) (4)
`
`

`

`
`
`Reviewer: Lauren Murphree Mihalcik, Ph.D.
`
`
`
`
`
`NDA 200678
`
`
`2.3.1 Drug Formulation
`
`The drug product is manufactured
`
` The sponsor proposes the following
`saxagliptin/metformin combinations: 5/500, 5/1000, and 2.5/1000 mg.
`
`Table 1. Drug formulation
`
`
`
`8
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 200678
`
`
`2.3.2 Comments on Novel Excipients
`
`There are no novel excipients.
`
`
`
`Reviewer: Lauren Murphree Mihalcik, Ph.D.
`
`2.3.3 Comments on Impurities/Degradants of Concern
`
`An impurity known as
`
`
`. This impurity was seen in Onglyza, as well, and falls below
`
`the qualification threshold.
`2.4 Proposed Clinical Population and Dosing Regimen
`
`The drug is proposed to be given to patients with Type 2 diabetes once daily. The proposed maximum
`recommended human doses (MRHD) are up to 5 mg saxagliptin (81 and 438 ng.h/mL for saxagliptin and
`its major metabolite, BMS-510849) and 2000 mg metformin (20451 ng.h/mL)
`2.5 Regulatory Background
`
`As part of the post marketing requirements for Onglyza®, the sponsor was required to perform additional
`embryofetal development studies in rats and rabbits using a combination of saxagliptin and metformin,
`due to a possible signal for neural tube defects in the rat study submitted with the monotherapy
`application (a study considered inadequate by the Division due to inadequate control groups and dosing
`levels). This study identified neural tube defects in 2 fetuses (from one litter) in the group receiving 25
`mg/kg saxagliptin (~100X) and 200 mg/kg metformin (~3X MRHD).
`
`3
`
`Studies Submitted
`
`3.1 Studies Reviewed
`
`All submitted studies were reviewed.
`3.2 Studies Not Reviewed
`
`This NDA references NDA 22350 (Onglyza®). With the exception of the embryofetal development study
`using saxagliptin and metformin in combination, nonclinical studies included in that submission are not
`reviewed here but are listed below.
`
`
`Identification of rat CYP enzymes that generate BMS-510849 (saxagliptin metabolite)
`Single dose cyanide formation in rats
`Single dose IV cardiovascular study in monkeys
`TK study in pregnant rabbits with saxagliptin
`TK study in pregnant rats with saxagliptin
`Multiple dose saxagliptin-related cyanide release and CNS lesions, part of 2 year rat study
`1-3 month cynomolgus monkeys study
`3-Month Monkey toxicity study
`6-Week comparative study in monkeys with saxagliptin, vildagliptin, and sitagliptin
`6-month rat study
`12-month dog study
`5-Day Toxicology study in rats with active metabolite, BMS-510849
`Chronic Investigational Central Nervous System Toxicity Study in Rats
`Genotoxicity studies with saxagliptin and active metabolite, BMS-510849
`2-Year mouse carcinogenicity study
`
`9
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`(b) (4)
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`

`

`NDA 200678
`
`
`
`
`Reviewer: Lauren Murphree Mihalcik, Ph.D.
`
`2-Year rat carcinogenicity study
`Fertility studies in male and female rats
`Embryo-fetal development study in rats
`Embryo-fetal development study in rabbits
`Pre- and postnatal development study in rats
`Embryo-fetal development study with saxagliptin and metformin combination in rats
`One Month Oral In-vivo/In-vitro Cytogenetics Study in Rat Peripheral Blood Lymphocytes
`Intermittent Dose Oral Immunotoxicity Study in Monkeys with BMS-477118
`3.3 Previous Reviews Referenced
`
`Nonclinical data supporting the safety and efficacy of saxagliptin alone is reviewed under NDA 22350 by
`Dr. Fred Alavi.
`
`4
`
`Pharmacology
`
`4.1 Primary Pharmacology
`
`No new primary pharmacology information was submitted, so pharmacology information is based on
`studies submitted in support of NDA 22-350 (saxagliptin) and literature references for both drugs.
`
`The new drug product is a combination of saxagliptin (Onglyza®) and extended release metformin.
`Saxagliptin is a reversible inhibitor (Ki= 1.3 ± 0.3 nM) of dipeptidyl peptidase 4 (DPP4). This enzyme is
`expressed on the membrane of numerous cell types (e.g., lymphocytes, endothelial cells, and epithelial
`cells) and has numerous substrates. Although many of the DPP-4 substrates are physiologically
`important (including neuropeptide Y and growth hormone releasing hormone), the efficacy of DPP4
`inhibitors in treatment of diabetes is thought to derive primarily from inhibition of the degradation of
`glucacon like peptide 1 (GLP-1) and, to a lesser extent, glucose-dependent insulinotropic polypeptide
`(GIP).
`
`Metformin is an antihyperglycemic agent with a poorly defined mechanism of action but a long history of
`clinical use. Metformin increases insulin sensitivity in skeletal muscle and reduces gluconeogenesis in
`the liver.
`
`4.2 Secondary Pharmacology
`
`No new secondary pharmacology information was submitted.
`
`Saxagliptin can inhibit other members of the DPP class (especially DPP8 and DPP9) at concentrations
`391X and 75X higher than those required for inhibition of DPP4, as shown in the sponsor's table below.
`Note that clinical Cmax is approximately 24 ng/mL (70 nM) for saxagliptin and approximately 47 ng/mL
`(140 nM) for BMS-510849, so although saxagliptin is fairly specific for DPP4, clinical concentrations
`approach those that could inhibit DPP9. There were no other significant off-target effects identified.
`
`10
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`

`NDA 200678
`
`
`
`
`Reviewer: Lauren Murphree Mihalcik, Ph.D.
`
`Table 2. In vitro Ki values for inhibition of DPP subtypes
`
`4.3 Safety Pharmacology
`
`The sponsor did not submit any dedicated safety pharmacology studies. Endpoints relevant to
`cardiovascular and respiratory safety were incorporated into the 3-month GLP combination toxicology
`study in dogs. There were no inter-group differences in respiratory parameters (including respiratory rate
`and O2 saturation) or cardiovascular endpoints (including ECG).
`5
`Pharmacokinetics/ADME/Toxicokinetics
`
`
`
`5.1 PK/ADME
`
`The sponsor did not submit pharmacokinetics and ADME studies on the combination of metformin and
`saxagliptin.
`
`5.2 Toxicokinetics
`
`Toxicokinetic parameters were measured in the course of the pivotal 3 month toxicity study and in
`pregnant rats and rabbits. AUC values for saxagliptin, its major metabolite, and metformin are shown in
`the sponsor's table below with calculated multiples of human exposure. Coadministration of both
`compounds does not appear to affect the in vivo exposures to the individual components. The reviewer
`concurs with the sponsor’s assessment of the NOAEL values. Note that there is not a NOAEL for
`pregnant rabbits.
`
`11
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`

`NDA 200678
`
`
`
`
`Reviewer: Lauren Murphree Mihalcik, Ph.D.
`
`Table 3. Interspecies comparisons of multiples of human exposure for saxagliptin, BMS-510840,
`and metformin in pivotal studies
`
`
`
`6 General Toxicology
`
`6.1 Single-Dose Toxicity
`
`Study title: Saxagliptin and Metformin: Single-dose oral toxicokinetic and tolerability
`study in dogs
`
`Study no.:
`Study report location:
`Conducting laboratory and location:
`Date of study initiation:
`GLP compliance:
`QA statement:
`Drug, lot #, and % purity:
`
`DN08032
`EDR, SN000
`BMS Drug Safety Evaluation, New Brunswick, NJ
`Not provided
`No
`No
`Saxagliptin, 4K85994, 94%
`Metformin, C13414, 99.4%
`
`Key Study Findings
`
`Dogs (2/sex/dose) were given a single dose of either saxagliptin (1, 5, or 10 mg/kg), metformin (10, 20, or
`40 mg/kg), or a combination (5 mg/kg saxagliptin and 20 mg/kg metformin). Unformed, mucoid, or bloody
`feces were reported in groups receiving ≥ 5 mg/kg saxagliptin and/or any dose of metformin...
`
`12
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`

`NDA 200678
`
`
`
`
`Reviewer: Lauren Murphree Mihalcik, Ph.D.
`
`Toxicokinetics parameters are shown in the sponsor's table below. Females receiving both drugs had
`slightly lower exposures to both drugs and the saxagliptin metabolite in this study, but TK parameters in
`males did not appear to be affected by coadministration.
`
`Table 4. Single dose dog toxicity study: Toxicokinetics
`
`6.2 Repeat-Dose Toxicity
`
`
`
`Study title: Saxagliptin and Metformin: Two-week oral investigative combination
`toxicokinetic and tolerability study in dogs
`
`Study no.:
`Study report location:
`Conducting laboratory and location:
`Date of study initiation:
`GLP compliance:
`QA statement:
`Drug, lot #, and % purity:
`
`DN08043
`EDR, SN000
`BMS Drug Safety Evaluation, New Brunswick, NJ
`Not provided
`No
`No
`Saxagliptin, 4K85994, 94%
`Metformin, C13414, 99.4%
`
`13
`
`

`

`NDA 200678
`
`
`Key Study Findings
`
`
`
`Reviewer: Lauren Murphree Mihalcik, Ph.D.
`
`Dogs (3/sex/dose) were given saxagliptin (5 mg/kg), metformin (20 mg/kg), or a combination (1 or 5
`mg/kg saxagliptin and 20 mg/kg metformin) once daily for 2 weeks in this non-terminal study. Unformed,
`mucoid, or bloody feces were reported in all groups without apparent relationship to treatment. Food
`consumption and body weight loss were seen in all groups during the first week, again without
`relationship to treatment. There were saxagliptin-related increases in eosinophils (up to 7.7X pretest) that
`were not exacerbated by cotreatment with metformin. Females receiving the 5/20 dose combination had
`12-19% decreases in RBC parameters.
`
`Toxicokinetics parameters are shown in the sponsor's table below. There were no significant toxicokinetic
`interactions caused by coadministration of the two drugs.
`
`Table 5. Two week dog study: Toxicokinetics
`
`
`
`14
`
`

`

`NDA 200678
`
`
`
`
`
`
`Reviewer: Lauren Murphree Mihalcik, Ph.D.
`
`Study title: Saxagliptin and metformin: Three-month Oral combination toxicity study in
`dogs
`
`Study no.:
`Study report location:
`Conducting laboratory and location:
`Date of study initiation:
`GLP compliance:
`QA statement:
`Drug, lot #, and % purity:
`
`DN08067 (803500)
`EDR, SN000
`
`30 September 2008
`Yes
`Yes
`Saxagliptin, 4K85994, 93.8% or 93.1%
`Metformin, C13414, 99.4%
`
`
`
`Key Study Findings
`
`• Dogs given up to 5 mg/kg saxagliptin with or without 20 mg/kg metformin had exposures to
`saxagliptin of up to ~70X MRHD (AUC basis), to BMS-510849 of ~16X MRHD, and to metformin of
`~1.5X MRHD. There was no vehicle control.
`• Tremor and shivering was observed more often in the combination treated group (11 instances vs. ≤
`1 instance in other groups), but the finding did not appear to correlate with hypoglycemia.
`• Effects on body weight gain were not statistically significantly different between groups.
`• There were no inter-group differences in respiratory parameters or cardiovascular endpoints
`(including ECG).
`• One combination treated female had mild necrosis of the fat in the dermis associated with
`inflammation.
`
`
`Reviewer Comments: This study provided adequate exposure levels to assess potential interactions of
`saxagliptin and metformin. There were no findings in the combination group that could be definitively
`attributed to treatment with the combination. The NOAEL for this study was 5/20 mg/kg of
`saxagliptin/metformin. Overall exposures were considered adequate for evaluation of possible
`interactions of saxagliptin and metformin by the Division at the pre-NDA meeting.
`
`
`Methods
`
`Doses:
`
`Frequency of dosing: Once daily
`Route of administration: Oral gavage
`Dose volume: 1 mL/kg per drug or vehicle (2 mL/kg/day total)
`Formulation/Vehicle: Saxagliptin: 0.003M HCl or 0.016M HCl (LD & HD) in deionized water
`Metformin: deionized water
`Species/Strain: Beagle dog
`Number/Sex/Group: 3/sex/group
`Age