CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`210913Orig1s000
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`
`
`
`
`
`

`

`NDA
`
`Submission Date
`
`Brand Name
`
`Generic Name
`
`Reviewer
`
`CLINICAL PHARMACOLOGY REVIEW
`
`210874
`
`07/02/2018
`
`QTERNWT XR
`
`Dapagliflozin, Saxagliptin and Metformin Hydrochloride
`
`Mohammad Absar, PhD.
`
`Team Leader (Acting)
`
`Manoj Khurana, PhD.
`
`OCP Division
`
`0ND Division
`
`Clinical Pharmacology 2
`
`Divan of Metabolic and Endocrine Products
`
`Applicant
`
`AsIIaZeneca
`
`Formulation; Strength
`
`Dapagliflozin/Saxagliptin/Metformin HCL 5/5/1000 mg
`
`Extended release oral tablet; four strengths—
`
`Dapagliflozin/SaxagliptinMetfonnin HCL 10/5/1000 mg
`
`Dosage Regime“ (Proposed)
`
`Dapagliflozin/Saxagliptin/Metfonnin HCL 2.5/2.5/1000 mg
`
`Dapagliflozm/Saxagliptin/Metfonnin HCL 5/2.5/1000 mg
`For patients not currently taking dapagliflozin,
`the
`recormnended starting total daily dose of QTERNMET XR
`is dapagliflozin/saxagliptin/Metformin HC15/5/1000 or
`2000 mg taken orally, once daily in the morning with food
`
`Relevant IND/NDA
`
`IND 131385
`
`Indication
`
`As an adjlmct to diet and exerc'se to improve glvcemic
`control in adults with T2DM
`M0
`
`Table of Contents
`
`1.
`
`EXECUTIVE SUWRY ........................................................................................................ 2
`
`1.1.
`
`Recommendations ................................................................................................................... 3
`
`1.2.
`
`1.3.
`
`Post Marketing Requirement................................................................................................... 3
`
`Summary of Important Clinical Pharmacology Findings ........................................................... 3
`
`2.
`
`QUESTION—BASED REVIEW................................................................................................. 5
`
`2.1.
`Background. ........................................................................................................................... 5
`2.1.1. What is the regulatory background pertinent to this application?.............................................. 6
`2.1.2. What are the clinical pharmacology/c linical studies submitted in the NDA?............................. 6
`
`2.2.
`
`General Attributes .................................................................................................................. 6
`
`2.2.1. What are the key physicochemicalproperties of dapagliflozin, saxagliptin and metformin? ...... 6
`2.2.2. What '3 the formulation for the drug product? ......................................................................... 7
`2.2.3. What are the proposed mechan'sms of action? ........................................................................ 7
`2.2.4. What are the proposed dosages and routes of administration? .................................................. 8
`
`1
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`Reference ID: 4410229
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`

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`General Clinical Pharmacology................................................................................................ 8
`2.3.
`2.3.1. What are the design features of the clinical pharmacology studies?.......................................... 8
`2.3.2. Are the active moieties in plasma and clinically relevant tissues appropriately identified and
`measured to assess pharmacokinetic parameter and exposure response relationships?............... 9
`2.4. What are the PK characteristics of the drug? ............................................................................ 9
`2.4.1. What are the PK parameters of dapagliflozin, saxagliptin and metformin in adult subjects? ...... 9
`2.4.2. What is the effect of food on the proposed drug product? .......................................................11
`2.4.3. How is the proposed to-be-marketed formulation linked to the clinical formulation? ...............11
`2.5.
`Bioanalytical..........................................................................................................................12
`2.5.1. What are the analytical methods used to measure dapagliflozin, saxagliptin and metformin in
`plasma? ................................................................................................................................12
`2.5.2. What are the results for the re-analysis of the incurred samples? .............................................13
`2.5.3. What are the findings from OSIS inspection?.........................................................................13
`
`List of Tables
`Table 1: Comparison of PK parameters of dapagliflozin, saxagliptin and metformin following single dose
`administration in healthy subjects .......................................................................................................... 4
`Table 2: List of FDA-approved products containing dapagliflozin and saxagliptin ................................... 5
`Table 3: Listing of clinical pharmacology/clinical studies ....................................................................... 6
`Table 4: Mean (CV%) PK parameters of dapagliflozin, saxagliptin and metformin in healthy subjects
`(Study D168AC00001) .......................................................................................................................... 9
`Table 5: Comparison of PK parameters of dapagliflozin, saxagliptin and metformin under fasted vs fed
`condition............................................................................................................................................. 11
`Table 6: Validation summary of bioanalytical method for dapagliflozin ................................................ 12
`Table 7: Validation summary of bioanalytical method for saxagliptin.................................................... 12
`Table 8: Validation summary of bioanalytical method for metformin .................................................... 13
`
`List of Figures
`Figure 1: Chemical structure of dapagliflozin, saxagliptin and metformin HCl ........................................ 7
`Figure 2: Schematic illustration of the formulation design principle of the Dapa/Saxa/Met XR tablet ....... 7
`Figure 3: Plasma concentration-time profile for dapagliflozin in healthy subjects (Study D168AC00001)
` ........................................................................................................................................................... 10
`Figure 4: Plasma concentration-time profile for saxagliptin in healthy subjects (Study D168AC00001).. 10
`Figure 5: Plasma concentration-time profile for metformin in healthy subjects (Study D168AC00001) .. 10
`
` EXECUTIVE SUMMARY
`1.
`AstraZeneca (Applicant) has submitted NDA 210874 under the 505(b)(1) pathway seeking marketing
`approval for dapagliflozin/saxagliptin/metformin hydrochloride (HCL) (Dapa/Saxa/Met) as an adjunct to
`diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM)
`
` The drug product is an extended
`release oral tablet with four strengths: Dapa/Saxa/Met 2.5/2.5/1000 mg, 5/2.5/1000 mg, 5/5/1000 mg and
`10/5/1000 mg. The proposed starting total daily dose for patients not currently taking dapagliflozin is
`Dapa/Saxa/Met 5/5/1000 or 2000 mg taken orally, once daily in the morning with food.
`The clinical pharmacology program included a single Phase 1 comparative pharmacokinetic (PK)/food
`effect study (D168AC00001) in which the systemic exposure of dapagliflozin, saxagliptin and metformin
`following administration of single oral dose of the triple combination product – Dapa/Saxa/Met 5/2.5/1000
`mg – were compared with that from administration of single oral dose of saxagliptin 2.5 mg (ONGLYZA)
`+ dapagliflozin/metformin HCL 5/1000 mg (XIGDUO XR) in healthy subjects under fed condition (Cohort
`2
`
`
`
`Reference ID: 4410229
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`(b) (4)
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`

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`1). Similar comparison was also performed following single oral dose administration of triple combination
`product – Dapa/Saxa/Met 10/5/1000 mg with that following single oral administration of Saxagliptin 5 mg
`(ONGLYZA) + dapagliflozin/metformin HCl 10/1000 mg (XIGDUO XR) in healthy subjects (Cohort 2).
`In addition, the effect of food on the triple combination product was evaluated in each cohort. This study
`was conducted to bridge the data generated in the two pivotal Phase 3 studies in T2DM patients (Studies
`D1683C00005 and CV181169) that used monocomponents of dapagliflozin, saxagliptin and metformin
`HCl.1 The Applicant requested biowaiver for the other two strengths – Dapa/Saxa/Met 2.5/2.5/1000 mg
`and 5/5/1000 mg. The following are the major findings from the current review –
`1. Following single dose administration of Dapa/Saxa/Met 5/2.5/1000 mg in healthy subjects under
`fed condition,
`the mean peak concentration (Cmax) and total systemic exposure (AUCinf) of
`dapagliflozin were 42.3 ng/mL and 239.9 ng.hr/mL, respectively, of saxagliptin were 10.6 ng/mL
`and 51.6 ng.hr/mL, respectively, and of metformin were 1098 ng/mL and 10930 ng.hr/mL,
`respectively (Cohort 1, Study D168AC00001).
`2. In the same study (Cohort 2), following single dose administration of Dapa/Saxa/Met 10/5/1000
`mg, the Cmax and AUCinf dapagliflozin were 75.7 ng/mL and 463.6 ng.hr/mL, respectively, of
`saxagliptin were 20.9 ng/mL and 102.6 ng.hr/mL, respectively, and of metformin were 1057 ng/mL
`and 10470 ng.hr/mL, respectively.
`3. The geometric mean ratio (GMR) of Cmax and AUCinf of dapagliflozin, saxagliptin and metformin
`were, in general, comparable between Dapa/Saxa/Met triple combination products (i.e., 5/2.5/1000
`mg and 10/5/1000 mg) and their respective reference arms (i.e., single dose administration of
`ONGLYZA+XIGDUO XR) under fed condition.
`4. There was no clinically meaningful effect of food on the systemic exposure of dapagliflozin,
`saxagliptin and metformin from the triple combination product. Under fed condition, the Cmax and
`AUCinf of saxagliptin and metformin were comparable to that under fasting condition for both
`strengths – Dapa/Saxa/Met 5/2.5/1000 mg and 10/5/1000 mg. While AUCinf of dapagliflozin was
`comparable, Cmax was reduced by approximately 38% under fed condition. This reduction in Cmax
`is consistent with previous findings of dapagliflozin and is not considered clinically meaningful.2
`
`
`1.1. Recommendations
`The Office of Clinical Pharmacology/Division of Clinical Pharmacology 2 (OCP/DCP2) has reviewed the
`clinical pharmacology data submitted under NDA 210874 and finds the data acceptable to support approval.
`
`1.2. Post Marketing Requirement
`None.
`
`1.3. Summary of Important Clinical Pharmacology Findings
`The clinical program for Dapa/Saxa/Met triple combination product includes two pivotal Phase 3
`efficacy/safety studies (D1683C00005 and CV181169) that utilized a dual add-on strategy to evaluate the
`combination of dapagliflozin and saxagliptin when added to metformin in adults with T2DM who had
`inadequate glycemic control.
` Both the Phase 3 studies were conducted using monoproducts of
`dapagliflozin, saxagliptin and metformin HCl; refer to the Clinical Review by Dr. Frank Pucino for
`additional detail.
`To bridge clinical data generated in the two pivotal Phase 3 studies with the proposed fixed dose triple
`combination product, the Applicant conducted a Phase 1 comparative pharmacokinetic (PK)/food effect
`
`1 Studies D1683C00005 and CV181169 were also submitted as an efficacy supplement under NDA 209091 (QTERN).
`2 Prescribing information of XIGDUO XR (dated 02/22/2019)
`3
`
`
`
`Reference ID: 4410229
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`

`

`study (D168AC00001) in which healthy subjects received a single oral dose of Dapa/Saxa/Met 5/2.5/1000
`mg under fasted and fed condition or saxagliptin 2.5 mg (ONGLYZA) + dapagliflozin/metformin HCL
`5/1000 mg ((XIGDUO XR) under fed condition in a crossover fashion (Cohort 1). In Cohort 2, healthy
`subjects received the highest strength of the triple combination product, Dapa/Saxa/Met 10/5/1000 mg,
`under fasted and fed condition, or saxagliptin 5 mg (ONGLYZA) + dapagliflozin/metformin HCl 10/1000
`mg (XIGDUO XR) under fed condition in a crossover fashion.
`The results from this study demonstrated that the geometric mean ratio (GMR) of Cmax of dapagliflozin
`following single dose administration of Dapa/Saxa/Met 5/2.5/1000 mg and 10/5/1000 mg to that of the
`respective reference arm (i.e., single dose administration of ONGLYZA + XIGDUO XR) under fed
`condition were 1.14 and 0.93, respectively, while that of AUCinf were 1.03 and 0.98, respectively. The
`GMR of Cmax of saxagliptin following single dose administration of Dapa/Saxa/Met 5/2.5/1000 mg and
`10/5/1000 mg to that of the respective reference arm were 1.00 and 0.94, respectively, while that of AUCinf
`were 1.00 and 1.01, respectively. The GMR of Cmax of metformin following single dose administration of
`Dapa/Saxa/Met 5/2.5/1000 mg and 10/5/1000 mg to that of the reference arm were 1.05 and 0.96,
`respectively, while that of AUCinf were 0.99 and 0.94, respectively.
`The comparison in PK parameters from this study is summarized in Table 1.
`Table 1: Comparison of PK parameters of dapagliflozin, saxagliptin and metformin following single
`dose administration in healthy subjects
`
`
`PK
`parameter
`
`
`
`
`
`GMR (90% CI)
`Dapa/Saxa/Met 5/2.5/1000 vs
`ONGLYZA 2.5 + XIGDUO
`XR 5/1000
`1.14 (1.01 – 1.28)
`Cmax
`1.03 (0.94 – 1.12)
`AUCt
`1.03 (0.94 – 1.12)
`AUC
`1.00 (0.85 – 1.17)
`Cmax
`1.00 (0.88 – 1.15)
`AUCt
`1.00 (0.88 – 1.14)
`AUC
`1.05 (0.95 – 1.17)
`Cmax
`0.99 (0.88 – 1.10)
`AUCt
`0.99 (0.88 – 1.12)
`AUC
`Source: NDA 210874, Module 2.7; Summary of Biopharmaceutic Studies
`
`GMR (90% CI)
`Dapa/Saxa/Met 10/5/1000 vs
`ONGLYZA 5 + XIGDUO
`XR 10/1000
`0.93 (0.83 – 1.03)
`0.98 (0.90 – 1.07)
`0.98 (0.90 – 1.07)
`0.94 (0.83 – 1.06)
`1.01 (0.91 – 1.11)
`1.01 (0.91 – 1.11)
`0.96 (0.86 – 1.07)
`0.96 (0.86 – 1.06)
`0.94 (0.84 – 1.06)
`
`Dapagliflozin
`
`Saxagliptin
`
`Metformin
`
`In general, PK of dapagliflozin, saxagliptin and metformin were comparable between the triple combination
`and ONGLYZA+XIGDUO XR. The 90% CI for GMR of Cmax, AUCt and AUCinf of saxagliptin and
`metformin were within the prespecified bioequivalence margin of 0.8 – 1.25 for both strengths. The upper
`bound of 90% CI for GMR of Cmax of dapagliflozin for the lower strength was 1.28, outside of the
`prespecified bioequivalence margin. However, the 90% CI for GMR of dapagliflozin AUCt and AUCinf
`both were within the margin of 0.8 – 1.25. In addition, for the highest strength product, the GMR of all
`three PK parameters (i.e., Cmax, AUCt and AUCinf) for dapagliflozin were within 0.8 – 1.25. Since this
`deviation is for peak exposures for one of the component of the FDC, not consistently observed for both
`strengths, and difference being on the higher side with regards to the relative exposure to reference single
`components, there are no efficacy related concerns due to assurance of total exposure being comparable by
`the bioequivalence criteria; the observed marginally higher Cmax from the lower strength does not appear to
`
`
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`Reference ID: 4410229
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`4
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`pose any additional safety concern being only noted for the lower strength, as safety from the higher dose
`of dapagliflozin has already been assessed
`
`Notably, this bridging study compared the systemic exposure of dapagliflozin, saxagliptin and metformin
`from the triple combination product to that from single dose admin'Btration of ONGLYZA + XIGDUO XR
`(dapagliflozin+ metformin HCl). However, the pivotal clinical studies 031683C00005 and CV181169) to
`which,
`the bridge is intended were conducted with monocomponents of dapagliflozin, saxagliptin and
`metformin, unlike combination of dapagliflozin + metformin (XIGDUO XR) as used in the bridging study.
`Nevertheless, no PK interaction between dapagliflozin 5 mg and metformin 500 mg or dapagliflozin 10 mg
`and metformin 1000 mg were observed in Studies 102092 and 102100, submitted imder NDA 205649 for
`XIGDUO XR.3 In addition, no clinically significant PK interaction between dapagliflozin and saxagliptin
`(Study CV181191)4 or between saxagliptin and metformin (Study CV181017)5 were observed during the
`clinical development program for QTERN and ONGLYZA, respectively.
`
`The Applicant’s biowaiver request for the two other strengths — Dapa/Saxa/Met 2.5/2.5/1000 mg and
`5/5/1000 mg —was deemed acceptable by the Biopharmaceutics review team (refer to the Biopharmaceutics
`Review by Dr. Sarah Ibrahim for additional detail).
`
`Taken together, a scientific bridge has been established between the triple combination product and the
`monoproducts used in the pivotal Phase 3 clinical studies. For clinical pharmacology related information
`in the proposed label,
`including tabulated presentation of the drug interaction data, the applicant relied on
`their previously approved products containing dapagliflozin, saxagliptin and/or metformin, and is generally
`cons'stent with the referenced products.
`
`the systemic exposure of dapagliflozin, saxagliptin and metformin were comparable
`Under fed condition,
`to that under fasting condition. Compared to fasted condition,
`the GMR for Cmax and AUCinfof saxagliptin
`lmder fed condition were 0.91 and 1.10, respectively, for Dapa/Saxa/Met 5/2.5/1000 mg, and were 0.84 and
`1.12, respectively, for Dapa/Saxa/Met 10/5/1000 mg. Similarly, the GMR ofCmax and AUCinfof metformin
`imder fed condition were 0.92 and 1.15, respectively, for Dapa/Saxa/Met 5/2.5/1000 mg, and were 0.90 and
`1.14, respectively, for Dapa/Saxa/Met 5/10/1000 mg. For dapagliflozin, while the GMR of AUCmfunder
`fed condition were 0.98 and 0.95 for Dapa/Saxa/Met 5/2. 5/1000 mg and Dapa/Saxa/Met 10/5/1000 mg,
`respectively, GMR of Cm was 0.62 and 0.61 respectively. This ~38% reduction in CM under fed
`condition is consistent with previous findings of dapagliflozin andis not considered clinically meaningful.3
`
`Overall, Clinical Pharmacology recommends approval of NDA 210874.
`
`2.
`
`QUESTION-BASED REVIEW
`
`2.1. Background
`
`Dapagliflozin and saxagliptin are currently approved in the United States both as monoproducts, and as
`combination of dapagliflozin/saxagliptin tablet. In addition, combination of dapagliflozin/metformin HCl
`and saxagliptin/metformin HCl are also approved. All these products were sponsored by AstraZeneca.
`Table 2 1th the currently approved products in the US that contain dapagliflozin and saxagliptin
`In this
`application,
`the Applicant proposes a triple combination of dapagliflozin/saxagliptin/metformin HCl
`
`Table 2: ListofFDA-a troved roducts containini daa-liflozin and sax- 'tlitin
`
`—« Aeiive ingredient
`
`”Widening“
`
`FARXIGA
`
`ONGLYZA
`
`202293
`
`22350
`
`5 and 10 ., tablet
`
`2.5 and 5 u ; tablet
`
`5
`
`3 NDA 205649 for XIGDUO XR; Clinical PhanmcologyReviewby Dr. Suryanarayana Sista
`4 NDA 209782 for QTERN: Clinical PhanmcologyReviewby Dr. Johnny Ian
`5 NDA 22350 for ONGLYZA; Clinical PhamncologyReviewby Dr. JayabharalhiVaidyanathan
`
`Reference ID: 4410229
`
`

`

`KOMBIGLYZE
`
`200678
`
`Saxagliptin/metformin
`
`QTERN
`XIGDUO XR
`
`209091
`205649
`
`Dapagliflozin/saxagliptin
`Dapagliflozin/metformin
`HCl
`
`10/5 mg tablet
`10/500,
`5/500, 5/1000,
`10/1000, 2.5/1000 mg XR
`tablet
`5/500, 5/1000, 2.5/1000
`XR tablet
`2.1.1. What is the regulatory background pertinent to this application?
`The applicant carried out the development program for the triple combination product under IND 131385.
`During a pre-IND correspondence dated 10/25/2016,
`the Agency deemed the proposed approach to
`establish bioequivalence between Dapa/Saxa/Met 10/5/1000 mg and ONGLYZA + XIGDUO XR as a
`reference, acceptable. In a response (dated 12/23/2016) to Applicant’s follow-up question, the Agency
`stated that evaluating the intermediate strength Dapa/Saxa/Met 5/2.5/1000 mg instead of 2.5/2.5/1000 mg
`strength would be acceptable for the bioequivalence assessment.
`
`2.1.2. What are the clinical pharmacology/clinical studies submitted in the NDA?
`The clinical pharmacology studies/clinical studies are summarized below:
`Table 3: Listing of clinical pharmacology/clinical studies
`
`Study ID
`Objectives
`Population
`Study Design
`
`PK study
`
`D168AC00001 PK, BE, Food
`effect
`
`HS (n=81)
`
`R, OL, 2 parallel
`cohorts, 3T, 3P,
`CO, SD
`
`D1683C00005 Efficacy,
`safety
`
`Patients with
`T2DM
`(n=754)
`
`R, DB, active-
`controlled, PG
`MC, 24-week
`
`Efficacy/safety
`study
`
`CV181169
`
`Efficacy,
`safety
`
`Patients with
`T2DM
`(n=490)
`
`R, DB, active-
`controlled, PG
`MC, 24-week
`
`Treatment and Device
`Cohort 1:
`Dapa/Saxa/Met: 5/2.5/1000 mg; fed
`Dapa/Saxa/Met: 5/2.5/1000 mg; fasted
`ONGLYZA+XIGDUO XR: 2.5 mg +
`5/1000 mg; fed
`Cohort 2:
`Dapa/Saxa/Met: 10/5/1000 mg; fed
`Dapa/Saxa/Met: 10/5/1000 mg; fasted
`ONGLYZA+XIGDUO XR: 5 mg +
`10/1000 mg; fed
`Dapagliflozin 5 mg + saxagliptin 5 mg +
`metformin >1500 mg per day
`(administered as monoproducts)
`Saxagliptin 5 mg + metformin >1500 mg
`per day (administered as monoproducts)
`Dapagliflozin 5 mg + metformin >1500
`mg per day (administered as
`monoproducts)
`Dapagliflozin 10 mg + saxagliptin 5 mg +
`metformin XR >1500 mg per day
`(administered as monoproducts)
`Saxagliptin 5 mg + metformin XR >1500
`mg per day (administered as
`monoproducts)
`Dapagliflozin 10 mg + metformin XR
`>1500 mg per day (administered as
`monoproducts)
`
`Source: NDA 210874, Module 5.2; Tabular listing of all clinical studies
`
`2.2. General Attributes
`2.2.1.What are the key physicochemical properties of dapagliflozin, saxagliptin and metformin?
`Dapagliflozin
`is
`described
`chemically
`as
`D-glucitol,
`1,5-anhydro-1-C-[4-chloro-3-
`[(4ethoxyphenyl)methyl]phenyl]-, (1S)-, compounded with (2S)-1,2-propanediol, hydrate (1:1:1). The
`empirical formula is C21H25ClO6.C3H8O2.H2O and the formula weight is 502.98.2 Saxagliptin monohydrate
`is described chemically as (1S,3S,5S)-2-[(2S)-2-Amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-1yl)acetyl]-2-
`6
`
`
`
`Reference ID: 4410229
`
`

`

`or
`monohydrate
`azabicyclo[3. 1.0]hexane-3-carbonitrile,
`(3hydroxyadamantan—l-yl)acetyl]—2—azabicyclo[3.1.0]hexane-3-carbonitrile
`formula is C18H25N302.H20 and the molecular weight is 333.43.
`
`(1S,3$,5S)-2-[(ZS)-2-Amino-2-
`hydrate.
`The
`empirical
`
`Saxagliptin monohydrate is a white to light yellow or light brown, non-hygroscopic, crystalline powder. It
`is sparingly soluble in water at 24°C i 3°C, slightly soluble in ethyl acetate, and soluble in methanol,
`ethanol, 'sopropyl alcohol, acetonitrile, acetone, and polyethylene glycol 400 (PEG 400).6
`
`Metformin hydrochloride (MN-dhnethylimidodicarbonimidic diamide hydrochloride) E a white to off-
`white crystalline compormd with a molecular formula of C4H11N5.HC1 and a molecular weight of 165.63.
`Metformin hydrochloride is freely soluble in water, slightly soluble in alcohol, and 's practically insoluble
`in acetone, ether, and chloroform The pKa of metformin is 12.4. The pH of a 1% aqueous solution of
`metformin hydrochloride is 6.68. The structural formula of dapagliflozin,
`saxagliptin and metformin is
`presented in Figure 1.
`
`Dapagliflozin
`
`Saxagliptin
`
`Metformin HCI
`
`
`
`L '
`
`0 H30
`
`no
`
`HZN
`
`/.
`
`N
`
`\ NM)
`
`'
`
`0
`
`('V
`
`/
`
`“30
`
`CH3
`'II
`
`"“2
`fl
`\H/ Y 'HC'
`
`NH
`
`NH
`
`Figure 1: Chemical structure of dapagliflon'n, saxagliptin and metformin HCl
`
`2.2.2. What is the formulation for the drug product?
`The proposed formulation
`
`(6)“)
`
`Refer to the Product Quality Review by Dr. Christopher
`Galliford for additional detail on drug product formulation compositions.
`
`(hm)
`
`Figure 2: Schematic illustration of the formulation design principle of the Dapa/Saxa/Met XR tablet
`Source: NDA 210874. Module 2.7: Suury ofBiophanmceutic Studies
`
`2.2.3. What are the proposed mechanisms ofaction?
`
`The proposed drug product combines three antihyperglycemic agents with complimentary mechanisms of
`action — dapagliflozin, a sodium-glucose cotransporter 2 (SGLTZ) inhibitor,
`saxagliptin, a dipeptidyl—
`peptidase-4 (DPP4) inhibitor, and metformin hydrochloride, abiguanide.
`
`‘ Prescribing infomntionfor ONGLYZA. dated 02/27/2017
`
`7
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`Reference ID: 4410229
`
`

`

`Sodium-glucose cotransporter 2 (SGLT2), expressed in the proximal renal tubules, is responsible for the
`majority of the reabsorption of filtered glucose from the tubular lumen. Dapagliflozin is an inhibitor of
`SGLT2. By inhibiting SGLT2, dapagliflozin reduces reabsorption of filtered glucose and lowers the renal
`threshold for glucose, and thereby increases urinary glucose excretion.2
`Increased concentrations of the incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-
`dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the small intestine in
`response to meals. These hormones cause insulin release from the pancreatic beta cells in a glucose-
`dependent manner but are inactivated by the DPP4 enzyme within minutes. GLP-1 also lowers glucagon
`secretion from pancreatic alpha cells, reducing hepatic glucose production. In patients with type 2 diabetes,
`concentrations of GLP-1 are reduced but the insulin response to GLP-1 is preserved. Saxagliptin is a
`competitive DPP4 inhibitor that slows the inactivation of the incretin hormones, thereby increasing their
`bloodstream concentrations and reducing fasting and postprandial glucose concentrations in a glucose-
`dependent manner in patients with type 2 diabetes mellitus.6
`Metformin improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial
`plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose,
`and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.2
`
`2.2.4. What are the proposed dosages and routes of administration?
`For patients not currently taking dapagliflozin, the proposed starting total daily dose is a dapagliflozin 5
`mg/saxagliptin 5 mg/metformin HCl 1000 mg or 2000 mg taken orally, once daily in the morning with
`food.
`
`2.3.General Clinical Pharmacology
`2.3.1. What are the design features of the clinical pharmacology studies?
`The Clinical Pharmacology package submitted for this NDA consisted of a single Phase 1 relative
`bioavailability study aimed to bridge the data generated from two pivotal Phase 3 efficacy/safety studies
`that was conducted using monoproducts of dapagliflozin, saxagliptin and metformin HCl instead of the to-
`be-marketed fixed dose triple combination product. The study was a randomized, open-label, single-dose,
`crossover study in 81 healthy male and female subjects performed at a single study center and conducted
`in two parallel cohorts. Subjects received the following treatments in a randomized fashion.
`Cohort 1:
`• Treatment A (reference): single dose of 2.5 mg ONGLYZA and 5/1000 mg XIGDUO XR tablet co-
`administered orally under fed condition
`• Treatment B (test): single dose of triple fixed dose tablet consisting of 2.5 mg saxagliptin/5 mg
`dapagliflozin/1000 mg metformin XR under fed condition
`• Treatment C (test): single dose of triple fixed dose tablet consisting of 2.5 mg saxagliptin/5 mg
`dapagliflozin/1000 mg metformin XR under fasted condition
`Cohort 2:
`• Treatment D (reference): single dose of 5 mg ONGLYZA and 10/1000 mg XIGDUO XR tablet co-
`administered orally under fed condition
`• Treatment E (test): single dose of triple fixed dose tablet consisting of 5 mg saxagliptin/10 mg
`dapagliflozin/1000 mg metformin XR under fed condition
`• Treatment F (test): single dose of triple fixed dose tablet consisting of 5 mg saxagliptin/10 mg
`dapagliflozin/1000 mg metformin XR under fasted condition
`In each study cohort, every subject received a single dose of one of the treatments. Each treatment was
`separated by a minimum washout period of 7 to 14 days. Blood samples were collected pre-dose and at
`0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60 and 72 hours post dose.
`8
`
`
`
`Reference ID: 4410229
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`

`In addition, two pivotal Phase 3 studies were submitted in support of this application, in which efficacy and
`safety of the triple combination product were evaluated in patients with T2DM. Refer to the Clinical
`Review by Dr. Frank Pucino for details on the Phase 3 studies.
`
`2.3.2. Are the active moieties in plasma and clinically relevant tissues appropriately identified and
`measured to assess pharmacokinetic parameter and exposure response relationships?
`Dapagliflozin, saxagliptin and metformin concentrations in plasma samples were measured. Concentration
`of the active metabolite of saxagliptin – 5-hydroxy saxagliptin – were also quantified.
`
`2.4. What are the PK characteristics of the drug?
`2.4.1. What are the PK parameters of dapagliflozin, saxagliptin and metformin in adult subjects?
`Single oral doses of Dapa/Saxa/Met 5/2.5/1000 mg and 10/5/1000 mg were administered to healthy subjects
`under fasted and fed conditions in Study D168AC00001. The mean PK parameters are summarized in
`Table 4 and the plasma concentration-time profiles of dapagliflozin, saxagliptin and metformin are shown
`in Figure 3, Figure 4 and Figure 5, respectively. The key pharmacokinetic characteristics of the three
`components of triple FDC are as follows:
`•
`In healthy subjects, Cmax and AUCinf of dapagliflozin were 42.3 ng/mL and 239.9 ng.hr/mL,
`respectively, for Dapa/Saxa/Met 5/2.5/1000 mg dose and were 75.7 ng/mL and 463 ng.hr/mL,
`respectively, for Dapa/Saxa/Met 10/5/1000 mg under fed condition.
`• The Cmax and AUCinf of saxagliptin were 10.6 ng/mL and 51.6 ng.hr/mL, respectively, for
`Dapa/Saxa/Met 5/2.5/1000 mg dose and were 20.9 ng/mL and 102.6 ng.hr/mL, respectively, for
`Dapa/Saxa/met 10/5/1000 mg dose.
`• The Cmax and AUCinf of metformin were 1098 ng/mL and 10930 ng.hr/mL, respectively, for
`Dapa/Saxa/Met 5/2.5/1000 mg and were 1057 ng/mL and 10470 ng.hr/mL, respectively, for
`Dapa/Saxa/Met 10/5/1000 mg dose. The pre-dose concentrations of dapagliflozin, saxagliptin and
`metformin between the study periods were not quantifiable, suggesting that the washout period of 7
`– 14 days was adequate and pre-dose concentrations did not contribute to the PK results.
`
`Dapagliflozin
`
`Saxagliptin
`
`Metformin
`
`
`Table 4: Mean (CV%) PK parameters of dapagliflozin, saxagliptin and metformin in healthy
`subjects (Study D168AC00001)
`Dapa/Saxa/Met
`
`PK parameter
`5/2.5/1000 mg
`42.3 (40)
`Cmax (ng/mL)
`232.5 (24)
`AUCt (ng.hr/mL)
`239.9 (24)
`AUC (ng.hr/mL)
`10.6 (37)
`Cmax (ng/mL)
`50.1 (36)
`AUCt (ng.hr/mL)
`51.6 (35)
`AUC (ng.hr/mL)
`1098 (27)
`Cmax (ng/mL)
`10780 (34)
`AUCt (ng.hr/mL)
`10930 (34)
`AUC (ng.hr/mL)
`Source: NDA 210874, Module 5.3; D168AC00001 Study report
`
`Dapa/Saxa/Met
`10/5/1000 mg
`75.7 (25)
`452.4 (22)
`463.6 (22)
`20.9 (27)
`100.9 (27)
`102.6 (26)
`1057 (24)
`10420 (30)
`10470 (31)
`
`
`
`
`
`Reference ID: 4410229
`
`9
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`

`

`00—-
`
`‘
`a;—
`_
`
`40—
`
`‘
`
`2.5 mg Onglyza ‘ 5/1000 mg
`_e_ Xigduo; Fed
`+ 25/5/1000 mg Saxa/Dapa/Met;
`Fed
`
`--13— 25/5/1000 mg Saxa/Dapa/Met;
`fasted
`
`‘44
`
`‘06
`
`7?
`
`,
`1
`:,.
`v
`
`.
`
`,I:
`
`
`
`5 mg Onglyza v 10/1000 mg
`@— Xigduo: Fed
`~3- 5/10/1000 mg Saxa/Dapa/Met:
`Fed
`
`g 13- 5/10/1000 mg Saxa/Dapa/Met:
`Fasted
`
`Figure 3: Plasma concentration-time profile
`
`for dapagliflozin in healthy subjects (Study
`
`D l 68AC00 00 1)
`Source: Reviewer analysis based on data fi‘omStudy D168AC00001
`
`
`
`2.5 mg Onglyza v 5/1000 mg
`Xigduo: Fed
`2.5/5/1000 mg Saxa/Dapa/Met:
`Fed
`rested
`
`_ D 2.5/511000 Saxa/‘Dapa/Met
`
`
`
`“fl.
`
`30 A
`-
`
`'
`20— ‘
`
`fi—
`
`5 mg Onglyza ? 10/1000 mg
`)nguo: Fed
`5/10/1000 mg Sam/Dapa/Met
`Fed
`Fasted
`{1- 5/10/1000 mg Sam/Dapa/Met
`
`Figure 4: Plasma conce ntration—time profile for saxagliptin in healthy subjects (Study D168AC00001)
`Source: Reviewer analysis based on data fi‘omStudy D168AC00001
`
`,5 1600
`
`1330
`
`960
`
`323
`
`
`
`
`
`2.5 mg Onglyza ’ 5/1000 mg
`Xigduo; Fed
`_ 2.5/5/1000 Sam/Dapa/Met
`Fed
`
`fl
`
`2.5/5/1000 Sam/Dapa/Me':
`Fasled
`
`1800
`
`1140
`
`1080
`
`72°
`
`360
`
`
`
`Figure 5: Plasma conce ntration—time profile for metformin in healthy subjects (Study D168AC00001)
`Source: Reviewer analysis based on data fi'omStudy D168AC00001
`
`PK of dapagliflozin, saxagliptin and metformin were in general comparable betweenthe triple combination
`product and co-administration of ONGLYZA + XIGDUO XR. The comparison of PK parameters is
`summarized in Table 1. Plasma concentration of the active metabolite of saxagliptin — 5—OH saxagliptin —
`was also measured and was f01md comparable between the proposed triple combination product
`to
`
`Reference ID: 4410229
`
`10
`
`

`

`ONGLYZA + XIGDUO XR, i.e., 90% CI for the GMR of Cmax and AUCinf were within 0.8 – 1.25 for both
`doses.
`
`2.4.2. What is the effect of food on the proposed drug product?
`The effect of food on the proposed triple combination drug product was evaluated in healthy subjects in
`Study D168AC10001, in which subjects received a single oral dose of Dapa/Saxa/Met 5/2.5/1000 mg or
`10/5/1000 mg under fasting and fed condition (lig