CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`210874Orig1s000
`
`SUMMARY REVIEW
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`Division Summary Memo
`NDA 210874 and sNDA 20909l/S-002
`
`Division Summary Memo for Regulatory Action
`and CDTL review
`
`
`April 29, 2019
`Patiick Archdeacon, MD
`
`Acting Clinical Team Lead
`
`Division of Metabolism and Endocrinology Products
`NDA 210874 and sNDA 209091/3-002
`
`:
`
`
`Date of Submission Receipt
`July 2, 2018
`PDUFA Goal Date
`Ma 2, 2019
`
`Proprietary Name /
`Established (USAN) names
`
`QTERNIVIET XR/Dapagliflozin + Saxagliptin +
`Metformin HCl extended release
`
`Dosage Form(s)
`
`Applicant Proposed
`Indications
`
`QTERNMET XR: The Applicant is seeking approval of
`film-coated tablets containing the following
`dapagliflozin/saxagliptin/metfonnin extended-release
`dosage strengths: 2.5 mg/2.5 mg/ 1000 mg; 5 mg/2.5
`mg/1000 mg; 5 mg/5 mg/1000 mg; 10 mg/5 mg/lOOO mg
`
`QTERN: Film-coated tablets containing 10 mg of
`dapagliflozin and 5 mg of saxagliptin are currently
`approved. The Applicant is seeking approval of a 5 mg
`da aliflozin /5 m saxa litin dosa'e stren h.
`
`QTERNIVIET XR: As an adjunct to diet and exercise to
`improve glycemic control in adults with type 2 diabetes
`mellitus (T2D)
`“9‘”
`
`QTERN: As an adjunct to diet and exercise to improve
`glycemic control in adults with type 2 diabetes mellitus(hm)
`
`
`
`
`Recommended Action
`Approval
`Recommended
`The recommended labeling change for Section 1 of
`Indication(s)/Populations(s)
`QTERNIVIET XR and QTERN to include:
`As an adjunct to diet and exercise to improve glycemic
`control in adults with type 2 diabetes mellitus.
`
`The recommended labeling change for Section 2.2 to
`include:
`
`No dose adjustment is needed in patients with an eGFR
`245 mL/min/l .73 m2 and to contraindicate use with an
`eGFR below 45 mL/min/1.73 m2.
`
`Page 1 of 17
`
`Reference ID: 4428062
`
`1
`
`

`

`Division Summary Memo
`NDA 210874 and sNDA 209091/S-002
`
`1. Introduction
`
`On July 2, 2018, Astra Zeneca Pharmaceuticals LP (hereafter referred to as the Applicant)
`submitted original NDA 210874, in support of marketing approval for QTERNMET XR
`(dapagliflozin/saxagliptin/metformin HCl extended-release], and sNDA 209091-8002, in
`support of an additional dosage strength of and an expanded indication for QTERN
`(dapagliflozin/saxagliptin).
`
`The component products of QTERNMET XR are three approved antihyperglycemic agents,
`each indicated as an adjunct to diet and exercise to improve glycemic control in adults with
`type 2 diabetes mellitus (T2D). The submission to NDA 210874 includes manufacturing data,
`clinical pharmacology data, and clinical trial data. The Applicant proposes that the clinical
`data demonstrate that the combination of dapagliflozin (an SGLT2 inhibitor), saxagliptin (a
`DPP-4 inhibitor) and metformin (a biguanide) have complementary mechanisms of action to
`improve glycemic control. The Applicant has proposed the following as the indication for
`QTERNMET XR: “An adjunct to diet and exercise to improve glycemic control in adults with
`T2D
`(m4)
`
`QTERNIVIET XR has been formulated as film-coated tablets available in a variety of dosage
`strengths: 2.5 mg/2.5 mg/ 1000 mg; 5 mg/2.5 mg/ 1000 mg; 5 mg/5 mg/ 1000 mg; 10 mg/5
`mg/1000 mg.
`
`NDA 209091 for QTERN was originally approved on February 27, 2017 with the indication
`“as an adjunct to diet and exercise to improve glycemic control in adults with T2D who have
`inadequate control with dapagliflozin or who are already treated with dapagliflozin and
`saxagliptin.” Only one dosage strength is currently marketed: a film-coated tablet containing
`10 mg of dapagliflozin and 5 mg of saxagliptin mapa lO/Saxa 5). The Applicant has now
`submitted clinical data to support a conclusion that a 5 mg dose of dapagliflozin in
`combination with 5 mg of saxagliptin is safe and effective, as well as manufacturing data
`supporting the quality of the new dosage strength tablets (Dapa S/Saxa 5). The new dosage
`strength allows the dosing of dapagliflozin as its starting dose of 5 mg. For that reason, the
`Applicant has also proposed revising the indication to “as an adjunct to diet and exercise to
`improve glycemic control in adults with type 2 diabetes mellitus
`(km)
`
`This memo references the following documents/sources:
`
`Subject
`
`I TERNMET XR Addendum
`
`Integrated Quality Assessment
`(QTERNMET XR)
`
`Ramsharan Mittal, Christopher
`Galliford, Ted Change, Sarah Ibrahim,
`Anika Lalmansin -
`, James Laurenson
`
`Integrated Quath Assessment
`
`Christopher Galliford
`
`March 26, 2019
`
`April 24, 2019
`
`Page 2 of 17
`
`Reference ID: 4428062
`
`2
`
`

`

`Division Summary Memo
`NDA 210874 and sNDA 209091/S—002
`
`CMC Review (QTERN)
`
`Emily Wu
`
`April 18, 2019
`
`Biopharmaceutics Review (QTERN)
`
`Ho-Pi Lin
`
`Pharmacology/Toxicology
`
`Jeff Quinn
`
`Clinical Pharmacology (QTERNMET
`XR
`
`Mohammad Absar
`
`March 28, 2019
`
`March 19, 2019
`
`March 27, 2019
`
`Clinical Pharmacology (QTERN)
`
`Mohammad Absar
`
`April 2, 2019
`
`January 23, 2019
`
`Statistics
`
`Clinical
`
`OSI
`
`OPDP
`
`DNIPP
`
`Jennifer Clark
`
`Frank Pucino
`
`March 28, 2019
`
`April 19, 2019
`
`Cynthia Kleppinger
`
`March 25, 2019
`
`Meera Savani
`
`Nyedra Booker
`
`April 11, 2019
`
`April 16, 2019
`
`DMEPA (QTERN)
`
`Stephanie DeGraw
`
`January 25, 2019
`
`DMEPA (QTERNMET XR)
`
`Ariane Conrad
`
`2. Background
`
`In addition to the CMC data, the Applicant submitted data fiom nine studies (see Table l):
`D1683C00005 and CV181169 are new pivotal Phase 3 trials intended to support the approval
`of QTERNMET XR and the expanded indication for QTERN; CV181168 is the pivotal Phase
`3 trial (previously submitted and reviewed) that served as the basis of the original approval of
`QTERN; one new trial intended (CV181365) and one previously submitted and reviewed trial
`(CV181369) intended to support efficacy and safety; three new trials intended primarily to
`support safety (CV181363 , MB 102 129, and D 168C00014); and a biopharmaceutical study
`03168AC00001) to support a conclusion of bioequivalence between two QTERNMET XR
`dose formulations and equivalent doses of dapagliflozin, saxagliptin, and metformin HCl. In
`addition to the biopharmaceutical study, the Applicant submitted biowaivers for demonstrating
`the bioequivalence of additional QTERNMET XR and QTERN dose formulations to
`monocomponents based on dissolution, compositional similarity, and physiochemical and
`pharmacokinetic (PK) bridges to dose formulations directly shown bioequivalent to
`monocomponents (either in D168AC00001 or biopharmaceutical trials previously submitted to
`NDA 209091). Importantly, D1683C00005 and CV181 169 were conducted with the
`monocomponents rather than the fixed combined drug products (FCDPs). The Applicant
`proposes that the results of D168AC00001, in conjunction with the biowaivers, provide a
`bridge between the clinical data generated in the two pivotal Phase 3 trials and the FCDPs.
`
`Page 3 of 17
`
`Reference ID: 4428062
`
`3
`
`

`

`Division Summary Memo
`NDA 210874 and sNDA 209091/S-002
`
`Table 1: Clinical Trials Submitted to NDA 210874 and sNDA 209091/S-002
`Trial
`Trial Design
`Regimen/ Schedule/ Route
`No. of Subjects
`Identifier
`Randomized/
`Completed
`
`Pivotal Efficacy and Safety Trials
`Phase 3, randomized, double-blind,
` Dapa 5 mg + Saxa 5 mg + OL Met ≥1500 mg
`active-controlled, parallel group,
` Saxa 5 mg + Met ≥1500 mg
`multicenter trial
` Dapa 5 mg + OL Met ≥1500 mg
`─ Add-on to Met (inadequate control
`on Met)
`Phase 3, randomized, double-blind,
`active-controlled, parallel group,
`multicenter efficacy and safety trial
`─ Add-on to Met (inadequate control
`on Met)
`
` Dapa 10 mg + Saxa 5 mg + OL Met XR ≥1500
`mg
` Saxa 5 mg + OL Met XR ≥1500 mg
` Dapa 10 mg + OL Met XR ≥1500 mg
`
`Supporting Efficacy and Safety Trials
`Phase 3, randomized, double-blind,
` Saxa 5 mg + OL Dapa 10 mg + OL Met IR
`placebo-controlled, parallel group,
`≥1500 mg
`multicenter efficacy and safety trial
` Placebo + OL Dapa 10 mg + OL Met IR
`─ Sequential add-on to Met
`≥1500 mg
`(inadequate control on Dapa +
`Met)
`Phase 3, randomized, double-blind,
`active-controlled, parallel group,
`multicenter trial
`─ Add-on to Met (inadequate control
`on Met)
`Phase 3, randomized, OL, active-
`controlled, parallel group,
`multicenter trial
`─ Add-on to Met (inadequate control
`on Met)
`
` Dapa 10 mg + Saxa 5 mg + OL Met ≥1500
`mg
` Glim 1-6 mg + OL Met ≥1500 mg
`
` Dapa 10 mg + Saxa 5 mg + Met XR ≥1500
`mg ± SU
` Insulin glargine + OL Met XR ≥1500 mg ± SU
`
`Supporting Safety Trials
`Phase 3, randomized, double-blind,
` Dapa 10 mg + OL Saxa 5 mg + OL Met IR
`placebo-controlled, parallel group,
`≥1500 mg
`multicenter efficacy and safety trial
` Placebo + OL Saxa 5 mg + OL Met IR ≥1500
`─ Sequential add-on to Saxa + Met
`mg
`(inadequate control on Saxa + Met)
`
`D1683C00005
`(Efficacy and
`Safety)
`
`CV181169
`(Efficacy and
`Safety)
`
`CV181168
`(Efficacy and
`Safety)
`
`CV181365
`(Efficacy and
`Safety)
`
`CV181369
`(Efficacy and
`Safety)
`
`MB102129
`(Efficacy and
`Safety)
`
`D1689C00014
`(Efficacy and
`Safety)
`
`
`CV181363
`(Efficacy and
`Safety)
`
`D168AC00001
`(Pivotal BE
`Study)
`
`Page 4 of 17
`
`Reference ID: 4428062
`
`883/832
`
`534/490
`
`ST: 315/298
`
`ST+LT: 297/280
`
`444/385
`
`650/584
`
`ST: 320/301
`
`ST+LT: 294/281
`
`939/867
`
`Phase 4, randomized, double-blind,
`active-controlled, parallel group,
`multicenter trial
`─ Add-on to Met (inadequate control
`on Met)
`Phase 3, randomized, double-blind,
`active-controlled, parallel group,
`multicenter trial
`─ Add-on to Met (inadequate control
`on Met)
`
` Dapa 10 mg + OL Met IR ≥1500 mg
` Dapa 10 mg + Saxa 5 mg + OL Met IR ≥1500
`mg
` Glim 1-6 mg + OL Met ≥1500 mg
`
` Dapa 10 mg + Saxa 5 mg + OL Met ≥1500
` Sita 100 mg + OL Met ≥1500 mg
`
`461/411
`
`Biopharmaceutics Study
`Cohort 1
`Phase 1, OL, randomized, 2 parallel
`cohorts, 3-treatment,
` Saxa + (Dapa+Met XR) 2.5/5/1000 mg; Fed
`3-period, crossover BE study
` Dapa+Saxa+Met XR 5/2.5/1000 mg; Fed
` Daxa+Saxa+Met XR 5/2.5/1000 mg; Fasted
`Cohort 2
` Saxa + (Dapa+Met XR) 5/10/1000 mg; Fed
`
`84/81
`
`4
`
`

`

`Division Summary Memo
`NDA 210874 and sNDA 209091/S-002
`
`
`Trial
`Identifier
`
`Trial Design
`
`Regimen] Schedule] Route
`
`No. of Subjects
`Randomized]
`
`Completed
`
`o Daxa+Saxa+Met XR 10/5/1000 mg; Fed
`
`o Daxa+Saxa+Met XR 10/5/1000 mg; Fasted
`
`(Adapted from Table 4 of FDA Clinical Review)
`
`(b)(4)
`
`In the interim, based on a clinical trial of
`
`patients with moderate renal impairment (D1690C00024; DERIVE), FDA approved new
`labeling on February 22, 2019 for FARXIGA (sNDA 202293-015; dapagliflozin) and
`XIGDUO XR (sNDA 205649-009; dapagliflozin/metformin extended-release) to reflect that
`no dose adjustment is needed for patients with an eGFR 2 45 ml/min/l .73 m2. The findings
`from the review of DERIVE have therefore also been applied during the review ofNDA
`210874 and sNDA 20909l/S-2. See also the discussion in Section 11 of this Summary Memo
`(Recommendations).
`
`3. CMC
`
`Dr. Chris Galliford from the Office of New Drug Products in the Office of Pharmaceutical
`Quality served as the Application Technical Lead for the CMC review of NDA 210874
`(QTERNMET XR). The Quality Review team also included Ramasharan Mittal, Ted Chang,
`Sarah Ibrahim, Anika Lalrnansingh, and James Laurenson; topics covered included Drug
`Substance, Drug Product, Process, Facility Inspections, Biopharrnaceutics (see Section 5), and
`Environmental Assessment. The team recommended (and I concur) to approve NDA 210874
`fiom a CMC perspective.
`
`QTERNIVIET XR (dapagliflozin/saxagliptin/metfonnin HCl) extended release tablets are
`manufactured in strengths of 2.5/2.5/1000 mg, 5/2.5/ 1000 mg, 5/5/1000 mg, and 10/5/1000
`mg. The tablets are manufactured by
`(km)
`
`The drug substances are the same dose and form found in currently approved
`drugs from the same Applicant. The drug product is a tablet dosage form for oral
`administration that combines dapagliflozin, saxagliptin, and metformin HCl XR. Long-tenn
`stability has been demonstrated when the product is packaged in high-density polyethylene
`(HDPE) bottles. Please see the Integrated Quality Assessment review for details regarding the
`full CMC review.
`
`Page 5 of 17
`
`Reference ID: 4428062
`
`5
`
`

`

`Division Summary Memo
`NDA 210874 and sNDA 209091/S-002
`
`Figure 1: Schematic illustration of the formulation design principle of
`QTERNMET XR
`
`
`
`Source: FDA Integrated Quality Assessment Review
`
`Dr. Wei-Hua Emily Wu from the Oflice of Lifecycle Drug Products in the Office of
`Pharmaceutical Quality conducted the CMC review of sNDA 209091-8002. Dr. Wu’s review
`leveraged the CMC review for
`b Dr. John Amarte and the overall uality
`assessmentb Dr. Suon Tran:
`
`
`
` CMC recommended approval from a quality perspective.
`
`
`Dr. Wu com ared the data submitted for the 5 m da a iflozin/S In saxa ' tin roduct1n
`
`sNDA 209091-8002:
`
`
`
`
`
`Overall, Dr. Wu concluded (and I concur) that the Applicant submitted
`adequate information to support the proposed new strength of QTERN (5 mg
`dapagliflozin/Smg saxagliptin).
`
`During the review of sNDA 209091-8002, Dr. Wu noted that the existing labeling for Section
`11 of the QTERN Prescribin Information
`stated that each film-coated table for TERN
`
`
`
`
`
`OP noted that
`
`this is im rtant, as the PI serves as the basis for the listin in the Orange Bookh
`m. Section 11 ofthe QTERNPI
`
`at eac ta et contams “5 mg saxag ptin (exists in the form of HCl
`en rev1se to state
`salt)”. Dr Galliford was advised of this finding and concurred. For that reason, the proposed
`labeling for Section 11 of QTERNMET XR P1 was similarly revised. See also Section 11
`(Recommendations) of this Summary Memo.
`
`
`
`Page 6 of 17
`
`Reference ID: 4428062
`
`6
`
`

`

`Division Summary Memo
`NDA 210874 and sNDA 209091/S-002
`4. Nonclinical Pharmacology/Toxicology
`
`Dr. Jeffrey Quinn from the Division of Metabolism and Endocrine Products (DMEP)
`evaluated NDA 210874. No new nonclinical studies were submitted in support of NDA
`210874. He noted that a full complement of nonclinical studies has been performed to support
`the approval of dapagliflozin (FARXIGA), saxagliptin (ONGLYZA), and metformin XR
`(GLUCOPHAGE XR) used alone or in combination. He concluded, and I concur, that the
`overall toxicology program that supported these previous approvals is sufficient to support the
`approval of NDA 210874.
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`Dr. Sarah Ibrahim from the Biopharmaceutics Branch II in the Office of Pharmaceutical
`Quality (OPQ) conducted the biopharmaceutical review of NDA 210984; Dr. Ho-Pi Lin from
`the Biopharmaceutics Branch II in the Office of Pharmaceutical Quality (OPQ) conducted the
`biopharmaceutical review of sNDA 209091-S002. Dr. Mohammad Absar from the Office of
`Clinical Pharmacology (OCP), Division of Clinical Pharmacology II, reviewed both NDA
`210874 and sNDA 209091-S002.
`
`The clinical pharmacology program for NDA 210874 comprised a single Phase 1 comparative
`PK/food effect study (D168AC00001) in which systematic exposure of dapagliflozin,
`saxagliptin, and metformin following a single oral dose of the triple combination product
`QTERNMET XR. Exposures after administration of a single dose of QTERNMET XR
`(dapagliflozin/saxagliptin/metformin XR) 5/2.5/1000 mg were compared with those from
`administration of single oral dose of ONGLYZA (saxagliptin) 2.5 mg + XIGDUO XR
`(dapagliflozin /metformin XR) 5/1000 mg in healthy subjects under fed conditions (Cohort 1);
`similarly exposures after administration of a single dose of QTERNMET XR
`(dapagliflozin/saxagliptin/metformin XR) 10/5/1000 mg were compared with those from a
`single oral dose of ONGLYZA (saxagliptin) 5 mg + XIGDUO XR (dapagliflozin/metformin
`XR) 10/1000 mg in healthy subjects under fed conditions (Cohort 2). The study also evaluated
`exposures under fasting conditions for both strengths of QTERNMET XR. The Applicant
`requested a biowaiver for the two strengths of QTERNMET XR not studied (2.5/2.5/1000 mg
`and 5/5/1000 mg).
`
`No clinical pharmacology studies were submitted in support of sNDA 209091-S002. The
`Applicant requested a biowaiver for its new strength of QTERN (dapagliflozin/saxagliptin) 5/5
`mg.
`
`Dr. Ibrahim evaluated the biowaiver request for QTERNMET XR
`(dapagliflozin/saxagliptin/metformin XR) 2.5/2.5/1000 mg and 5/5/1000 mg. Dr. Ibrahim
`determined that the request for biowaivers for the QTERNMET XR 2.5/2.5/1000 mg and
`5/5/1000 mg tablet strengths are adequate pending an acceptable clinical pharmacology review
`of D168AC00001. Overall, pending the favorable clinical pharmacology review, Dr. Ibrahim
`
`Page 7 of 17
`
`Reference ID: 4428062
`
`7
`
`

`

`Division Summary Memo
`NDA 210874 and sNDA 209091/S-002
`
`recommends (and I concur) approval ofNDA 210874 from the biophannaceutics perspective.
`Please see Dr. Ibrahim’s review for details.
`
`Dr. Lin evaluated the biowaiver request for QTERN (dapagliflozin/saxagliptin) 5/5 mg. (ml)
`
`recommends (and I concur) approval of sNDA 209091-8002 from a Biopharmaceutics
`perspective. Please see Dr. Lin’s review for details.
`
`Overall, Dr. Lin
`
`Dr. Absar evaluated the data from D168AC0001 (see Table 2). He concluded that the PK of
`dapagliflozin, saxagliptin, and metformin were comparable between QTERNMET XR and
`ONGLYZA+XIGDUO XR. The 90% CI for geometric mean ratio (GMR) of Cmax’ AUC‘, and
`AUCM of saxagliptin and metformin were within the prespecified bioequivalence margin 03E)
`of 0.8 — 1.25 for both strengths tested. While he noted that the upper bound of the 90% CI for
`GMR of Cm of dapagliflozin for the lower strength QTERNMET XR formulation was 1.28
`(outside of the prespecified BE margin), he also noted that the 90% CI for GMR of AUC‘ and
`AUCinfwere both within the prespecified BE margin and that the GMR of all three PK
`parameters were within the prespecified BE margin for the higher strength QTERNMET XR
`formulation. Dr. Absar concluded that the marginally higher Cmax observed with the lower
`strength QTERNIVIET XR formulation is unlikely to have clinical significance in terms of
`safety or efficacy.
`
`Table 2: Comparison of PK parameters of dapagliflozin, saxagliptin and
`metformin following single dose administration in healthy subjects
`
`GMR (90% CI)
`
`GMR (90% CI)
`
`Dapa/Saxa/Met 5/2.5/1000 vs Dapa/Saxa/Met 10/5/1000 vs
`PK
`parameter ONGLYZA 2.5 + XIGDI'O
`ONGLYZA 5 + XIGDUO
`XR 5/1000
`XR 10/1000
`
`1.14 (1.01 — 1.28)
`
`1.03 (0.94 — 1.12)
`
`0.93 (0.83 — 1.03)
`
`0.98 (0.90 — 1.07)
`
`
`
`Dapagliflozin
`
`Metfomiin
`
`1.00 (0.85 — 1.17)
`
`1.00 (0.88 — 1.15)
`
`1.00 (0.88 — 1.14)
`
`1.05 (0.95 — 1.17)
`
`0.99 (0.88 — 1.10)
`
`0.99 (0.88 _1.12)
`
`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)
`
`Source: NDA 210874. Module 2.7; Summary of Biophannac eutic Studies
`
`Dr. Absar noted that D168AC0001 compared the exposures achieved with QTERNMET XR
`FCDPs to those with ONGLYZA in conjunction with XIGDUO XR (another FCDP), rather
`than all drug monocomponents. Dr Absar concluded, however, that the data could still serve as
`a bridge to the pivotal clinical trials (D1683C00005 and CV181169) because no PK
`interactions were observed between dapagliflozin 5 mg and metformin 500 mg or
`dapagliflozin 10 mg and metformin 1000 mg in Studies 102092 and 102100, submitted to
`
`Page 8 of 17
`
`Reference ID: 4428062
`
`8
`
`

`

`Division Summary Memo
`NDA 210874 and sNDA 209091/S-002
`
`NDA 205649 (XIGDUO XR) or between saxagliptin and dapagliflozin in Study CV18] 191 ,
`submitted to NDA 209091 (QTERN) or between saxagliptin and metformin in Study
`CV181017, submitted to NDA 022350 (ONGLYZA). Dr. Absar concluded that the results of
`D168AC0001 and the acceptability of the biowaiver request for the remaining two strengths of
`QTERNNIET XR together provide an adequate scientific bridge between QTERNMET XR
`and the monoproducts used in the pivotal Phase 3 clinical studies. Overall, Dr. Absar
`recommends (and I concur) approval ofNDA 210874.
`
`6. Clinical/Statistical— Efficacy
`
`Dr. Jennifer Clark from Division of Biometrics 2 (DB2) in the Office of Biostatistics and Dr.
`Frank Pucino from the Division of Metabolism and Endocrinology Products (DIVIEP) in the
`Office of New Drugs reviewed the efficacy data for NDA 218074 and sNDA 209091—$002.
`Dr. Clark and Dr. Pucino both concluded (and I concur) that the clinical trial data support the
`efficacy of QTERNMET XR.
`
`As described in Section 2: Background, the Applicant submitted data from 9 clinical studies,
`of which the Applicant cited two as the pivotal Phase 3 trials (D1683C0005 and CV181169)
`and three additional trials (CV181168, CV181365, and CV181369) as supporting the labeling
`claims of NDA 210874. While the same trials were also submitted in support of the labeling
`claims of sNDA 209091-$002, only D1683C0005 studied dapagliflozin 5 mg (the
`recommended starting dose) and therefore has particular relevance for the proposed broadened
`indication for QTERN. The other four trials all studied dapagliflozin 10 mg (the maximum
`recommended dose). All five trials studied saxagliptin 5 mg, as saxagliptin 2.5 mg is typically
`recommended for patients with eGFR <45 mL/min/1.73 m2) and all five trials excluded
`subjects CrCl or eGFR <45 mL/min/ 1.73 m2.
`
`Dr. Clark evaluated the efficacy results for four of the five clinical trials: D1683C00005,
`CV181169, CV181365, and CV181369. Dr. Clark did not evaluate CV181168, as the trial was
`previously reviewed by Dr. Anna Ketterman for the original NDA approval of NDA 209091
`(QTERN): the results from this trial are in the current QTERN label and the new proposed
`labeling related to this trial uses the same results. Dr Clark did evaluate CV181169, even
`though that trial was previously reviewed by Dr. Brad McEvoy for NDAs 202293, 22350, and
`200678 (review signed on August 6, 2015), because the results from CV181169 are not
`currently included in any approved labels and the Applicant’s proposed labeling includes this
`trial.
`
`Dr. Pucino focused his review on the efficacy and safety findings (i.e., the prespecified
`primary and secondary endpoints) from all five Phase 3 clinical studies — D1683C00005,
`CV181169, CV181168, CV181365, and CV181369
`
`"M
`
`D1683C00005 was a double-blind, randomized, active-controlled, multi—center, 24—week,
`
`parallel group factorial design trial to evaluate the efficacy and safety of dapagliflozin 5 mg
`co-administered with saxagliptin 5 mg daily as add-on therapy to metformin in subjects with
`
`Page 9 of 17
`
`Reference ID: 4428062
`
`9
`
`

`

`Division Summary Memo
`NDA 210874 and sNDA 209091/S-002
`
`T2D inadequately controlled on metformin alone. The Applicant considers D1683C0005 one
`of the two pivotal Phase 3 trials to support NDA 210874.
`
`CV181169 was a double-blind, randomized, active-controlled, 24-week, parallel group, add-on
`to metformin factorial design trial that compared the efficacy and safety of the concomitant
`addition of dapagliflozin 10 mg plus saxagliptin 5 mg daily to saxagliptin 5 mg daily to
`dapagliflozin 10 mg daily in adults with T2D inadequately controlled on stable doses of
`metformin (≥1500 mg/day for at least eight weeks).
`
`CV181168 was the pivotal trial for the original QTERN NDA. This trial consisted of a 24-
`week, randomized, double-blind, placebo-controlled, short-term (ST) treatment period,
`followed by a 28-week long-term (LT) site- and subject-blind treatment period (i.e., 52-week
`total treatment duration). It assessed efficacy and safety based on the sequential (stepwise)
`addition of saxagliptin 5 mg/day or placebo in adult subjects with T2D who have inadequate
`glycemic control (i.e., HbA1c ≥7.0% to ≤10.5%) on maximum tolerated doses of dapagliflozin
`(i.e., 10 mg/day) and metformin (≥1500 mg/day).
`
`CV181365 was a 52-week randomized, double-blind, active-controlled, parallel group study
`with a blinded 104-week extension phase. This trial compared orally once daily dapagliflozin
`10 mg and saxagliptin 5 mg coadministered in combination with metformin to once daily
`glimepiride (titrated from 1mg to 6 mg or highest tolerable dose over 12 weeks) plus placebo
`with metformin (≥1500 mg per day) in T2D subjects with inadequate glycemic control
`(HbA1c ≥7.5% and ≤10.5%) on a stable dose of metformin alone (≥1500 mg/day for at least
`eight weeks). The glimepiride/placebo dose was kept constant, except for down-titration in the
`event of hypoglycemia.
`CV181369 was a 24-week randomized, open label, active-controlled, parallel group study with
`a 28-week extension period that compared orally once daily dapagliflozin 10 mg and
`saxagliptin 5 mg coadministered with metformin with or without a sulfonylurea to titrated
`subcutaneous insulin glargine coadministered with metformin with or without a sulfonylurea
`in adult T2D subjects with inadequate glycemic control (HbA1c ≥8.0% and ≤12.0%).
`
`In her evaluations of efficacy, Dr. Clark followed the statistical testing hierarchy of primary
`and secondary endpoints according to the Statistical Analysis Plans (SAPs), as detailed in
`Table 3.
`
`Table 3: Statistical Testing Hierarchy of Primary and Secondary Endpoints
`
`Source: FDA Statistical Review
`
`Page 10 of 17
`
`Reference ID: 4428062
`
`10
`
`

`

`Division Summary Memo
`NDA 210874 and sNDA 209091/S-002
`
`the primary HbA1c endpoints, Dr. Clark considered multiple statistical
`testing
`In
`methodologies: 1) the “ITT estimand” used by the Applicant that relied on mixed model
`repeated measures (MMRM); 2) the ITT estimand preferred by FDA that relies on a retrieved
`dropout-type analysis (see Dr. Clark’s review for additional details). Dr. Clark also noted that
`Applicant’s analyses used population and data assumptions incongruent with an ITT-type
`estimand. She reported that she successfully reproduced the Applicant’s analyses and provided
`results according the FDA’s preferred methodology (see Table 4). Dr. Clark concluded that all
`four studies met the primary endpoint comparing the dapagliflozin + saxagliptin + metformin
`arm to the control arms.
`
`Table 4: Results for Primary change in HbA1c Endpoint
`
`
`
`Source: FDA Statistical Review
`
`Dr. Clark included in her review results related to important secondary endpoints, including
`bodyweight, responders with HbA1c<7%, and systolic blood pressure (see Table 5, Table 6,
`
`Page 11 of 17
`
`Reference ID: 4428062
`
`11
`
`

`

`Division Summary Memo
`NDA 210874 and sNDA 209091/S-002
`
`and Table 7). She noted that for CV181169, the first secondary endpoint was not met, so all
`further endpoints were only considered nominally significant and therefore appear in Table 5
`and Table 6 in greyed out boxes. For both D1683C0005 and CV181169, moreover, an
`assessment of the contribution of saxagliptin to weight loss was not pre-specified as part of the
`hierarchy: for that reason, Dr. Clark put the results of that analysis in blue in Table 5 to
`indicate that these were exploratory analyses. As shown in the Tables, Dr. Clark concluded
`that the secondary endpoints of change in bodyweight and responders with HbA1c<7% were
`only nominally significant in CV181169 (which studied the higher dapagliflozin dose) but
`were statistically significant in D1683C0005 (which studied the lower dapagliflozin dose) in
`the same treatment arms. She found that the saxagliptin component did not appear to have an
`effect on body weight in either of the trials.
`
`Table 5: Results for change in bodyweight
`
`
`
`Source: FDA Statistical Review
`
`Page 12 of 17
`
`Reference ID: 4428062
`
`12
`
`

`

`Division Summary Memo
`NDA 210874 and sNDA 209091/S-002
`
`Table 6: Results for responders with HbA1c<7%
`
`Source: FDA Statistical Review
`
`Table 7: Results for Change in Systolic Blood Pressure at Week 52
`
`Source: FDA Statistical Review
`
`Overall, Dr. Clark concluded (and I concur) that the results support the conclusion that the
`combination of dapagliflozin + saxagliptin + metformin is superior for reducing HbA1c
`compared with dapagliflozin + metformin, saxagliptin + metformin, and glimepiride +
`metformin and non-inferior for reducing HbA1c compared with insulin + metformin. Dr. Clark
`recommended (and I concur) that the treatment effects should be labeled using the results from
`the preferred FDA analyses provided in Tables 4-7.
`
`Dr. Pucino relied on the analyses of Dr. Clark to inform his conclusions about the efficacy
`results of the clinical trials. He therefore concurred that the results of the primary efficacy
`analyses showed that triple combination therapy with dapagliflozin (5 mg or 10 mg) plus
`
`Page 13 of 17
`
`Reference ID: 4428062
`
`13
`
`

`

`Division Summary Memo
`NDA 210874 and sNDA 209091/S-002
`
`saxagliptin (5 mg) plus metformin compared to either dapagliflozin (5 mg or 10 mg) plus
`metformin or saxagliptin 5 mg plus metformin resulted in modest but statistically significant
`reductions in HbAlc. He also concurred that the triple therapy arm was superior to glimepiride
`plus metformin and noninferior to insulin plus metformin. Overall, he concluded that the
`Applicant has provided sufficient evidence of effectiveness to support approval of
`QTERNMET XR and an amended indication for QTERN.
`
`In addition, Dr. Pucino agreed with Dr. Clark that the triple combination therapy arms
`generally resulted in modest reduction in bodyweight, higher proportions of subjects achieving
`an HbAlc<7%, and lower SBP.
`(mo
`
`With respect to the finding that the secondary endpoints of CV181168 should not be
`considered statistically significant due to the stopping of formal statistical testing after the 2-
`hour PPG analysis was determined to be non-significant, Dr. Pucino nonetheless
`recommended inclusion of descriptive statistics in Section 14 of the P1 to show the proportion
`of subjects who achieve HbAlc <7%, in order to be consistent with SGLT2/DPP—4 class
`labeling. Dr. Clark and Dr. Pucino agreed (and I concur) that inclusion of these descriptive
`statistics in Section 14 of the PI, with accompanying clarification that formal statistical testing
`was not performed, is appropriate.
`
`7. Safety
`
`Dr. Frank Pucino from the Division of Metabolism and Endocrinology Products (DMEP) in
`the Office of New Drugs also reviewed the safety data for NDA 218074 and sNDA 209091-
`8002. The safety evaluation for both applications was primarily based on the integrated safety
`data from the following three study pools:
`
`1) 3-study pool: CV181168, CV181169, and MB102129
`2) 5-study pool: CV181169, CV181363, CV181365, D1683C00005, and D1689C00014
`3) 7—study pool: CV181168, CV181169, CV181363, CV181365, D1683C00005,
`D1689C00014, and 1\/IB102129
`
`The 3—study pool is the same safety pool previously used for the original approval of QTERN.
`In a response to a request from the Agency, the Applicant also created the 5-study pool to
`evaluate trials in which dapagliflozin and saxagliptin were initiated simultaneously. The 7-
`study pool was the broadest pool and intended to detect uncommon/rare adverse events (AEs).
`The sitagliptin + metformin arm of CV181363 and the glimepiride + metformin arms of
`CV181365 and D168C00014 were not included in the safety pools, as the Applicant felt this
`would render the pool uninterpretable. CV181369 was not included in the safety pools due to
`its open—label design and use of sulfonylurea as background therapy. Dr. Pucino concurred
`with these exclusions. Please see Dr. Pucino’s clinical review for details regarding the
`composition of the safety pools, including size, duration of exposure, demographics, and
`clinical characteristics. See Dr. Pucino’s clinical review also for detailed tables summarizing
`AEs, serious adverse events (SAEs), discontinuations due to AEs, treatment emergent AEs
`(TEAEs), and marked laboratory abnormalities in the 5- and 7-study safety pools.
`
`Page 14 of 17
`
`Reference ID: 4428062
`
`14
`
`

`

`Division Summary Memo
`NDA 210874 and sNDA 209091/S-002
`
`Dr. Pucino also evaluated adverse events of special interest (AESI) in the 7-study safety pool.
`The AESI included: genital infections, UTIs, hypoglycemia, renal impairment/failure,
`malignancies, fractures, heart failure, confirmed adjudicated cardiovascular (CV) events,
`decreased lymphocyte counts, decreased thrombocyte counts, pancreatitis, severe cutaneous
`adverse reactions, hypersensitivity reactions, liver injury/hepatic disorder, volume depletion
`(hypotension, dehydration, and hypovolemia), diabetic ketoacidosis, and lactic acidosis.
`
`Finally, Dr. Pucino specifically interrogated the safety data to investigate the main safety
`concern that arose during the QTERN development program: an imbalance in the number of
`subjects who experienced marked serum CK elevations, including an unexplained event of
`rhabdomyolysis. Dr. Pucino found that no new events of marked serum CK elevations or cases
`of rhabdomyolysis were observed in the new clinical trials. In addition, there were no
`additional cases reported in the Applicant’s pharmacovigilance program.
`
`Based on these evaluations, Dr. Pucino concluded that the safety profile of QTERNMET XR
`reflects the safety profile of its components (dapagliflozin, saxagliptin, and metformin).
`Overall, Dr. Pucino concluded (and