CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`206073Orig1s000
`
`PHARMACOLOGY REVIEW(S)
`
`
`
`
`
`
`

`

`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`Food and Drug Administration
`
`Memorandum
`
`Pharmacology/Toxicology
`Center for Drug Evaluation and Research
`Division of Metabolic & Endocrine Products
`
`Date 13 October 2014
`NDA # 206073
`Sponsor Boehringer Ingelheim
`Drug Empagliflozin/linagliptin FDC tablet
`Primary Reviewer David B. Carlson, PhD
`Secondary Reviewer Patricia Brundage, PhD
`
`Boehringer Ingelheim is seeking approval for the fixed-dose combination product of linagliptin
`and empagliflozin as a treatment for type 2 diabetes. Both pharmaceutical components are
`currently approved for the chronic treatment of type 2. Linagliptin is a dipeptidylpeptidase-4
`(DPP4) inhibitor approved in 2011 (NDA 201280) and empagliflozin is a sodium-glucose co-
`transporter 2 (SGLT2) inhibitor (NDA 204629) approved during the review cycle. The
`mechanisms of action of the two different drug classes are distinct but complementary on
`glucose control. Boehringer Ingelheim is the primary NDA holder for both linagliptin and
`empagliflozin.
`
`Dr. David Carlson, the primary nonclinical reviewer, recommends approval of NDA 206073. I
`concur with Dr. Carlson’s recommendation. The recommendation is based on the information
`for linagliptin and empagliflozin as monotherapies, and on the toxicology studies conducted with
`the drugs in combination to assess general toxicity and embryofetal development.
`
`The toxicology of linagliptin and empagliflozin in combination was evaluated in a 3-month study
`in rats. Each drug was evaluated separately and in combination for comparison. No additive or
`unique toxicity was observed with the drugs in combination. Toxicity associated with the
`co-administration of the two drugs at exposures ≥14-times the clinical exposure was attributable
`to the SGLT2 inhibitor empagliflozin and is consistent with the established toxicology profile of
`empagliflozin.
`
`Co-administration of the drugs in rats caused an increase in empagliflozin exposure (2- to
`3-fold), which was associated with an increase in renal and hepatic toxicity at the highest dose
`combination (>50X clinical exposure) compared to that of empagliflozin alone. There was also a
`less consistent decrease in linagliptin exposure (up to 3-fold) with co-administration of the drugs.
`Similar changes in the pharmacokinetic profiles of the two drugs when co-administered were not
`observed in humans in the bioequivalence and pharmacokinetic trials with the
`linagliptin/empagliflozin FDC. Clinical drug-drug interactions between empagliflozin and
`linagliptin at clinical doses is unlikely based on in vitro metabolic enzyme induction and
`inhibition assays with the individual drugs, and on co-incubation assays of the two drugs in
`human hepatocytes. Although there is presently no mechanistic explanation for the systemic
`drug exposure changes in the rats, the clinical relevance is considered negligible.
`
`Reference ID: 3642810
`
`

`

`An embyrofetal development study in rats was conducted by the applicant. The administration
`of linagliptin and empagliflozin alone and in combination was not teratogenic, which is
`concordant with the previous findings with the individual drugs in rats and rabbits.
`
`As both drugs target the kidney, the embyrofetal development study included histopathological
`examination of fetal kidneys. Linagliptin accumulates in kidney tubules due to high DPP4
`expression and DPP4-specific binding. Empagliflozin, which targets SGLT2 in the renal
`proximal tubules, causes changes in renal histology with chronic exposure and may affect fetal
`renal development and maturation, as determined from prior juvenile rat toxicology studies in
`this drug class. There was no evidence of kidney toxicity with linagliptin and empagliflozin
`administered alone or in combination at very high multiples of clinical exposure in the
`embyrofetal development study, suggesting a low likelihood of an overt toxicological interaction
`between the two drugs on renal development.
`
`The combination linagliptin and empagliflozin toxicity studies in rats did not identify any
`potential interactions between the drugs to suggest an elevated clinical risk with FDC treatment.
`Labeling for the combination product will be consistent with the labeling for the individual
`monotherapies of linagliptin and empagliflozin.
`
`Reference ID: 3642810
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`PATRICIA M BRUNDAGE
`10/13/2014
`
`Reference ID: 3642810
`
`

`

`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
`
`Application number: 206-073
`
`Supporting document/s: SDN-1
`Applicant’s letter date
`(CDER Stamp Date): 30 January, 2014
`Product: Empagliflozin / linagliptin FDC tablets
`
`Indication: Type 2 Diabetes Mellitus treatment
`
`Applicant: Boehringer Ingelheim Pharmaceuticals (BI)
`
`Review Division: Metabolism and Endocrinology Products
`
`Reviewer: David B. Carlson, Ph.D.
`
`Supervisor/Team Leader: Todd Bourcier, Ph.D.
`Division Director /
`Jean-Marc Guettier, M.D.
`Deputy Director:
`Eric Colman, M.D.
`Project Manager: Raymond Chiang, M.S.
`
`Review Completion Date: 05 October, 2014
`
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 206073 are owned by BI or are data for which BI has
`obtained a written right of reference. Any information or data necessary for approval of
`NDA 206073 that BI 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 reviews or publicly available summaries of a
`previously approved application is for descriptive purposes only and is not relied upon
`for approval of NDA 206073.
`
`Reference ID: 3642512
`
`1
`
`

`

`Review Notes and Abbreviations/Key
`
`Some of the sponsor’s tables and figures from the electronic NDA submission have
`been included and cited in this review. All drug-related trends are discussed with
`respect to combination empagliflozin and linagliptin coadministration in relation to
`concurrent vehicle control groups and individual drug substances unless otherwise
`noted. Vehicle for oral gavage administration was water for phentermine and 0.5%
`hydroxyethylcellulose unless otherwise noted. Common animal strains were used and
`abbreviated by common animal name, unless noted, as follows: Wistar Han rat, CD-1
`mouse, Beagle dog, New Zealand White rabbit.
`
`Key: Empagliflozin (empa), linagliptin (lina); fixed-dose combination (FDC), once daily
`dosing (QD); dosing groups – LD (low dose), MD (mid dose), LMD (low mid
`dose), HMD (high mid dose), HD (high dose); mg/kg (mg/kg/day); MRHD
`(maximum recommended human dose); NOAEL (no observed adverse effect
`level); LOAEL (lowest observed adverse effect level); statistically significant (ss);
`not statistically significant (nss); PD (pharmacodynamic), PK (pharmacokinetic),
`TK (toxicokinetic); BW (body weight); GD (gestation day)
`
`Reference ID: 3642512
`
`2
`
`

`

`NDA #206073
`Review #1
`
`Reviewer: David B. Carlson, Ph.D.
`
`TABLE OF CONTENTS
`
`TABLE OF CONTENTS.................................................................................................. 3
`
`TABLE OF TABLES....................................................................................................... 5
`
`TABLE OF FIGURES ..................................................................................................... 6
`
`1
`
`EXECUTIVE SUMMARY ......................................................................................... 7
`1.1
`INTRODUCTION.................................................................................................... 7
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 7
`1.3
`RECOMMENDATIONS............................................................................................ 8
`1.3.1 Approvability ........................................................................................................... 8
`1.3.2 Additional Non Clinical Recommendations.............................................................. 8
`1.3.3 Labeling.................................................................................................................. 8
`2 DRUG INFORMATION ............................................................................................ 9
`2.1
`DRUG................................................................................................................. 9
`2.1.1 CAS Registry Number............................................................................................. 9
`2.1.2 Generic Name ........................................................................................................ 9
`2.1.3 Code Name ............................................................................................................ 9
`2.1.4 Chemical Name ...................................................................................................... 9
`2.1.5 Molecular Formula/Molecular Weight...................................................................... 9
`2.1.6 Structure (or Biochemical Description).................................................................... 9
`2.1.7 Pharmacologic class..............................................................................................10
`2.2
`RELEVANT IND/S, NDA/S, AND DMF/S ............................................................... 10
`2.2
`DRUG FORMULATION ......................................................................................... 10
`2.4 Comments on Novel Excipients .................................................................................12
`2.5 Comments on Impurities/Degradants of Concern ......................................................12
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN.................... 12
`
`2.6
`
`2.7
`
`REGULATORY BACKGROUND ....................................................................... 13
`
`3
`
`STUDIES SUBMITTED.......................................................................................... 14
`
`3.1
`
`3.2
`
`3.3
`
`STUDIES REVIEWED........................................................................................ 14
`
`STUDIES NOT REVIEWED ............................................................................... 14
`
`PREVIOUS REVIEWS REFERENCED.............................................................. 14
`
`4
`
`5
`
`PHARMACOLOGY................................................................................................ 15
`4.1
`PRIMARY PHARMACOLOGY................................................................................. 15
`Combination of BI 10773 and linagliptin (BI 1356) in a diabetic rat model (ZDF):
`Effect on glucose tolerance (Study # MD2012-16-ppss, Doc. No. U12-1784-01) ...15
`PHARMACOKINETICS/ADME/TOXICOKINETICS .............................................. 17
`
`Reference ID: 3642512
`
`3
`
`

`

`Reviewer: David B. Carlson, Ph.D.
`
`NDA #206073
`Review #1
`5.1
`PK/ADME........................................................................................................ 17
`BI 1356 BS 96-well method for rat, dog, and minipig plasma (Study # V203_03BE;
`Doc. No. U04-1551-02)..........................................................................................17
`BI 1356 BS and CD 1750 XX 96-well method for rat plasma (Study # M217_06MI;
`Doc. No. U07-1768-02)..........................................................................................17
`Assay method validation for the quantitation of BI 10773 in EDTA Wistar rat plasma
`(Study # DM-06-1016; Doc. No. U08-3272-01) ......................................................17
`Effect of BI 10773 XX on the in vitro metabolism of [14C]BI 1356 BS by human
`hepatocytes (Study # A252-08LU; Doc. No. U09-2263-01)....................................17
`Effect of BI 1356 BS on the in vitro metabolism of [14C]BI 10773 by human
`hepatocytes (Study # A253-08LU; Doc. No. U10-1340-01)....................................18
`TOXICOKINETICS ............................................................................................... 18
`Pharmacokinetics of BI 1356 (linagliptin) with concomitant administration of BI
`10773 in rats (Study # A229-10RB; Doc. No. U10-2636-01) ..................................18
`6 GENERAL TOXICOLOGY..................................................................................... 22
`6.2
`REPEAT-DOSE TOXICITY.................................................................................... 22
`2-Week rat combination empagliflozin + linagliptin toxicity.....................................22
`13-Week rat combination empagliflozin + linagliptin toxicity...................................23
`8 CARCINOGENICITY ............................................................................................. 26
`
`5.2
`
`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY ................................ 28
`9.2
`EMBRYONIC FETAL DEVELOPMENT ..................................................................... 28
`Embryofetal rat development range-finding (Seg 2 combination empa + lina)........28
`Embryofetal development in rat (Seg 2 rat combination empa + lina) ....................34
`INTEGRATED SUMMARY AND SAFETY EVALUATION ............................................... 44
`
`11
`
`Reference ID: 3642512
`
`4
`
`

`

`NDA #206073
`Review #1
`
`Reviewer: David B. Carlson, Ph.D.
`
`Table of Tables
`
`Table 1 – Drug product composition.............................................................................. 11
`Table 2 – Film coating excipients List............................................................................ 11
`Table 3 – Linagliptin + BI 10773 PK summary (Sponsor table)..................................... 19
`Table 4 – Embryofetal rat fetal abnormalities summary ................................................ 40
`Table 5 – Embryofetal rat fetal visceral variations summary ......................................... 41
`Table 6 – Embryofetal rat fetal malformations summary ............................................... 43
`Table 7 – Human Exposure Summary .......................................................................... 45
`
`Reference ID: 3642512
`
`5
`
`

`

`NDA #206073
`Review #1
`
`Reviewer: David B. Carlson, Ph.D.
`
`Table of Figures
`
`Figure 1 – Empagliflozin + linagliptin improves glucose response in ZDF rats.............. 16
`Figure 2 – Linagliptin in rat plasma (LD oral coadministration with empagliflozin) ........ 20
`Figure 3 – Linagliptin in rat plasma (HD oral coadministration with empagliflozin)........ 21
`Figure 4 – Body weight effects (embryofetal rat rangefinding) ...................................... 31
`Figure 5 – TK summary of empagliflozin and linagliptin in pregnant rats ...................... 38
`
`Reference ID: 3642512
`
`6
`
`

`

`NDA #206073
`Review #1
`
`1
`
`Executive Summary
`
`Reviewer: David B. Carlson, Ph.D.
`
`Introduction
`1.1
`Boehringer Ingelheim (BI) has developed a Fixed Dose Combination (FDC) formulation
`of two of its drugs, linagliptin and empagliflozin. Linagliptin is a dipeptidyl peptidase 4
`(DPP4) inhibitor approved under NDA 201280 for treatment of type 2 diabetes mellitus
`(T2DM). Empagliflozin is a sodium-glucose co-transporter 2 inhibitor (SGLT2 inhibitor)
`that was approved under NDA 204629 during this review cycle for treatment of T2DM.
`The nonclinical recommendation will rely in part on FDA’s prior determination of safety
`and effectiveness for the individual drugs and the focus of this review is potential
`interactions between empagliflozin and linagliptin in a FDC tablet based on nonclinical
`data submitted in support of the FDC drug product.
`1.2 Brief Discussion of Nonclinical Findings
`Linagliptin and empagliflozin have distinct, complementary mechanisms of action on
`glucose metabolism and coadministration in a FDC tablet is expected to provide robust
`glucose control in diabetic patients. Estimated clinical exposures to individual drugs
`were originally established in monotherapy trials and the same clinical exposures were
`used in this review – 4750 nM*h empagliflozin at the maximum approved 25 mg dose
`and 158 nM*h linagliptin at the approved 5 mg dose.
`
`There were no clear signals of increased toxicity when empagliflozin and linagliptin were
`coadministered to rats in subchronic (13-week) and embryofetal development toxicity
`studies. Toxicity in rats was driven by the SGLT2 inhibitor, empagliflozin, with
`empagliflozin-mediated toxicity responsible for the lowest observed adverse effect
`levels (LOAELs) determined in the bridging toxicity studies. Toxicity in the combination
`empagliflozin and linagliptin groups was consistently more severe (higher incidence,
`higher severity) than similar individual drug groups which was consistent with increased
`empagliflozin exposure in rats due to an unknown pharmacokinetic/toxicokinetic
`(PK/TK) interaction.
`
`Toxicokinetic interactions were not predicted from in vitro metabolism based on
`metabolizing enzyme inhibition or induction or from hepatocyte coincubations. However,
`TK interactions were consistently evident in combination toxicity studies in rats.
`Linagliptin coadministration caused 2- to 3-fold increased plasma empagliflozin
`maximum (Cmax) and total (AUC0-24 h) exposure in rats. Empagliflozin effects on
`linagliptin were less consistent, but coadministration reduced linagliptin total plasma
`exposure (AUC) up to 3-fold, often without any change in Cmax.
`
`There were no apparent drug-drug interactions on plasma exposure in humans based
`on bioequivalence and pharmacokinetic trials with the FDC formulation. It is not clear if
`there are species differences between rat and human responses to coadministration or
`if findings in rats may simply be due to different responses to excessive dosing
`compared to clinical dosing. Drug interactions on rat exposure were not assessed at
`
`Reference ID: 3642512
`
`7
`
`

`

`NDA #206073
`Review #1
`lower dose combinations and the large effects on plasma exposure occurred at
`exposures 100-fold or greater than maximum clinical exposures. Because drug
`interactions have not been observed in controlled clinical trials the applicability of drug
`interactions on rat exposures seem limited.
`
`Reviewer: David B. Carlson, Ph.D.
`
`Nonclinical issues relevant to clinical use are consistent with the known individual drug
`risks and with known risks for DPP4 inhibitor and SGLT2 inhibitor drug classes.
`Potential linagliptin clinical concerns include hypersensitivity/pseudoallergy, DPP4-
`specific targets distinct from incretin metabolism (e.g., immune system), and
`pancreatitis. Potential empagliflozin clinical concerns include glucosuria, urinary tract
`infections, and kidney toxicity (in adults or from exposure during fetal development). No
`new risks were clearly identified at clinical exposures of coadministered drugs, however,
`kidney toxicity risks may be increased due to combined empagliflozin and linagliptin
`exposure. Linagliptin accumulates in kidney tubules due to high DPP4 expression and
`DPP4-specific binding, while proximal tubules are also the empagliflozin site of action.
`Rat kidney toxicity was also increased with combination treatment, albeit at very high
`multiples of clinical exposure (> 100X MRHD) and at increased empagliflozin exposures
`compared to individual drug treatment. However, a search of the publically available
`literature did not uncover any evidence of increased nonclinical kidney toxicity with
`DPP4 inhibitor and SGLT2 inhibitor coadministration. Thus, potential increased clinical
`renal toxicity with empagliflozin and linagliptin FDC treatment exists but is largely
`theoretical in nature.
`1.3 Recommendations
`
`1.3.1 Approvability
`
`Approval is recommended from a nonclinical perspective.
`
`1.3.2 Additional Non Clinical Recommendations
`
`None.
`
`1.3.3 Labeling
`
`Nonclinical labeling recommendations were included on the proposed label in the
`Division’s shared document system (i.e., ‘Sharepoint’ file). Labeling recommendations
`were limited to combination empagliflozin and linagliptin toxicity studies relevant to the
`proposed FDC drug product. Current labels for monotherapy empagliflozin and
`linagliptin were relied on for prior findings of safety and effectiveness.
`
`Reference ID: 3642512
`
`8
`
`

`

`NDA #206073
`Review #1
`
`2
`
`Drug Information
`
`Reviewer: David B. Carlson, Ph.D.
`
`2.1 Drug
`Glyxambi™ (proposed); Empagliflozin + linagliptin FDC tablets
`
`2.1.1 CAS Registry Number
`
`Empagliflozin – 864070-44-0
`Linagliptin – 668270-12-0
`
`2.1.2 Generic Name
`
`Empagliflozin + linagliptin FDC
`
`2.1.3 Code Name
`
`Empagliflozin – BI 10773; BI 10773 XX
`Linagliptin – BI 1356 BS; BI 1356
`
`2.1.4 Chemical Name
`
`Empagliflozin – (1S)-1,5-anhydro-1-(4-chloro-3-{4-[(3S)-tetrahydrofuran-3-
`yloxy]benzyl}phenyl)-D-glucitol
`Linagliptin – 1H-purine-2,6-dione, 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butynyl)-3,7-
`dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]-
`
`2.1.5 Molecular Formula/Molecular Weight
`
`Empagliflozin – C23H27ClO7 / 450.91 g/mol
`Linagliptin – C25H28N8O2 / 472.54 g/mol
`2.1.6 Structure (or Biochemical Description)
`
`Empagliflozin
`
`Reference ID: 3642512
`
`9
`
`

`

`NDA #206073
`Review #1
`
`Reviewer: David B. Carlson, Ph.D.
`
`Linagliptin
`
`2.1.7 Pharmacologic class
`
`Sodium-glucose co-transporter 2 inhibitor (SGLT2 inhibitor) and dipeptidyl peptidase 4
`inhibitor (DPP4 inhibitor)
`2.2 Relevant IND/s, NDA/s, and DMF/s
`Empagliflozin – NDA 204629, Jardiance® (IND 102145)
`Linagliptin – NDA 201280, Tradjenta® (IND 70963); NDA 201281, Jentadueto®
`– linagliptin + metformin HCl FDC)
`Linagliptin / Empagliflozin FDC – IND 108,388
`2.2 Drug Formulation
`Two dosage strength FDC film-coated tablets for once daily oral dosing:
`
`
`
`25 mg empagliflozin / 5 mg linagliptin
`
`10 mg empagliflozin / 5 mg linagliptin
`
`Both drug substances are approved for use in the United States and only the
`manufacturing of the two strengths of FDC tablet drug products is unique to this
`application. There are no novel excipient in the drug product formulation. All excipients
`are compendial and are similar to those used in linagliptin and empagliflozin drug
`products. All of the ingredients in the tablet core and in the
` coatings have
`been previously used in oral drugs at similar or higher concentrations and printing inks
`are food grade.
`
`Reference ID: 3642512
`
`10
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA #206073
`Review #1
`
`Reviewer: David B. Carlson, PhD.
`
`Table 1 - Drug product composition
`
`Composition of empagliflozin linagliptin film-coated tablets.
`10 mg 5 mg and 25 mg 5 m2
`
`Reference to
`Standards
`
`
`
`
`———
`—lml_——
`
`
`d
`
`Wm
`
`
`
`
`
`(b) (4)
`Liannitol
`
`
`
`Pregelatinized starch
`Com starch
`
`
`
`Copovidone
`
`Crospovidone
`Talc
`
`Magnesium stemte
`
`[ingl'tablet]
`
`
`
`Total film-coated tablet
`
`185.0
`
`185.0
`
`I —-mm
`
`(b) (4)
`
`Table 2 — Film coating excipients List
`.
`.
`‘
`Composmon 01
`
`(mm
`
`M“)
`
`film coat
`
`0’) (4) Function
`
`Reference to
`Standards
`
`Ingredient
`
`I
`
`Mannitol
`
`Talc
`
`Titanium dioxide
`
` [mm [mgmbm— Hypromellose
`
`
`
`Polyethylene glycol
`Ferric oxide. yellow
`
`0’) (4)
`
`Ferric oxide. red
`
`Total
`
`Reference ID: 3642512
`
`1 1
`
`

`

`NDA #206073
`Review #1
`2.4
`Comments on Novel Excipients
`
`Reviewer: David B. Carlson, Ph.D.
`
`There are no novel excipients in the proposed tablet formulations.
`
`2.5
`
`Comments on Impurities/Degradants of Concern
`
`No new degradants or impurities that have not been previously qualified in the drug
`substances were identified by the FDA chemistry (CMC) reviewer.
`2.6
`Proposed Clinical Population and Dosing Regimen
`
`The proposed clinical population of type 2 diabetes mellitus patients are similar to those
`indicated for use of the individual drugs. The FDC tablets are intended for patients with
`inadequate glucose control on individual drugs or background therapies and for whom a
`single combination tablet is desired. Results of pivotal clinical trials to support
`bioequivalence, pharmacokinetics and relative bioavailability, and safety and efficacy
`are summarized briefly below.
`
`Empagliflozin and Linagliptin FDC Clinical studies
`1275.3 – Bioequivalence Trial (U11-1690-01)
`
` Single dose bioequivalence in healthy adults
`o Cross-over design (each patient received 3 of 4 treatments)
`o Oral Dosing, QD (empagliflozin/linagliptin)
` FDC formulation A1 (25 mg / 5 mg)
` Fasted (n=42)
` Coadministration 25 mg empagliflozin tablet + 5 mg linagliptin tablet
` Fasted (n=41)
` FDC formulation A1 (25 mg / 5 mg)
` Fed (n=18)
` FDC formulation A3 (25 mg / 5 mg) – slow dissolving tablet
` Fasted (n=24)
`o Summary results
` Bioequivalence between FDC A1 and individual tablets
` 90% CI met acceptance of 80-125%
` No difference in AUC or Cmax between A1 and slow dissolving tablet
`FDC A3
` FDC A1 Cmax was lower but AUC was equivalent for both drugs in
`fed state compared to fasted
`
`1245.30 – Pharmacokinetics Trial (U10-2248-01)
`
` 1-Week PK and relative bioavailability in healthy adults (n=16)
`o Crossover design
`o Oral Dosing, QD
` 50 mg empagliflozin (5 days)
`
`Reference ID: 3642512
`
`12
`
`

`

`NDA #206073
`Review #1
`
`Reviewer: David B. Carlson, Ph.D.
`
` 5 mg linagliptin (7 days)
` 50 mg / 5 mg empagliflozin/linagliptin (7 days)
` Total 12 days empagliflozin (± linagliptin) and 14 days
`linagliptin (± empagliflozin) treatment in crossover design
`o Summary results
` Linagliptin steady state bioavailability was not affected by
`concomitant empagliflozin treatment
` 90% CI met acceptance of 80-125%
` Empagliflozin total exposure (AUC) was unaffected by linagliptin
`coadministration but maximum plasma exposure was decreased
` Empagliflozin Cmax was reduced 12% with linagliptin
`coadministration
`
`1275.1 – Efficacy and Safety Trial (U13-2755-01)
`
` 52-Week efficacy and safety in T2DM (n=2504)
`o Treatment naïve or metformin background
`o Oral Dosing, QD (empagliflozin/linagliptin)
` 25 mg / 5 mg or
` 10 mg / 5 mg
`o Summary results
` FDC treatment lowered plasma glucose (HbA1c and FPG)
`compared to either monotherapy ± metformin background
` Overall safety profile similar in FDC compared to known profiles for
`monotherapies
` No new safety issues identified
`2.7 Regulatory Background
`
`Both linagliptin and empagliflozin have been approved for treatment of T2DM as
`monotherapy. Linagliptin has also been approved for treatment of T2DM as a fixed-dose
`combination with metformin HCl. Empagliflozin was under review in NDA 204629 after
`an initial review cycle “Complete Response” letter (3/4/2014) for manufacturing
`deficiencies and it was approved for monotherapy use on (8/1/2014) during the review
`cycle for this FDC NDA.
`
`Reference ID: 3642512
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`13
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`

`

`Reviewer: David B. Carlson, Ph.D.
`
`NDA #206073
`Review #1
`
`3
`
`Studies Submitted
`
`3.1
`
`Studies Reviewed
`
`See Table of Contents.
`3.2
`Studies Not Reviewed
`
`None.
`3.3
`
`Previous Reviews Referenced
`
`Carlson, DB. NDA 201280, Pharmacology/Toxicology Review and Evaluation. March 7,
`2011.
`
`Carlson, DB. IND 108388, Pharmacology/Toxicology Review and Evaluation. July 22,
`2011.
`
`Summan, M. NDA 206429, Pharmacology/Toxicology Review and Evaluation.
`November 4, 2013.
`
`Reference ID: 3642512
`
`14
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`

`

`NDA #206073
`Review #1
`
`4
`
`Pharmacology
`
`Reviewer: David B. Carlson, Ph.D.
`
`4.1 Primary Pharmacology
`Empagliflozin is a reversible, competitive inhibitor of sodium-glucose co-transporter 2
`(SGLT2); IC50 = 1.3 nM in vitro. Empagliflozin shows approximately 5000-fold selectivity
`for SGLT2 inhibition compared to SGLT1 inhibition (IC50 = 6278 nM). SGLT2 is localized
`to kidney proximal tubules where it facilitates reuptake of glucose prior to excretion in
`urine. Inhibition of SGLT2 prevents glucose reuptake in proximal tubules and results in
`increased glucose excretion, or glucosuria.
`
`Linagliptin is a potent, selective inhibitor of dipeptidyl peptidase 4 (DPP4). DPP4 is a
`protease that metabolizes gut incretin hormones glucagon-like peptide 1 (GLP1) and
`gastric inhibitory peptide (GIP), among other substrates. Inhibition of DPP4 prolongs
`postprandial, glucose-dependent GLP-1 expression, leading to enhanced insulin
`response and glucose tolerance.
`
`Combination of BI 10773 and linagliptin (BI 1356) in a diabetic rat model (ZDF):
`Effect on glucose tolerance (Study # MD2012-16-ppss, Doc. No. U12-1784-01)
`Non-GLP
`
`Summary: Empagliflozin, linagliptin, and combined empagliflozin + linagliptin treatment
`were investigated for glucose lowering efficacy in 8-9 week old male Zucker Diabetic
`Fatty rats (ZDF-Leprfa/Crl). Response to an oral glucose tolerance test (OGTT) of a
`single oral gavage dose of empagliflozin (3 mg/kg) ± linagliptin (1 mg/kg) was compared
`to vehicle (0.015% Tween 80, 5% hydroxyethylcellulose (Natrosol 250 HX)) and
`linagliptin alone. Rats were fasted overnight for 12 h, treated by gavage, and given 2
`g/kg glucose orally (5 ml/kg) 30 min post-dose. Blood glucose was assessed at pre-
`dose, 30, 60, 90, and 120 min post-dose by tail bleed. AUC0-180 min for glucose excursion
`was reduced 30%, 33%, or 49% by empagliflozin, linagliptin, or combined empagliflozin
`plus linagliptin, respectively. Results showed improved efficacy for glycemic control with
`approximate additive effect of combination treatment of the two drugs with distinct
`mechanisms. A single combination treatment resulted in virtually no blood glucose
`elevation 30 min or more after bolus oral glucose challenge. It is possible there was a
`blood glucose spike within the first 30 min after glucose challenge, as was seen at 15
`min post-dose sampling in other empagliflozin studies. Results imply a robust insulin
`response in diabetic rats after combined empagliflozin plus linagliptin treatment.
`
`Reference ID: 3642512
`
`15
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`

`NDA #206073
`Review #1
`Figure 1 – Empagliflozin + linagliptin improves glucose response in ZDF rats
`
`Reviewer: David B. Carlson, Ph.D.
`
`Reference ID: 3642512
`
`16
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`

`

`NDA #206073
`Review #1
`
`Reviewer: David B. Carlson, Ph.D.
`
`5
`
`Pharmacokinetics/ADME/Toxicokinetics
`
`5.1 PK/ADME
`Analytical Methods and Validation
`Analytical methods were validated previously for individual drugs for all relevant
`species. Additional analytical methods reports are briefly summarized here.
`
`BI 1356 BS 96-well method for rat, dog, and minipig plasma (Study # V203_03BE;
`Doc. No. U04-1551-02)
`No GLP compliance statement; signed, 6/29/09
`
`Summary: Validation of 96-well plate method for BI 1356 BS quantification in rat, dog,
`and minipig plasma from 0.5 to 500 nmol/L (from 50 μl plasma). Stability was confirmed
`in plasma for long term storage up to 14 months for rat and dog plasma. Long term
`minipig plasma storage was not evaluated because the species was not continued for
`toxicity assessment.
`
`BI 1356 BS and CD 1750 XX 96-well method for rat plasma (Study # M217_06MI;
`Doc. No. U07-1768-02)
`No GLP compliance statement; signed 1/14/10
`
`Summary: Validation of 96-well plate method for BI 1356 BS and CD 1750 XX
`quantification in rat plasma from 2.5 to 2500 nmol/L for BI 1356 BS and 1.0 to 1000
`nmol/l for metabolite CD 1750 XX (from 50 μl plasma). Stability was confirmed in
`plasma for long term storage up to 6 months.
`
`Assay method validation for the quantitation of BI 10773 in EDTA Wistar rat
`plasma (Study # DM-06-1016; Doc. No. U08-3272-01)
`GLP compliant; QA statement, signed 4/28/08
`
`Summary: Empagliflozin quantification from Wistar rat plasma with EDTA coagulant
`was validated using a protein precipitation method and HPLC/MS/MS analysis.
`Empagliflozin was quantifiable from 50 µl rat plasma across a range of 50 to 50,000
`ng/ml. Stability was confirmed in plasma for long term storage up to 6 months.
`Metabolism
`Effect of BI 10773 XX on the in vitro metabolism of [14C]BI 1356 BS by human
`hepatocytes (Study # A252-08LU; Doc. No. U09-2263-01)
`Non-GLP; signed 11/2/09
`
`Summary: Linagliptin turnover by human hepatocytes was very low in vitro. Effects of
`10 µM empagliflozin on hepatocyte metabolism of 10 and 50 µM linagliptin were
`assessed. There were no apparent differences in linagliptin metabolism profile in the
`presence or absence of empagliflozin. Data suggest limited potential drug-drug
`
`Reference ID: 3642512
`
`17