. CENTER FOR DRUG EVALUATION AND
`I
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-350
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW1_SQ I
`
`

`

`CLINICAL PHARMACOLOGY REVIEW
`
`Dale J
`
`6/30/08, 10/24/08, 11/19/08,
`11/24/08, 12/2/08, 1/26/09
`
`
`
`Saxagliptin; EMS-4771 18
`
`Jayabharathi Vaidyanathan, Ph.D.
`Immo Zdro‘ewski, Ph.D.
`
`~
`
`521$”:thsz 71306; Code
`’
`
`Original 505 (b) (l) S
`NIVIE
`
`Famg/gz‘z'aiz; fire/1.1% .r_
`
`Immediate release tablets; 2.5 mg and 5 mg
`Treatment of Type 2 diabetes
`
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`Table of Contents
`
`1
`
`2
`
`Executive Summary ..............................’.......................................................................2
`1.1
`Recommendations............................................................................................... 2
`1.2
`Phase IV Commitments...................................................................................... 2
`1.3
`Summary of Clinical Pharmacology and Biopharmaceutics Findings ............... 2
`Question-Based Review ............................................................................................... 8
`2.1
`General Attributes of the drug ............................................................................ 8
`2.2
`General Clinical Pharmacology ........................................................................ 10
`2.3
`Intrinsic Factors ................................................................................................ 28
`2.4
`Extrinsic Factors ............................................................................................... 37
`
`General Biopharmaceutics ................................................................................ 42
`2.5
`Analytical Section ............................................................................................. 45
`2.6
`Detailed Labeling Recommendations ........................................................................47
`3
`4 _ Appendices ................................................................................................................. 57
`4.1
`Proposed PaCkage Insert .................................................................................. 57
`4.2.
`Individual Study Reviews ............................................................................
`89
`4.3
`Pharmacometric‘Review ................................................................................. 171
`4.4
`OCP Filing/Review Form ............................................................................... 197
`
`

`

`1
`
`Executive Summary
`
`Saxagliptin belongs to the DPP—4 inhibitor class of anti-diabetic agents. Januvia
`(sitagliptin) is the’first approved DPP-4 inhibitor (NDA 21-995; approval date, Oct 16,
`2006) by the FDA and the Agency '(
`J
`
`X
`
`J
`
`0(4)
`
`Saxagliptin is intended to improve glycemic control for patients with type 2 diabetes
`mellitus (T2DM). Sponsor is proposing saxagliptin as monotherapy, as an adjunct to diet
`and exercise;
`in combination with metformin, a thiazolidinedione (TZD), or a
`sulfonylurea (SU) when the single agent alone, with diet and exercise does not provide
`adequate glycemic control; and also as initial combination with metformin, as an adjunct
`to diet and exercise, when treatment with dual saxagliptin and metformin therapy is
`appropriate.
`‘
`
`1.1
`
`Recommendation
`
`The Office of Clinical Pharmacology / Division of Clinical Pharmacology 2 (OCP/DCP-
`2) has reviewed NDA 22-350 for Onglyza (saxagliptin) and finds it acceptable provided
`that the Agency and the sponsor agree on the labeling. The recommendation and the
`following comments should be sent to the sponsor as appropriate.
`
`0
`
`It is recommended to reduce the dose to 2.5 mg when co-administered with strong
`CYP3A4/5 inhibitors.
`
`- Labeling comments on page 47.
`
`Required office level OCP briefing was held on Thursday, March 26 2009 and the
`attendees were Drs. Chandra Sahajwalla, Suresh Doddapaneni, Wei Qiu, Hylton Joffe,
`Naomi Lowy, Fred Alavi, Todd Bourcier, Joga Gobburu, Mehul Mehta, Atik Rahman,
`Gil- Burckhart, Kellie Reynolds, Sally Choe, Jayabharathi Vaidyanathan, Justin Earp,
`Michael Pacanowski, Johnny Lau, Sang Chung, Ritesh Jain, Immo Zdrojewski and Yun
`Xu.
`
`1.2
`
`Phase IV Commitments
`
`None
`
`, 1.3
`
`Summary of Important Clinical Pharmacology Findings
`
`The clinical pharmacology of saxagliptin has been characterized in 27 studies in healthy
`volunteers and TZDM patients. In addition, there are 23 bioanalytical study reports, 17 1'17
`
`

`

`Vii/'0 metabolism/permeability studies, and one protein binding study. Based on these
`studies, saxagliptin demonstrates the following properties:
`
`Pier/natal?!”etlk/fil'qpfidrmaceua’arPique/fie;
`
`0 Single dose and multiple dose pharmacokinetics of saxagliptin were similar and
`there was no accumulation afier once-daily dosing for 14 days. Following
`repeated administration, steady-state trough levels on day 2 was similar to that on
`day 4. The median Tmax was between 1.5-2.0 h following the 2.5 and 5 mg dose.
`The elimination half-life in patients was 2.3 — 3.3 h. The pharmacokinetics of
`saxagliptin in T2DM patients was similar to that observed in healthy subjects.
`Overall the AUC and Cmax increased proportionally with dose in the dose range
`of 2.5 mg to 50 mg in T2DM patients and 40 mg to 400 mg in healthy volunteers.
`The following Tables 1 and 2 present the PK parameters of saxagliptin in healthy
`subjects and T2DM patients, respectively.
`
`Table 1: Summary statistics of saxagliptin PK parameters in healthy subjects (Study
`010)
`
`r
`Mame or
`
`,,
`81%;?“ (ex-1 95)
`
`.~
`-
`'
`AU '1‘. L-
`mocézeutc-{inaifigg ea)
`
`-
`
`'
`
`A1. tor AUCKTAIB
`Geomm': Mm {C17, 2-3)
`
`Tmax)
`Median on Max)
`
`-
`_
`
`'
`
` P
`
`Day 1
`n=10 for 40 in;
`n=6 {or all other doses
`2'25 (40)
`585 (19)
`694 CS)
`1201 01)
`1245 (20)
`132: as)
`739 {35)
`1899 (13)
`2543 (n)
`use (15)
`6652 (22)
`8364 14
`
`'
`
`Day Ll
`will for 10 mg
`u=6 for an other doses a
`2:4 (33)
`487 (1+)
`614 (39)
`925 (:2
`1630 (31;
`1363 (22
`800 (24)
`1993 (It)
`2532 (9)
`mo (in)
`6539 (25)
`3533 13
`
`-
`
`O, .-.CO)
`1.50 (0.50.100)
`1.50 (1.00.150)
`1.50 1.00.150)
`_
`(012)
`.7 (0.14)
`
`.
`
`3.0:} (15)
`..03 (15)
`1.00 (13)
`0.99 {19)
`0.98 (14)
`1.02 8
`0.82 (050.100)
`_
`.
`1:0 (150. 2.0-3)
`1.23 (0.75, 2.00
`1.50 (0.5.2.00)
`1.75 (1.00.100)
`1.50 0.75.2.6“:
`2.45 (0.29)
`3.03 (1.29)
`2.69 {091)
`5.58 (13.5)
`538 (3.44)
`5.48 '23:?
`2'5 (1-)
`23 (S)
`22 (8)
`29 (6)
`26 (a)
`20
`0)
`
`

`

`-
`-
`.»
`C1R(mmeg'£m{SD-)
`‘
`
`-
`
`_.
`
`259 m)
`183 (50)
`129 (54)
`199 (69)
`-
`191 (03)
`313.1”) .,
`
`220 (vs)
`, 221 (90)
`230 (32)
`241 (36)
`100 (37)
`
`I Pharmacolzintflt
`Parameter
`
`002)
`
`Geometric Mean
`(av. 90)
`
`" (ESWEIL)
`j Geomric Mun
`
`T-E-ZALF (11)
`
`Mean
`
`(10)
`.
`(9)
`1.00“
`(5)
`1.01
`(7)
`1.10
`(5)
`0.97
`(100,400)
`(1.50.300)
`(150,100)
`(100,300)
`(1.50.300)
`3.0.7a
`(1.43)
`235
`(0.43)
`2.40
`(0.40)
`233
`(030)
`(054)
`
`(0.75.200)
`1.50
`2.003 (1.00.300)
`2.00 (0.15, 3.00)
`3.00
`(200,430)
`2.50 (1.00.300)
`
`.
`
`.
`*.
`
`E"M_Ia3;3::
`
`2.00 (150,400);
`1.75
`(1.00.100)
`2.00.
`(1.00.3110)
`150° (1.50.300)
`
`(57')
`
`(50)
`
`o The mean exposure of the major active metabolite, BMS-S 10849 was 1.7 - 3 fold
`and 4-7 fold higher than the parent
`in healthy subjects and TZDM patients,
`respectively. The molar ratio of EMS-510849 to saxagliptin was similar on Days
`1, 7 and 14 within each dose. The median Tmax was 3 h and the mean apparent
`terminal half-life was 3.6 h following 5 mg dose.
`0 Co-administration of a 10 mg tablet with a high fat meal resulted in a 27%
`increase in AUC of saxagliptin and a decrease in exposure of BMS-510849
`(Cmax decreased by 18%). The median Tmax of saxagliptin was prolonged fiom
`0.53 h to 0.99 h, while the median Tmax of BMS-510849 increased fi'om 1.47 h
`to 1.98 h when saxagliptin was administered following a high-fat meal. The
`sponsor is requesting biowaiver for conducting additional clinical food effect
`
`

`

`studies with the proposed 2.5 mg and 5 mg tablets and to apply the findings flom
`the 10 mg food effect study to these lower strength tablets. The biowaiver is
`acceptable. Sponsor’s proposed administration of saxagliptin regardless of food is
`acceptable.
`The serum protein binding for saxagliptin and EMS-510849 was negligible in
`plasma.
`A mass balance study indicates approximately 75% of the radioactivity recovered
`in the urine and about 22% in feces. The major metabolite observed in plasma
`was BMS-S 10849.
`
`impaired subjects indicated that renal function
`A single dose study in renal
`affected saxagliptin exposure significantly. Saxagliptin mean AUC increased by
`15%, 40%, and 110% (2.1 fold) in subjects with mild, moderate, and severe renal
`impairment respectively, as compared to that of control subjects. Cmax also
`increased by 39%, 7%, and 38% in subjects with mild, moderate, and severe,
`respectively, compared to that of subjects with normal renal function. Compared
`to subjects with normal renal function, ESRD subjects had 15%, 21% and 23%
`lower mean Cmax, AUCinf and AUC(0.T) values of saxagliptin, respectively.
`Compared to subjects with normal renal function, subjects with mild, moderate,
`. severe renal function and ESRD had 40%, 47%, 46%, and 36% , respectively,
`higher mean Cmax values of EMS-510849 and 67%, 191% (2.9-fold), 347% (4.5-
`fold), and 306% (4.1-fold), respectively, higher mean AUC(0_T) values of EMS-
`510849. The sponsor has proposed 2.5 mg for moderate, severe and ESRD
`patients and no dosage adjustments are being proposed for mild renal impairment.
`This is acceptable.
`Saxagliptin is predominantly metabolized in the liver by CYP3A4/5 and the
`exposure is expected to increase in hepatic impaired subjects. Compared to
`matched healthy subjects,
`there was a trend towards higher exposure for
`saxagliptin and lower exposure for EMS-510849 with increasing severity of
`hepatic impairment, indicating a reduced capacity to metabolize saxagliptin as
`hepatic function declines. For subjects with severe hepatic impairment, compared
`to matching healthy subjects, geometric mean Cmax of saxagliptin was 6% lower
`and geometric mean AUCinf and AUC(0_T) was 77% and 72% higher, respectively.
`No dosage adjustments are proposed based on hepatic impairment. This is
`acceptable.
`Elderly subjects had higher systemic exposures to saxagliptin (approximately
`60%T) and BMS-510849 (35%?) compared to young subjects. Adjustment for
`CLcr and body weight reduced the saxagliptin PK difference between elderly and
`young to 12%, 29% and 30% for Cmax, AUCinf and AUC(0_T), respectively.
`There was interaction between age and sex on saxagliptin exposure as indicated
`by 84-87% increase in elderly females as compared to young males. There was
`simultaneously about 68-70% increase in EMS-510849 exposure in elderly
`female subjects. No dosage adjustments are proposed by the sponsor based on age
`and gender. This is acceptable.
`Race did not havean effect on the clearance of saxagliptin based on population
`pharmacokinetic analysis.
`
`

`

`Saxagliptin is a CYP3A4/5 substrate as well as a P-glycoprotein substrate. The
`effect of strong CYP3A inhibitors and inducers on saxagliptin concentrations is
`an important issue.
`0 Drug interaction was evaluated with the following: ketoconazole,
`diltiazem, rifampicin, maalox Max, famotidine, omeprazole, glyburide,
`pioglitazone, metfonnin, digoxin and simvastatin. The most significant
`changes in the saxagliptin exposure occurred in presence of metabolic
`modulators. The DDI with ketoconazole was conducted with 100 mg and
`20 mg saxagliptin and there was about 2.5-fold and 3.8-fold increase in
`saxagliptin exposure, respectively. The extent of increase in exposure of
`saxagliptin 5 mg in presence of ketoconazole is unknown. In addition,
`considering the adverse events that resulted in presence of ketoconazole', it
`is recommended to reduce the dose to 2.5 mg when patients will be
`prescribed strong CYP3A4/5 inhibitors. In addition, there was a statistical
`decrease in Cmax of saxagliptin in the presence of Maalox max (26% 1)
`and metformin (21% l). The 90% CI for these fell outside of the 80~125%
`limit for Cmax in presence of these drugs with no impact on the AUC of
`saxagliptin. This change is not likely to be clinically significant.
`Induction of CYP3A4/5 by rifampin caused an 80% decrease in
`saxagliptin exposure. Although this was not associated with corresponding
`increase in EMS-510849 exposure, there was about 40% increase in its
`Cmax. Induction also resulted in a decrease in saxagliptin half life from
`3.02 to 1.7 h. This metabolic induction is also evident in a 5-fold increase
`
`in the metabolite-to-parent AUC ratio. The clinical significance of these
`changes is unknown. However, if the exposure of the total active moiety
`(molar parent exposure + one half molar metabolite exposure)
`is
`considered, there was about 25% decrease in the total exposure, which is
`unlikely to cause an clinically significant changes.
`The final to-be~marketed tablets were similar to the formulation used in phase 3
`trials except for the color and embossing. Saxagliptin molecule contains chiral
`centers. Chiral conversion was examined and there was no conversion 1'12 Vii/o.
`
`Ewart/re Maid-RewonseKe/artiolisfija
`
`o The thorough QT study shows saxagliptin does not prolong QTc based on the
`concentration-dQTc relationship, with doses up to 8-fold of the therapeutic dose.
`Dose-response relationship shows that the HbAlc lowering effect was increased
`with increase in dose from 2.5 mg to 5 mg QD.
`'
`Dosing with saxagliptin appeared to have a dose-dependent effect on plasma
`DPP-4 activity. As expected, DPP-4 inhibition was negligible for subjects
`receiving placebo. For subjects receiving saxagliptin, DPP-4 inhibition peaked, on
`average, between 1.5 and 6 hours after dosing. The amount remaining inhibited at
`the end of the dose interval (24 h) was 37% and 65% at the proposed clinical dose
`of 2.5 mg and 5 mg respectively.
`The exposure—efficacy response modeling for AIC LOCF after 24 weeks of
`saxagliptin administration at QD doses of 2.5, 5, and 10 mg showed that the
`
`

`

`reduction of AlC was linearly related to the log of AUCT, the total active moiety
`exposure after saxagliptin administration. Model identified significant covariates
`on the AlC were baseline AlC and duration of T2DM. For subjects (with
`duration of TZDM of 3 months, baseline AlC of 8%) receiving saxagliptin 5 mg
`QD treatment for 24 weeks, the expected AlC (95th prediction interval) was
`predicted to be 7.34 (7.23 - 7.46) %.
`‘
`The exposure-safety response modeling on the absolute lymphocyte counts after 6
`months of saxagliptin administration at QD doses of 2.5, 5, and 10 mg showed
`that the decrease of absolute lymphocyte counts is linear to the increase of the
`total active moiety exposures within the tested QD dose range of 25-10 mg,
`however the magnitude of the change, approximately 4% placebo-adjusted
`decrease for subjects receiving 5 mg QD treatment of 6 months is unlikely to be
`clinically relevant. Exposure-safety response modeling did not find a correlation
`between the platelet counts and serum creatinine concentration to the total active
`moiety exposure after 6 months of saxagliptin administration at QD doses of 2.5,
`5, and 10 mg. It was concluded that the responses of platelet counts and serum
`creatinine concentration after 6 month of saxagliptin administration at QD doses
`of 2.5, 5, and 10 mg were not found to be related to the Saxagliptin administration.
`Based on the results of the population pharmacokinetic analyses and the
`exposure-response analyses, the efficacy outcomes (AlC and FPG) and safety
`outcome (absolute lymphocyte counts) after 6 months of saxagliptin treatment
`were predicted at given saxagliptin regimen and relevant covariates (baseline
`AIC, duration of T2DM, baseline body weight, baseline absolute lymphocyte
`counts). The predicted outcomes were transformed into the percent change from
`baseline, and the summary statistics of the percent change from baseline is
`presented in Figure I. It shows that as saxagliptin dose increases, the reduction of
`A10 and FPG from baseline is expected to increase, with overlapping prediction
`intervals at 2.5, 5, and 10 mg. There is a slight decrease of absolute lymphocyte
`counts as dose increases, but the magnitude is unlikely to be clinically relevant, as
`the predicted decrease of absolute lymphocyte counts after 6 months of
`saxagliptin treatment at 5 mg QD dose is only about 4% more than the predicted
`value for placebo treatment.
`Figure 1. Model Predicted Efficacy and Safety Outcomes after 6 Months of
`Saxagliptin Treatment.
`Solid symbols and vertical bars represent
`the
`median and 95% prediction intervals.
`10
`...
`
`lmmBaselineatManlh6m)c':-OO Ii:In
`Panama;-Chang-
`
`
`-O- AIC (Baseline: 7.85%)
`
`... she (Baseline: 173 mgldL)
`
`+Absolute Lymphocyte
`Counts (Baseline: 2.16
`1 0‘3 cIuL)
`
`10
`
`D
`l0'
`
`.» 0"
`
`D
`
`7.5
`5
`2.5
`' saxagliptin 00 Does (mg)
`
`

`

`0
`
`[ympfleqxte count: 14 of 15 subjects experienced a decline in lymphocyte count
`on Day 10 following administration of a single dose of 100 mg saxagliptin + 200
`mg ketoconazole q12h (study 005).
`In another
`study (022),
`following
`administration of a single 20 mg dose of saxagliptin one week earlier, co-
`administration of a second single dose of 20 mg saxagliptin and 200 mg
`ketoconazole q12h dosed to steady-state resulted in a decrease (30.6%)
`in
`absolute lymphocyte counts. The levels returned to baseline levels within 72 h.
`Overall, there was a decrease in lymphocyte count when saxagliptin was co-
`administered with ketoconazole as well as when there was an interrupted dosing
`of saxagliptin.
`
`Overall, the cumulative data regarding the clinical pharmacology of saxagliptin support
`the proposed use of this drug in T2DM patients.
`
`2
`
`Question Based Review
`
`2.1
`
`General Attributes of the Drug
`
`2.1.1 We! per/Ike”! regulate/y background or artery eon/”fizzle; to [lie 62/176121
`amen/”ell! oftfle e/Ehz‘ea/pfiermaeo/og/ afldélbpflar/Izeeez/lzey ofthis div/g7
`
`Saxagliptin (Onglyza) is a new chemical entity developed by BMS for the indication of
`treatment of type 2 diabetes. Saxagliptin belongs to a new class of drugs known as DPP-4
`(dipeptidyl peptidase—4)
`inhibitors. Currently only one DPP-4 inhibitor (Januvia)
`is
`approved in the USA. A standard review status was granted for this NDA.
`-
`
`2.1.2 We! are Me age/gm 0fMeprayer/1e; ey’t/ze dmg or tflefimzx/atfwz 4: Me}
`relate to efi'rzz’ee/péamaeo/o‘g/ review?
`
`\ )
`
`Saxagliptin drug substance is a‘
`
`‘
`
`‘
`
`"
`
`~
`
`,
`
`Forthe initial clinical studies (up to the end of Phase 2b), drug substance1n
`(designated as_ “—— was employed in the clinical
`development program. A capsule dosage form containing the/ of saxagliptin
`M was developed and used -to evaluate the initial
`safety and
`phannacokinetics of saxagliptin. Subsequently, drug substance, as the ,/-“
`monohydrate (designated as /"”D , was selected for further development.
`Saxagliptin drug products developed for Phase 3 clinical studies were film coated
`immediate release tabletsin three strengths: 2. 5 mg, 5 mg and 10 mg (calculated as the
`/ These tablets differed from the early clinical tablets in the amount and color of
`coating material.
`
`M4)
`
`

`

`Saxagliptin is a chiral molecule with four stereogenic centers (SSSSconfiguration), two
`being fixed in relative stereochemistry as part of the cyclopropane ring. The presence of
`two of the diastereomers (EMS-573659 and EMS-644448) in human plasma and urine
`samples from human ADME study as well as from late stage clinical trials were re-
`examined for the presence of radioactivity or MS signal at
`the retention times
`corresponding to the standards. In both conditions, no signals were detected at the
`retention times of EMS-573659 and EMS-644448.
`'
`
`Figure 2: Structure of saxagliptin
`
`.1120
`
`2. l .3 W4!are tflepropoyea’mecflamkmflr/ (9/461le andMargaret/(12’ [Irradiation/5']?
`
`Saxagliptin is an orally active inhibitor of DPP-4 enzyme intended for the treatment of
`type 2 diabetes in adults. Saxagliptin is indicated as an adjunct to diet and exercise to '
`improve glycemic control in patients with type 2 diabetes.
`
`DPP-4 is found free in the plasma and as a cell surface enzyme mainly located on
`vascular endothelium and on epithelial cells in a variety of organs. It is the enzyme
`primarily responsible for the degradation and inactivation of the incretin hormones
`glucagon-like peptide—1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)
`which play a critical role in glucose homeostasis. InhibitiOn of DPP—4 prolongs the life of
`these polypeptide hormones in the circulation leading to improving glucose dependent
`insulin secretion and reduction of inappropriate glucagon secretion. These hormones
`contribute to the control of postprandial glucose excursions in a glucose dependent
`manner, mitigating the risk of hypoglycemia.
`
`insulin release, GLP-l also reduces glucagon
`In addition to enhancing postprandial
`release from the pancreatic G-CCUS, thereby reducing hepatic glucose production. This
`effect is also glucose-dependent, such that when plasma glucose is normal or low, the
`counter-regulatory response of glucagon release is not impaired.
`‘
`
`[/2 who enzymological assays using the chromogenic dipeptide gly-pro—pNA pseudo
`substrate and the endogenous GLP—l substrate, with recombinant human DPP-4 indicated
`that saxagliptin exhibited a Ki value of 1.3 :I: 0.3 nM. Saxagliptin is metabolized to EMS
`510849, a monohydroxylated metabolite that is present in human plasma at levels 2 to 7X
`the level of the parent drug. This metabolite is also an inhibitor of DPP4, and is 2x less
`potent than saxagliptin, and has a Ki of 2.6i1.0 nM. Saxagliptin and BMS-S 10849
`exhibited selectivity (391 and 948X, respectively) for DPP4 over DPP8, and (75 and
`163 X, respectively) for DPP4 over DPP9 at 37°C. Saxagliptin had a Ki for inhibition of
`
`

`

`plasma DPP activity of 1.7 nM (ICso 13 nM) and 0.9 nM (leo 9 nM) in human and
`cynomolgus monkey plasma, respectively.
`2. l .4 Wat are [flap/goosea’dmage (”Id/”owe 0/‘00’1721'71431/4/1'0/2?
`
`The proposed usual clinical dose is 5 mg once daily given orally. The recommended dose
`is 2.5 mg once daily in subjects with moderate or severe renal impairment, and end—stage
`renal disease requiring hemodialysis.
`
`2.2
`
`General Clinical Pharmacology
`
`2.2. 1 W41are [fie a’eyzg/z/éa/urey (ft/16 cfikz'ca/pflar/flaco/ogy afla’clinical/$111492;
`media yzgppor/ dosi/zg or claims?
`
`0
`
`Twenty-seven (27) clinical pharmacology studies were conducted in healthy volunteers
`as well as type 2 diabetic patients. The studies include
`0 Single ascending dose, multiple ascending dose, and ADME mass balance
`.studies.
`.
`Special populations PK study (renal impairment, hepatic impairment, age and
`gender).
`Drug-drug interaction studies.
`0 Pharmacodynamic studies investigating saxagliptin’s effect on DPP-4 inhibitory
`activity.
`'
`0 Effect of saxagliptin on cardiac QT interval.
`0 Relative bioavailability studies.
`
`In addition, there are 23 bioanalytical study reports, 17 in vitro metabolism/penneability
`studies, and one protein binding study.
`
`In the dose-ranging study, doses in the range of 2.5 mg — 40 mg were evaluated for 12
`weeks. In the Phase 3 program, saxagliptin doses of 2.5, 5, and 10 mg administered once
`daily were evaluated to fiilly characterize the efficacy, safety, and benefit/risk profile of
`saxagliptin within the dose—response range established in Phase 2. The different phase 2b-
`3 trials to support dosing claims are summarized in the table below.
`
`10
`
`

`

`Table 3: Summary of Controlled Phase 2b-3 Clinical Trials
`Study No.
`Study abjudrn
`Randomized
`Duration shm-
`Suamfin (mg) dosage
`(reputerim)
`and mated
`um
`subjects
`(total)
`All E San
`
`
`Monomers” placebo-controlled
`cvmoos
`Don-mm
`+23 1' 315
`I
`12 weeks
`25, 5, 30, 20, or 40 Q!)
`samy m‘l cflmcy
`or
`or
`
`(MC 5595-2793)
`6 “uh
`300 QD
`evasion
`smymmaucy
`401.109
`24mm
`2.5, 5, or won
`
`(an: 793-109.)
`(:05 weeks)
`CVISIOSS
`Safety and efficacy
`365 .v' 291
`2% mos
`2.5, 5, or 2.5:‘5 0AM.
`
`(AlC il'o-lcti)
`(76 weeks)
`or S QPM
`music-n
`. amen of
`36 i 20
`22 necks
`S QD
`action
`(1 16 nah)
`
`(arc verses)
`
`Add-on combuu‘flan plaubwontrolkd
`cvxstoxa
`Safetyndifiucy
`SGSISSI
`24 week;
`2.5 m5 QD(. 320)
`
`(MC tea-10.593)
`(.76 weeks)
`(1.131014
`Salary and cmucy
`743 J 564
`2+ nah
`22‘, 5. or 1(- QB
`
`(Alt fro-10%)
`(2% main)
`(Mun)
`CV181040
`Safety and dime-y
`1'68 .-‘ 501
`24 mm
`2.5 er 5 0130;511:1132)
`
`(Alt 7593-1093)
`(76 weeks)
`new combination nethe—conmlkd
`
`CV131039
`Sm and efficacy
`1306193
`24 mm
`5 or 10 Q1) (Mum)
`(All: 8984293)
`(7'6 weeks)
`ex 10 In; Q1)
`
`new; Sfimbjem mam: exam: sWSmaysii ‘
`V
`'—
`QD - M2! daily. QAM a once Myth the naming, QPM I one: duly in the evening
`
`
`
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`ezzdpaz’lz/x or homer/7631:? {alkali/341 cal/edpflamacaafiwamm PD] arm/flow
`are {flay measured1'71 c/z'zzzba/pflarmaco/og/ andc/z'zzica/mar/02195.?
`
`The American Diabetes Association (ADA) recommends the use of HbAlc levels as an
`indicator of glycemic control. The sponsor has used the change from baseline in HbAlc
`at the end of double-blind treatment as the primary efficacy variable in all key efficacy
`studies. In addition, PD parameters based on the mechanism of action of drugwere
`measured in some clinical pharmacology studies. They include DPP—4 enzyme activity,
`levels of GLP—1, GIP, insulin, glucagon, and glucose.
`
`2 .2.3 Are t/ie active ”2012911?! 1'): Map/057224 {or 0153/éio/ogl'ca/jfizz'afl app/‘qarl'w‘eé/
`[Veil/fledandmean/red1‘0 amempflamaco/éi/ze/zbparametem afldarpayz/re
`I'eJPOIIJ'e re/a/z'o/zsflljm?
`
`Yes. Please refer to the Analytical section for details.
`
`11
`
`

`

`2.2.4 Wat are Me cfldrac/e/zlm'cy 0f/fle egamzzre—mspoflye re/a/z'olzyflg'a {dare
`ragga/256, cancezztra/z’axz—raspwzse/f
`
`0 Efficacy
`
`57/251 0f5'arag/zp1‘1}: or: DPP-lt'lzfizZt'tt'o/t: Saxagliptin inhibited plasma DPP-4 activity
`in a dose-dependent manner. The pharmacodynamic A effect of saxagliptin was
`investigated in normal volunteers as well as TZDM patients. Following single dose
`administration (study 001) in healthy subjects, maximum of 73% and 79% inhibition was
`achieved during the first 0.75 — 2 h after administration of saxagliptin at doses 2.5 mg and
`5 mg, respectively. Inhibition was 35% and 44% after 24 h post-dose following 2.5 mg
`and 5 mg dose, respectively (Figure 3).
`
`Figure 3: Plot of Mean Percent Changes from Baseline for Plasma DPP—4 Activity
`following single oral dose of saxagliptin
`Fasled
`
`204
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`
`the DPP-4
`Following multiple dose administration (study 010) in healthy subjects,
`inhibition peaked, on average, between 0.75 and 4 hours after dosing on both Day 1 and
`Day 14. Plasma DPP-4 inhibition on Days 1 and 14 appeared to be dose-dependent both
`in terms of the maximum inhibition and the amount remaining inhibited at the end of the
`dose interval (24 h) from 40 to 150 mg QD saxagliptin. Dosing with saxagliptin at 100,
`150, 200, 300 and 400 mg resulted in larger inhibition of plasma DPP—4 activity than
`dosing with saxagliptin 40 mg, no clear difference was observed between the 150 mg ——
`400 mg doses. For all doses, plasma DPP-4 activity was inhibited by at least 74% at 24
`hours after a single dose and following two weeks of daily dosing. The peak inhibition of
`plasma DPP—IV activity on Days 1 and 14 was between 1 and 2 h post-dose which tended
`to coincide with the Tmax values for both saxagliptin and EMS-510849 (Figure 4).
`
`12
`
`

`

`Figure 4: Plot of Mean Percent Changes from Baseline for Plasma DPP-4 Activity
`on Day 14
`Day M
`
`humBarium-e
`Muun‘x.Change
`
`
`PLOT
`
`q-c—o P .250
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`“
`
`Following multiple dose administration (study 002) in TZDM patients, the plasma DPP—4
`inhibition was dose—dependent. As expected, DPP-4 inhibition was negligible for subjects
`receiving placebo. For subjects receiving saxagliptin, DPP-4 inhibition peaked, on
`average, between 1.5 and 6 hours after dosing. The amount remaining inhibited at the end
`of the dose interval (24 h) was 37% and 65% at the proposed clinical dose of 2.5 mg and
`5 mg respectively (Figure 5).
`
`Figure 5: Plot of Mean Percent Changes from Baseline for Plasma DPP-IV Activity
`on Day 14
`Day 14
`
`armour":
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`lema'actz’ve GZP-I com-elitmtionx' In general, dosing with saxagliptin (in the? dose
`ranges of 40 to 200 mg) in healthy subjects produced an increase in mean changes from
`baseline (although not dose-dependent effect) for postprandial AUC(0-3h) plasma active
`GLP-l over those observed for subjects on placebo for all meals.
`
`Saxagliptin did not appear to have a dose-dependent effect on plasma active GLP-l
`concentrations in TZDM patients. For patients receiving saxagliptin, plasma active GLP-l
`concentrations generally peaked, on average, at 6 hours after dosing. Exceptions were the
`50 mg dose-group which produced plasma active GLP-l concentrations which peaked, on
`average, at 1 hour alter closing on Days 1 and 14, and the 2.5 mg dose-group which
`produced plasma active GLP—l concentrations which peaked, on average, at 45 minutes
`afier dosing on Day 1.
`
`13
`
`

`

`atflerfflpammetem Dosing with saxagliptin did not appear to have a‘dose dependent
`or time-dependent (day of dosing) effect on glucose over 24 hours from the time of
`dosing. Dosing with saxagliptin did not appear to have a dose-dependent or time-
`dependent effect on HOMA, glucose AUCO-4 values, serum insulin or C-peptide over 4
`hours from the time of meal.
`
`157/211 at: Hédlc.‘
`
`flare flit/1215' In the dose-finding study (008), the safety and efficacy of saxagliptin
`monotherapy in treatment-naive subjects with T2DM who had inadequate glycemic
`control. Subjects were randomized to receive 1 of 5 doses of saxagliptin (2.5, 5, 10, 20,
`' and 40 mg) or placebo once daily for 12 weeks (0—40 mg cohort). An additional 85 .
`subjects were randomized to receive saxagliptin 100 mg or placebo once daily for 6 '
`weeks (0,100 mg cohort). The results indicate that the largest effect on glycemic control
`(decreases in HbAlc, fasting plasma - glucose and postprandial serum glucose) was
`generally seen at a dose of 5 mg or 10 mg, with no apparent increase in efficacy at doses
`higher than 10 mg in the 0-40 mg cohort (Figure 6). There was also significant inhibition
`of plasma DPP—4 activity at trough (24 h post-dose), with the largest effect seen at 10 mg,
`with no apparent increases at doses higher than 10 mg. On this basis, once-daily regimens
`of 2.5, 5, and 10 mg saxagliptin administered to subjects with T2DM were characterized
`in the core phase 3 studies.
`
`Figure 6: Adjusted mean change (SE) from baseline in HbAlc at week 12 or week 6
`(100 mg) (LOCF): 0-40 mg cohort (left) and 0-100 mg cohort (right)
`a
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`Pflare .i’ stud/ex The primary endpoint in the core studies (011, 038, 013, 014, 040 and
`039) was the change in HbAlc from baseline to week 24. Statistically significant
`reductions from baseline in HbAlc were seen across all studies in the saxagliptin
`treatment group compared to control. Treatment with 5 mg saxagliptin led to placebo-
`subtracted adjusted mean changes in AlC that ranged from -0.40% to -O.83%. The
`saxagliptin 5 mg groups achieved greater reductions from baseline in AlC than the
`saxagliptin 2.5 mg groups in five of the six studies (Figure 7 & 8). There was no
`consistent evidence for incremental efficacy benefit at 10 mg beyond that seen for 5 mg.
`Similar overall glycemic lowering efficacy was achieved when the saxagliptin 5 mg dose
`was given in the morning (QAM) and evening (QPM) in study 038 (Figure 7).
`
`l4
`
`

`

`Figure 7: HbAlc adjusted mean changes from baseline (95%CI) at Week 24
`(LOCF) - Phase 3 monotherapy studies
`04181-011
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`Studies 013, 014, and 040 evaluated the safety and efficacy of saxagliptin in combination
`With thiazolidinedione (TZD), metformin, or sulfonylurea (SU), respectively, in subjects
`with inadequate glycemic control on TZD, metformin, or SU alone (Figure 8). Study 039
`evaluated the safety and efficacy of saxagliptin in combination with metformin as initial
`therapy versus initial therapy with saxagliptin or metforrnin as monotherapies.
`
`Figure 8: HbAlc adjusted mean changes from baseline (95%CI) at Week 24
`(LOCF) - Phase 3 add-on combination therapy studies
`01151-013
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