CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`200678Orig1s000
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`SUMMARY REVIEW
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`

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`Cross Discipline Team Leader Review
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`Cross-Discipline Team Leader Review
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`
`Date
`From
`Subject
`NDA/BLA #
`Supplement#
`Applicant
`Date of Submission
`PDUFA Goal Date
`
`Proprietary Name /
`Established (USAN) names
`Dosage forms / Strength
`Proposed Indication(s)
`
`Recommended:
`
`
`October 28, 2010
`Hylton V. Joffe, M.D., M.M.Sc.
`Cross-Discipline Team Leader Review
`200678
`
`Bristol-Myers Squibb
`December 29, 2009
`October 29, 2010
`
`Kombiglyze XR (saxagliptin/metformin XR fixed-dose
`combination product)
`2.5/1000 mg, 5/500 mg, 5/1000 mg
`As an adjunct to diet and exercise to improve glycemic
`control in adults with type 2 diabetes mellitus when
`treatment with both saxagliptin and metformin is
`appropriate
`Approval
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`Cross Discipline Team Leader Review Template
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`1. Introduction
`
`
`This memorandum reviews a new drug application (NDA) for the saxagliptin-metformin
`extended-release (metformin XR) fixed dose-combination (FDC) tablet. This NDA was
`submitted by Bristol-Myers Squibb (BMS), which has an alliance with AstraZeneca for
`commercializing saxagliptin-related products. This is a 505(b)(1) application because BMS
`has the right of reference for both the saxagliptin (NDA 22350) and metformin XR
`(Glucophage XR NDA 21202) components of the FDC product.
`
`The sponsor has conducted a typical development program for the FDC. Specifically, there is a
`series of clinical pharmacology studies that attempt to bridge the FDC to co-administration of
`the individual components. In addition, the sponsor is relying on efficacy data from two phase
`3 trials conducted as part of the saxagliptin NDA (a saxagliptin add-on to metformin trial in
`patients with inadequate glycemic control on metformin alone and a saxagliptin plus
`metformin co-administration trial in patients naïve to anti-diabetic medication). The sponsor is
`relying on safety data from these two trials as well as safety data from recently completed and
`ongoing trials that involve co-administration of saxagliptin and metformin. Note that the FDC
`product contains metformin XR and is proposed for once daily dosing with the evening meal.
`In contrast, most of the supporting clinical data are derived from once daily saxagliptin co-
`administered with twice-daily metformin immediate-release (metformin IR). Other
`components of the development program include a chemistry/manufacturing/controls package
`to support the FDC formulation as well as a standard bridging non-clinical toxicology
`program. This memorandum will focus on the adequacy of all these findings to support
`approvability of the FDC product.
`2. Background
`
`
`Saxagliptin is a dipeptidyl-peptidase 4 (DPP-4) inhibitor approved in July 2009 as an adjunct
`to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The
`recommended dose of saxagliptin is 2.5 mg or 5 mg once daily regardless of meals. The
`maximum recommended dose is 2.5 mg once daily for patients with moderate or severe renal
`impairment and for patients on strong CYP3A4/5 inhibitors. Adverse events of interest for
`saxagliptin and/or other DPP-4 inhibitors include pancreatitis, hypersensitivity reactions (e.g.,
`angioedema, anaphylaxis), skin lesions (some DPP-4 inhibitors cause necrotic skin lesions in
`monkeys – saxagliptin does so but with large safety margins), infections (chemokines are
`substrates of DPP-4 and DPP-4 is also expressed on a subset of T-cells and natural killer cells;
`saxagliptin can cause mild lymphopenia at approved doses), and liver safety (at least one DPP-
`4 inhibitor – vildagliptin - has a signal for hepatotoxicity in the premarketing program).
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`Metformin, a biguanide, is recommended by the American Diabetes Association as first-line
`therapy for the treatment of type 2 diabetes. Metformin is generally well tolerated but can
`cause gastrointestinal symptoms such as nausea and diarrhea. These side effects are minimized
`by taking metformin with meals and by slowly uptitrating the dose. Gastrointestinal side
`effects may also be reduced by using metformin XR, which has a 20% lower Cmax but
`comparable overall exposure (area under the time-concentration curve or AUC) to metformin
`IR. Metformin XR is usually dosed once daily with the evening meal whereas metformin IR is
`usually dosed twice daily with breakfast and dinner. Glucophage XR, which is the metformin
`XR produced by BMS, is available as 500 mg and 750 mg tablets. The usual starting dose is
`500 mg once daily with the evening meal with weekly uptitration by 500 mg to a maximum of
`2000 mg once daily or a maximum of 1000 mg twice daily. The most serious adverse reaction
`of metformin therapy is lactic acidosis, which is rare, but is the basis for a contraindication in
`patients with renal impairment (metformin is substantially renally cleared).
`
`The sponsor has proposed 3 dosage strengths for the FDC:
`• Saxagliptin 5 mg / metformin XR 500 mg
`• Saxagliptin 5 mg / metformin XR 1000 mg
`• Saxagliptin 2.5 mg / metformin XR 1000 mg
`
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`3. CMC
`
`
`The Chemistry reviewers recommend approval without the need for postmarketing
`commitments. Please see Dr. Elsbeth Chikhale’s review for details.
`
`The drug product consists of a
`
`
`
` The commercial drug product will be manufactured at the BMS Mount Vernon facility.
`A Quality by Design approach was used for
`
`
`The saxagliptin drug substance and manufacturing site is identical to that used for the
`saxagliptin NDA. The metformin drug substance information is provided in Drug Master Files
` and found by the CMC reviewers to be acceptable for
`use in this FDC NDA. The metformin XR
` is manufactured as per the current commercial
`process for Glucophage XR 500 mg. There is no currently marketed Glucophage XR 1000 mg
`tablet but there is a marketed Glucophage XR 750 mg tablet. The metformin XR 1000 mg
`
`for the FDC product is manufactured
`
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`.
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`CMC found all excipients to be acceptable.
`
`Based on the stability data, Dr. Chikhale recommends a shelf-life of 15 months for the blisters
`and 21 months for the bottles when stored at 20-25 degrees Celsius,
`
`.
`
`
`Dr. Chikhale agrees with the sponsor’s claim that the application qualifies for a categorical
`exclusion from an environmental assessment report.
`4. Nonclinical Pharmacology/Toxicology
`
`
`The nonclinical pharmacology/toxicology reviewers recommend approval of the NDA. Please
`see the reviews by Drs. Lauren Murphree Mihalcik and Todd Bourcier reviews for details.
`
`Most of the nonclinical pharmacology and toxicology data for the FDC are derived from data
`established for saxagliptin and metformin XR as individual components. The sponsor
`conducted a bridging 3-month general toxicology study in dogs assessing saxagliptin and
`metformin separately and in combination. The doses used in this study achieved saxagliptin,
`BMS-510849 (the major saxagliptin metabolite) and metformin exposures (AUC) that were 70
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`Cross Discipline Team Leader Review
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`times, 16 times, and 1.5 times the maximum recommended human dose, respectively. Dr.
`Mihalcik and Bourcier did not identify unique toxicities when the drugs were co-administered
`and noted that the toxicity of each drug alone was reasonably similar to the toxicology profile
`that supported approval of the individual drugs.
`
`During the review cycle for NDA 22350, the sponsor submitted results from an embryofetal
`study in rats showing neural tube defects in 2 fetuses (from 1 litter) with coadministered
`saxagliptin and metformin. The study lacked separate treatment arms for saxagliptin and
`metformin precluding the ability to determine whether the observed neural tube defects were
`related to combination therapy with saxagliptin and metformin or to one of the individual
`therapies. Therefore, under the saxagliptin NDA we required the sponsor to conduct
`postmarketing embryofetal studies in rats and rabbits with the drugs alone and in combination.
`According to Dr. Mihalcik, these completed studies did not identify a drug-related neural tube
`defect despite using in the repeat rat study higher doses of metformin (10 times the maximum
`recommended human dose based on AUC) than that used in the original rat study. In addition,
`the incidence of neural tube defects observed in the original rat study was shown to be
`consistent with updated historical control data from the study site. Therefore, the nonclinical
`pharmacology/toxicology reviewers have concluded that the saxagliptin/metformin
`combination is not teratogenic in animals. The pregnancy labeling for the FDC will reflect the
`most current embryofetal animal data. The sponsor has requested that the embryofetal animal
`data also be updated in the saxagliptin label and has included the revised language as part of an
`efficacy supplement that is currently in-house under review. Once the agreed-upon labeling is
`approved under the saxagliptin NDA, the sponsor’s postmarketing required embryofetal
`studies will be considered fulfilled and administratively closed out.
`
`Other findings of note from the embryofetal studies include additive decreases in weight gain
`observed in the drug-treated groups and a slight increase in wavy ribs in the combination drug
`group. The wavy ribs were not considered an adverse effect because this finding is commonly
`observed in the offspring of dams with reduced body weight gain and typically resolves
`postnatally in the rat. In the rabbit study, there was a neural tube defect in a single fetus but
`this incidence was within the historical control range. In this study, there was a significant
`increase of offspring with small or absent gallbladder in the saxagliptin-alone group (but not in
`the combination group). This is similar to the finding in the saxagliptin alone study but human
`risk is considered low because of high multiples of drug exposure (200 times the maximum
`recommended dose based on AUC). In the rabbit study, the metformin dose was
`approximately equivalent to the maximum recommended human dose based on AUC and the
`saxagliptin dose was at least 200 times the maximum recommended human dose. In this 13-
`day study, 12 of the 30 rabbits given both saxagliptin and metformin died compared to 1 death
`in the metformin-only group and no deaths in the saxagliptin-only group. Some of the animals
`that died had sporadic low bicarbonate concentrations suggesting that lactic acidosis may have
`contributed to some of the deaths although the combination-treated rabbits did not have higher
`plasma concentrations of metformin. This higher incidence of death is unexplained but in
`further discussions with Drs. Mihalcik and Bourcier, they confirmed that clinical relevance is
`unlikely given that the finding is species-specific (not seen in rats, dogs, or humans) with high
`saxagliptin doses used in combination with metformin and the fact that there are reassuring
`clinical data from phase 3 trials that co-administered saxagliptin and metformin.
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`5. Clinical Pharmacology/Biopharmaceutics
`
`
`The clinical pharmacology reviewers have found the clinical pharmacology data to be
`unacceptable because the batch sizes of the formulation used in the two pivotal bioequivalence
`studies did not meet the biobatch size criteria of
` of the proposed commercial production
`batch or
` units, whichever is greater. Specifically, the batch sizes were
` to
`tablets when they should have been
` tablets because the commercial batch
` tablets. The clinical pharmacology reviewers communicated this
`size is
`finding to the biopharmaceutics team in the Office of New Drug Quality Assessment
`(ONDQA), which is responsible for the review of the biobatch criteria. Dr. Patrick Marroum
`provided a rationale for why the smaller batch sizes is justified in this instance and concluded
`that the sponsor does not need to repeat these pivotal clinical pharmacology studies. See the
`clinical pharmacology review by Dr. Ritesh Jain and the biopharmaceutics memorandum by
`Dr. Marroum for details.
`
`The clinical pharmacology program for the FDC product consists of two pivotal and five
`supporting clinical pharmacology studies. The phase 3 trials used metformin IR tablets and
`one supportive 4-week trial used the approved metformin XR 500 mg tablets manufactured in
`Evansville, Indiana. The proposed to-be-marketed FDC tablets will be manufactured in Mt.
`Vernon, Indiana. During the Pre-NDA meeting, the clinical pharmacology reviewers
`determined that there was no direct bridge between the FDC tablets (manufactured in Mt.
`Vernon) and the approved metformin XR 500 mg formulation (manufactured in Evansville).
`The sponsor chose to address these concerns by conducting two new pivotal bioequivalence
`studies, CV181111 and CV181112, which are summarized below. Because these two studies
`provide direct bridging for the FDC, the clinical pharmacology reviewers did not review the
`five supporting studies, which attempted to indirectly bridge the FDC to the approved
`metformin XR formulation.
`
`Pivotal study CV181111 was an open-label, randomized, crossover study in healthy volunteers
`that compared the bioequivalence of the FDC 5/500 mg tablet to co-administered saxagliptin 5
`mg and metformin XR 500 mg using a low-fat meal.
`
`Pivotal study CV181112 was an open-label, randomized, crossover study in healthy volunteers
`that compared the bioequivalence of the FDC 5/1000 mg tablet to co-administered saxagliptin
`5 mg and two tablets of metformin XR 500 mg (there is no approved metformin XR 1000 mg
`tablet) using a low-fat meal. The clinical pharmacology reviewers requested a Division of
`Scientific Investigations (DSI) inspection of the clinical and analytical portions of this trial.
`DSI did not identify major issues and concluded that the results from this study can be
`accepted for review.
`
`As shown in Figures 1 and 2, adapted from Dr. Jain’s review, the sponsor met the standard
`bioequivalence criteria for both pivotal bioequivalence studies because the 90% confidence
`intervals for the ratios of geometric least-square means for area under the time-concentration
`curve (AUC) and Cmax were contained within 0.80-1.25.
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`Study CV181111 compared the pharmacokinetics of saxagliptin and metformin when the FDC
`5/500 mg tablet was given under fed vs. fasted conditions. Based on these data, Dr. Jain has
`concluded that there is no significant food effect for the FDC (clinically, it is recommended
`that all metformin-containing products be taken with meals to reduce gastrointestinal side
`effects). Note that food-effect is usually tested with a high-fat meal. The sponsor chose to use a
`low-fat meal in this study claiming that these medications should be used as an adjunct to diet.
`However, there are many patients using anti-diabetic medications who are likely not compliant
`with diet. Nonetheless, the clinical pharmacology reviewers are not recommending that the
`sponsor repeat the study with a high-fat meal. Their rationale is that it is unlikely that FDC
`exposures with a high-fat meal will exceed those seen when saxagliptin alone and metformin
`XR alone were tested with a high-fat meal under their individual NDAs.
`
`Figure 1. Study CV181111: Ratios of geometric means for the FDC 5/500 mg tablet
`relative to the individual components together with 90% confidence intervals (from Dr.
`Jain’s review).
`
`
`
`
`Figure 2. Study CV181112: Ratios of geometric means for the FDC 5/1000 mg tablet
`relative to the individual components (metformin XR given as two 500 mg tablets)
`together with 90% confidence intervals (from Dr. Jain’s review).
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`Study CV181112 also evaluated the steady-state pharmacokinetics of saxagliptin and
`metformin after the FDC was administered for 4 days under fed conditions. There was no
`evidence of accumulation for metformin, saxagliptin and major saxagliptin metabolite BMS
`510849. The single-dose and steady-state findings with the FDC were consistent with those
`described for saxagliptin and Glucophage XR.
`
`The sponsor conducted a drug-drug interaction study between saxagliptin and metformin under
`the saxagliptin NDA. In this study, saxagliptin did not have any effect on the pharmacokinetics
`of metformin. Metformin decreased the Cmax for saxagliptin by ~20% but did not alter overall
`saxagliptin exposure (AUC). Therefore, the effect of metformin on saxagliptin
`pharmacokinetics was considered to be not clinically meaningful.
`
`Dr. Houda Mahayni in the Biopharmaceutics group reviewed the sponsor’s request for a
`biowaiver from studying the FDC 2.5/1000 mg tablet in a bioequivalence trial. She concurs
`that a biowaiver for this dose of the FDC tablet is acceptable. Dr. Mahayni also reviewed data
`from in vitro dissolution studies with the FDC 5/500 mg and 5/1000 mg tablets to assess
`whether ethanol (5-25% concentrations) could lead to dose-dumping or accelerated release of
`metformin and found no evidence for concern. Please see Dr. Mahayni’s review for details.
`6. Clinical Microbiology
`
`
`The clinical microbiology reviewers recommend approval. Please see the review by Dr. Jessica
`Cole for additional details. The drug product is a
` tablet. The
` and
`microbial testing specifications were deemed to be acceptable.
`7. Clinical/Statistical- Efficacy
`
`
`To support the FDC, the sponsor is predominantly relying on efficacy findings from the short-
`term (24-week) treatment periods of the following multi-national, randomized, controlled,
`double-blind trials that have already been reviewed for the saxagliptin NDA. Note that none of
`these three trials tested the FDC or tested saxagliptin in combination with metformin XR. In
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`addition, saxagliptin was to be administered with the morning meal in these trials except for
`one of the treatment arms in Study CV181038, which administered saxagliptin with dinner.
`
`Study CV181014: Add-on to metformin trial
`• This trial randomized patients with type 2 diabetes and inadequate glycemic control on
`stable metformin monotherapy (1,500-2,550 mg for ≥8 weeks prior to screening) to add-on
`therapy with saxagliptin 2.5 mg, 5 mg, or 10 mg vs. add-on placebo.
`
`
`Study CV181039: Initial combination with metformin trial
`• This trial randomized patients with type 2 diabetes to saxagliptin 5 mg + metformin,
`saxagliptin 10 mg + metformin, saxagliptin 10 mg + placebo, and metformin + placebo.
`• Patients were to have had minimal exposure to prior anti-diabetic therapy (≤3 consecutive
`days and <7 non-consecutive days of anti-diabetic therapy within the 8 weeks prior to
`screening, and <6 months total of prior anti-diabetic therapy).
`• The 3 treatment arms randomized to metformin started 500 mg of the immediate-release
`formulation that was blindly uptitrated through Week 5 to a maximum of 2,000 mg/day in
`divided doses based on prespecified criteria for fasting plasma or whole blood glucose.
`
`
`Study CV181038: Monotherapy trial in treatment-naïve patients
`• This monotherapy trial compared saxagliptin 2.5 mg AM (dosed prior to the morning
`meal), 5 mg AM, 5 mg PM (dosed prior to the evening meal), and 2.5 mg AM with
`possible titration to 5 mg AM (based on prespecified fasting plasma or whole blood
`glucose values at Weeks 4, 8, 12, and 24) vs. placebo.
`• The primary objective was to compare the AM treatment arms to placebo. A secondary
`objective compared the PM treatment arm to placebo. The protocol did not prespecify a
`comparison between the AM and PM dosing regimens. However, FDA statisticians
`conducted a post hoc analysis for AM vs. PM dosing as part of the original saxagliptin
`NDA review.
`• Note that Study CV181038 does not evaluate saxagliptin and metformin co-administration.
`Instead, the sponsor is submitting these data to support evening dosing of saxagliptin given
`that the proposed dosing for the FDC is with the evening meal (because of the metformin
`XR component).
`
`
`This memorandum will show only the primary efficacy data (HbA1c) for these three trials and
`summarize the evidence of efficacy to support the FDC product. Please refer to the clinical and
`statistical reviews of the original saxagliptin NDA for further details.
`
`Tables 1 and 2 show the primary efficacy results (change from baseline in HbA1c at Week 24)
`for the above 3 trials using the intent-to-treat population with the last-observation-carried-
`forward method.
`
`Using the data in Study -038, Ms. Joy Mele calculated the reduction in HbA1c with dosing
`saxagliptin 5 mg prior to breakfast compared to the reduction in HbA1c with dosing 5 mg
`prior to dinner. The treatment difference was -0.1% (favoring the breakfast dosing) with a 95%
`confidence interval of -0.3 to +0.2, showing essentially no difference between the two
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`treatment regimens. Therefore, these data provide support for evening dosing of saxagliptin in
`the FDC product.
`
`In the add-on to metformin trial, saxagliptin 2.5 mg and 5 mg resulted in a statistically
`significant mean reduction in HbA1c of 0.7-0.8% relative to placebo (p<0.001). As shown in
`the original saxagliptin NDA reviews, this efficacy compares favorably to the efficacy
`achieved in the monotherapy and other combination therapy treatment settings. As discussed
`in the original saxagliptin NDA reviews, there is no convincing evidence of additional
`lowering of HbA1c with 10 mg of saxagliptin beyond that achieved with 5 mg in the add-on to
`metformin trial or in any of the other phase 3 trials. The 5 mg dose of saxagliptin was
`marginally more effective than the 2.5 mg dose in some, but not all, phase 3 trials. Based on
`the available data, both the 2.5 and 5 mg doses were approved because it was concluded that 5
`mg may be more efficacious than 2.5 mg in some patients and both doses had favorable
`benefit-risk profiles.
`
`In the initial combination with metformin trial, the mean reduction in HbA1c when saxagliptin
`5 mg or 10 mg was initiated with metformin, was approximately 0.5% greater than the
`reduction in HbA1c with metformin alone (p<0.0001) and approximately 0.8% greater than
`the reduction with saxagliptin 10 mg alone (p<0.0001). The mean reduction from baseline in
`HbA1c with metformin alone was approximately 0.3% greater than the mean reduction with
`saxagliptin 10 mg alone (p<0.0001). Note that this trial did not include a saxagliptin 5 mg +
`placebo treatment arm, which limits the ability to directly assess the contribution of saxagliptin
`5 mg to the saxagliptin 5 mg + metformin arm.
`
`The sponsor has also submitted supportive efficacy data from a newly completed trial, Study
`CV181066. This randomized, double-blind, placebo-controlled trial enrolled patients with type
`2 diabetes and inadequate glycemic control on a stable (≥8 weeks) dose of metformin ≥1500
`mg per day. At the beginning of the 4-week run-in period, those patients on metformin IR
`were switched to the nearest equivalent dose of metformin XR while those already on
`metformin XR continued their same dose. At the end of the run-in period, patients were
`randomized to saxagliptin 5 mg or placebo as add-on therapy to metformin XR. Because the
`FDC product contains metformin XR and not metformin IR, the sponsor chose to submit data
`from this trial to support the FDC NDA. Note that the data from this trial are not pivotal
`because the trial had only a 4-week treatment period, used a non-traditional primary efficacy
`endpoint of 24-hour mean-weighted blood glucose, and randomized only 46 patients to the
`saxagliptin arm and only 47 patients to the placebo arm.
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`
`Table 1. HbA1c (%) results for the monotherapy and add-on to metformin trials used to support the
`fixed-dose combination product (intent-to-treat population with last-observation-carried-forward)
`Difference in adjusted
`Change from
`Baseline
`mean change
`baseline
`mean ± SE
`(95% CI)
`Adj. mean ± SE
`
`p-value
`
`-0.7±0.1
`-0.6±0.1
`-0.7±0.1
`-0.6±0.1
`-0.3±0.1
`
`-0.6±0.1
`-0.7±0.1
`-0.6±0.1
`+0.1±0.1
`
`-0.5 (-0.7, -0.2)
`-0.4 (-0.7, -0.1)
`-0.4 (-0.7, -0.1)
`-0.4 (-0.6, -0.1)
`
`
`-0.7 (-0.9, -0.5)
`-0.8 (-1.0, -0.6)
`-0.7 (-0.9, -0.5)
`
`
`<0.01
`0.01
`<0.01
`0.02
`
`
`<0.001
`<0.001
`<0.001
`
`
`Study
`
`N
`
`Study CV181038 (monotherapy)
`8.0±0.1
`Saxa 2.5 mg (AM)
`67
`8.0±0.1
`Saxa 2.5 mg→5 mg (AM)
`69
`7.9±0.1
`Saxa 5 mg (AM)
`69
`7.9±0.1
`Saxa 5 mg (PM)
`70
`7.8±0.1
`Placebo
`68
`Study CV181014 (add-on to metformin)
`Saxa 2.5 mg
`186
`8.1±0.1
`Saxa 5 mg
`186
`8.1±0.1
`Saxa 10 mg
`180
`8.0±0.1
`Placebo
`175
`8.1±0.1
`SE=standard error; CI=confidence interval
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`Table 2. HbA1c (%) results for the initial combination with metformin trial (Study CV181039) used to support the fixed-dose
`combination product (intent-to-treat population with last-observation-carried-forward)
`Baseline
`Change from baseline
`Vs. Metformin
`Vs. Saxagliptin 10 mg
`N
`Study
`mean ± SE
`LS mean ± SE
`LS mean (95% CI); p-value
`LS mean (95% CI); p-value
`306
`9.4±0.1
`-2.5±0.1
`-0.5 (-0.7, -0.3); <0.0001
`-0.8 (-1.0, -0.6); <0.0001
`Saxa 5 mg + met
`315
`9.5±0.1
`-2.5±0.1
`-0.5 (-0.7, -0.3); <0.0001
`-0.8 (-1.0, -0.6); <0.0001
`Saxa 10 mg + met
`317
`9.6±0.1
`-1.7±0.1
`+0.3 (0.2, 0.5); <0.0001
`-
`Saxa 10 mg
`313
`9.4±0.1
`-2.0±0.1
`-
`-
`Metformin
`SE=standard error; CI=confidence interval
`
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`Cross Discipline Team Leader Review
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`8. Safety
`
`
`The sponsor has not conducted clinical trials with the FDC. Most of the safety data are derived
`from clinical trials in which saxagliptin is either given as add-on therapy in patients with
`inadequate glycemic control on metformin IR or co-administered with metformin IR as initial
`therapy in treatment-naïve patients. This section of the memorandum will summarize key
`findings from these supportive trials. Please refer to Dr. Arlet Nedeltcheva’s clinical review
`for additional details.
`
`Study CV181066: This is a 4-week, randomized, double-blind, placebo-controlled trial in
`patients with inadequate glycemic control on metformin. A total of 93 patients were
`randomized to saxagliptin or placebo, both dosed with dinner together with metformin XR.
`The sponsor submitted this completed trial to support evening dosing of the FDC. There were
`no saxagliptin-treated patients who died, reported serious adverse events (SAEs), withdrew
`due to adverse events, reported hypoglycemia (defined as a fingerstick glucose ≤50 mg/dL in
`the presence of symptoms), had lymphopenia, or had serum alanine aminotransferase (ALT)
`>3x ULN. Diarrhea was reported in two patients (4.3%) in both treatment groups. This trial’s
`small sample sizes and short treatment duration limit conclusions.
`
`Study CV181038: This randomized, double-blind, placebo-controlled monotherapy trial in
`treatment-naïve patients had 5 treatment arms – placebo, saxagliptin 5 mg in the evening,
`saxagliptin 2.5 mg in the morning, saxagliptin 5 mg in the morning, and saxagliptin 2.5 mg in
`the morning with possible titration to 5 mg. At the beginning of the long-term period (which
`remained blinded), placebo-treated patients started blinded metformin 500 mg. In the
`saxagliptin arms there was blinded uptitration to 10 mg during the long-term period based on
`pre-specified glycemic rescue criteria with ~80% of patients in the 5 mg QAM arm and 74%
`of patients in the 5 mg QPM arm undergoing uptitration. Note that sample sizes are relatively
`small, which limits conclusions. Approximately 75 patients were randomized per treatment
`arm into the short-term period with ~60-65 patients per treatment arm entering the long-term
`period and ~40-50 patients per treatment arm completing the long-term extension.
`
`The complete study report for the short-term (24-week) treatment period and an interim report
`for the long-term treatment period were submitted and reviewed for the saxagliptin NDA. The
`120-day safety update for the FDC contains the data from the completed long-term period.
`Here I will focus on new safety data for the long-term period available since the interim
`analysis conducted for the saxagliptin NDA.
`
`Deaths: Since the interim analysis, there has been one death in a saxagliptin-treated patient
`attributed to metastatic pancreatic cancer. Dr. Nedeltcheva notes that this patient had received
`saxagliptin for only 13 days at the time of diagnosis, which essentially excludes any
`relationship to treatment.
`
`Serious adverse events: In the completed short-term plus long-term period, there were 26
`reported SAEs (8.9%) in the combined saxagliptin group (n=291) and 5 reported SAEs (6.8%)
`in the control group (n=74). Review of the new SAEs occurring since the saxagliptin NDA
`
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`Cross Discipline Team Leader Review
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`interim analysis does not raise new safety concerns for saxagliptin regardless of dosing in the
`morning or afternoon. One saxagliptin-treated patient developed serum ALT of 403 U/L (8.4x
`ULN) with total bilirubin of 2.4 mg/dL on Day 345, thereby meeting the biochemical
`definition for Hy’s Law. However, he had a probable alternate etiology for these abnormalities
`because he was hospitalized for acute calculous cholecystitis on Day 351 and underwent
`uncomplicated cholecystectomy on Day 357. Study medication was temporarily discontinued
`on Day 351 and restarted on Day 361. His liver tests were normal on Day 435.
`
`Discontinuations due to adverse events: In the completed short-term plus long-term period,
`twelve saxagliptin-treated patients (4.1%) and 3 control patients (4.1%) discontinued due to
`adverse events. There were only two saxagliptin-treated patients who discontinued after the
`interim analysis for the saxagliptin NDA – one patient with onychomycosis and one patient
`with elevated serum ALT. The patient with increased ALT had a baseline serum ALT of 59
`U/L that increased to 67 U/L on Day 89 and 150 U/L on Day 208. Study medication was
`discontinued on Day 369 when the ALT was 144 U/L. Total bilirubin was consistently normal;
`therefore, the patient did not meet criteria for Hy’s Law. An abdominal ultrasound on Day 257
`showed fatty liver.
`
`Hypoglycemia: In the completed short-term plus long-term period, confirmed fingerstick blood
`glucose ≤50 mg/dL in the presence of symptoms occurred in two saxagliptin-treated patients -
`one receiving 5 mg in the morning (1.4%) and the other receiving 5 mg in the evening (1.4%).
`Both events were mild and self-treated. There was also one event in a control-treated patient
`(1.4%).
`
`Liver: There were three patients in the combined short-term plus long-term period with serum
`ALT >5x ULN – one patient in the saxagliptin 5 mg QAM arm (1.4%), one patient in the 2.5/5
`mg QAM arm, and one patient in the control group (1.4%). One of these saxagliptin-treated
`patients is discussed under the Serious Adverse Events section. The other saxagliptin-treated
`patient had a normal serum ALT at baseline and on Day 362 but developed an ALT of 209
`U/L (5.6x ULN) - with normal total bilirubin - on Day 455. On Day 470, the ALT had
`normalized but the total bilirubin was now elevated at 2.5 mg/dL. The investigator reported an
`event of “calculous cholecystitis non active” on Day 473. All liver tests had normalized on
`Day 490 despite continuing study medication.
`
`Pancreatitis: In the combined short-term plus long-term period there were no reports of
`pancreatitis.
`
`Lymphopenia: Since the interim analysis for the saxagliptin NDA, there were no new reports
`of lymphopenia. During the short-term plus long-term period combined, the saxagliptin 5 mg
`QAM arm