CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
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`209091Orig1s000
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`SUMMARY REVIEW
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`Division Director Review
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`Summary Review for Regulatory Action
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`
`Stamp Date
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`Jean-Marc Guettier, MDCM
`
`Subject
`Division Director Summary Review
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`NDA/BLA #
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`NDA 209091
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`NDA 022350/Supplement 18
`Supplement #
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`NDA 200678/Supplement 18
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`AstraZeneca Pharmaceuticals LP
`Applicant Name
`
`Date of Submission
`April 27, 2016
`
`PDUFA Goal Date
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`Proprietary Name /
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`Established (USAN) Name
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`February 27, 2017
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`QTERN (dapagliflozin and saxagliptin)
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`Dosage Forms / Strength
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`Tablets, for oral use / 10 mg dapagliflozin and 5 mg
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`saxagliptin
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`Proposed lndication(s)
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`As an adjunct to diet and exercise to improve glycemic
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`control in adults with type 2 diabetes mellitus (TZDM)
`(mo
`
`
`
`Approved lndication(s)
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`As an adjunct to diet and exercise to improve glycemic
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`control in adults with type 2 diabetes mellitus (TZDM)
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`who have inadequate control with dapagliflozin or
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`who are already treated with dapagliflozin and
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`Action/Recommended Action for Approval
`NME:
`
`saxagliptin
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`1. Introduction
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`Astra Zeneca |nc., submitted a new drug application pursuant to Section 505(b)(1) of the
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`Food Drug and Cosmetic Act for QTERN. QTERN is a fixed combination drug product
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`combining two approved oral antidiabetic drugs used for the treatment of adults with type 2
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`diabetes mellitus; Dapagliflozin approved on 08 January 2014 (NDA# 202293) and Saxagliptin
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`approved on 31 July 2009 (NDA# 22350).
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`The proposed adult indication is; ”as an adjunct to diet and exercise to improve glycemic
`control in adults with type 2 diabetes mellitus (TZDM)
`M"
`II
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`Page 1 of 5
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`Reference ID: 40621 20
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`Division Director Review
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`2. Background
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`Drs. Chong and Pucino have summarized the regulatory background for the application. See
`these reviews for full details. QTERN has been previously reviewed under NDA
` The
`application received a complete response letter on 15 October 2015
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`
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`An end of review meeting was held on 17 December 2015 to review deficiencies listed in the
`complete response letter and discuss possible paths forward. The Division agreed that new
`data from an ongoing pivotal study (CV181168) along with supportive data could be used
`establish the safety and effectiveness of a dapagliflozin 10 mg/saxagliptin 5 mg strength
`
`
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`3. CMC/Device
`
`No CMC deficiencies to preclude approval were identified. CMC data were previously
`reviewed. For a detailed discussion of CMC findings refer to primary reviews by Drs.
`Amartey, Peng, Duan and Dholakia filed for NDA
` Refer to Dr. Chong’s memorandum
`for a summary of the issues.
`
`4. Nonclinical Pharmacology/Toxicology
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`Refer to reviews by Drs. Alavi and Quinn. No nonclinical pharmacology/toxicology
`deficiencies to preclude approval were identified.
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`5. Clinical Pharmacology/Biopharmaceutics
`
`No nonclinical pharmacology/toxicology deficiencies to preclude approval were identified.
`The clinical pharmacology/biopharmaceutics data were reviewed by Drs. Lau and Deng and
`summarized in Dr. Chong’s memorandum, see these reviews for details.
`
`6. Clinical/Statistical-Efficacy
`
`Efficacy was reviewed by Drs. Kettermann and Pucino and summarized in Dr. Chong’s CDTL
`memorandum. A single trial is used to inform the new indication (study CV181168). Two
`other studies provide information on dapagliflozin/saxaglitpin combination use when the
`maximum strength of each component is used (studies MB102129 and CV181169
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`Page 2 of 5
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`Reference ID: 4062120
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`Division Director Review
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`efficacy and safety data.
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` the studies provide supportive
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`Study CV181168 was a 24-week, randomized, double-blind, placebo-controlled, parallel-
`group, multi-center, multi-national study.
`In the trial, 315 adult subjects with type 2
`diabetes, inadequately controlled (HbA1c > 7%) on maximally effective doses of metformin
`(>1500 mg per day) and dapagliflozin (i.e., 10 mg per day) were randomized 1:1 to 5 mg of
`saxagliptin (N=153) or placebo (N=162). The primary objective of the trial was to compare
`the change in HbA1c from baseline to Week 24 between subjects randomized to saxagliptin
`and subjects randomized to placebo. Dr. Kettermann noted that 6.5% (n=10) of subjects
`randomized to saxagliptin and 3.1% (n=5) randomized to placebo arm did not have HbA1c
`data at week 24.
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`At the end of 24 weeks, subjects randomized to saxagliptin were observed to have greater
`reduction in HbA1c compared to patients randomized to placebo. Drs. Chong and
`Kettermann reviewed the validity of the clinical and statistical assumptions made in the
`analytical methods used by the applicant to handle missing 24 week data. The conclusion of
`superiority was not sensitive to varying the assumptions made in the handling missing HbA1c
`data. Secondary analyses examining HbA1c responders and other glucose lowering
`endpoints (e.g., fasting plasma glucose) were directionally consistent with mean HbA1c
`results (i.e., greater improvement in subjects randomized to saxagliptin). Examination of
`HbA1c effects based on subgroups defined by age, sex, race and geographical regions were
`qualitatively similar. The result of the primary analysis based on Dr. Kettermann’ s multiple
`imputation model using all available 24 week HbA1c data is shown below.
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`Table 1: Change in HbA1c from Baseline to Week 24 observed in Study CV181168
`Number
`Baseline
`Mean (SD)
`Adjusted1
`of subjects
`HbA1c
`Change from
`Mean
`Mean (SD)
`Baseline
`Difference
`
`7.9 (0.9)
`-0.5 (0.8)
`---
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`-0.2 (0.8)
`8.0 (0.8)
`-0.4
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`Trial/
`Treatment Group
`Placebo
`Saxagliptin
`
`162
`153
`
`95% CI
`
`---
`(-0.5, -0.2)
`
`P-value
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`---
`<0.0001
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`7. Safety
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`The safety findings for combination use have been previously reviewed under NDA 202293.
`Dr. Pucino has reviewed the safety data in this submission in detail and Dr. Chong has
`summarized the salient safety findings. In the previous NDA, a potential signal for muscle
`related injury with combination use was identified from the examination of creatine kinase
`outlier data. In the Complete Response Letter, the applicant was asked to provide updated
`
`1 Analysis of Covariance model with treatment and baseline HbA1c as covariates and all post-baseline data
`regardless of rescue or treatment discontinuation. Model estimates calculated using multiple imputations to
`model washout of the treatment effect using placebo data for all subjects having missing week 24 data.
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`Page 3 of 5
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`Reference ID: 4062120
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`(b) (4)
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`Division Director Review
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`clinical trial data
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`Safety information on an additional ~ 100 patient-year of exposure is available from the
`updated dapagliflozin/saxagliptin combination use pooled clinical trial dataset. No additional
`cases of elevated creatine kinase were identified with the additional exposure. Dr. Pucino
`provides narrative and graphical summaries for the previously reviewed cases of
`rhabdomyolysis and markedly elevated CK in the integrated clinical trial dataset (refer to
`Appendix 13.7 of his review). The majority of cases were confounded by the presence of
`acute co-morbid conditions around the time of the event, antecedent CK abnormalities, and
`concomitant medications (i.e., statins). Cases resolved despite continued use of dapagliflozin
`and saxagliptin and otherwise lacked a clear temporal association with combination
`treatment onset. These data do not support the existence of a clear causal relationship
`between combination use and muscle injury. Dr. Pucino also compared occurrence of
`incident musculoskeletal adverse events across the pooled safety dataset
`informing
`combination use. This analysis was unrevealing. Finally, a search of FDA’s adverse Event
`Reporting System database for events of rhabdomyolysis associated with saxagliptin and
`dapagliflozin use was conducted. Eleven cases were identified but were often insufficiently
`detailed to fully evaluate the event or the presence of an association with one or more drug
`(refer to Appendix 13.8 in Dr. Pucino’s review for details). The data and re-analysis do not
`neither support the presence of a strong association between muscle related injury and
`combination treatment nor completely exclude it. The review team recommends labeling the
`observed CK imbalance in Section 6 of the full prescribing information. I concur with this
`plan.
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`8. Advisory Committee Meeting
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`No efficacy or safety issues requiring the input from an advisory panel was needed for this
`application. Therefore no advisory committee was convened.
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`9. Pediatrics
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`Refer to Dr. Chong’s memorandum for details.
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`10.
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`Other Relevant Regulatory Issues
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`No other relevant regulatory issues were identified.
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`11.
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`Labeling
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`Dr. Chong has summarized labeling discussions. The data in the application support the
`following indication; “As an adjunct to diet and exercise to improve glycemic control in adults
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`Page 4 of 5
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`Reference ID: 4062120
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`(b) (4)
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`Division Director Review
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`with type 2 diabetes mellitus (T2DM) who have inadequate control with dapagliflozin or who
`are already treated with dapagliflozin and saxagliptin”
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`12.
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`Decision/Action/Risk Benefit Assessment
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` Regulatory Action
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`I recommend approval.
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` Risk Benefit Assessment
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`I agree with all review disciplines and Dr. William Chong, cross-discipline team leader for the
`application, who recommends approval. The applicant has shown that adding saxagliptin to
`dapagliflozin and metformin improves glucose control at Week 24 in adult subjects with type
`2 diabetes inadequately controlled on these agents at baseline. Inadequate glycemic control
`over years results in microvascular complications in some patients which can lead to loss of
`vision and loss of nerve and kidney function. Landmark trials in type 1 and type 2 diabetes
`have shown that reduction in ambient glucose levels over years reduces the risk of
`microvascular disease complications. In the current regulatory paradigm, HbA1c reduction
`over six months is accepted as a substitute for reduction in microvascular disease risk.
`
`In the safety evaluation for this application, adverse drug related risks associated with
`combination use were found to be additive and not synergistic and were expected based on
`the known side effect profiles of individual components. In the study, the risks of adding
`saxagliptin to a regimen of metformin and dapagliflozin in patients whose glucose was not
`adequately controlled were not found to outweigh the benefits attributed to glucose
`lowering. Risks that were
`identified can be monitored, are reversible with drug
`discontinuation and can be adequately mitigated through labeling.
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` Recommendation for Postmarketing Risk Evaluation and Mitigation Strategies
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`None are recommended at this time.
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` Recommendation for other Postmarketing Requirements and Commitments
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`None are recommended at this time.
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`Page 5 of 5
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`Reference ID: 4062120
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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
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`JEAN-MARC P GUETTIER
`02/27/2017
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`Reference ID: 4062120
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