ESR-15-11293 - Saxa/Dapa, Safety and Efficacy Study

The study is intended to demonstrate complimentary action of saxagliptin/dapagliflozin added
to metformin versus dapagliflozin added to metformin with regard to EGP.

Many medications are approved for the treatment of T2DM; however, the challenge of achieving
and maintaining treatment goals within the current sequential therapy approach is linked to
shortcomings of older classes of drugs. Metformin is in the biguanide drug class that acts to
decrease hepatic glucose output and subsequently, decreases fasting hyperglycemia. Metformin,
the oral first-line gold standard agent, is recommended as the initial pharmacological
therapy because of its glycemic efficacy, weight neutrality, low risk of hypoglycemia, and
beneficial cardiovascular (CV) profile. Current sequential add-on second and third line oral
therapy includes oral drugs such as sulfonylureas (SUs) and thiazolidinediones (TZDs). These
therapies and insulin are associated with increased risks for weight gain and hypoglycemia;
therefore, caution is recommended when using combination therapy with other agents known to
cause hypoglycemia. Hypoglycemia is a clinically important issue in optimizing treatment and
there is emerging evidence that hypoglycemia is associated with negative CV outcomes. Efforts
by patients to lose weight as part of a therapeutic lifestyle program are undermined by
therapies that lead to weight gain. The majority of patients with T2DM are overweight or
obese, and additional weight gain often results in reduced treatment efficacy.

Over the past few years, it has been widely recognized that the management approach for each
T2DM patients' needs to be personalized based on his or her clinical characteristics (e.g.,
the likelihood of weight gain, risk for hypoglycemia, and lifestyle preferences [e.g., many
patients may be reluctant to use injections]) (Inzucchi et al 2012). Based on data from the
National Health and Nutrition Examination Survey in 2007 to 2010, HbA1c is not appropriately
controlled in approximately one-third of patients using even less stringent targets (Ali et
al 2013).

Because of the challenge to achieve glycemic control in patients with T2DM, the progressive
nature of the disease, and the limitations of available oral and non-oral therapies, there is
a significant medical need for oral combination treatment options and dual add-on therapy in
patients with high baseline HbA1c. Expert groups have increasingly suggested making use of
combination therapy early after diagnosis to improve glycemic control (Inzucchi et al 2012,
Rodbard et al 2009). In a recent study, initiating triple therapy (pathophysiological-based
approach) in patients with new onset T2DM versus metformin followed by sequential addition of
SUs and basal insulin (treat-to-fail approach) demonstrated a more durable HbA1c reduction
over 24 months and less hypoglycemia with initial triple therapy (Abdul-Ghani et al 2014).
Initial combination therapy with saxagliptin and dapagliflozin added to metformin may have
similar potential for durable glucose lowering in combination with low risk of hypoglycemia.

Treatment with saxagliptin and dapagliflozin, both individually and in combination with
metformin, have demonstrated a favorable safety and tolerability profile. These drugs had a
low propensity for hypoglycemia, therefore addressing a potential key concern when adding 2
glucose lowering agents simultaneously. These drugs have demonstrated weight neutrality
(saxagliptin) or moderate weight reduction (dapagliflozin). Dapagliflozin has also been shown
to cause a persistent reduction in HbA1c and weight after 2 years of therapy. Dapagliflozin
was recently shown to increase EGP, which, in part, may be mediated by increased plasma
glucagon (Merovci et al). In contrast, saxagliptin has been demonstrated to reduce glucagon
levels, e.g., in response to a meal (Sjöstrand et al 2014) and vildagliptin, also a DPP-4
inhibitor, has been shown to inhibit EGP (Balas et al 2007).

A second-line oral dual add-on therapy with saxagliptin co-administered with dapagliflozin
could be a new option, as part of a triple therapy combination that includes drugs with
complementary mechanisms of action, opposing effects on plasma glucagon concentration, and
possibly EGP, low risk of hypoglycemia, and the potential for moderate weight loss, providing
a more effective and patient-friendly approach to the treatment of T2DM.

Inclusion Criteria:

1. Provision of informed consent prior to any study-specific procedures.

2. Is able to read, understand, and sign the Informed Consent Forms (ICFs) and, if
applicable, an Authorization to Use and Disclose Protected Health Information form
(consistent with Health Insurance Portability and Accountability Act of 1996
legislation), communicate with the Investigator, and understand and comply with
protocol requirements, including the use of diary and glucose meter measurements.

3. Age = 18-70 years.

4. Has a diagnosis of T2DM.

5. Has HbA1c ≥7.5% and ≤11.0% obtained at Screening.

6. Treated with a stable dose of metformin ≥1000 mg/day or stable dose of metformin (≥
1000 mg/day) plus sulfonylurea (glipizide, ≥ 5 mg/day; glyburide, ≥ 5 mg/day;
glimepiride, ≥ 4 mg/day) for at least 8 weeks prior to Screening.

7. Has a BMI of 20 to 45 kg/m2 (inclusive) at Screening.

8. Is male, or is female, and meets all the following criteria:

- Not pregnant or breastfeeding.

- Negative pregnancy test result at Visit 1 (Screening).

- Women of childbearing potential (WOCBP; [including perimenopausal women who have
had a menstrual period within 1 year]) must practice and be willing to continue
to practice appropriate birth control (defined as a method that results in a low
failure rate, i.e., less than 1% per year, when used consistently and correctly,
such as implants, injectables, hormonal contraceptives [pills, vaginal rings, or
patches], some intrauterine contraceptive devices [levonorgestrel-releasing or
copper-T], tubal ligation or occlusion, or a vasectomized partner) during the
entire duration of the study. As applicable, all methods must be in effect prior
to receiving the first dose of study medication.

Exclusion Criteria:

Target Disease Exceptions

1. Clinically diagnosed with Type I diabetes .

2. History of diabetic ketoacidosis, hyperosmolar nonketotic coma, or corticosteroid
induced Type 2 diabetes.

Medical History and Concurrent Diseases

3. History of bariatric surgery or lap-band surgery, or either procedure is planned
during the time period of the study.

4. History of any unstable endocrine, psychiatric, rapidly progressing, or unstable renal
disease, or rheumatic disorder, as judged by the Investigator.

5. Patients who, in the judgment of the Investigator, may be at risk for dehydration or
volume depletion that may affect the patient's safety and/or the interpretation of
efficacy or safety data.

6. Has evidence of current abuse of drugs or alcohol or a history of abuse within the
past 52 weeks that, in the Investigator's opinion, would cause the individual to be
noncompliant.

Cardiovascular Conditions

7. Cardiovascular disease within 3 months of Screening (i.e., MI, cardiac surgery,
revascularization, unstable angina, stroke, transient ischemic attack, or arrhythmia).

8. Presence or history of severe congestive heart failure (New York Heart Association
Class III and IV [CCNYHA 1994]), unstable or acute congestive heart failure, and/or
known left ventricular ejection fraction of ≤40%.

Note: Eligible patients with congestive heart failure, especially those who are on
diuretic therapy, should have careful monitoring of their volume status throughout the
study.

Kidney Conditions

9. Estimated (eGFR) <60±5 mL/min/1.73 m2 or a measured serum creatinine of >1.4 mg/dL for
female patients and >1.5 mg/dL for male patients. If the serum creatinine is ≤ 1.4
(female) or ≤ 1.5 (male) and the eGFR is ≥ 60±5 ml/min/1.73m2, the subject is eligible
to participate in the study.

10. Congenital renal glucosuria. Hepatic Conditions

11. Significant hepatic disease, including, but not limited to, severe hepatic
insufficiency and/or significant abnormal liver function defined as aspartate
aminotransferase (AST) and/or alanine aminotransferase (ALT) of >3x upper limit of
normal (ULN).

12. Serum total bilirubin (TB) >2 mg/dL.

13. History of, or currently have, acute or chronic pancreatitis or have triglyceride
concentrations ≥500 mg/dL at Visit 1 (Screening).

14. Suspicion that the patient is infected with an infectious substance according to World
Health Organization risk categories A and B (see Appendix C).

15. Known severe hepatic disease, including chronic active hepatitis.

16. Positive serologic evidence of current infectious liver disease, including patients
positive for hepatitis B viral antibody IgM, hepatitis B surface antigen, and
hepatitis C virus antibody.

Hematological/Oncological Conditions

17. Malignancy within 5 years of Visit 1 (Screening), with the exception of treated in
situ basal cell or squamous cell carcinoma of the skin.

18. Hematocrit of <34% for both males and females. Prohibited Medications

19. Administration of any antihyperglycemic therapy, other than metformin or
metformin/sulfonylurea, for more than 14 days (consecutive or not) during the 12 weeks
prior to Visit 1 (Screening) and during the study unless per protocol for rescue.

20. Current treatment with potent cytochrome P450 3A4/5 inhibitors (e.g., atazanavir,
clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir,
saquinavir, and telithromycin).

21. Administration of any other investigational drug or participation in any
interventional clinical studies 30 days prior to Visit 1 (Screening).

22. Treatment with systemic corticosteroids for the last 3 months prior to Visit 1
(Screening).

23. Prescription or over-the-counter weight loss medications within 3 months prior to
Visit 1 (Screening).

Other

24. Patients with abnormal thyroid stimulating hormone (TSH) or free thyroxine (T4) values
at Visit 1 (Screening) will be excluded.

25. Has a clinically significant medical condition that could potentially affect study
participation and/or personal well-being, as judged by the Investigator.

26. Has clinically significant abnormal laboratory test values (clinical chemistry,
hematology, and urinalysis) as judged by the Investigator at Visit 1 (Screening).

27. Has known contraindications, allergies, or hypersensitivities to any study medication
or excipient as outlined in the IBs or local package inserts for saxagliptin and
dapagliflozin.

28. Has a contraindication to metformin use, including known metabolic or lactic acidosis,
or any condition associated with hypoperfusion, hypoxemia, dehydration, or sepsis.

29. Is currently pregnant (confirmed with positive pregnancy test) or breast feeding.

30. Is on a commercial weight loss program with ongoing weight loss more than 5% over the
last 3 months prior to Visit 1 (Screening), or is on an intensive exercise program.

31. Involvement in the planning and/or conduct of the study (applies to both the study
sponsor staff and/or staff at the study site).

32. Patient with any condition that, in the judgment of the Investigator, may render the
patient unable to complete the study or which may pose a significant risk to the
patient or patient suspected or with confirmed poor protocol or medication compliance.

33. Previous randomization in the present study.