A Dose Range Finding Study to Evaluate the Effect of Bexagliflozin Tablets in Subjects With Type 2 Diabetes Mellitus

THR-1442-C-449 is a phase 2b multicenter, double-blind, placebo-controlled, dose range
finding study to assess the efficacy and safety of once daily bexagliflozin in either
treatment- naïve type 2 diabetic subjects or subjects previously treated with one oral
hypoglycemic agent (OHA). The primary efficacy endpoint will be placebo-adjusted reduction
in HbA1c, measured after 12 weeks of treatment. Treatment naïve subjects are those who have
never received prescription anti-diabetic medications or who have received no more than 14
days of prescription medications for diabetes in the 12 weeks prior to enrollment. The study
will enroll men and women with type 2 diabetes mellitus (T2DM) and with HbA1c between 7% and
8.5% (inclusive) at the screening visit (for subjects who are treatment naïve) or with T2DM
and with HbA1c between 6.5% and 8.5% (inclusive) at screening visit (for subjects who have
received one OHA and who are willing and able to undergo a washout period.) Approximately
400 subjects who meet all the inclusion criteria, none of the exclusion criteria, and who
consent to participate in the study are eligible to be enrolled to complete a 6 to 10 week
washout if needed and a 2 week run-in period prior to being randomized. Subjects who can
adhere to the run-in medication dosing schedule (i.e., miss no more than one dosage in 2
weeks) and who have HbA1c between 7 and 8.5% at baseline (visit S5) will be eligible for
randomization and receive investigational product. A 20% screen fail rate is expected by the
end of run-in, leading to approximately 320 subjects eligible for randomization to receive
oral bexagliflozin tablets, 5, 10, 20 mg or placebo once daily for 12 weeks in an outpatient
setting. Subjects who experience hyperglycemia during the study may receive approved
anti-diabetic medication. Subjects will visit their study site at weeks 2, 6, and 12 for
safety and efficacy evaluation, with a follow up visit at week 14.

Measurement of bexagliflozin plasma concentration over time (sparsely sampled) will be
conducted at 20 centers and will include approximately 240 subjects who consent to
participate the pharmacokinetics (PK) study. Three samples from each subject will be drawn
at weeks 2, 6, or 12.

Inclusion Criteria:

1. Men or women ≥ 20 years of age at screening. Women of childbearing potential must
test negative by urine pregnancy test.

2. Treatment naïve or currently taking one oral anti-diabetic medication in combination
with diet and exercise

3. Diagnosed with T2DM with HbA1c levels at screening between 7.0% and 8.5% (inclusive)
if treatment naïve or with HbA1c levels between 6.5 and 8.5% (inclusive) if on one
oral anti-diabetic medication

4. Currently having a body mass index (BMI) ≤ 40 kg/m2

5. Taking stable doses of medication for hypertension or hyperlipidemia that has not
changed for at least 30 days prior to screening (if applicable)

6. Able to comprehend the study participation requirements and willing to provide
written informed consent in accordance with institutional and regulatory guidelines

7. Able to maintain adequate glycemic control at the run-in visit (for subjects who
complete the washout)

8. Having an HbA1c between 7.0 and 8.5% (inclusive) prior to randomization (day -3 to
-5)

9. Capable of adhering to the investigational product administration requirements as
evidenced by omission of no more than one dose of run-in medication

Exclusion Criteria:

1. A diagnosis of type 1 diabetes mellitus or maturity-onset diabetes of the young

2. Current use of parenteral therapy for treatment of diabetes

3. Pregnancy or current breastfeeding status

4. Hemoglobinopathy or carrier status for hemoglobin alleles that affect HbA1c
measurement

5. Genitourinary tract infection within 6 weeks of screening or history of ≥3
genitourinary infections requiring treatment within 6 months of screening

6. Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 at screening.

7. Uncontrolled hypertension at screening

8. A positive result on hepatitis B surface antigen, hepatitis C, or positive result
from screen for drugs of abuse

9. History of human immunodeficiency virus infection

10. Life expectancy < 2 years

11. History of New York Heart Association Class 4 heart failure within 3 months of
screening

12. History of myocardial infarction, unstable angina, stroke, or hospitalization for
heart failure within 3 months of screening

13. History of treatment with an investigational drug within 30 days or within 7 half
lives of the investigational drug, whichever is longer

14. Previous treatment with bexagliflozin or study drug EGT0001474

15. Currently or within 6 months of taking any Sodium Glucose Transporter 2 (SGLT2)
inhibitors from screening

16. Currently participating in another interventional trial

17. Not able to comply with the study scheduled visits

18. Affected by any condition, disease, disorder, or clinically relevant abnormality
that, in the opinion of the investigator, would jeopardize the subject's appropriate
participation in this study.

19. Liver function tests resulting in Alanine transaminase (ALT) or aspartate
transaminase (AST) ≥ 2.5 x upper limit of normal (ULN) or total bilirubin ≥ 1.5 x
ULN, with the exception of isolated Gilbert's syndrome ,at screening

20. Exhibiting fasting plasma glucose ≥ 250 mg/dL (13.9 mmol/L) on two or more
consecutive days prior to randomization or exhibiting severe clinical signs or
symptoms of hyperglycemia during the washout or run-in periods, including weight
loss, blurred vision, increased thirst, or increased urination, or fatigue

21. Fasting Plasma Glucose ≥ 250 mg/dL at randomization

22. Prior renal transplantation or evidence of nephrotic syndrome, defined as a urine
albumin-to-creatinine ratio (UACR) > 2000 mg/g at screening