An Add-on Study of MLR-1023 in Adults With Uncontrolled Type 2 Diabetes on Metformin Therapy

Medical management of T2DM involves diet, exercise, weight management, and pharmacotherapy.
Pharmacological agents, such as metformin, α-glucosidase inhibitors, orlistat, and
thiazolidinediones, have been shown to decrease incident diabetes. Metformin has the
strongest evidence base and demonstrated long-term safety as pharmacological therapy for
diabetes treatment. The American Diabetes association position statement on diabetes care
recommends that if Hemoglobin A1C (HbA1C) targets are not achieved after approximately 3
months of metformin anti-diabetic monotherapy, a combination of metformin and one of several
oral treatment options should be considered.

In this study, subjects with a diagnosis of T2DM who are not adequately controlled (HbA1C
between 7.0% and 10.0%, inclusive) and started metformin therapy at least 3 months prior to
Screening will be recruited into the study. Subjects will continue taking metformin for the
duration of the study and once daily oral MLR 1023 or placebo will be added to metformin.

The efficacious dose-level range of MLR 1023 in diabetic subjects is anticipated to be
between 25 and 100 mg. Therefore, the efficacy, safety, and tolerability of 25 mg and 50 mg
doses in addition to the 100 mg dose that was shown to be effective in the Phase 2a proof of
concept study will be assessed.

Inclusion Criteria:

1. Male or female, age 18 to 75 years, inclusive.

2. Diagnosis of T2DM.

3. Body mass index (BMI) between 20 and 40 kg/m2.

4. HbA1C between 7.0% and 10.0%.

5. Treated with metformin as the only anti-diabetic therapy.

6. Metformin dosage must have been stable and unchanged for at least 3 months prior to
Screening and at a dose of at least 1,500 mg/day or the maximum tolerated dose if less
than 1,500 mg/day.

7. Able and willing to comply with the study protocol for the duration of the study
including scheduled clinic appointments.

8. Able and willing to provide written informed consent for study participation prior to
performance of any study-related assessments.

Exclusion Criteria:

1. Subject has signs of or is diagnosed with Type 1 diabetes mellitus or latent
autoimmune diabetes in adults.

2. History of hospitalizations or emergency room visits that would impact subject safety
or data interpretation, including:

- Poor glucose control in the 6 months prior to Screening (per investigator
discretion) or

- Any bariatric surgical procedures for weight loss.

3. History of significant change of body weight (> 10%) in the 3 months prior to
Screening.

4. History of or active proliferative retinopathy or maculopathy within the 6 months
before Screening or requiring acute treatment, or severe neuropathy.

5. History of previous gastrointestinal bleeding or ulceration within 3 months prior to
Screening.

6. History of acute or chronic pancreatitis.

7. History of significant cardiovascular events defined as:

- Myocardial infarction, coronary angioplasty or bypass grafts, valvular disease or
repair, unstable angina pectoris, transient ischemic attack, or cerebrovascular
accidents within 6 months prior to Screening.

- Congestive heart failure defined as New York Heart Association (NYHA) Stages III
and IV.

- Uncontrolled hypertension defined as a systolic blood pressure > 160 mmHg and/or
a diastolic blood pressure > 100 mmHg.

- Symptomatic postural hypotension - The difference between supine blood pressure
and standing blood pressure is 20 mmHg in systolic or 10 mmHg in diastolic with
any symptom.

8. Evidence of uncorrected hypothyroidism or hyperthyroidism based on clinical evaluation
and/or an abnormal thyroid stimulating hormone result as determined at Screening;
subjects receiving dose-stable thyroid replacement therapy for at least 3 months prior
to Screening will be allowed to participate in the study.

9. History of significant other major or unstable neurological, metabolic, hepatic,
renal, hematological, pulmonary, cardiovascular, gastrointestinal, or urological
disorder that would impact subject safety or data interpretation.

10. History of cancer, other than squamous cell or basal cell carcinoma of the skin, that
has not been in full remission for at least 5 years prior to Screening ( subjects with
a history of treated cervical intraepithelial neoplasia will be allowed to participate
in the study).

11. Active liver disease and/or significant abnormal liver function defined as aspartate
aminotransferase (AST) > 2.5 × upper limit of normal (ULN) and/or alanine
aminotransferase (ALT) > 2.5 × ULN and/or total bilirubin > 2.0 mg/dL.

12. Positive blood screen for anti-hepatitis C virus (HCV) antibody, hepatitis B surface
antigen (HBsAg), and human immunodeficiency (HIV) antibody.

13. Evidence of organ dysfunction or any clinically significant deviation from normal in
physical examination, ECG, or clinical laboratory assessments.

14. Long QT syndrome or prolongation of QTc interval (defined as QTc interval > 460 ms for
males and > 480 ms for females).

15. The following medication exclusions apply:

- Use of weight control treatment 3 months prior to Screening, including any
medication with a labeled reference to weight loss or gain, herbal preparations,
and over the counter medications.

- Use of other anti-diabetic agents (except metformin) within 3 months prior to
Screening (if the subject was previously treated with thiazolidinedione, he/she
must have stopped this treatment at least 6 months before Screening).

- Use of insulin within 12 months prior to Screening (the following cases can be
included in this study: Insulin treatment during hospitalization, insulin
treatment for a medical condition that did not require hospitalization [< 2 weeks
treatment period], or insulin treatment for gestational diabetes).

16. Treatment with an investigational agent within the longest time frame of either 5 half
lives or 30 days of initiating study drug.

17. Use of prohibited concomitant medications (further details about prohibited medication
are provided in Section 5.8.1):

- Current use of hyperglycemia-causing agents, hypoglycemia-causing agents, Class
II and III antiarrhythmic agents (these agents will be allowed if they have been
used for hypertension treatment), agents that reduce gastrointestinal motility,
central nervous system stimulants (with the exception of caffeinated beverages),
and niacin ≥ 1 g/day.

- Current use of drugs with a narrow therapeutic index (eg, digoxin, lithium,
phenytoin, theophylline, and warfarin).

- Current use of drugs that are known to prolong the QT interval.

18. Known recreational substance use or psychiatric illness that, in the opinion of the
Investigator, may impact the safety of the subject or the study objectives (eg, cannot
comply with scheduled study visits).

19. History of drug abuse.

20. Women who are pregnant (confirmed by laboratory testing), nursing or are planning to
become pregnant.

21. Subject is not willing to use an "effective" method of contraception during the course
of the study. Sexually active male subjects are required to use a condom, abstain from
intercourse, or previously undergone male sterilization. Male subjects should refrain
from sperm donation for the purposes of conception for at least 90 days after their
last dose of study drug. Females subjects must be surgically sterile (ie, hysterectomy
or bilateral tubal ligation), postmenopausal, or for women of childbearing potential
using a medically acceptable method of contraception (ie, intrauterine device, barrier
methods with spermicide or abstinence). Female subjects of childbearing potential
taking stable oral, implantable, or injectable contraceptives must additionally use a
double-barrier method of contraception.

22. Subject has an FPG ≥ 270 mg/dL at the Screening visit.

23. Has a serum creatinine above (or creatinine clearance below) what is approved in the
metformin product labeling in the respective country.

24. Known allergy or hypersensitivity to MLR-1023 or components of the formulation.