A Study to Evaluate the Efficacy and Safety of ORMD-0801 (Oral Insulin) in Patients With Type 2 Diabetes Mellitus

Of the 285 subjects, approximately 265 subjects with T2DM will initially undergo a 2-week,
single-blind placebo run-in period (Visits 1 and 2), followed by a 12-week treatment period
(Visits 3 through 9). The total 12-week treatment period will include a Part 1 "dose
escalation" interval (2 weeks, Visits 3 and 4) and a Part 2 stable dose "maintenance"
interval (10 weeks, Visits 5 through 9). The stable dose interval will be sufficient to allow
for a robust assessment of treatment effect based on the mean change from baseline in HbA1C
(A1C).

In addition, per FDA request, the remaining 20 subjects will receive excipient-matched
placebo in a non-randomized single-blind fashion, TID, according to the same schedule as
described above.

Inclusion Criteria:

- Male and female subjects aged 18 and older.

- Established diagnosis of T2DM for at least 6 months prior to Screening, with an HbA1C
≥ 7.5%.

- Stable dose of metformin (at least 1500 mg or maximally tolerated dose)/oral
antidiabetic (OAD) for a period of at least 3 months prior to screening.

- Taking metformin only or metformin in addition to no more than two of the following:
DPP-4, SGLT-2, or TZD.

- Body mass index (BMI) of up to 40 kg/m2 at Screening and stable weight, with no more
than 5 kg gain or loss in the 3 months prior to Screening.

- Renal function - eGFR > 30 ml/min/1.73 m2

- Females of childbearing potential must have a negative serum pregnancy test result at
Screening.

Exclusion Criteria:

- Subjects with insulin-dependent diabetes

1. has a history of type 1 diabetes mellitus or a history of ketoacidosis, or
subject is assessed by the investigator as possibly having type 1 diabetes
mellitus confirmed by a C-peptide <0.7 ng/mL (0.23 nmol/L).

2. has a history of other specific types of diabetes (e.g., genetic syndromes,
secondary pancreatic diabetes, diabetes due to endocrinopathies, drug- or
chemicalinduced, and post-organ transplant).

- Treatment with glucosidase inhibitor, insulin secretagogues (other than
sulfonylureas), glucagon-like peptide 1 (GLP-1) agonists within 3 months prior to
Visit 1.

- History of any basal, pre-mix or prandial insulin (greater than 7 days) within 6
months prior to Screening.

- History of >2 episodes of severe hypoglycemia within 6 months prior to Screening.

- History of hypoglycemic unawareness (episodes of severe hypoglycemia with seizure or
requiring third party intervention or documented low blood glucose without associated
autonomic symptoms)

- Subjects with the following secondary complications of diabetes:

1. Active proliferative retinopathy as confirmed by a dilated ophthalmoscopy/retinal
photography examination performed (by a qualified person as per the country
legislation) within 6 months prior to Screening.

2. Renal dysfunction: eGFR < 30 ml/min/1.73 m2

3. History of proliferative retinopathy or severe form of neuropathy or cardiac
autonomic neuropathy (CAN)

4. Uncontrolled or untreated severe hypertension defined as systolic blood pressure
above or equal to 180 mmHg and/or diastolic blood pressure above or equal to 120
mmHg

5. Presence of unstable angina or myocardial infarction within 6 months prior to
Screening, Grade 3 or 4 congestive heart failure (CHF) according to the New York
Heart Association (NYHA) criteria, valvular heart disease, cardiac arrhythmia
requiring treatment, pulmonary hypertension, cardiac surgery, history/occurrence
of coronary angioplasty and/or stroke or transient ischemic attack (TIA) within 6
months prior to Screening.

- Subjects with psychiatric disorders which, per investigator judgment, may have impact
on the safety of the subject or interfere with subject's participation or compliance
in the study.

- Subjects who needed (in the last 12 months) or may require systemic (oral,
intravenous, intramuscular) glucocorticoid therapy for more than 2 weeks during the
study period.

- 9. Laboratory abnormalities at Screening including:

1. C-peptide < 1.0 ng/mL

2. Abnormal serum thyrotropin (TSH) levels below the lower limit of normal or >1.5X
the upper limit of normal

3. Elevated liver enzymes (alanine transaminase (ALT), alanine aminotransferase
(AST), alkaline phosphatase) >2X the upper limit of normal.

4. Very high triglyceride levels (>600 mg/dL); a single repeat test is allowable.

5. Any relevant abnormality that would interfere with the efficacy or the safety
assessments during study treatment administration.

- Positive history of active liver disease (other than non-alcoholic hepatic steatosis),
including chronic hepatitis B or C, primary biliary cirrhosis, or active symptomatic
gallbladder disease.

- Positive history of HIV.

- Use of the following medications:

1. History of any basal, pre-mix or prandial insulin (greater than 7 days) within 6
months prior to Screening.

2. Administration of thyroid preparations or thyroxine (except in subjects on stable
replacement therapy) within 6 weeks prior to Screening.

3. Administration of systemic long-acting corticosteroids within two months or
prolonged use (more than one week) of other systemic corticosteroids or inhaled
corticosteroids (if daily dosage is > 1,000 μg equivalent beclomethasone) within
30 days prior to Screening. Intra-articular and/or topical corticosteroids are
not considered systemic.

4. Use of medications known to modify glucose metabolism or to decrease the ability
to recover from hypoglycemia such as oral, parenteral, and inhaled steroids (as
discussed above), and immunosuppressive or immunomodulating agents.

- Known allergy to soy.

- Subject is on a weight loss program and is not in the maintenance phase, or subject
has started weight loss medication (e.g., orlistat or liraglutide), within 8 weeks
prior to Screening.

- Subject has had bariatric surgery.

- Subject is pregnant or breast-feeding.

- Subject is a user of recreational or illicit drugs or has had a recent history (within
1 year of Screening) of drug or alcohol abuse or dependence. (Note: Alcohol abuse
includes heavy alcohol intake as defined by >3 drinks per day or >14 drinks per week,
or binge drinking) at Screening. Occasional intermittent use of cannabinoid products
will be allowed provided that no cannabinoid products have been used during the 1 week
prior to each visit.

- One or more contraindications to metformin as per local label.

- History of gastrointestinal disorders (e.g. hypochlorhydria) with the potential to
interfere with drug absorption.

- At the Principal Investigator's discretion, any condition or other factors that are
deemed unsuitable for subject enrollment into the study.