A DOUBLE-BLINDED, PLACEBO-CONTROLLED, SINGLE DOSE AND MULTIPLE-DOSE STUDY TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, PHARMACODYNAMICS AND PROOF OF CONCEPT OF DM-199 IN HEALTHY SUBJECTS AND PATIENTS WITH TYPE 2 DIABETES MELLITUS

DM-199 is a new investigational compound that may eventually be used for the
treatment of Diabetes Mellitus Type 2. This is the first time that this
compound is being given to humans.

Primary:
To evaluate the safety and tolerability of single and multiple subcutaneous
doses of DM 199 in healthy subjects and type 2 diabetes mellitus patients

To determine the plasma pharmacokinetic profile of DM-199 after administration
of single and multiple doses of DM-199

Secondary:
To determine the effect of DM-199 on glucose homeostasis (via fasting glucose,
fasting insulin and HbA1C levels), standardized meal tolerance test, C-peptide,
fructosamine, GLP-1 (active and total), glucagon, adiponectin, aldosterone,
renin and lipids measurements, and homeostatic model assessment of insulin
resistance/ beta cell function (HOMA) determination in type 2 diabetes mellitus
patients

To assess the formation of antibodies to DM-199 after administration of
multiple doses of DM-199 in healthy subjects and type 2 diabetes mellitus
patients

To determine changes in immune cell populations by fluorescence-activated cell
sorting analysis following multiple doses of DM-199 in healthy subjects and
type 2 diabetes mellitus patients

A DOUBLE-BLINDED, PLACEBO-CONTROLLED, SINGLE DOSE AND MULTIPLE-DOSE STUDY TO
EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, PHARMACODYNAMICS AND PROOF
OF CONCEPT OF DM-199 IN HEALTHY SUBJECTS AND PATIENTS WITH TYPE 2 DIABETES
MELLITUS

The study consists of 4 parts. Each part (A, B, C and D) will consist of one or
several periods. The research will be conducted in both healthy male and female
volunteers (Part A and C) and in male and female diabetes mellitus type 2
patients (Part B and D).

Observation period:
Part A: Group 1 and 2: 3 periods in the clinic each being from Day -1 until 72
hours (Day 4) after drug administration
Part A: Group 7: 1 period in the clinic from Day -1 until 72 hours (Day 4)
after drug administration
Part B: 1 period in the clinic from Day -1 until 72 hours (Day 11) after the
last drug administration on Day 8
Part C: 1 period in the clinic from Day -1 until 72 hours (Day 19) after the
last drug administration on Day 16, followed by 2 ambulant visit on Days 21 and
23.
Part D: 1 period in the clinic from Day -2 until 72 hours (Day 31) after the
last drug administration on Day 28, followed by 2 ambulant visits on Days 35
and 42

In Part B, an ambulatory visit will be scheduled on Day -15 for type 2 diabetes
mellitus patients receiving anti-diabetic medication (such as metformin,
sulphonylureas etc.). Subjects will be discontinued from this treatment
(starting on Day -14). Subjects will receive dietary advice and explanation of
the glucometer. They will perform glucose measurements with a glucometer once a
day, in the morning (while fasting) from Day 14 to Day -1.

In Part D, an ambulatory visit will be scheduled on Day -29 for type 2 diabetes
mellitus patients receiving anti-diabetic medication (such as metformin,
sulphonylureas etc.). Subjects will be discontinued from this treatment
(starting on Day -28). Subjects will receive dietary advice and explanation of
the glucometer. They will perform glucose measurements with a glucometer once a
day, in the morning (while fasting) from Day 28 to Day 30.

Part A:
Group 1:
Period 1: a single sc dose of 0.015 mg/kg DM-199 (n=6) or matching placebo
(n=3)
Period 2: a single sc dose of 0.15 mg/kg DM-199 (n=6) or matching placebo (n=3)
Period 3: a single sc dose of 0.015 mg/kg DM-199 (n=3), 0.15 mg/kg DM 199 (n=3)
or matching placebo (n=3)

During Period 1 of Group 1, two volunteers will be dosed (one DM-199 and one
placebo) first. After dosing, the safety and tolerability of study drug in
these subjects will be closely monitored. If there are no concerns about the
safety and tolerability, the remaining 7 subjects (5 DM-199 and 2 placebo) will
be dosed the day after the first two subjects.

Group 2
Period 1: a single sc dose of 0.005 mg/kg DM-199 (n=6) or matching placebo (n=3)
Period 2: a single sc dose of 0.005 mg/kg DM-199 (n=3), 0.45 mg/kg DM 199 (n=3)
or matching placebo (n=3)
Period 3: a single sc dose of 0.45 mg/kg DM-199 (n=6) or matching placebo (n=3)

Group 7a: a single sc dose of 0,0015 or 0.005 mg/kg DM-199 (n=6) (based on PK
data from Group 1 and 2) or matching placebo (n=1)
Group 7b: a single sc dose of 0.015 mg /kg DM-199 (n=6) or matching placebo
(n=1)

Part B:
Group 3:
Day 1: a single sc dose of placebo (n=10)
Day 2: a single sc dose of A* DM-199 (n=7) or matching placebo (n=3)
Day 5: a single sc dose of B* DM-199 (n=7) or matching placebo (n=3)
Day 8: a single sc dose of C* DM-199 (n=7) or matching placebo (n=3)

* The dose levels (A, B and C) of Part B will be decided based on the safety
and tolerability data of Part A.
A total of 3 patients will receive placebo throughout the study and 7 patients
will be given placebo on Day 1 and DM-199 on Days 2, 5 and 8.

Part C:
Group 4 sc doses of 0.003 mg/kg DM-199 (n=6) or matching placebo (n=3) once
every 72 hours for a total of 6 doses
Group 5 sc doses of 0.015 mg/kg# DM-199 (n=6) or matching placebo (n=3) once on
Days 1, 4 and 7 and sc doses of 0.025 mg/kg# DM-199 (n=6) or matching placebo
(n=3) once on Days 10, 13 and 16

# If issues with tolerability are noted following any of the doses in Group 5,
the next DM-199 dose(s) may be adjusted downward to 0.015 mg/kg or 0.010 mg/kg
DM-199. Changes in DM-199 dose levels will always be discussed between the
Principal Investigator and the Sponsor.

Part D:
Group 6:
multiple sc doses of F* DM-199 (n=12), G* DM-199 (n=12) or matching placebo
(n=6) once daily once every 72 hours for a total of 10 doses over 28 days (ie,
Days 1, 4, 7, 10, 13, 16, 19, 22, 25 and 28).

* The dose levels (F and G) of Part D will be decided based on safety,
tolerability, PK and PD data of Parts A, B and C. If the study medication is
well tolerated after each third dose (thus doses of Day 7, 16 and 25), the dose
may be titrated upwards.

During the investigation, various assessments can be experienced as more or
less stressful.

Blood draw, indwelling canula:
During this study blood will be drawn. Each period 1 time an indwelling canula
will be used and a number of blood draws
will be drawn by direct puncture of the vein. The insertion of the canula may
be associated with pain, minor bleeding,
bruising, possible infection.

There will be also a subcutaneous (in the abdominal wall) injection for the
administration of the study drug or placebo. The site of injection will be
checked regularly during the study for local reactions, such as redness,
swelling, itching, or bruising. In addition, the severity of pain will be
evaluated.

Single DM-199 doses up to 0.05 mg/kg were administered to healthy subjects in
Part A of this study. Up to 0.015 mg/kg, DM-199 doses were well-tolerated
whereas at higher dose levels, not all subjects tolerated DM-199 well. The
following adverse events were reported mainly at the higher DM-199 dose levels:
orthostatic hypotension and orthostatic hypotension related symptoms such as
postural dizziness, abdominal discomfort, headache, nausea, vomiting, tingling
in the fingers, warm sensation and tinnitus.
In Part B of this study, single doses up to 0.015 mg/kg DM-199 were
administered to type 2 diabetes mellitus patients and well-tolerated. In Part C
of this study, multiple doses up to 0.015 mg/kg DM-199 every 72 hours in
healthy subjects were also well-tolerated; Part C is still ongoing at the time
of writing this document and a higher dose of 0.025 mg/kg DM-199 is planned.
The following adverse events were reported in Parts B and C: dizziness,
tiredness, headache and skin irritation at the injection site. All reported
events in Parts B and C were of mild intensity.