A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, SEQUENTIAL DOSE ESCALATION STUDY OF THE SAFETY, TOLERABILITY, PHARMACODYNAMICS AND PHARMACOKINETICS OF SINGLE SUBCUTANEOUS DOSES OF HM11260C IN ADULT PATIENTS WITH TYPE 2 DIABETES MELLITUS

Exenatide is a GLP-1R agonist derived from the saliva of the Gila monster
lizard and resistant to dipeptyl peptidase-4 (DPP-IV). Exenatide slows stomach
emptying, increase in satiety and release of insulin. Exenatide was approved by
FDA for type 2 diabetes due to favourable effect on diabetes. However,
exenatide requires bid (bis in die [twice daily]) administration due to the
short half-life in vivo although it has resistancy against DPP-IV. The frequent
administration causes inconvenience to patients and can not elicit maximal
therapeutic efficacy due to fluctuation of the glucose level. The development
of long-acting exenatide given at once a week or once a month would offer
advantage of convenient dosing and may enhance both compliance and clinical
efficacy compared with bid administered exenatide.

HM11260C is being developed by conjugating the CA Exendin-4 (Exendin-4 analog)
and the constant region of human immunoglobulin G4 fragment (named as HMC001)
via a non-peptidyl 3.4 KDa polyethyleneglycol (PEG) linker which is based on a
novel strategy for developing long-acting proteins. Human immunoglobulin G4
fragment (HMC001) was chosen as the stabilizing agent, because it is the most
prevalent blood protein and has an in vivo half-life of several weeks without
effector function such as complement-dependent cytotoxicity (CDC) or
antibody-dependent cellular cytotoxicity (ADCC).

HM11260C and exenatide belong to the therapeutic class of insulinotropic
factors. HM11260C is a sustained duration form of CA Exendin-4 through
decreased renal and vascular endothelium clearance. HM11260C and exenatide have
shown to have identical modes of actions by sharing human GLP-1 receptor. And
HM11260C showed marked increase of potency as well as sustained duration of
action.

HM11260C is expected to be administered once a week to once a month by
adjusting dosages and to be compatible with conventional prefilled syringe
which has a fine needle due to the high solubility of HM11260C. In addition,
the pharmacodynamic (PD) study of HM11260C showed that it has superior
therapeutic profile compared with exenatide. In conclusion, HM11260C is
expected to have a favourable therapeutic profile as well as convenience in
dosing regimen when it is applied to clinic.

Primary:
To evaluate the safety and tolerability profile of single escalating
subcutaneous (sc) dose levels of HM11260C in adult patients with type 2
diabetes mellitus

Secondary:
To evaluate the dose response relationship of single escalating sc dose levels
of HM11260C on pharmacodynamic (PD) parameters including 24-h glucose profiles
(including fasting and post-prandial blood glucose), fasting fructosamine,
C-peptide, fasting insulin, glucagon, lipids, gastric emptying, body weight,
waist circumference, and a battery of safety laboratory parameters, incl.
amylase, lipase, liver enzymes and hematologic parameters

To evaluate the pharmacokinetic (PK) profiles of single dose levels of HM11260C

To determine the pharmacologically active dose (PAD) of HM11260C (based on
fasting glucose) as defined by the dose that results in a mean reduction in
fasting glucose of more than 30 mg/dL (1.66 mmol/L) or 20% reduction from
baseline, whichever is greater

To assess the immunogenicity (anti-HM11260C antibodies and anti-HM11260C
neutralizing antibodies) of a single sc dose of HM11260C

Study design:
eligibility screening period
a wash-out period for anti-diabetes drug(s)
Treatment period,
involving administration of a single sc dose of HM11260C according to a
randomized, double-blind, placebo-controlled, sequential dose escalation
design,
3 in clinic periods of 3 days (2 nights) per period,
5 ambulatory visits
follow-up visit.

Screening period:
Medical history, physical examination, vital signs, ECG, serology (including
hepatitis B surface antigen [HBsAg]), anti-hepatitis C virus [anti-HCV], and
anti human immunodeficiency virus 1/2 (anti-HIV 1/2), drug and alcohol screen,
pregnancy test (females only).
A blood and a urine sample will be taken for routine haematology and clinical
chemistry tests (including fasting glucose and FSH (FSH for women only)). In
addition, HbA1c will be measured (at screening only).

Wash out period:
Subject will discontinue their hypoglycaemic treatment starting on Day -14. In
the period from Day -14 to Day -3, these subjects will have to telephone the
clinical research facility if their fasting blood glucose level reaches 11
mmol/L or higher. If in this period a patient reports a fasting blood glucose
level higher than 13.3 mmol/L, he/she will be advised to restart his/her prior
diabetes medication immediately and will not be dosed in the study.

Treatment period:
The subjects will arrive at the clinic in the afternoon of Day -2 (Day 1 is the
day of drug administration) and will leave 168 h after drug administration on
Day 8. In addition, the subjects will stay in the clinic from Days 13-15,
20-22, 27-29. There will be ambulatory visits on Days -15, 10, 35, 42 and 49.
If glucose >14 mmol/L on 2 consecutive days he/she will be advised to restart
their prior hypoglycaemic medication immediately.

In this first-in-patient study, safety, tolerability, PK and PD of single sc
doses of HM11260C will be studied in diabetes patients.

Four cohorts of each six patients. Based on the results of the first four
groups, the study is optionally extended with a cohort of 6 patients (four
verum and two placebo).

Subjects will be genotyped/phenotyped for a total of 1069 alleles that have
been associated with altered drug metabolism and disposition, in case the
Sponsor deems this necessary.

Follow-up
The follow up medical examination will be performed between 4 and 6 weeks after
the last blood sample has been taken. Follow-up medical examination will
consist of: physical examination, vital signs, ECG and clinical laboratory
tests.

Treatments Administered
The following treatments will be administered (as a single dose) according to
the randomisation schedule.
Group 1: a single sc injection 2 µg/kg HM11260C (n=5) or placebo (n=1) on Day 1
Group 2: a single sc injection 4 µg/kg HM11260C (n=5) or placebo (n=1) on Day 1
Group 3: a single sc injection 8 µg/kg HM11260C (n=5) or placebo (n=1) on Day 1
Group 4: a single sc injection 14 µg/kg HM11260C (n=5) or placebo (n=1) on Day 1

The study may be extended with the following cohort:
Group 5: 6 patients (4 on active and 2 on placebo who will be treated with
minimally 2 µg/kg and maximally 20 µg/kg HM11260C, depending on the results of
Group 1, 2, 3 or 4.

Blood sampling:
PK blood sampling: pre-dose untill 1152 h post-dose

PD blood sampling for glucose, insulin and C-peptide: 24-h profiles

PD blood sampling for glucose (without insulin and C-peptide): 24-h profiles

PD blood sampling for fructosamine and lipids (total cholesterol, HDL, LDL,
VLDL, free fatty acids, triglycerides)



Other PD assessments:
PD assessments (body weight and waist circumference)

PD assessments (Hunger, Craving and Fullness Questionnaire)

On days with PD assessments standardized meals, with Ensure Plus® and a muffin
as breakfast, will be provided on Days -1, 1, 4, 7, 14, 21 and 28. On Days -1,
1 and 14, the muffin should be an Expiroger muffin containing 13C-octanoic acid.

13C-octanoic acid meal and breath test (Gastric emptying) will be assessed

Safety assessments:
Vital signs (including blood pressure, pulse rate, body temperature and ECG)

For patients taken off their hypoglycaemic medication: glucose measurements
with a glucometer once a day

Clinical laboratory (including clinical chemistry, haematology and urinalysis)

Immunogenicity blood samples for determining anti drug antibodies and anti drug
neutralizing antibodies

Physical examination

Study Medication
Active substance: HM11260C
Activity: long-acting GLP-1R agonist
Indication: type 2 diabetes mellitus
Strength: unknown
Dosage form: sc injection

Procedures: pain, light bleeding, heamatoma and possibly an infection.

Possible (adverse) effects: body weight loss, decrease in food consumption,
slight dehydration and a slight pallor.