An Exploratory Phase 2, Randomised, Double-blind, Placebo-controlled, and Open-label Active Comparator Study to Evaluate the Effect of MEDI0382 on Hepatic Glycogen Metabolism in Overweight and Obese Subjects with Type 2 Diabetes Mellitus

* Disease background
The rising prevalence of type 2 diabetes mellitus (T2DM) and obesity is a cause
of substantial health and economic burden worldwide. In many cases of T2DM,
significant weight loss (typically 5% of body weight or more) can promote
improvements in glycaemic control, cardiovascular risk, and mortality rates,
and may even slow or reverse disease progression (Petersen et al, 2005). Many
existing therapies for T2DM focus upon lowering blood glucose; however, there
is a major unmet need for treatments that both improve glycaemic control and
achieve disease-modifying weight loss.

* MEDI0382 background
MEDI0382 is a synthetic peptide with both glucagon-like peptide-1 (GLP-1) and
glucagon receptor agonist activity which is under development for the treatment
of T2DM and non-alcoholic steatohepatitis (NASH). GLP-1 receptor agonists are
established treatments for T2DM that improve glycaemic control, delay gastric
emptying, and depress appetite leading to modest, but often non-sustained
weight loss (typically 3% versus baseline at one year). Glucagon has similar
effects to GLP-1 on gastric emptying and appetite, and has also been shown to
promote increased energy expenditure (Lynch et al, 2014; Habegger et al, 2013).
Oxyntomodulin, a naturally occurring peptide with GLP-1 and glucagon receptor
co-agonist activity, has been shown to promote weight loss through effects on
appetite and energy expenditure (Wynne et al, 2006) and co-infusion of GLP-1
and glucagon has synergistic effects on reducing food intake and promoting
weight loss in human subjects (Bagger et al, 2015).

* Primary Objective:
To assess the effect of MEDI0382 on hepatic glycogen levels versus placebo
after 28 days (Part A) and 35 days (Part B) of treatment

* Secundary Objective:
- To assess the effect of MEDI0382 on hepatic glycogen levels versus
liraglutide after 35 days of treatment (Part B only)
- To assess the effect of MEDI0382 on hepatic fat fraction versus placebo
after 35 days of treatment (Part B only)
- To evaluate the safety and tolerability of MEDI0382 titrated up to a dose
level of 300 *g
- To characterise the immunogenicity profile of MEDI0382 exposure titrated up
to a dose level of 300 *g

* Exploratory Objectives:
- To assess the effect of MEDI0382 on hepatic glycogen levels at different
time points postprandially versus placebo (Part A and B) and liraglutide
(Part B only) after 28 days (Part A) or 35 days (Part B) of treatment
- To assess the effect of MEDI0382 on 24-hour hepatic glycogen levels versus
placebo (Part A and B) and liraglutide (Part B only) after 28 days (Part
A) or 35 days (Part B) days of treatment
- To assess the effect of MEDI0382 on glucose lowering versus placebo (Part A
and B) and liraglutide (Part B only) after 28 days (Part A) or 35 days
(Part B) of treatment
- To assess the effect of MEDI0382 on hepatic fat fraction versus liraglutide
after 35 days of treatment (Part Bonly)
- To assess the effect of MEDI0382 on liver volume versus placebo (Part A and
B) and liraglutide (Part B only) at specific time points postprandially
after 28 days (Part A) or 35 days (Part B) of treatment
- To assess the effect of MEDI0382 on gluconeogenesis versus placebo (Part A
and B) and liraglutide (Part B) after 28 days (Part A) or 35 days (Part B)
of treatment
- To assess the effect of MEDI0382 on glycogenolysis versus placebo (Part A
and B) or liraglutide (Part B) after 28 days (Part A) or 35 days (Part B) of
treatment
- To assess the effect of MEDI0382 on energy-related and gluconeogenic
metabolites versus placebo (Part A and B) and liraglutide (Part B) after 28
days (Part A) or 35 days (Part B)
of treatment
- To assess systemic exposure of MEDI0382 up-titrated to 300 µg

This is a 2-part (Part A and Part B) exploratory Phase 2 study.
Part A is a randomised, double-blind, placebo-controlled study to evaluate the
effect of MEDI0382 administered once daily SC for 28 days on hepatic glycogen
metabolism in overweight and obese subjects with T2DM. Part A is planned to
randomise up to 20 subjects. Subjects will be consented, screened for
suitability, and randomised within 60 days if eligible. Subjects from Part A
will not be re-enrolled in Part B.
Part B is an exploratory Phase 2 randomised, double blind, placebo-controlled
and an open-label active comparator study to evaluate the effect of MEDI0382 on
hepatic glycogen metabolism in overweight and obese subjects with T2DM. Part B
is planned to randomise approximately 30 subjects (not to exceed a maximum of
35 subjects). Subjects in Part B will be randomised to receive double-blind
MEDI0382 titrated from 50 to 300 µg or placebo, or open label liraglutide
titrated from 0.6 to 1.8 mg once daily for 35 days.
The study will involve measurement of hepatic glycogen content using a carbon
(C) 13 MRS based technique before and after completion of the treatment period.
In Part A, MEDI0382 will be titrated in 7 day intervals from 100 to 300 *g in
comparison to placebo. In Part B MEDI0382 will be titrated in 7 day intervals
from 50 to 300 *g and compared to placebo and liraglutide at a dose of 1.8 mg
once daily titrated from 0.6 mg to 1.8 mg in 7 day intervals.
In Parts A and B subjects will undergo a 5 day washout period where metformin
therapy will be suspended at the beginning of the study starting from Day 4
(metformin dosing to resume on Day 2). This washout is repeated at the end of
the treatment period starting from Day 24 in Part A and Day 32 in Part B.
Across Part A of the study (up to 126 days in total including screening)
subjects will have a total of 6 study visits, 6 nights of inpatient stay and
will undergo a total of 10 MRS scans alongside additional assessments and blood
sampling. In Part B, subjects will participate in the study for approximately
133 days and will have a total of 7 study visits (including 2 remote contacts),
6 nights of inpatient stay and will undergo a total of 8 MRS scans alongside
additional assessments and blood sampling. The duration of MRS scans will be
approximately 40 minutes with the exception of the baseline and end of
treatment scans used for liver fat evaluation (Part B only) which will be
prolonged and up to 1 hour 45 minutes in duration. Subjects will also be given
the option to stay overnight prior to study visits if more convenient for them.
From Day 2 to Day 1 (and again on Day 8 to Day 15, Day 27 to Day 29 [Part A]
and Day 34 to Day 36 [Part B] subjects will be asked to provide a stool sample
for microbiome research purposes; this component of the study is optional.
On Day -3 in both parts of the study, subjects will be admitted to the clinical
unit for 3 nights inpatient stay and will undergo initial safety assessments
and receive training in SC injection administration. On Day 3 and Day 2,
subjects will be provided with standardised solid meals (balanced with respect
to nutrient content, but not calorie restricted) for breakfast, lunch, and
evening meal and be expected to consume the entire meal and abstain from
consumption of additional meals during this period. On the evening of Day -2,
subjects will undergo a baseline blood test for 2H-glucose prior to consuming
deuterated water (2H2O) divided into two aliquots and separated by a 4 hour
interval. Subjects will be expected to fast for 14 hours overnight (except for
drinks of deuterated water).
On Day -1 subjects will undergo a baseline MRS scan to measure liver volume and
glycogen (and liver fat in part B only) and will have blood samples collected
for 2H-glucose and baseline assessments prior to undergoing a standardised
mixed meal tolerance test (MMTT). The MMTT will consist of a liquid meal (400
mL Ensure Plus milkshake) (at Time [T] = 0). Blood will then be collected at
specified time points to measure glucose levels. In Part A, at T = 4 hours
after the MMTT a repeat MRS scan will be performed to measure liver volume and
glycogen. For the remainder of the day serial MRS scans will be performed and
blood samples will be collected at T = 9, and 14 hours and subjects will be
given standardised solid meals for lunch and evening meal. In Part B, a repeat
MRS scan to measure liver volume, fat and glycogen will be taken at T= 5 hours
after the MMTT. A further MRS scan will be performed, and blood samples will be
collected at T = 14 and subjects will be given standardised solid meals for
lunch and evening meal.
On the morning of Day 1, following an overnight fast of at least 14 hours,
subjects will have a final MRS scan performed (T = 24 hours) and blood
sampling. On Day -1 or Day 1, eligibility criteria will be verified (the final
eligibility check may occur at any time from Day -3 to Day 1) and subjects will
be randomised to receive investigational product (MEDI0382 or placebo in Part A
or MEDI0382, placebo, or liraglutide in Part B). Following predose safety
measures, the subjects will receive their first dose of investigational product
via SC injection and will be discharged from the clinical unit with a
sufficient supply of investigational product to self administer once daily by
SC injection at home in the morning.
In Part A subjects will return for an outpatient visit at weekly intervals (Day
8 and Day 15) for safety assessments, dose up-titration until a dose of 300 µg
MEDI0382 is reached in Part A. . Subjects will receive sufficient supply of
investigational product at each outpatient visit.
On Day 26 subjects will be re-admitted to the clinical unit for a further 3
nights inpatient stay and as before will receive standardised solid meals
during this period. On the evening of Day 27, subjects will fast and be given
2H2O water to drink at 2 times during the overnight period. On Day 28,
following an MRS scan and blood sampling, subjects will receive an SC dose of
investigational product and then undergo a MMTT as before at T = 0 and serial
MRS scans and blood samples will be collected at T = 4, 9, and 14 hours. On Day
29, following an overnight fast, a final MRS scan will be performed alongside a
blood test at T = 24 hours.
In Part B subjects will return for an outpatient visit on Day 8 for safety
assessments, dose up-titration, and will receive an adequate supply of
investigational product. On Days 14/15 and 21/22 remote contacts will be
performed to advise on further dose uptitration as required and to collect
AE/serious adverse events (SAEs) and concomitant medication information.
On Day 33 subjects will be re-admitted to the clinical unit for a further 3
nights inpatient stay and as before will receive standardised solid meals
during this period. On the evening of Day 34, subjects will fast and be given
2H2O water to drink at 2 times during the overnight period. On Day 35,
following an MRS scan and blood sampling, subjects will receive an SC dose of
investigational product and then undergo a MMTT as before at T = 0 and serial
MRS scans and blood samples will be collected at T = 5 and 14 hours. On Day 36,
following an overnight fast, a final MRS scan will be performed alongside a
blood test at T = 24 hours.
A follow up visit will be performed 28 days after the last dose of
investigational product for safety assessments.

Following a screening period of up to 60 days, subjects will be randomised to
receive either MEDI0382, placebo, or open label liraglutide once daily in the
morning via SC injection as follows:
* MEDI0382 50 *g for 7 days, followed by 100 *g for 7 days, followed by 200 *g
for 7 days, followed by 300 *g for 14 days (N = 10)
* Placebo for 35 days (N = 10)
* Open label liraglutide 0.6 mg for 7 days, followed by 1.2 mg for 7 days,
followed by 1.8 mg for 21 days (N = 10)

If a patient participate in this study it does not mean that his/her T2DM will
be better but it will help MedImmune to answer the research question(s). As the
treatment duration for this study is very short, it is unlikely that the
patient will experience much improvement in his/her condition. He/she will
contribute to more knowledge and help T2DM patients in the future.

Disadvantages of participation in the study may be
- possible side effects of the study drug;
- possible side effects/discomforts of the evaluations in the study.

Participation in the study also means:
- that patient lose additional time;
- an additional or an extended hospitalisation;
- (additional) testing;
- that the patient has appointments that he/she has to attend;