AZD4076 in Type 2 Diabetic Subjects With Non-Alcoholic Fatty Liver Disease.

This is a phase I/IIa, randomized, single-blind, placebo-controlled, multiple-ascending dose
study conducted at a single site. The study plans to include up to approximately 46
evaluable subjects with Type 2 Diabetes Mellitus (HbA1c 7-11%) and Non-Alcoholic Fatty Liver
disease (liver fat content > = 8%) on metformin monotherapy

Three initial cohorts are planned:

- Cohort 1: 6 subjects receiving AZD4076 and 4 subjects receiving placebo

- Cohort 2: 12 subjects receiving AZD4076 and 10 subjects receiving placebo

- Cohort 3: 10 subjects receiving AZD4076 and 10 subjects receiving placebo, with the
possibility to add additional subjects if drop-out rates are higher than expected.

Pending review by SRC, an additional 2 cohorts, each consisting of 18 evaluable subjects may
be included in the study.

The planned study consists of a screening visit, followed by 12 subsequent study visits.
There will be a total of three residential periods: (1) Loading phase of the treatment
(visit 2, days -4 to 14), (2) maintenance phase of treatment (visit 6, days 42-43), and (3)
8 weeks post-first dose of study drug (visit 9, days 53-56). Dosing of study drug will take
place on days 1, 3, 5, 7, and 9 in the loading phase; and on days 14, 21, 28, 35, and 42
during the maintenance phase. Following the maintenance phase, subjects will have four
follow-up visits.

Study Objectives:

The primary objectives of this clinical trial are to investigate the safety and tolerability
of AZD4076 following subcutaneous administration of multiple ascending doses; to assess the
effect of AZD4076 on whole body insulin sensitivity using hyperinsulinemic euglycemic clamp
with tracer technique; and to assess the effect of AZD4076 on liver fat content using
magnetic resonance imaging. Secondary objectives of this trial are to characterize multiple
dose PK of AZD4076 and its longmer and shortmer metabolites and assess the time required to
reach steady state and the degree of accumulation; to assess the efficacy of AZD4076 on
24-hour glucose; and to assess the effect of AZD4076 on homeostatic model assessment insulin
resistant (HOMA-IR) and Matsuda index.

Study Population:

Subjects participating in this study are adult males and females of non-child bearing
potential, who are 18-70 years of age, body mass index 23-40 kg/m2, diagnosed with T2DM who
are inadequately controlled (HbA1C 7-11%) on a stable metformin regimen, and who have
hepatic steatosis (defined as liver fat content of >=8% per MRI).

Duration of treatment:

The screening visit will occur within 42 days prior to the administration of the study drug.
Total length of the treatment period is 6 weeks. The treatment period is divided in two
phases: the loading phase, in which participants will receive the study drug every other day
for 9 days (Days 1, 3, 5 , 7 and 9); thereafter subjects will enter the maintenance phase,
where dosing will occur once weekly for four weeks (Days 14, 21, 28, 35 and 42). To ensure
safety, subjects will be followed for approximately 5 months post the last dose of study
drug.

Investigational product, dosage and mode of administration:

The study will utilize two study drugs: AZD4076 and placebo. Both drugs will be administered
subcutaneously in the abdomen.

Safety analysis:

The key outcomes for the safety analyses are: adverse events, vital signs, safety laboratory
parameters, ECGs, telemetry; and structured neurological and physical examination, as well
as injection site assessment. Pharmacodynamic parameters will be derived from data generated
from the clamp procedure, MRI, HOMA, OGTT and 24-hour glucose AUC. For pharmacokinetic
parameters, plasma and urine concentrations of AZD4076 and its metabolites will be measured

Inclusion criteria

1. Provision of signed and dated, written informed consent prior to any study specific
procedures.

2. Males or females of non-child bearing potential.

3. Age 18-70 years with suitable veins for cannulation or repeated venipuncture.

4. BMI 23-40 kg/m2 inclusive.

5. Diagnosed T2D (HbA1c 7-11%) treated with a stable dose of metformin for at least one
month prior to screening.

6. Hepatic steatosis of ≥8%.

Exclusion criteria

1. Any clinically significant illness, medical/surgical procedure, or trauma within 4
weeks of the first administration of IMP.

2. History or presence of hepatic or renal disease (with the exception of hepatic
steatosis).

3. Presence of acute proliferative retinopathy or maculopathy, severe gastroparesis,
and/or severe neuropathy, in particular autonomic neuropathy.

4. Clinically significant cardiovascular event within the last 6 months prior to
screening.

5. History or presence of significant neurological or psychiatric disease/mental illness
(as assessed using the C-SSRS).

6. History of malignancy within the last 5 years, excluding successful treatment of
basal cell skin carcinoma or in situ carcinoma of cervix.

7. Suspicion of or known Gilbert's syndrome.

8. Supine systolic blood pressure greater than 160 mmHg or diastolic blood pressure
greater than 95 mmHg confirmed in the screening period.

9. Changes in any current medication (initiation, dose change or cessation) that may
impact the study readouts (as judged by the Investigator) within three months prior
to MRI assessment of steatosis screening. The criterion does not apply to medication
prescribed for occasional use.

10 Treatment with antidiabetics (except for metformin) during the last three months prior
to screening or treatment with sulfonylurea (SU) drugs within the 4 weeks prior to
screening.

11. Used or plan to use drugs that cause weight loss, participating in, or have
participated in weight loss program within the last 3 months.

12. Use of anabolic steroids and systemic treatment with glucosteroids within three months
prior to screening. Intra articular, topical, and inhaled steroids are permissible.

13. Any confirmed clinically significant abnormalities in clinical chemistry, hematology,
or urinalysis results, as judged by the Investigator.

14. Any positive result on screening for serum hepatitis B surface antigen (HBsAg),
hepatitis C antibody and human immunodeficiency virus (HIV).

15. Confirmed serum creatinine greater than the ULN. 16. A confirmed eGFR <60 calculated
according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.

17. Confirmed platelet count outside the normal range. 18. Confirmed ALT or AST greater
than 1.5x ULN. 19. Confirmed total bilirubin greater than ULN 20. Any clinically
significant abnormalities in rhythm, conduction or morphology of the resting ECG and any
clinically significant abnormalities in the 12-lead ECG, as considered by the investigator
that may interfere with the interpretation of QTc interval changes, including abnormal
ST-T-wave morphology, particularly in the protocol defined primary lead, or left
ventricular hypertrophy.

21. Prolonged QTcF > 450 ms for males and > 470 ms for females or family history of long
QT syndrome.

22. PR(PQ) interval shortening < 120 ms (PR > 110 ms but < 120 ms is acceptable if there
is no evidence of ventricular pre-excitation.

23. PR (PQ) interval prolongation (> 240 ms) intermittent second (Wenckebach block while
asleep is not exclusive) or third degree AV block, or AV dissociation.

24. Persistent or intermittent complete bundle branch block (BBB) with QRS > 120 ms.

25. Known or suspected history of drug abuse within the past 5 years, as judged by the
Investigator.

26. Smokes >10 cigarettes/day and unable to comply with the nicotine restriction during
the study.

27. History of alcohol abuse or excessive intake of alcohol. Definition of excessive
intake: an average weekly intake of >14 drinks/week for men or >7 drinks/week for women.
One drink is equivalent to (12 g alcohol) = 5 ounces (150 mL) of wine or 12 ounces (360
mL) of beer or 1.5 ounces (45 mL) of 80 proof distilled spirits.

28. Positive screen for drugs of abuse at screening or admission to the unit or positive
screen for alcohol at screening or on admission to the unit prior to the first
administration of IMP.

29. History of severe allergy/hypersensitivity or ongoing clinically significant
allergy/hypersensitivity, as judged by the investigator or history of hypersensitivity to
drugs with a similar chemical structure or class to AZD4076.

30. Excessive intake of caffeine containing drinks or food (e.g., coffee, tea), as judged
by the Investigator.

31. Use of drugs with enzyme inducing properties such as St John's Wort within 3 weeks
prior to the first administration of IMP.

32. Plasma donation within one month of screening or any blood donation/blood loss > 500
mL during the 56 days prior to screening.

33. Has received another new chemical entity (defined as a compound which has not been
approved for marketing) within one month of the administration of IMP in this study. The
period of exclusion begins one month after the final dose or one month after the last
visit whichever is the longest.

34. Use of implants or devices that are incompatible with the MRI procedure. 35.
Vulnerable subjects, e.g., kept in detention, protected adults under guardianship,
trusteeship, or committed to an institution by governmental or juridical order.

36. Involvement of any Astra Zeneca, PROFIL INSTITUTE or study site employee or their
close relatives.

37. Judgment by the Investigator that the subject should not participate in the study if
they have any ongoing or recent (i.e., during the screening period) minor medical
complaints that may interfere with the interpretation of study data or are considered
unlikely to comply with study procedures, restrictions and requirements.

38. Subjects not willing to comply with the dietary requirements in the study as judged by
the Investigator.

39. Subjects who cannot communicate reliably with the Investigator or designee. 40.
Previous bone marrow transplant. 41. Non-leukocyte depleted whole blood transfusion within
120 days of the date of the genetic sample collection.