This is a Phase 1, randomized, blinded, placebo-controlled study in up to approximately 51 non-diabetic obese participants with a body mass index (BMI) ≥ 35 kg/m^2. The participants will be observed among 3 separate cohorts and participate in the study for up to approximately 27 weeks, including a screening period (including a run-in), treatment period, and safety follow-up.

This is a Phase 1, randomized, blinded, placebo-controlled study in up to approximately 51 non-diabetic obese participants with a BMI ≥ 35 kg/m2. Participants will be blinded, but investigators/site staff and sponsor will be unblinded for Cohort 1. In Cohorts 2 and 3 participants, investigators, and contract research organization personnel are blinded to investigational product and sponsor is unblinded. The participants will participate in the study for up to approximately 27 weeks, including a screening period (including a run-in), treatment period, and safety follow-up.

Participants will be randomized 4:1 to MEDI0382 (n=12) or placebo (n=3) for Cohort 1 and randomized 2:1 to MEDI0382 (n=12) or placebo (n=6) for Cohorts 2 and 3. In Cohort 1 participants randomized to MEDI0382 or placebo will be dosed daily with a weekly titration schedule until the highest clinically tolerated dose (CTD) is established. In Cohort 2 participants randomized to MEDI0382 or placebo will be dosed daily with a 2 week titration schedule up to the highest CTD is established in Cohort 1. In Cohort 3 participants randomized to MEDI0382 or placebo will be dosed daily with a 4 week participants schedule up to the highest CTD established in Cohort 1. Once the highest CTD is identified, participants will continue on the highest CTD for an additional 2 weeks of treatment for Cohort 1 and 3 and additional 4 weeks treatment for Cohort 2. All participants will return 28 days post last dose for a safety follow-up visit.

Key Inclusion Criteria:

1. Provision of written informed consent
2. Male and female participants age 18 through 65 years
3. BMI ≥ 35 kg/m^2
4. Hemoglobin A1c level of < 6.5%
5. Female participants must have a negative pregnancy test and must not be lactating.
6. Females of childbearing potential using appropriate birth control to avoid pregnancy during the study.
7. Stable body weight
8. Willing and able to adhere to the visit/protocol schedule, including following lifestyle advice with respect to diet and exercise for the duration of the study
9. Willing and able to self-administer daily SC injections following an initial self-injection training

Key Exclusion Criteria:

1. Any clinically important illness, medical/surgical procedure, or trauma within 4 weeks prior to Study Day 1 dosing.
2. Any condition that, in the opinion of the investigator, would interfere with the evaluation of the investigational product or interpretation of participants safety or study results.
3. Active participation in any other investigation clinical study.
4. Any prescription or non-prescription drugs for weight loss including herbal or other dietary supplements used within the past 3 months prior to screening.
5. Previous glucagon-like peptide-1 (GLP-1) use within 3 months prior to screening.
6. Any positive results for serum hepatitis B surface antigen, hepatitis C virus antibody and/or human immunodeficiency virus (HIV) antibody at screening.
7. Laboratory tests results as specified in the protocol (laboratory tests may be repeated once for confirmation of out of range values at screening).
8. Significant hepatic or renal impairment
9. Poorly controlled hypertension
10. Known or suspected history of drug or alcohol abuse within the past year or positive current test
11. Previous surgical procedures for weight loss

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal.

All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

In Cohort 1 participants are blinded however site staff, investigator, and sponsor are unblinded. In Cohorts 2 and 3 participants, investigators, site staff, and clinical research organization staff are blinded and sponsor is unblinded.