The purpose of this study is to investigate how safe, and how well tolerated, the new study drug NNC0480-0389 is when it is given together with semaglutide. This will be investigated in healthy participants, participants with high bodyweight and participants with type 2 diabetes (T2D). NNC0480-0389 has not been given to humans before. It has been previously tested in the laboratory and on animals. NNC0480-0389 will be tested at various dose levels. Semaglutide is a new approved drug and is already available on the market for treatment of diabetes. It will also be investigated how quickly and to what extent NNC0480-0389 and semaglutide are taken up and eliminated from the body. This is called pharmacokinetics. The effect of NNC0480-0389 given together with semaglutide will also be investigated on body weight and glucose levels in the blood. This is called pharmacodynamics. The effects of NNC0480-0389 and/or semaglutide will be compared to the effects of a placebo. A placebo is a "dummy" medicine without any active medicine. Placebo looks like NNC0480-0389 and/or semaglutide. There are 4 possibilities for which treatment participants will get; participants will receive NNC0480-0389 and semaglutide or NNC0480-0389 and placebo or placebo with semaglutide, or placebo with placebo. Participants and the responsible doctor will not know which combination participants will be given. This is called a double-blinded study. However, this information can be looked up during the study if it is important for participants' health. The study medicines will be given as injections under the skin. Participants will be in the study for about 25 weeks.

Inclusion Criteria:

Part 1:

• Male aged 18-45 years (both inclusive) at the time of signing informed consent.
• Body mass index between 20.0 kg/m^2 and 29.9 kg/m^2 (both inclusive).
• Considered to be generally healthy based on the medical history, physical examination, and the results of vital signs, electrocardiogram and clinical laboratory tests performed during the screening visit, as judged by the investigator.

Part 2 (not applicable for proof-of-concept (PoC) cohort):

• Body mass index between 20.0 kg/m^2 and 39.9 kg/m^2 (both inclusive).
• Female of non-childbearing potential or male aged 18-55 years (both inclusive) at the time of signing informed consent.
• Considered to be eligible based on the medical history, physical examination, and the results of vital signs, electrocardiogram and clinical laboratory tests performed during the screening visit, as judged by the investigator.

Part 2 (only applicable for PoC cohort):

• Body mass index between 25.0 kg/m^2 and 39.9 kg/m^2 (both inclusive). Overweight or obesity should be due to excess adipose tissue, as judged by the investigator.
• Female of non-childbearing potential or male aged 18-64 years (both inclusive) at the time of signing informed consent.
• Considered to be eligible based on the medical history, physical examination, and the results of vital signs, electrocardiogram and clinical laboratory tests performed during the screening visit, as judged by the investigator.
• Diagnosed with type 2 diabetes at least 90 days prior to the day of screening.
• Subjects treated with diet and exercise as monotherapy or in combination with 1-2 of the following anti-diabetic drug(s) at a stable dose for at least 30 days prior to screening: metformin, sulfonylureas, meglitinides, DPP-4 inhibitors, alpha-glucosidase inhibitors, thiazolidinediones, GLP-1 receptor agonists or SLGT-2 inhibitors. The metformin dose should be between 1500 mg to 3000 mg or maximum tolerated or effective dose documented in subject's medical record.
• Glycosylated haemoglobin (HbA1c) in the range of 6.5% (inclusive) and 10% (non-inclusive).

Exclusion Criteria:

Part 1:

• Any disorder which in the investigator's opinion might jeopardise subject's safety or compliance with the protocol.
• HbA1c equal to or above 6.5 % (48 mmol/mol) at screening.
• Use of prescription medicinal products or non-prescription drugs, except routine vitamins, occasional use of acetaminophen, ibuprofen and acetylsalicylic acid, or topical medication not reaching systemic circulation within 14 days prior to the day of screening. Presence or history of any clinically relevant respiratory, metabolic, renal, hepatic, cardiovascular, gastrointestinal, or endocrinological conditions.

Part 2 (not applicable for PoC cohort):

• Any disorder (except for conditions associated with T2D for the PoC cohort) which in the investigator's opinion might jeopardise subject's safety or compliance with the protocol.
• Presence or history of any clinically relevant respiratory, metabolic, renal, hepatic, cardiovascular, gastrointestinal, or endocrinological conditions (except conditions associated with T2D for PoC Cohort).
• Use of prescription medicinal products or non-prescription drugs, except routine vitamins, occasional use of acetaminophen, ibuprofen and acetylsalicylic acid, or topical medication not reaching systemic circulation within 14 days prior to the day of screening.
• HbA1c equal to or above 6.5 % (48 mmol/mol) at screening.

Part 2 (only applicable for PoC cohort):

• Any disorder (except for conditions associated with T2D for the PoC cohort) which in the investigator's opinion might jeopardise subject's safety or compliance with the protocol.
• Presence or history of any clinically relevant respiratory, metabolic, renal, hepatic, gastrointestinal, or endocrinological conditions (except conditions associated with T2D for PoC Cohort).
• Use of any prohibited medications as listed in the protocol within 14 days of screening.
• Use of prescribed medications at the time of screening at a dose that had not been stable within 30 days prior to screening.

According to the Novo Nordisk disclosure commitment on novonordisk-trials.com

Sponsor staff involved in the clinical trial is masked according to company standard procedures.