To Investigate the Safety, Tolerability and Pharmacodynamics of GSK2890457 in Healthy Volunteers and Subjects With Type 2 Diabetes

A Double-blind [Sponsor Unblinded], Randomized, Placebo-controlled, Staggered-parallel Study to Investigate the Safety, Tolerability, and Pharmacodynamics of GSK2890457 in Healthy Volunteers and Subjects With Type 2 Diabetes

This study is the first administration of GSK2890457 in humans. The study will be conducted in 3 parts: - Part A (conducted at a single investigative site) will determine the safety and tolerability of GSK2890457 alone in healthy subjects during six weeks of dosing, as well as evaluating the potential for a pharmacokinetic interaction with metformin. Part A consists of Screening, Treatment (6 weeks) and Follow-up periods. - Part B (conducted at multiple sites) will determine safety, tolerability, and pharmacodynamics (PD) in subjects with Type 2 diabetes (T2D) when co-dosed for six weeks with liraglutide (Victoza). Part B consists of Screening, Run-in (1 week), Stabilization (12 weeks), Treatment (6 weeks) and Follow-up periods. - Part C (conducted at multiple sites) will determine safety, tolerability, and PD in subjects with T2D when co-dosed for 6 weeks with metformin. Part C consists of Screening, Run-in (1 week), Stabilization (12 weeks), Treatment (6 weeks) and Follow-up periods.

Inclusion Criteria:Part A (Healthy Subjects)

• Subject able to understand and voluntarily provide the consent to participate in the study
• 18 - 70 years of age, inclusive, at the time of signing the informed consent and Body Mass Index (BMI) between 18.0 and 35.0 Kilogram (kg) per m^2, inclusive
• Understands and is willing, able and likely to be compliant with taking study drug and comply with all study procedures and restrictions
• Subject is willing to consume the foods that are part of the standardized breakfast, lunch, and dinner
• In good general health with no clinically significant and relevant abnormalities of medical history or physical examination which includes adequate renal function, alanine transaminase (ALT), alkaline phosphatase and bilirubin <=1.5x Upper Limit of Normal (ULN )
• QTcF < 450 millisecond (msec); or QTcF < 480msec for subjects with right Bundle Branch Block
• Females must be post-menopausal
• Females on hormone replacement therapy (HRT) must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment
• Females who are > 3 months postpartum and who have undergone a surgical sterilization procedure are eligible to participate in consultation with the GSK Medical Monitor

Parts B and C (Type 2 Diabetic Subjects)

• All the criteria mentioned in Part A except Body Mass Index (BMI) should be between 30.0 and 42.0 kg per m^2
• Diagnosis of T2D for at least 3 months, as defined by the American Diabetes Association
• All T2D subjects must meet label recommendations for metformin
• For Part B, subjects must be willing to discontinue metformin and replace it with daily liraglutide administered by subcutaneous injection and they must meet label recommendations
• No personal history or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2

Exclusion Criteria:

• History of gastrointestinal disease, current or chronic history of liver disease, history of serious, severe or unstable physical or psychiatric illness , significant cardiovascular disease, surgery for weight loss or gastrointestinal surgery within 3 months of screening, any documented or reported eating disorder, uncontrolled hypertension, as evidenced by systolic pressure>160 or diastolic pressure >90 mmHg
• Positive test for HIV, Hepatitis B, or Hepatitis C at Screening
• Subjects with significant ECG abnormalities
• For subjects in Part C (continuing metformin), history of untreated pernicious anemia or who have laboratory parameters suggestive of subclinical megaloblastic anemia
• Presence of or symptoms of an active infection
• Uncorrected Thyroid Dysfunction
• History of chronic or acute pancreatitis
• Currently dieting to lose weight including, but not limited to, participation in a program designed to alter body weight within the last 60 days and unwilling to maintain relatively consistent exercise patterns throughout the study
• Current or recent history (within one year of screening) of alcohol or other substance abuse
• Unable to refrain from the use of non-prescription drugs
• Current participation in another clinical study or participation in a clinical study involving an investigational drug within 30 days of the screening visit
• History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy
• An employee of the sponsor or the study site or members of their immediate family.