TAK-648 in Healthy Japanese Participants and Non-Japanese Participants With Type 2 Diabetes Mellitus

The drug being evaluated in this study is TAK-648 for the treatment of T2DM.

This study will consist of 2 parts: (1) multiple ascending doses in participants with T2DM,
(2) multiple ascending doses in healthy participants of Japanese descent.

Part 1 of this study will consist of 2 multiple dose treatment cohorts (Cohorts 1-2
designated as P1C1and P1C2) dosed sequentially in escalating order. The projected doses of
TAK-648 for Part 1 are 0.15 and 0.35 mg of TAK-648, but may be adjusted higher or lower, and
additional cohorts may be added, based on available safety and pharmacokinetic (PK) data.
All cohorts in Part 1 will consist of 8 (2 placebo) T2DM participants.

Part 2 of this study will consist of 3 multiple dose treatment cohorts (Cohorts 1-3
designated as P2C1, P2C2 and P2C3) in healthy participants of Japanese descent dosed
sequentially in escalating order. The projected doses of TAK-648 chosen for Part 2 are 0.05,
0.15 and 0.35 mg of TAK-648, but may be adjusted higher or lower based on available safety
and PK data. All cohorts in Part 2 will consist of 8 (2 placebo) healthy participants of
Japanese descent.

Additional cohorts may be recruited and studied as necessary to better evaluate safety,
tolerability, PK, and/or PD parameters.

Inclusion Criteria:

Part 1:

- has a historical diagnosis of T2DM disease, on diet and exercise or on metformin

- weighs at least 55 kg and has a body mass index (BMI) from 25.0 to 30.0 kg/m^2,
inclusive at Screening

- has a systolic blood pressure >90 and ≤150 mm Hg and a diastolic blood pressure of
>60 and ≤90 mm Hg at Screening and at Check-in (Day -2)

- has a calculated creatinine clearance >60 mL/min at Screening and Check-in (Day -2)

- hemoglobin A1c (HbA1c) level between 7.0% and 10.0%, inclusive

Part 2:

- Health participants of Japanese origin

Exclusion Criteria:

Part 1 and Part 2:

- has received any investigational compound within 30 days prior to the first dose of
study medication

- history of significant gastrointestinal (GI) disorders Part 1, has diagnosis of major
depression and risk of suicide, Part 1, is pregnant or lactating or intending to
become pregnant before, during, or within 12 weeks after participating in this study;
or intending to donate ova during such time period

- intends to donate sperm during the course of this study or for 12 weeks thereafter

- has a history of cancer, except basal cell carcinoma that has been in remission for
at least 5 years prior to Day 1

- has a positive test result for hepatitis B surface antigen (HBsAg), antibody to
hepatitis C virus (anti-HCV), at Screening or a known history of human
immunodeficiency virus infection

- has used nicotine-containing products (including but not limited to cigarettes,
pipes, cigars, chewing tobacco, nicotine patch or nicotine gum) within 28 days prior
to Check-in (Day -2). Cotinine test is positive at Screening or Check-in (Day -2)

- history of T1DM, hypoglycemia unawareness, diabetic ketoacidosis, or hyperosmolar
coma

- has received any antihyperglycemic medication with the exception of metformin within
the previous 12 weeks of Check-in (Day -2)