The trial was planned to be conducted in 4 cohorts but was terminated after completion of Cohort 2 for strategic reasons due to limited PD effects.

KeyBioscience is developing KBP-089, a dual activator of both the amylin and calcitonin receptors, for the treatment of type II diabetes mellitus, using a subcutaneous injectable mode of administration.

This is a double-blind, placebo-controlled, randomised, multiple-ascending dose phase I trial to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of KBP-089 in patients with type 2 diabetes, who are on stable therapy with metformin.

Subjects will receive daily subcutaneous injections in the abdomen over a period of 28 days. The planned maximum doses of KBP-089 to be investigated in the trial are 20 µg in cohort 1, 60 µg in cohort 2, and 150 µg in cohort 3. For cohort 1, the dose is planned to be escalated every 7 ±1 days, and for cohort 2 and cohort 3, every 3 days. Doses may be modified according to individual tolerability, but the dose regimen will not exceed 28 days.

The IMP is administered by daily subcutaneous injections taken in the morning before breakfast.

The trial is performed in Germany and at least 36 patients will be enrolled in the trial. The trial will be randomised 1:1:1 between maximum doses of KBP-089 of 20 µg, 60 µg, 150 µg and placebo. Within each of the three cohorts, 12 patients will be randomised 3:1 to KBP-089 and placebo.

Inclusion Criteria:

• Signed and dated informed consent obtained before any trial-related activities. (Trial-related activities are any procedures that would not have been performed during normal management of the patient).
• Male or female patient with T2DM.
• Age between 18 and 64 years, both inclusive.
• Body Mass Index (BMI) >= 25.0 kg/m^2.
• HbA1c >= 7 and <=9.5%.
• Stable therapy with metformin ± treatment with a second oral anti-diabetes drug (OAD) belonging to the class of dipeptidyl-peptidase 4 (DPP-4) inhibitors or sulfonylureas for at least 2 months prior to inclusion into the trial or not treated with glucose-lowering medications. Patients who are receiving stable treatment with a second OAD will be asked to discontinue the DPP-4 inhibitor or a sulfonylurea for at least 14 days prior the Initial Inpatient Dosing Visit.
• Considered generally healthy (apart from T2DM) upon completion of medical history, physical examination, vital signs, ECG and analysis of laboratory safety variables, as judged by the Investigator.

Exclusion Criteria:

• Known or suspected hypersensitivity or allergy to paracetamol or related products.
• Prior treatment with a dual amylin and calcitonin receptor agonist (DACRA) or salmon calcitonin.
• Receipt of any medicinal product in clinical development within 30 days or 5 half-lives of the medicinal product (whichever is longer) before randomisation in this trial.
• History of multiple and/or severe allergies to drugs or foods or a history of severe anaphylactic reaction.
• Any history or presence of clinically relevant cardiovascular, pulmonary, respiratory, gastrointestinal, hepatic, renal, metabolic, endocrinological (with the exception of conditions associated with diabetes mellitus), haematological, dermatological, neurological, osteomuscular, articular, psychiatric, systemic, ocular, gynaecologic (if female), or infectious disease, or signs of acute illness as judged by the Investigator.
• Medically unable or unwilling to discontinue current anti-diabetic therapy with DPP-4 inhibitor or sulfonylurea for at least 14 days prior to admission to the research facility (Day -2) and remain off medication until the follow-up visit. Patients taking metformin therapy at entry will continue their metformin at the usual individual dose throughout the trial.
• Have had a significant change in weight, defined as a gain or loss of at least 5% body weight in the 3 months prior to screening.
• A positive result in the alcohol and/or urine drug screen at the screening visit.
• Positive to the screening test for Hepatitis Bs antigen (HBsAg) or Hepatitis C antibodies and/or a positive result to the test for human immunodeficiency virus (HIV)-1/2 antibodies or HIV-1 antigen.
• Have had a blood transfusion or severe blood loss within the past 6 months or have known hemoglobinopathy, hemolytic anemia, sickle cell anemia, or have a hemoglobin value <11 g/dL (males) or <10 g/dL (females), or any other condition known to interfere with HbA1c methodology.
• Blood donation or blood loss of more than 500 mL within the last 3 months or any blood donation within the last month prior to screening.
• Females of childbearing potential.
• Males with pregnant partners.

To preserve the blinding of the study for KBP-089 and placebo, all study site personnel, except pharmacy staff who prepare and dispense study medication, and the Sponsor's medical monitor who interacts with site personnel will be blinded to treatment allocation. Blinding of KBP-089 and placebo will be maintained throughout the conduct of the trial until after the completion of the trial and final data review.

Treatment assignment will be kept strictly confidential and accessible only to authorised persons until after the time of unblinding. Codes with treatment assignment will, however, be readily available to the blinded personnel in case of an emergency.