A Clinical Study to Evaluate the Safety, Tolerability, PK, PD, and Efficacy of KBP-089 in Patients With T2DM

Study Overview
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Brief Summary
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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.

Official Title
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A Double-blind, Placebo-controlled, Randomised, Multiple-ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of KBP-089 in Patients With Type II Diabetes

Conditions
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Type II Diabetes Mellitus

Intervention / Treatment
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* Drug: Daily injection of KBP/placebo for up to 28 days


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomised, patient-blind, investigator-blind, placebo-controlled, multiple ascending dose study. There will be 3 cohorts in which patients are randomised to receive either treatment with KBP-089 or placebo.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: KBP-089<br>Three cohorts: Cohort 1: starting dose 5 µg, maximum dose 20 µg, uptitration step 7 days, dose increment 5 µg Cohort 2: starting dose 7.5 µg, maximum dose 60 µg, uptitration step 3 days, dose increment 7.5 µg Cohort 3: starting dose 5 µg, maximum dose 120 µg, uptitration step 3 days, dose increment 5, 10, 15 and 20 µg | Drug: Daily injection of KBP/placebo for up to 28 days<br>* Daily sub-cutaneous injection of KBP-089/Placebo into a lifted skin fold of the abdominal wall.The injection will be administered in the morning before breakfast.<br>|
| Placebo Comparator: Placebo<br>For all the cohorts, sentinel dosing for the first two patients will be performed 1:1 in a blinded manner. | Drug: Daily injection of KBP/placebo for up to 28 days<br>* Daily sub-cutaneous injection of KBP-089/Placebo into a lifted skin fold of the abdominal wall.The injection will be administered in the morning before breakfast.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Emergent Adverse Events (TEAEs). | All TEAEs will be coded using MedDRA and summarized by treatment and dose. | Day -1 to day 28 | 
| Vital sign - Blood Pressure. | Diastolic and systolic blood pressure (mmHg) are measured after at least 5 min rest in a supine position. Vital signs will be summarised by descriptive statistics by treatment, dose and timepoint. | Day -1 to day 28 | 
| Vital sign - Pulse (beats per min). | measured after at least 5 min rest in a supine position. Vital signs will be summarised by descriptive statistics by treatment, dose and timepoint. | Day -1 to day 28 | 
| Vital sign - Body Temperature. | Body temperature, tympanic (in Celcius). Vital signs will be summarised by descriptive statistics by treatment, dose and timepoint. | Day -1 to day 28 | 
| Vital sign - Respiratory frequency. | Respiratory frequency measured as breaths per min. Vital signs will be summarised by descriptive statistics by treatment, dose and timepoint. | Day -1 to day 28 | 
| Electrocardiogram (ECG) - PQ interval. | PQ interval (in msec) and any abnormality will be recorded and described in the CRF including the Investigator's assessment of clinical significance ('abnormal, not clinically significant' or 'abnormal, clinically significant'). | Day -1 to day 28 | 
| Electrocardiogram (ECG) - QRS complex. | QRS interval (in msec) and any abnormality will be recorded and described in the CRF including the Investigator's assessment of clinical significance ('abnormal, not clinically significant' or 'abnormal, clinically significant'). | Day -1 to day 28 | 
| Electrocardiogram (ECG) - QT interval. | QT interval (in msec) and any abnormality will be recorded and described in the CRF including the Investigator's assessment of clinical significance ('abnormal, not clinically significant' or 'abnormal, clinically significant'). | Day -1 to day 28 | 
| Safety laboratory parameter - lipids. | Standard Lipid assessments will be summarized by treatment (including dose) using descriptive statistics (number, mean, standard deviation, minimum, median and maximum). (Lipid parameters measured: Total cholesterol, High-density lipoprotein (HDL) cholesterol, Low-density lipoprotein (LDL) cholesterol, Triglycerides). | Day -1 to day 28 | 
| Safety laboratory parameter - haematology. | Standard Biochemistry assessments will be summarized by treatment (including dose) using descriptive statistics (number, mean, standard deviation, minimum, median and maximum). (Haematology parameters measured: Haematocrit, Haemoglobin, Erythrocytes, Mean corpuscular volume (MCV), Mean corpuscular haemoglobin (MCH), Mean corpuscular haemoglobin concentration (MCHC), Thrombocytes (platelets), Leucocytes, Neutrophile granulocytes (total count and relative), Lymphocytes (total count and relative), Monocytes (total count and relative), Eosinophile granulocytes (total count and relative), Basophile granulocytes (total count and relative)) | Day -1 to day 28 | 
| Safety laboratory parameter - coagulation. | Standard coagulation assessments will be summarized by treatment (including dose) using descriptive statistics (number, mean, standard deviation, minimum, median and maximum). (coagulation parameters measured: International normalised ratio (INR), Activated partial thromboplastin time (APTT) | Day -1 to day 28 | 
| Safety laboratory parameter - urinalysis. | Standard Biochemistry assessments will be summarized by treatment (including dose) using descriptive statistics (number, mean, standard deviation, minimum, median and maximum). (Urinalysis parameters measured: Protein, Glucose, Erythrocytes, Leucocytes, pH, Ketones) | Day -1 to day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic Evaluation - KBP-089 Area Under Curve. | PK parameter (AUC 0-24) will be derived by non-compartmental analysis of the plasma concentration data for KBP-089 | Day -1 to day 28 | 
| Pharmacokinetic Evaluation - KBP-089 Cmax. | PK parameter (Cmax) will be derived by non-compartmental analysis of the plasma concentration data for KBP-089 | Day -1 to day 28 | 
| Gastric emptying - Paracetamol Cmax. | Gastric emptying is measured using paracetamol Cmax at baseline (Day -1), Day 1, and Day 28 for Cohorts 1 and 2 only | Day -1 to day 28 | 
| Gastric emptying - Paracetamol Tmax. | Gastric emptying is measured using paracetamol Tmax at baseline (Day -1), Day 1, and Day 28 for Cohorts 1 and 2 only | Day -1 to day 28 | 
| Gastric emptying - Paracetamol Area Under Curve (AUC). | Gastric emptying is measured using paracetamol AUC at baseline (Day -1), Day 1, and Day 28 for Cohorts 1 and 2 only | Day -1 to day 28 | 
| Fasting and postprandial glucose concentration. | Fasting and postprandial glucose following OGTT at baseline (Days -1) and Day 28 | Day -1 to day 28 | 
| Fasting and postprandial insulin concentration. | Insulin following OGTT at baseline (Days -1) and Day 28 | Day -1 to day 28 | 
| Fasting and postprandial C-peptide concentration. | Fasting and postprandial C-peptide following OGTT at baseline (Days -1) and Day 28 | Day -1 to day 28 | 
| Fasting and postprandial glucagon concentration. | Fasting and postprandial glucagon following OGTT at baseline (Days -1) and Day 28 | Day -1 to day 28 | 
| Body weight. | Body weight at Day -1 (baseline) and Day 28 (in kg) | Day -1 to day 28 | 
| N-(1-deoxy)-fructosyl-haemoglobin (HbA1c). | HbA1c at Day -1 (baseline) and Day 28 (in mmol/mol) | Day -1 to day 28 | 
| Fridericia's corrected QT interval (QTcF). | Fridericia's corrected QT interval (QTcF) at Day 1 and Day 27 (in msec) | Day 1 to day 27 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sub-cutaneous injection, Metformin, KBP-089, randomised, placebo-controlled, multiple-ascending dose