A First-In-Human Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GUB014295

Study Overview
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Brief Summary
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This is a single center, double-blind, randomized, placebo-controlled, single ascending subcutaneous dose study in lean to overweight or obese but otherwise healthy men. It is planned to enroll 4 cohorts of 8 subjects (Regimens A, B, C and D), with 2 additional optional cohorts of 8 subjects (Regimens E and F). Within each cohort, subjects will be randomized in a ratio of 6 active to 2 placebo. The primary objective is to assess the safety. Secondary objectives are to characterize the pharmacokinetics (PK) and to investigate pharmacodynamic effects.

Detailed Description
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This is a first in human clinical trial assessing a single dose of a new long-acting amylin analogue GUB014295. Trial design: This is a single center, double-blind, randomized, placebo-controlled, single ascending subcutaneous dose study in lean to overweight or obese but otherwise healthy men. It is planned to enroll 4 cohorts of 8 subjects (Regimens A, B, C and D), with 2 additional optional cohorts of 8 subjects (Regimens E and F). Within each cohort, subjects will be randomized in a ratio of 6 active to 2 placebo. The primary objective is to assess the safety of a new long-acting amylin-analogue GUB014295. Secondary objectives are to characterize the pharmacokinetics (PK) of the long-acting amylin-analogue GUB014295 and to investigate if the long-acting amylin-analogue GUB014295 has possible pharmacodynamic effects measured as weight changes and changes in gastric emptying (paracetamol concentration) and changes in glucose, insulin, C-peptide, and glucagon during a mixed meal test.

Official Title
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A First-in-Human Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Ascending Subcutaneous Doses of GUB014295 in Lean to Overweight or Obese But Otherwise Healthy Men

Conditions
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Healthy Volunteers, Overweight

Intervention / Treatment
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* Drug: GUB014295
* Drug: GUB014295-PLACEBO


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Lean to overweight or obese but otherwise healthy males BMI of 22.0 to 32.0 kg/m2 as measured at screening. Overweight or obese as assessed by BMI should be due to excess adipose tissue, as judged by the investigator Weight ≥70 kg at screening Exclusion Criteria: Medical/Surgical History and Mental Health Serious adverse reaction or serious hypersensitivity to any drug or formulation excipients Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hay fever is allowed unless it is active Known or suspected hypersensitivity or allergy to paracetamol Presence or history of clinically significant cardiovascular, renal, hepatic, dermatological, respiratory, neurological, psychiatric, malignant, metabolic, endocrinological, haematological or venereal disorder, as judged by the investigator Presence or history of any clinically relevant gastrointestinal diseases or symptoms of gastrointestinal disorders potentially affecting interpretation of study data. Presence or history of diseases associated with impaired calcium homeostasis and/or increased bone turnover (e.g. Paget´s disease, osteoporosis) History of major depressive disorder within 2 years prior to screening Subjects unable to take paracetamol for any reason Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator or delegate at screening Subjects with tattoos or scars on the abdomen which may interfere with injection site assessments as determined by the investigator or delegate at screening Clinically significant abnormal clinical chemistry, haematology, coagulation or urinalysis as judged by the investigator . Subjects with Gilbert's Syndrome are not allowed. HbA1c ≥48 mmol/mol (≥6.5%) and/or fasting plasma glucose ≥7.0 mmol/L at screening Prolongation of the QTcF over 450 msec or any other clinically significant abnormal ECG results as judged by the investigator Supine blood pressure (after ≥5 min rest) <90 mmHg or >150 mmHg (systolic) and/or <50 mmHg or >90 mmHg (diastolic) Heart rate (ECG-recorded after ≥5 min rest) <45 or >90 beats per minute Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) 1 and 2 antibody results Evidence of renal impairment at screening, as indicated by an estimated glomerular filtration rate (eGFR) of <80 mL/min/1.73m2 Subjects who have received any investigational medicinal product (IMP) in a clinical research study within the 90 days prior to Day 1, or less than 5 elimination half-lives prior to Day 1, whichever is longer Subjects who have previously been administered IMP in this study Donation of blood or plasma within the previous 3 months or loss of greater than 400 mL of blood Subjects who are taking, or have taken, any prescribed or over-the-counter drug or herbal remedies/vitamins in the 14 days before IMP administration. Paracetamol (up to 4 g per day) will be permitted except in the 48 h prior to the mixed meal tests on Day -1 and Day 4 for Cohorts 2 to 6 where paracetamol is not permitted. NSAIDs can be given at the discretion of the investigator to treat any AEs if necessary; Subject reports prior receipt of an amylin and/or calcitonin receptor agonist within the last 6 months History of any drug or alcohol abuse in the past 2 years Regular alcohol consumption >21 units per week A confirmed positive alcohol breath test at screening or admission Current smokers and those who have smoked within the last 12 months Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months A confirmed breath carbon monoxide reading of greater than 10 ppm at screening or admission Confirmed positive drugs of abuse test result at screening or admission Anticipated change in lifestyle (such as eating, exercise or sleeping pattern) during the trial and/or clinically significant body weight change (≥5% self-reported change) or comprehensive dieting attempts (e.g. participation in a weight reduction program or treatment with any medication indicated for weight management) within the last 90 days prior to screening Subjects who do not agree to consume the liquid mixed meal Male subjects with pregnant or lactating partners Any disorder, unwillingness or inability, not covered by any of the other exclusion criteria, that the investigator evaluates might jeopardise the subject's safety or compliance with the protocol

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: This first-in-human (FIH) study, will be conducted to assess the safety, tolerability, and pharmacokinetics (PK) of single ascending subcutaneous doses of GUB014295
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>placebo solution | Drug: GUB014295-PLACEBO<br>* GUB014295-PLACEBO is matching GUB014295 in appearance, a single subcutaneous dose is administered.<br>|
| Active Comparator: GUB014295<br>GUB014295 solution 5 mg/mL | Drug: GUB014295<br>* GUB014295 is a long-acting amylin analogue in development, a single subcutaneous dose is administered.<br>* Other names: GUBamy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety - Adverse Events (AE) incidence | To provide safety information for GUB014295 by assessing: incidence of AEs categorized in System Organ Class (SOC) according to MedDRA (and evaluating severity and duration for SOC). No formal hypothesis will be tested in the study. Descriptive summaries for all safety safety data for all placebo, each active treatment and all active will be provided (including changes from baseline) | from baseline (day 0) to end of trial (day 29) | 
| Safety - changes in vital signs | To provide safety information for GUB014295 by assessing: Any changes from baseline for vital signs including: Blood pressure, Pulse/heart rate, oral temperature and respiratory frequency summarized as a ratio (baseline/day 29). No formal hypothesis will be tested in the study. Descriptive summaries (as a relative change (ratio: 0 - 1) from day 0 to day 29) for all safety safety data for all placebo, each active treatment and all active will be provided. | from baseline (day 0) to end of trial (day 29) | 
| Safety - Safety laboratory parameters | To provide safety information for GUB014295 by assessing a wide range of laboratory parameters within hematology, coagulation, clinical chemistry, virology, urinalysis. No formal hypothesis will be tested in the study. Descriptive summaries (as a relative change (ratio: 0 - 1) from day 0 to day 29)) for all safety safety data for all placebo, each active treatment and all active will be provided. | from baseline (day 0) to end of trial (day 29) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic (PK) - Tmax and Cmax | PK parameters: Tmax, (time of observed maximum concentration), Cmax (maximum observed concentration), for GUB014295. | from dosing (day 0) until maximum concentration (estimated day 4) | 
| Pharmacokinetic (PK) - area under the concentration curve (AUC) | PK parameters: AUC(0-72) area under the curve for the GUB014295 measured from dosing, until 72 hours post dose, AUC(0-168) area under the curve for the GUB014295 measured from dosing, until 168 hours post dose, AUC(0-last) area under the curve for the GUB014295 measured from dosing, until the time of last measurable concentration, AUC(0-inf) area under the curve for the GUB014295 concentration from dosing, extrapolated until infinity. | from dosing (day 0) until end of trial (day 29) | 
| Pharmacokinetic (PK) - T1/2 | PK parameters: T1/2: Terminal elimination half-life, | from dosing (day 0) until end of trial (day 29) | 
| Pharmacokinetic (PK) - CL/F | PK parameters: CL/F: Total body clearance (CL) calculated after single subcutaneous administration where F (fraction of bioavailability) is unknown, | from dosing (day 0) until end of trial (day 29) | 
| Pharmacokinetic (PK) - Vz/F | PK parameters: Vz/F: apparent volume of distribution (Vz) based on terminal phase calculated using AUC(0-inf) after a single subcutaneous administration where F (fraction of bioavailability) is unknown, | from dosing (day 0) until end of trial (day 29) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Weight management