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

This is a phase 1 clinical trial of a new long-acting amylin analogue GUB014295 in two parts.

Trial design: Part 1 is a double-blind (within cohorts), randomised, placebo-controlled, single ascending dose (SAD) study. It is planned to enrol 4 cohorts of 8 subjects (Regimens A, B, C and D), with 2 additional optional cohorts of 8 subjects (Regimens E and F). Part 2A is a double-blind (within cohorts), randomised, placebo-controlled, multiple ascending dose (MAD) study. It is planned to enrol 2 cohorts of 8 subjects (Regimens G and H). Part 2B is a double-blind (within cohorts), randomised, placebo-controlled, MAD study.

It is planned to enrol 3 cohorts of 12 subjects (Regimens I, J and K). Part 2C is a double-blind (within cohorts), randomised, placebo-controlled, MAD study. It is planned to enrol 2 cohorts of up to 12 subjects (Regimens L and M).

The primary objective is to assess the safety and tolerability 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.

Inclusion criteria

• Males (Part 1 only) aged 18 to 55 years, and males and females (Part 2 only) aged 18 to 65 years inclusive at the time of signing informed consent
• Must agree to adhere to the contraception requirements
• Lean to overweight or obese but otherwise healthy males (Part 1 and 2) or nonpregnant, non-lactating females (Part 2 only)
• BMI of 22.0 to 32.0 kg/m2 for Part 1 and Part 2A, and a BMI of 27.0 to 35.0 kg/m2 for Part 2B and Part 2C, as measured at screening. Overweight or obese as assessed by BMI should be due to excess adipose tissue, as judged by the investigator
• Weight for males ≥70 kg (all parts), and for females ≥60 kg (Part 2 only) at screening

Exclusion criteria

• 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
• Part 2B only: Subjects with haemoglobin <LLN at screening and/or admission
• Prolongation of the QTcF over 450 msec for males and 470 msec for females 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 <70 mL/min/1.73m2
• Part 2 only: Females who are pregnant or lactating (all female subjects must have a negative highly sensitive urine or serum pregnancy test)
• 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 (Part 1 Cohorts 2 to 6), Day 39 (Part 2A) and Day 81 (Part 2B) 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 and in females >14 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