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

This is a two-part, single centre, double-blind (within cohorts), randomised, placebo-controlled, single (Part 1) and multiple (Part 2) ascending subcutaneous dose study in lean to overweight or obese but otherwise healthy men (Part 1) and men and non-pregnant, non-lactating women (Part 2). The primary objective is to assess the safety and tolerability. Secondary objectives are to characterize the pharmacokinetics (PK) and to investigate pharmacodynamic effects.

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). 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.

Eligibility Criteria:
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, 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 and ≤110 kg (all parts), and for females ≥60 kg and ≤110 kg (Part 2A and 2B 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 2A and 2B 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
* 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