a two-part first-in-human study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of gub014295

Conditions: Healthy Volunteers; Overweight

Summary: 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). 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.

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 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) \ 150 mmhg (systolic) and/or \ 90 mmhg (diastolic) * heart rate (ecg-recorded after ≥5 min rest) \ 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

Keywords: weight management