Safety and Pharmacokinetic Study of Y242 in Adult Subjects

Study Overview
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Brief Summary
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Obesity causes 600 premature deaths per week in the UK and existing treatments are not effective. When humans eat, the bowels naturally secrete chemicals into the bloodstream which make people feel full and which stop eating. One of these chemicals is known as Peptide YY (PYY). The investigators have previously shown that injections of PYY reduce appetite and food intake in human volunteers. The investigators have now developed a very similar chemical, Y242, as a treatment for obesity. Y242 has been tested in animals and has been shown to be safe, to reduce their appetite, and to last for much longer than PYY itself. This study will test Y242 to ensure that it is well tolerated in humans, and to see how long it lasts in the blood stream after being injected under the skin. It will also look for any effects on appetite.

Detailed Description
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Obesity causes 600 premature deaths per week in the UK and existing treatments are less than ideal. Intravenous infusion of a hormone called PYY reduces food intake but its effects only last for a few hours and it can cause nausea. Y242 is a longacting analogue of PYY. Given subcutaneously in rodents, it has a profile of action of at least 72 hours and strongly inhibits food intake. It causes weight loss without behavioural effects. With MRC funding, Y242 has passed Good Laboratory Practice toxicology testing and the present proposal is a first in human study to investigate its safety, tolerability and pharmacokinetics in overweight but otherwise healthy men. The study is a combined single ascending dose (part A) and multiple ascending dose (part B) Phase 1 investigation. The primary objective is to investigate safety and tolerability. The secondary objective is to assess Y242's pharmacokinetic (PK) profile. Possible effects on food consumption will be explored. For part A up to 48 subjects are planned, with up to 40 subjects for part B. In each part subjects are divided into groups, each of which is dosed with the same level, starting with a single dose (part A) much lower than is expected to cause an effect. Subjects are admitted to a Unit so they can be closely observed for adverse effects and safety tests, blood concentrations of the drug and food and liquid intake and output will be monitored. Subjects are allocated at random (like tossing a coin) to receive Y242 or placebo (dummy). Safety, tolerability and pharmacokinetic data will be summarised and available results considered in deciding dose escalation, with stopping rules designed to enable us to explore the relationship between dose and adverse effect (eg nausea) without causing unacceptable nausea or other symptoms in the volunteers.

Official Title
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A Randomised, Placebo Controlled Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Y242 in Adult Subjects

Conditions
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Obesity

Intervention / Treatment
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* Drug: Y242
* Drug: 0.9% saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult males aged 18 to 50 years inclusive with BMI between 23.0 and 30.0 kg/m^2 inclusive; Subjects who are healthy as determined by pre study medical history, physical examination and 12 lead ECG; Subjects whose clinical laboratory test results are either within the normal range or if outside this range the abnormalities are judged to be not clinically relevant and are acceptable to the Investigator; Subjects who are negative for hepatitis B surface antigen (HBsAg), hepatitis C antibody and human immunodeficiency virus (HIV) I and II tests at screening; Subjects who are negative for drugs of abuse and alcohol tests at screening and admissions; Subjects who are non-smokers for at least 3 months preceding screening; Subjects who agree to use medically acceptable methods of contraception for at least 3 months after study drug administration; Subjects who are able and willing to give written informed consent. Exclusion Criteria: Subjects who do not conform to the above inclusion criteria; Subjects who have a clinically relevant history or presence of gastrointestinal (especially associated with vomiting), respiratory, renal, hepatic, haematological, lymphatic, neurological (especially if associated with balance disorders or vomiting e.g. migraine or labyrinthitis), cardiovascular, psychiatric, musculoskeletal, genitourinary, immunological, dermatological, connective tissue diseases or disorders; Subjects who have a clinically relevant surgical history; Subjects who have a clinically relevant family history; Subjects who have a history of relevant atopy; Subjects who have a history of relevant drug hypersensitivity; Subjects who have a history of alcoholism; Subjects who have a history of drug abuse; Subjects who have a history of migraine; Subjects who consume more than 21 units of alcohol a week (unit = 1 glass of wine (125 mL) = 1 measure of spirits = ½ pint of beer); Subjects who have a significant infection or known inflammatory process on screening; Subjects who have acute gastrointestinal symptoms at the time of screening or admission (e.g. nausea, vomiting, diarrhoea, heartburn); Subjects who have an acute infection such as influenza at the time of screening or admission; Subjects who have used prescription drugs within 4 weeks of first dosing; Subjects who have used over the counter medication excluding routine vitamins and paracetamol but including megadose (intake of 20 to 600 times the recommended daily dose) vitamin therapy within 7 days of first dosing, unless agreed as not clinically relevant by the Principal Investigator and Sponsor; Subjects who have donated blood or blood products within 3 months of Day -2 (admission); Subjects who have used any investigational drug in any clinical trial within 3 months of Day -2 (admission); Subjects who have received the last dose of investigational drug greater than 3 months ago but who are on extended follow-up; Subjects who have previously received Y242; Subjects who are vegans or have any dietary restrictions; Subjects who cannot communicate reliably with the Investigator; Subjects who are unlikely to co-operate with the requirements of the study; History or evidence of abnormal eating behaviour, as observed through the Dutch Eating Behaviour (DEBQ) and SCOFF questionnaires at screening.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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: Part A was a single blind, randomised, placebo controlled, single ascending dose (SAD) study. Part B was a double blind, randomised, placebo controlled, multiple ascending dose (MAD) study
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 2mg Y242 (Part A)<br>Y242 single dose, subcutaneous | Drug: Y242<br>* Single ascending dose: subcutaneous injection of 2, 7.5, 15, 30, 60 and 90 mg Y242 (Part A); Multiple ascending dose: Y242 single subcutaneous dose, administered once a week for 5 weeks (Part B)<br>|
| Experimental: 7.5mg Y242 (Part A)<br>Y242 single dose, subcutaneous | Drug: Y242<br>* Single ascending dose: subcutaneous injection of 2, 7.5, 15, 30, 60 and 90 mg Y242 (Part A); Multiple ascending dose: Y242 single subcutaneous dose, administered once a week for 5 weeks (Part B)<br>|
| Experimental: 15mg Y242 (Part A)<br>Y242 single dose, subcutaneous | Drug: Y242<br>* Single ascending dose: subcutaneous injection of 2, 7.5, 15, 30, 60 and 90 mg Y242 (Part A); Multiple ascending dose: Y242 single subcutaneous dose, administered once a week for 5 weeks (Part B)<br>|
| Experimental: 30mg Y242 (Part A)<br>Y242 single dose, subcutaneous | Drug: Y242<br>* Single ascending dose: subcutaneous injection of 2, 7.5, 15, 30, 60 and 90 mg Y242 (Part A); Multiple ascending dose: Y242 single subcutaneous dose, administered once a week for 5 weeks (Part B)<br>|
| Experimental: 60mg Y242 (Part A)<br>Y242 single dose, subcutaneous | Drug: Y242<br>* Single ascending dose: subcutaneous injection of 2, 7.5, 15, 30, 60 and 90 mg Y242 (Part A); Multiple ascending dose: Y242 single subcutaneous dose, administered once a week for 5 weeks (Part B)<br>|
| Experimental: 90mg Y242 (Part A)<br>Y242 single dose, subcutaneous | Drug: Y242<br>* Single ascending dose: subcutaneous injection of 2, 7.5, 15, 30, 60 and 90 mg Y242 (Part A); Multiple ascending dose: Y242 single subcutaneous dose, administered once a week for 5 weeks (Part B)<br>|
| Placebo Comparator: Placebo - Part A<br>0.9% saline | Drug: 0.9% saline<br>* Identical volume to that of Y242<br>|
| Experimental: 60mg Y242 (Part B1)<br>Y242 single subcutaneous dose, administered once a week for 5 weeks | Drug: Y242<br>* Single ascending dose: subcutaneous injection of 2, 7.5, 15, 30, 60 and 90 mg Y242 (Part A); Multiple ascending dose: Y242 single subcutaneous dose, administered once a week for 5 weeks (Part B)<br>|
| Experimental: 90mg Y242 (Part B2-B4)<br>Y242 single subcutaneous dose, administered once a week for 5 weeks | Drug: Y242<br>* Single ascending dose: subcutaneous injection of 2, 7.5, 15, 30, 60 and 90 mg Y242 (Part A); Multiple ascending dose: Y242 single subcutaneous dose, administered once a week for 5 weeks (Part B)<br>|
| Placebo Comparator: Placebo - Part B<br>0.9% saline | Drug: 0.9% saline<br>* Identical volume to that of Y242<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | A treatment-emergent AE (TEAE) as defined as an AE that started after administration of IMP; in Part B this was an AE that started after the first dose of IMP. Adverse events with onset prior to dosing were considered as pre-treatment AEs. | Up to 73 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Body Weight | Summary of Time-Matched % Change from Baseline in Body Weight (Baseline = Day -1) following multiple dose of Y242 (Part B) | up to 32 day | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Food intake, Obesity, Peptide YY, Safety, Pharmacokinetics