A 6-Part Study In Healthy Volunteers To Evaluate Safety, Tolerability and Uptake Of MEDI7219 in the Body When Given as Single and Multiple Doses

Study Overview
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Brief Summary
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This is a 6-part study to evaluate the safety, tolerability, and PK of MEDI7219 in healthy subjects. Parts A, B, C & E are the single-dose parts of the study. Parts D & F are the multiple ascending dose (MAD) parts of the study. The starting dose and formulation for Parts D & F will be selected from data emerging from Parts A, B and E. Enrollment of approximately 198 subjects is anticipated.

Detailed Description
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MEDI7219 is being developed for the potential treatment of type 2 diabetes. The study is a first in human, single and multiple ascending dose study that will try to identify the safety, tolerability and pharmacokinetics (how the drug moves through the body) of MEDI7219. The study will also look at the impact of changes to the formulation as well as differences related to the route of administration. The study will consist of 6 parts involving approximately 198 healthy male and female subjects (and up to 146 additional subjects). In Part A, 6 cohorts of 10 subjects each (with an optional 2 cohorts) will be randomized to receive MEDI7219 or one of two placebos. Each cohort will receive a different formulation of the study drug. In part B, a single cohort of 16 subjects (with an optional second cohort) will receive a different formulation of MEDI7219 per period in up to 5 periods. In Part C, up to 12 subjects will be dosed with MEDI7219. In Part D, one cohort of 30 subjects (with an optional second cohort) will be randomized to receive MEDI7219 or placebo. Subjects will start on a dose based on data from previous parts and will receive ascending doses for 35 days. In Part E, 2 cohorts of 6 subjects each (with an optional third & fourth cohort of 12 subjects each) will receive a different formulation of MEDI7219 per period. Part E, cohort 5 12 subjects each period (2 periods) has been added to assess 2 different formulations In Part F, two cohorts of 16 subjects each will be randomized to receive MEDI7219 or placebo. Subjects will start on a dose based on data from previous parts and will receive ascending doses for 35 days.

Official Title
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A Phase 1 Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability and Pharmacokinetics of MEDI7219 in Healthy Subjects, Including Assessment of the Impact of Changes to the Oral Formulation and Determination of Intravenous Pharmacokinetics

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: MEDI7219
* Drug: Placebo
* Drug: Formulation without Active Drug


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy volunteers age 18-55 years BMI 18-32 kg/m2 Females not of childbearing potential Able and willing to adhere to the protocol Must provide written informed consent Exclusion Criteria: Any concurrent condition that in the opinion of the investigator would interfere with the evaluation of the investigational product Abnormal lab values, physical exam, vital signs Positive drug or alcohol screen. Current enrollment in another clinical study or enrollment within the past 3 months Any clinically important illness, medical/surgical procedure, or trauma within 4 weeks prior to dosing Abnormal ECG Positive Hepatitis B, Hepatitis C or HIV test Positive Drug or Alcohol screen Current smokers or those who have smoked within the last 12 months Recent plasma or blood donation Evidence of current SARS-CoV-2 infection (Part E Cohort 5 and Part F Cohort 2 only)

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

Sexes Eligible for Study
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All

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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MEDI7219<br>Experimental Drug | Drug: MEDI7219<br>* Experimental Drug<br>|
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo<br>* Placebo<br>|
| Placebo Comparator: Formulation without Active Drug<br>Formulation without Active Drug | Drug: Formulation without Active Drug<br>* Formulation without Active Drug<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with Adverse Events as a measure of safety and tolerability of MEDI7219 | Treatment emergent adverse events (TEAEs) and serious adverse events (TESAEs) | Baseline to last follow up visit (Parts A and C - Day 28) (Part D & F Day 63) and (Parts B and E 28 days post last dose) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of MEDI7219: Cmax | PK parameters will be calculated from the plasma concentration versus time data for Cmax (maximum observed concentration) | Pre-dose to 144 hours post-dose (Parts A, B, C and Part E cohorts 1 & 2 only); Pre-dose to 168 hours post-dose (Part E optional cohorts only); Parts D & F pre-dose to Day 63/EOS visit | 
| Pharmacokinetics of MEDI7219: Tmax | PK parameters will be calculated from the plasma concentration versus time data for Tmax (time to maximum observed concentration) | Pre-dose to 144 hours post-dose (Parts A, B, C and Part E cohorts 1 & 2 only); Pre-dose to 168 hours post-dose (Part E optional cohorts only); Parts D & F pre-dose to Day 63/EOS visit, Parts F cohort 2 ONLY: Pre-dose and 8 hours post-dose | 
| Pharmacokinetics of MEDI7219: t1/2 | PK parameters will be calculated from the plasma concentration versus time data for T1/2 (terminal half-life) | Pre-dose to 144 hours post-dose (Parts A, B, C and Part E cohorts 1 & 2 only); Pre-dose to 168 hours post-dose (Part E optional cohorts only); Parts D & F pre-dose to Day 63/EOS visit | 
| Pharmacokinetics of MEDI7219: AUC (0-inf) | PK parameters will be calculated from the plasma concentration versus time data for AUC (0-inf) [area under the curve (AUC) extrapolated to infinity] | Pre-dose to 144 hours post-dose (Parts A, B, C and Part E cohorts 1 & 2 only); Pre-dose to 168 hours post-dose (Part E optional cohorts only); Parts D & F pre-dose to Day 63/EOS visit | 
| Pharmacokinetics of MEDI7219: AUC(0-last) | PK parameters will be calculated from the plasma concentration versus time data for AUC (0-last) [area under the curve (AUC) from time 0 to last measurable concentration] | Pre-dose to 144 hours post-dose (Parts A, B, C and Part E cohorts 1 & 2 only); Pre-dose to 168 hours post-dose (Part E optional cohorts only); Parts D & F pre-dose to Day 63/EOS visit | 
| Pharmacokinetics of MEDI7219: AUC(0-24h) | PK parameters will be calculated from the plasma concentration versus time data for (AUC 0-24) [area under the curve (AUC) from time 0 to 24 hours post dose] | Pre-dose to 144 hours post-dose (Parts A, B, C and Part E cohorts 1 & 2 only); Pre-dose to 168 hours post-dose (Part E optional cohorts only); Parts D & F pre-dose to Day 63/EOS visit | 
| Pharmacokinetics of MEDI7219: AUC (%extrap) | PK parameters will be calculated from the plasma concentration versus time data for AUC%extrapolated [The percentage of AUC(0-inf) accounted for by extrapolation] | Pre-dose to 144 hours post-dose (Parts A, B, C and Part E cohorts 1 & 2 only); Pre-dose to 168 hours post-dose (Part E optional cohorts only) | 
| Pharmacokinetics of MEDI7219: Lambda-z | PK parameters will be calculated from the plasma concentration versus time data for Lambda-z [Slope of the regression line passing through the apparent elimination phase in a concentration vs time plot] | Pre-dose to 144 hours post-dose (Parts A, B, C and Part E cohorts 1 & 2 only); Pre-dose to 168 hours post-dose (Part E optional cohorts only) | 
| Pharmacokinetics of MEDI7219: CL/F | PK parameters will be calculated from the plasma concentration for CL/F (apparent clearance) | Pre-dose to 144 hours post-dose (Parts A, B and Part E cohorts 1 & 2 only); Pre-dose to 168 hours post-dose (Part E optional cohorts only) | 
| Pharmacokinetics of MEDI7219: Vz/F | PK parameters will be calculated from the plasma concentration for Vz/F (volume of distribution) | Pre-dose to 144 hours post-dose (Parts A, B and Part E cohorts 1 & 2 only); Pre-dose to 168 hours post-dose (Part E optional cohorts only); Pre-dose to Day 63/EOS visit (Parts D & F) | 
| Pharmacokinetics of MEDI7219: Frel | PK parameters will be calculated from the plasma concentration for Frel (relative bioavailability) | Pre-dose to 144 hours post-dose (Parts B and Part E cohorts 1 & 2 only); Pre-dose to 168 hours post-dose (Part E optional cohorts only) | 
| Pharmacokinetics of MEDI7219: Vd | PK parameters will be calculated from the plasma concentration for Vd (volume of distribution) | Pre-dose to 144 hours (Part C) | 
| Pharmacokinetics of MEDI7219: F | PK parameters will be calculated from the plasma concentration for F (absolute bioavailability) | Pre-dose to 144 hours (Part C ) | 
| Pharmacokinetics of MEDI7219: AUC (0-tau) | PK parameters will be calculated from the plasma concentration versus time data for AUC (0-tau) [area under the curve (AUC) for a dosing interval] | Pre-dose to Day 63/EOS visit (Parts D & F) | 
| Immunogenicity | Presence of Anti-drug antibody to MEDI7219 | Day -1 to Day 28/EOS Visit (Parts A and C); Day -1 to Day 63/EOS Visit (Parts D & F); Day -1 to 28 days post last dose of final period/EOS Visit (Parts B and E) | 
| Pharmacokinetics of Formulation Component: Cmax | PK parameters will be calculated from the plasma concentration versus time data for Cmax (maximum observed concentration) | Predose to 8 hours post dose Day 1 (Parts A, B and E); Pre-dose to 8 hours post dose on Days 1, 7, 8, 14, 15, 21, 22, 28, 29 and 35 (Part D and F Cohort 1); Pre-dose to 24 hours post dose on Days 1, 14, 28 and 35 (Part F Cohort 2, respectively) | 
| Pharmacokinetics of Formulation Component: Tmax | PK parameters will be calculated from the plasma concentration versus time data for Tmax (time to maximum observed concentration) | Predose to 8 hours post dose Day 1 (Parts A, B and E); Pre-dose to 8 hours post dose on Days 1, 7, 8, 14, 15, 21, 22, 28, 29 and 35 (Part D and F Cohort 1); Pre-dose to 24 hours post dose on Days 1, 14, 28 and 35 (Part F Cohort 2, respectively) | 
| Pharmacokinetics of Formulation Component: T(1/2) | PK parameters will be calculated from the plasma concentration versus time data for T1/2 (terminal half-life) | Predose to 8 hours post dose Day 1 (Parts A, B and E); Pre-dose to 8 hours post dose on Days 1, 7, 8, 14, 15, 21, 22, 28, 29 and 35 (Part D and F Cohort 1); Pre-dose to 24 hours post dose on Days 1, 14, 28 and 35 (Part F Cohort 2, respectively) | 
| Pharmacokinetics of Formulation Component: AUC (0-inf) | PK parameters will be calculated from the plasma concentration versus time data for AUC (0-inf) [area under the curve (AUC) extrapolated to infinity] | Predose to 8 hours post dose Day 1 (Parts A, B and E); Pre-dose to 8 hours post dose on Days 1, 7, 8, 14, 15, 21, 22, 28, 29 and 35 (Part D and F Cohort 1); Pre-dose to 24 hours post dose on Days 1, 14, 28 and 35 (Part F Cohort 2, respectively) | 
| Pharmacokinetics of Formulation Component: AUC (0-last) | PK parameters will be calculated from the plasma concentration versus time data for AUC (0-last) [area under the curve (AUC) from time 0 to last measurable concentration] | Predose to 8 hours post dose Day 1 (Parts A, B and E); Pre-dose to 8 hours post dose on Days 1, 7, 8, 14, 15, 21, 22, 28, 29 and 35 (Part D and F Cohort 1); Pre-dose to 24 hours post dose on Days 1, 14, 28 and 35 (Part F Cohort 2, respectively) | 
| Pharmacokinetics of Formulation Component: AUC (0-8h) | PK parameters will be calculated from the plasma concentration versus time data for (AUC 0-24) [area under the curve (AUC) from time 0 to 8 hours post dose] | Predose to 8 hours post dose Day 1 (Parts A, B and E); Pre-dose to 8 hours post dose on Days 1, 7, 8, 14, 15, 21, 22, 28, 29 and 35 (Part D and F Cohort 1); Pre-dose to 24 hours post dose on Days 1, 14, 28 and 35 (Part F Cohort 2, respectively) | 
| Pharmacokinetics of MEDI7219: CL | PK parameters will be calculated from the plasma concentration from CL (apparent clearance) | Pre-dose to 144 hours post-dose (Part C) |