A Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics of Subcutaneous AZD6912 in Healthy Participants

Study Overview
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Brief Summary
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This study will evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single ascending doses of AZD6912 administered subcutaneously (SC) in healthy participants.

Detailed Description
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In this First-In-Human (FiH) study, eligible participants will be randomly assigned to 6 cohorts in a 3:1 ratio to receive either a single dose of AZD6912 SC or placebo. The first 2 participants in each cohort will be dosed as a sentinel pair, with one receiving AZD6912 SC and the other receiving placebo. The study will comprise of, a screening period of 70 days, a treatment period where participants will stay at the Clinical Unit from the day before study intervention administration until at least 240 hours and will be discharged on Day 11. Outpatient visits would start weekly from Day 15, then bi-weekly from Day 43, 4-weekly from Day 99, and 6-weekly from Day 155, with additional follow-up visits as needed. The study will last approximately 22 months, with each participant participating for about 38 weeks.

Official Title
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A Phase I, Randomised, Double-blind, Placebo-controlled, Single Ascending Dose Study of Safety, Tolerability, Pharmacokinetics, Pharmacodynamics of Subcutaneous AZD6912 in Healthy Participants

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: AZD6912
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Females must have a negative pregnancy test. Contraceptive use by males and females should be consistent with local regulations. Have a body mass index (BMI) between 18 and 30 kg/m2 inclusive and weigh at least 50 kg. For optional Japanese participants only: Participants must be of Japanese descent defined as: first generation (born to 2 Japanese parents and 4 Japanese grandparents). Born in Japan, and not have lived outside Japan for more than 5 years. Lifestyle, including diet, must not have significantly changed since leaving Japan. Exclusion Criteria: History of any clinically important disease or disorder. Current or recurrent disease of clinical significance that could affect clinical assessments or clinical laboratory evaluations. Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of the first administration of study intervention. History of congenital or acquired immunodeficiency or complement deficiency or an underlying condition that predisposes to infection. History of any Neisseria infection, unexplained, recurrent infections, or infection requiring treatment with systemic antibiotics. Evidence of hepatitis B infection (positive for HBsAg or positive for anti-HBcAb) or hepatitis C viral infection (HCV Abs or hepatitis C RNA positive) or HIV infection (positive for HIV type 1 or type 2 Abs). Participants testing positive for COVID-19 prior to dosing. Any cardiac abnormalities. A CAP activity < 60% at screening. Known or suspected history of drug abuse, history of alcohol abuse or smoking.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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: Sequential Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AZD6912 Dose 1<br>Participants will receive AZD6912 Dose 1. | Drug: AZD6912<br>* AZD6912 will be administered as a single sub-cutaneous dose.<br>|
| Experimental: AZD6912 Dose 2<br>Participants will receive AZD6912 Dose 2. | Drug: AZD6912<br>* AZD6912 will be administered as a single sub-cutaneous dose.<br>|
| Experimental: AZD6912 Dose 3<br>Participants will receive AZD6912 Dose 3. | Drug: AZD6912<br>* AZD6912 will be administered as a single sub-cutaneous dose.<br>|
| Experimental: AZD6912 Dose 4<br>Participants will receive AZD6912 Dose 4. | Drug: AZD6912<br>* AZD6912 will be administered as a single sub-cutaneous dose.<br>|
| Experimental: AZD6912 Dose 5<br>Participants will receive AZD6912 Dose 5. | Drug: AZD6912<br>* AZD6912 will be administered as a single sub-cutaneous dose.<br>|
| Experimental: AZD6912 Dose 6<br>Participants will receive AZD6912 Dose 6. | Drug: AZD6912<br>* AZD6912 will be administered as a single sub-cutaneous dose.<br>|
| Placebo Comparator: Placebo<br>Participants will receive Placebo. | Drug: Placebo<br>* Placebo will be administered as a single sub-cutaneous dose.<br>|
| Experimental: AZD6912 additional cohort 1 -including Japanese Participants<br>Participants will receive AZD6912. | Drug: AZD6912<br>* AZD6912 will be administered as a single sub-cutaneous dose.<br>|
| Experimental: AZD6912 additional cohort 2 -including Japanese Participants<br>Participants will receive AZD6912. | Drug: AZD6912<br>* AZD6912 will be administered as a single sub-cutaneous dose.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events (AEs) | To assess the safety and tolerability of AZD6912 in healthy participants. | From screening (Day -70) to last follow up visit (Day 197- approximately 38 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum observed plasma (peak) drug concentration (Cmax) of AZD6912 | To characterise the Cmax of single ascending doses of AZD6912 in healthy participants. | From randomization to Day 197 (up to 28 weeks) | 
| Area under plasma concentration-time curve from zero to infinity (AUCinf) of AZD6912 | To characterise AUCinf of single ascending doses of AZD6912 in healthy participants. | From randomization to Day 197 (up to 28 weeks) | 
| Area under the plasma concentration-curve from zero to the last quantifiable concentration (AUClast) of AZD6912 | To characterise the AUClast of single ascending doses of AZD6912 in healthy participants. | From randomization to Day 197 (up to 28 weeks) | 
| Time to reach peak or maximum observed concentration or response following drug administration (tmax) of AZD6912 | To characterise tmax of single ascending doses of AZD6912 in healthy participants. | From randomization to Day 197 (up to 28 weeks) | 
| Time of last measurable concentration (tlast) of AZD6912 | To characterise tlast of single ascending doses of AZD6912 in healthy participants. | From randomization to Day 197 (up to 28 weeks) | 
| Terminal elimination half-life (t½λz) of AZD6912 | To characterise t½λz of single ascending doses of AZD6912 in healthy participants. | From randomization to Day 197 (up to 28 weeks) | 
| Dose normalised AUClast (AUClast/D) of AZD6912 | To characterise AUClast/D of single ascending doses of AZD6912 in healthy participants. | From randomization to Day 197 (up to 28 weeks) | 
| Dose normalised AUCinf (AUCinf/D) of AZD6912 | To characterise AUCinf/D of single ascending doses of AZD6912 in healthy participants. | From randomization to Day 197 (up to 28 weeks) | 
| Dose normalised Cmax (Cmax/D) of AZD6912 | To characterise Cmax/D of single ascending doses of AZD6912 in healthy participants. | From randomization to Day 197 (up to 28 weeks) | 
| Apparent total body clearance of drug from plasma after extravascular administration (CL/F) of AZD6912 | To characterise CL/F of single ascending doses of AZD6912 in healthy participants. | From randomization to Day 197 (up to 28 weeks) | 
| Volume of distribution (apparent) at steady state following extravascular administration (based on terminal phase) (Vz/F) of AZD6912 | To characterise Vz/F of single ascending doses of AZD6912 in healthy participants. | From randomization to Day 197 (up to 28 weeks) | 
| Percent change from baseline in plasma concentrations of Complement factor B (CFB) protein | To assess the PD effects of single ascending doses of AZD6912 in healthy participants. | From randomization to Day 197 (up to 28 weeks) | 
| Percent change from baseline in serum of Complement functional activity (CAP) | To assess the PD effects of single ascending doses of AZD6912 in healthy participants. | From randomization to Day 197 (up to 28 weeks) | 
| Number of participants with positive Anti-Drug Anitbody (ADA) | To evaluate the immunogenicity of single ascending doses of AZD6912 in healthy participants. | From randomization to Day 197 (up to 28 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Complement factor B, Small interfering ribonucleic acid, CFB messenger ribonucleic acid