A Randomised, Double-blind, Placebo-controlled, Phase 1 Study to Assess the Safety, Tolerability, and Pharmacokinetics of Subcutaneous, Ascending Single Doses of AP13 in Healthy Adults

INTERVENTION: This is a randomised, double‐blind, placebo‐controlled study of AP13 administered subcutaneously (SC) as single or multiple doses. The study will be conducted in 2 parts: Part A Single ascending dose (SAD) will comprise of up to 5 cohorts. Each cohort will enrol 8 participants, with 6 randomised to receive a single dose of AP13 and 2 to receive placebo on Day 1 with a dose range of 0.3 ‐ 12 mg/kg. Part B Multiple ascending dose (MAD) will comprise of up to 3 cohorts. Each cohort will enrol 10 participants, with 8 randomised to receive one SC dose of AP13 and 2 to receive placebo every two weeks (Q2W) on Days 1, 15 and 29 (total of 3 doses) with a dose range of 3‐12 mg/kg. Part B may commence following review of available data from Day 15 of Part A SAD Cohort 3 by the Safety Review Committee. Cohorts will be dosed in an escalating order with participants only able to enrol in one dose cohort. Adherence to the intervention will be done via supervised drug administration. CONDITION: Cardiovascular ‐ Hypertension Pulmonary Hypertension; ; Pulmonary Hypertension PRIMARY OUTCOME: To evaluate the safety and tolerability of AP13 (MAD)[Composite Primary Outcome; Safety endpoints:; • Assessment of AEs and Serious Adverse Events (SAEs) (including withdrawals due to AEs); • Local tolerability (site of SC injections); • Assessment of vital sign measurements (systolic and diastolic blood pressure, heart rate, respiratory rate, body temperature and blood oxygen saturation); • Assessment of electrocardiogram (ECG) parameters; • Assessment of clinical laboratory parameters (haematology, serum chemistry, coagulation and urinalysis) Adverse events ‐ will be graded using a three‐point severity scale (mild, moderate, severe) and assessed continuously as they are reported or observed and reviewed daily from Screening until Day 125 post‐dose (End of Study/Early Termination visit [EOS/ETV]).; ; Local tolerability will be graded based on the FDA Guidance for Industry document entitled Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (2007) with assessments to include measures of pain, tenderness, pruritus, erythema and induration measured within 0.5 hrs pre‐dose Day 1 ‐ 2, 4, 8, and 12 hours post‐dose, Day 2 ‐ Day 14 post‐dose, 0.5 hr pre‐second dose Day 15 ‐ 2, 4 hours post‐second dose. Days 16, 22 and Day 28 post‐second dose, 0.5 hr pre‐third dose Day 29 ‐ 2, 4 hours post‐third dose, Day 30 ‐ Day 125 post‐dose (EOS/ETV).; ; Vital signs ‐ Blood pressure and heart rate is measured using sphygmomanometer respiratory rate by manual breath count, temperature by thermometer and blood oxygen saturation by pulse oximeter. Measured at Screening, Day ‐1, pre‐dose Day 1 ‐ 1, 2, 4, 8, and 12 hrs post‐dose, Day 2 ‐ Day 14 post‐dose, pre‐second dose Day 15 ‐ 1, 2 and 4 hrs post‐second dose, Day 16 ‐ Day 28 post‐second dose, pre‐third dose Day 29 ‐ 1, 2 and 4 hrs post‐third dose, Day 30 ‐ Day 125 post‐dose (EOS/ETV).; ; Electrocardiogram (ECG) ‐ 12‐lead ECG recordings will be obtained in triplicate at screening, pre‐dose Day 1 2 hrs post‐dose, Day 15, 29 and Day 37 post‐dose. Single recordings will be obtained from Day ‐1, Day 2 post‐dose, and Day 125 post‐dose (EOS/ETV).; ; Clinical laboratory evaluations (haematology, serum chemistry, coagulation and urinalysis) ‐ blood and urine samples will be collected from Screening, Day ‐1, Days 2, 3, 8, 14, 28, 37, 57, 71, 101 and Day 125 post dose (EOS/ETV).] To evaluate the safety and tolerability of AP13 (SAD)[Composite Primary Outcome; Safety endpoints:; • Assessment of AEs and Serious Adverse Events (SAEs) (including withdrawals due to AEs); • Local tolerability (site of SC injections); • Assessment of vital sign measurements (systolic and diastolic blood pressure, heart rate, respiratory rate, body temperature and blood oxygen saturation); • Assessment of electrocardiogram (ECG) parameters; • Assessment of clinical laboratory parameters (haematology, serum chemistry, coagulation and urinalysis) Adverse events ‐ will be graded using a three‐point severity scale (mild, moderate, severe) and assessed continuously as they are reported or observed and reviewed daily from Screening until Day 96 post‐dose (End of Study/Early Termination visit [EOS/ETV]).; ; Local tolerability will be graded based on the FDA Guidance for Industry document entitled Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (2007) with assessments to include measures of pain, tenderness, pruritus, erythema and induration measured within 0.5 hrs pre‐dose Day 1 ‐ 2, 4, 8, and 12 hours post‐dose, Day 2 ‐ Day 96 post‐dose (EOS/ETV).; ; Vital signs ‐ Blood pressure and heart rate is measured using sphygmomanometer respiratory rate by manual breath count, temperature by thermometer and blood oxygen saturation by pulse oximeter. Measured at Screening, Day ‐1, pre‐dose Day 1 ‐ 1, 2, 4, 8, and 12 hrs post‐dose, Day 2 ‐ Day 96 post dose (EOS/ETV).; ; Electrocardiogram (ECG) ‐ 12‐lead ECG recordings will be obtained in triplicate at screening, pre‐dose Day 1 2 hrs post‐dose, Days 6, 8 and Day 10 post‐dose. Single recordings will be obtained from Day ‐1, Day 2 post‐dose, and Day 96 post‐dose (EOS/ETV).; ; Clinical laboratory evaluations (haematology, serum chemistry, coagulation and urinalysis) ‐ blood and urine samples will be collected from Screening, Day ‐1, Days 2, 3, 8, 15, 29, 43, 72 and Day 96 post dose (EOS/ETV).; ; ] INCLUSION CRITERIA: 1. Healthy adult males and females, 18 to 55 years of age (inclusive) at screening. 2. Body mass inde X(BMI) greater than or equal to 18.0 and less than or equal to 30.0 kg/m2, with a body weight 50 to 100 kg at screening. 3. Is medically healthy (in the opinion of the PI [or delegate]), as determined by pre‐study medical history, and without clinically significant abnormalities including: a. Physical examination without any clinically relevant findings. b. Systolic blood pressure in the range of 90 to 140 mmHg and diastolic blood pressure in the range of 40 to 90 mmHg after 5 minutes in semi‐supine position. c. Heart rate in the range of 40 to 90 bpm after 5 minutes rest in semi‐supine position. d. Body temperature (tympanic), between 35.5°C and 37.7°C. SECONDARY OUTCOME: To evaluate the immunogenicity of AP13 (MAD)[Composite Secondary Outcome ; • Incidence of anti‐drug antibody (ADA) against AP13 (including titres) ; • Incidence of neutralising antibody (NAb) against AP13 Blood plasma will be collected 0.5 hr pre‐dose Day 1, 0.5 hr pre‐third dose Day 29, then Days 43, 71 and Day 125 post dose (End of Study/Early Termination visit [EOS/ETV]).] To evaluate the immunogenicity of AP13 (SAD)[Composite Secondary Outcome ; • Incidence of anti‐drug antibody (ADA) against AP13 (including titres) ; • Incidence of neutralising antibody (NAb) against AP13 Blood plasma will be collected 0.5 hr pre‐dose Day 1, Days 29, 43, 72 and Day 96 post dose (End of Study/Early Termination visit [EOS/ETV]).] To evaluate the pharmacokinetic (PK) profile of AP13 (MAD)[Plasma PK endpoints include (but are not limited to): ; • Maximum observed concentration (Cmax) ; • Minimum observed concentration (Cmin) (MAD part only) ; • Area under the concentration‐time curve from 0 to time of last quantifiable concentration (AUClast) ; • Area under the concentration versus time curve from 0 to 14 days post‐dose (AUCtau) ; • Time to Cma X(Tmax) ; • Apparent terminal elimination half‐life (t1/2) ; • Total apparent body clearance at steady state (CLss/F) (MAD part only) ; • Volume of distribution (Vz/F) ; • Accumulation ratio of AUC0‐tau (MAD part only) ; • Accumulation ratio of Cma X(MAD part only) Blood plasma will be collected 0.5 hr pre‐dose Day 1 ‐ 2, 4, 8, 12 hrs post‐dose, Day 2 24hrs post‐dose, Day 3 48 hrs post‐dose, Day 8 post‐dose, 0.5 hr pre‐second dose Day 15, 0.5 hr pre‐third dose Day 29, then Day 35 ‐ Day 125 post dose (End of Study/Early Termination visit [EOS/ETV]).] To evaluate the pharmacokinetic (PK) profile of AP13 (SAD)[Plasma PK endpoints include (but are not limited to): ; • Maximum observed concentration (Cmax) ; • Area under the concentration‐time curve from 0 to time of last quantifiable concentration (AUClast) ; • Area under the concentration‐time curve from 0 to infinity (AUCinf) (SAD part only). ; • Area under the concentration versus time curve from 0 to 14 days post‐dose (AUCtau) ; • Time to Cma X(Tmax) ; • Apparent terminal elimination half‐life (t1/2) ; • Total apparent body clearance (CL/F) (SAD part only) ; • Volume of distribution (Vz/F) Blood plasma will be collected 0.5 hr pre‐dose Day 1 ‐ 2, 4, 8, 12 hrs post‐dose, Day 2 24hrs post‐dose, Day 3 48 hrs post‐dose, then Day 4 ‐ Day 96 post dose (End of Study/Early Termination visit [EOS/ETV]).]