A Phase 1, Open-Label Study to Assess the Pharmacokinetics (PK), Pharmacodynamics (PD), Safety and Tolerability of Eplontersen Following Subcutaneous Administration of a Single Dose in Healthy Chinese Volunteers
Overview
- Phase
- Phase 1
- Intervention
- Eplontersen Solution for Injection
- Conditions
- Transthyretin-mediated Amyloidosis
- Sponsor
- AstraZeneca
- Enrollment
- 12
- Locations
- 1
- Primary Endpoint
- PK parameters: Plasma Half-life Associated with the Apparent Terminal Elimination Phase (t½λz)
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
This is a Phase 1 study to assess the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of eplontersen following single dosing in healthy Chinese participants. The objectives of the study are: to characterize the pharmacokinetic (PK) profiles and the pharmacodynamic (PD) profiles, and to evaluate the safety and tolerability and the immunogenicity of eplontersen following subcutaneous administration of a single 45 mg dose in healthy Chinese participants.
Detailed Description
This is a Phase 1, open-label, single-dose, single-arm study to assess the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of eplontersen following subcutaneous (SC) administration in healthy Chinese male and female participants. Approximately 12 healthy Chinese participants, aged 18 to 60 years, will be assigned to study intervention of a signle dose of eplontersen 45 mg following subcutaneous administration. Including the administration dosing day, the follow-up period is total of 92 days. The primary objective of this study is to characterize the PK profile of eplontersen, the PK parameters for eplontersen including, but not limited to: Cmax, tmax, t½λz, AUC0-24h, and AUC0-168h. The secondary objective of this study is to characterize the PD profiles of eplontersen, this includes the measures of change and percent change from baseline in serum TTR levels at specified timepoints. The safety objective of this study is to evaluate the safety and tolerability of eplontersen, this includes the measures of AEs/SAEs, vital signs, physical examinations, safety laboratory assessments and 12-lead ECG. Also the exploratory objective of this study is to evaluate the immunogenicity of eplontersen, this includes the measures of but not limited to anti-drug antibodies (ADA) prevalence and incidence, different ADA status at specified timepoints.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Must have given written informed consent (signed and dated) and any authorizations required by local law and be able to comply with all study requirements.
- •Healthy\* Chinese males or females of non-childbearing potential, aged 18 to 60 inclusive at the time of informed consent.
- •\*Participants will be confirmed to be healthy according to the medical history, electrocardiogram (ECG), vital signs, laboratory results, and physical examination as determined by the Investigator.
- •Females must be non-pregnant and non-lactating, and either surgically sterile (eg, tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or postmenopausal (defined as 12 months of spontaneous amenorrhea without an alternative medical cause and follicle-stimulating hormone (FSH) levels in the postmenopausal range for the laboratory involved. Males must be surgically sterile or abstinent\*, or if engaged in sexual relations with a female of child-bearing potential, the participant must be using an highly effective contraceptive method from the time of signing the informed consent form until at least 24 weeks after study intervention administration.
- •\* Abstinence is only acceptable as true abstinence, ie, when this is in line with the preferred and usual lifestyle of the participant. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of a study and withdrawal are not acceptable methods of contraception.
- •Willing to refrain from strenuous exercise/activity (eg, heavy lifting, weight training, intense aerobics classes) for at least 72 hours prior to study visits.
- •Weight ≥ 50 kg and body mass index (BMI) of 19 to 30 kg/m2 at screening (including cutoff).
- •BMI = weight (kg)/height2 (m2).
- •Willingness to take vitamin A supplements (recommended daily allowance \[RDA\] of approximately 3000 IU/day until the last post-treatment follow-up visit \[Day 92; 13 weeks after the dosing\]).
Exclusion Criteria
- •Clinically significant abnormalities in medical history (eg, major surgery within 6 months of screening, history or presence of hepatic, renal, hematological, endocrine, or cardiovascular disease) or physical examination.
- •Screening laboratory results as follows, or any other clinically significant abnormalities in screening laboratory values that would render a participant unsuitable for inclusion:
- •Random spot urine protein/creatinine ratio (UPCR) ≥ 200 mg/g. In the event of UPCR above this threshold ineligibility may be confirmed by a repeat random spot UPCR ≥ 200 mg/g or a 24-hour urine protein ≥ 200 mg/24 hour;
- •Positive test for blood (including trace) on urinalysis that is subsequently confirmed with urine microscopy showing \> 5 red blood cells per high power field;
- •Alanine transaminase (ALT), aspartate aminotransferase (AST), bilirubin, alkaline phosphatase (ALP), serum creatinine, and blood urea \> upper limit of normal (ULN);
- •Fasting blood glucose \> ULN;
- •Platelet count \< lower limit of normal (LLN);
- •Estimated glomerular filtration rate (eGFR) (Chronic Kidney Disease Epidemiology Collaboration \[CKD-EPI\] equation) ≤ 60 mL/min/1.73m
- •Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Day
- •Unwillingness to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator.
Arms & Interventions
Eplontersen
Single arm
Intervention: Eplontersen Solution for Injection
Outcomes
Primary Outcomes
PK parameters: Plasma Half-life Associated with the Apparent Terminal Elimination Phase (t½λz)
Time Frame: collect PK sample in pre-dose of Day 1 and 0.5 hours, 1 hours, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 24 hours, 36 hours, 48 hours of post-dose, and in Day 8, Day 15, Day 29, Day 50, Day 71, Day 92
To characterize the pharmacokinetic (PK) profiles of eplontersen following subcutaneous administration of a single 45 mg dose in healthy Chinese participants
PK parameters: Area Under Plasma Concentration-time Curve (0-24 hours) (AUC0-24h)
Time Frame: collect PK sample in pre-dose of Day 1 and 0.5 hours, 1 hours, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 24 hours, 36 hours, 48 hours of post-dose, and in Day 8, Day 15, Day 29, Day 50, Day 71, Day 92
To characterize the pharmacokinetic (PK) profiles of eplontersen following subcutaneous administration of a single 45 mg dose in healthy Chinese participants
PK parameters: Maximum Observed Concentration(Cmax)
Time Frame: collect PK sample in pre-dose of Day 1 and 0.5 hours, 1 hours, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 24 hours, 36 hours, 48 hours of post-dose, and in Day 8, Day 15, Day 29, Day 50, Day 71, Day 92
To characterize the pharmacokinetic (PK) profiles of eplontersen following subcutaneous administration of a single 45 mg dose in healthy Chinese participants
PK parameters: Time to Maximal Concentration (tmax)
Time Frame: collect PK sample in pre-dose of Day 1 and 0.5 hours, 1 hours, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 24 hours, 36 hours, 48 hours of post-dose, and in Day 8, Day 15, Day 29, Day 50, Day 71, Day 92
To characterize the pharmacokinetic (PK) profiles of eplontersen following subcutaneous administration of a single 45 mg dose in healthy Chinese participants
PK parameters: Area Under Plasma Concentration-time Curve (0-168 hours) (AUC0-168h)
Time Frame: collect PK sample in pre-dose of Day 1 and 0.5 hours, 1 hours, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 24 hours, 36 hours, 48 hours of post-dose, and in Day 8, Day 15, Day 29, Day 50, Day 71, Day 92
To characterize the pharmacokinetic (PK) profiles of eplontersen following subcutaneous administration of a single 45 mg dose in healthy Chinese participants
Secondary Outcomes
- The change and percent change from baseline in serum (Transthyretin) TTR levels at specified timepoints(collect PD sample in screening visit, pre-dose of Day 1 and Day 8, Day 15, Day 29, Day 50, Day 71, Day 92)