A Single and Multiple Ascending Doses Phase I Study to Evaluate the Safety and Pharmacokinetics of RBD4059 in Healthy Subjects

Study Overview
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Brief Summary
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This is a Randomized, Single-blind, Placebo-Controlled Phase I Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Ascending Doses of Subcutaneously Administered RBD4059 in Healthy Subjects. The study will be performed in 2 phases: single ascending dose (SAD) phase and multiple ascending doses (MAD) phase in healthy subjects. The decision to escalate to subsequent dose levels will be made by the SRC based on the review of all available safety information and PK/PD data in each cohort. RBD4059, a GalNAc conjugated siRNA, is an FXI-targeted new molecular entity independently developed by Ribo using its proprietary siRNA delivery system - RIBO-GalSTARTM.

Detailed Description
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RBD4059, a GalNAc conjugated siRNA, is an FXI-targeted new molecular entity independently developed by Ribo using its proprietary siRNA delivery system - RIBO-GalSTARTM. As a GalNAc-based liver targeting delivery system, RIBO-GalSTARTM incorporates a unique technology for the delivery of oligonucleotide therapeutics for various targets and indications associated with the liver, thus enabling highly specific and highly durable enrichment of the siRNA in hepatocytes, the primary source of FXI. RBD4059 is, therefore, proposed to be a novel effective and durable antithrombotic treatment, with low bleeding risk via inhibition of FXI activity and prolongation of APTT.

Official Title
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A Randomized, Single-blind, Placebo-Controlled Phase I Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Ascending Doses of Subcutaneously Administered RBD4059 in Healthy Subjects

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: RBD4059
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female (non-childbearing potential only), aged 18 to 65 years, inclusive. Body mass index (BMI) between 18 and 32 kg/m2, inclusive. APTT, Prothrombin time(PT), INR, thrombin time (TT)，FXI activity must be within the normal reference range (as per the local laboratory reference range) at screening . Adequate complete blood counts (CBCs) and platelet are within the normal reference range (If CBCs are outside the reference range, unless not clinically significant determined by the Investigator ). Healthy as determined by pre-study medical history, vital signs, physical examination, clinical laboratory assessments, and 12-lead electrocardiogram (ECG). Subjects who are willing to cooperate with the study staff, comply with the study requirements, complete the study according to the relevant procedures specified in the protocol, and correctly understand and sign the informed consent form in writing. Exclusion Criteria: Any uncontrolled or serious disease that may interfere with participation in the clinical study and/or put the subject at significant risk (according to Investigator's judgment) if he/she participates in the clinical study. History or presence of cardiovascular disease (including peripheral artery and cerebrovascular disease). Systolic blood pressure (SBP) is less than 90 or greater than 140 mmHg and/or diastolic blood pressure (DBP) is less than 40 or greater than 90 mmHg after 10 minutes of supine rest, unless determined by the Investigator to be not clinically significant. Diagnosis of diabetes mellitus, history of gestational diabetes that is fully resolved is not permitted. Any conditions which, in the opinion of the Investigator, would make the subject unsuitable for enrollment or could interfere with the subject's participation in or completion of the study. Note: additional inclusion/exclusion criteria may apply, per protocol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RBD4059 SAD experimental group<br>Subjects in SAD experimental groups will receive a single subcutaneous injection of RBD4059 on Day 1. | Drug: RBD4059<br>* Subcutaneously Administered RBD4059 in Healthy Subjects.<br>|
| Experimental: RBD4059 MAD experimental group<br>Subjects in MAD experimental groups will receive one subcutaneous injection of RBD4059 on Day 1 and another subcutaneous injection of RBD4059 on Day 29. | Drug: RBD4059<br>* Subcutaneously Administered RBD4059 in Healthy Subjects.<br>|
| Placebo Comparator: Placebo SAD group<br>Subjects in SAD placebo groups will receive a single subcutaneous injection of placebo on Day 1. | Drug: Placebo<br>* Subcutaneously Administered Placebo in Healthys Subject.<br>|
| Placebo Comparator: Placebo MAD group<br>Subjects in MAD placebo groups will receive one subcutaneous injection of placebo on Day 1 and another subcutaneous injection of placebo on Day 29. | Drug: Placebo<br>* Subcutaneously Administered Placebo in Healthys Subject.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Treatment Related Adverse Events as Assessed by CTCAE v5.0 |  | SAD: Up to Day 169 ; | 
| Number of Participants with Treatment Related Adverse Events as Assessed by CTCAE v5.0 |  | MAD: Up to Day 197 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To characterize the pharmacokinetics (PK) of RBD4059 in healthy subjects:Cmax |  | Up to 48 hours post-dose | 
| To characterize the pharmacokinetics (PK) of RBD4059 in healthy subjects:Tmax |  | Up to 48 hours post-dose | 
| To characterize the pharmacokinetics (PK) of RBD4059 in healthy subjects:AUC0-t |  | Up to 48 hours post-dose | 
| To characterize the pharmacokinetics (PK) of RBD4059 in healthy subjects:AUC0-inf |  | Up to 48 hours post-dose | 
| To characterize the pharmacokinetics (PK) of RBD4059 in healthy subjects:t1/2 |  | Up to 48 hours post-dose | 
| To characterize the pharmacokinetics (PK) of RBD4059 in healthy subjects:MRT |  | Up to 48 hours post-dose | 
| To characterize the pharmacokinetics (PK) of RBD4059 in healthy subjects:λz |  | Up to 48 hours post-dose | 
| To characterize the pharmacokinetics (PK) of RBD4059 in healthy subjects:CL/F |  | Up to 48 hours post-dose | 
| To characterize the pharmacokinetics (PK) of RBD4059 in healthy subjects:Vz |  | Up to 48 hours post-dose | 
| To evaluate the pharmacodynamics (PD) effect of RBD4059 on levels of Coagulation factor XI (FXI) antigen in healthy subjects. |  | SAD: Up to Day 169 ; MAD: Up to Day 197 | 
| To evaluate the pharmacodynamics (PD) effect of RBD4059 on levels of FXI activity in healthy subjects. |  | SAD: Up to Day 169 ; MAD: Up to Day 197 | 
| To evaluate the pharmacodynamics (PD) effect of RBD4059 on levels of Activated partial thromboplastin time (APTT) in healthy subjects. |  | SAD: Up to Day 169 ; MAD: Up to Day 197 |