A Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Doses of IONIS FXI-LRx in up to 84 Healthy Volunteers

Study Overview
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Brief Summary
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To evaluate the safety and tolerability, pharmacokinetics, and pharmacodynamics, including Factor XI activity and antigen levels, activated partial thromboplastin time, prothrombin time and international normalized ratio of single and multiple doses of Factor XI antisense inhibitor administered subcutaneously to healthy volunteers.

Detailed Description
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This will be a Phase 1, double-blind, randomized, placebo-controlled, dose-escalation study conducted at a single center. The study consists of 4 escalating single-dose cohorts (n = 8 per cohort, randomized 3 IONIS FXI-LRx active:1 placebo), 3 escalating multiple-dose cohorts with weekly Study Drug (IONIS FXI-LRx or placebo) administration for 8 healthy volunteers per cohort, randomized 3 active:1 placebo, and 1 multiple-dose cohort of 10 healthy volunteers randomized 3 active:2 placebo with Study Drug administration every 4 weeks. Approximately 66 healthy volunteers are planned to be enrolled in this study. Additional healthy volunteers may be added to better assess the safety, tolerability or pharmacokinetic profile of IONIS FXI-LRx to meet study objectives.

Official Title
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A Double-Blind, Placebo-Controlled, Dose-Escalation Phase 1 Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Doses of ION-957943 (IONIS FXI-LRX, a GalNAc Conjugated 2'-MOE Chimeric Antisense Oligonucleotide Inhibitor of Factor XI) Administered Subcutaneously to Healthy Volunteers

Conditions
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Healthy Participants

Intervention / Treatment
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* Drug: IONIS FXI-LRx
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Body mass index (BMI) ≤ 35 kg/m2 Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal Males must be surgically sterile, abstinent or, if engaged in sexual relations with a female of child-bearing potential, the subject must be using an acceptable contraceptive method from the time of signing the informed consent form until at least 30 days (single-dose cohorts) or 13 weeks (multiple-dose cohorts) after the last dose of Study Drug Willing to refrain from strenuous exercise/activity for at least 72 hrs prior to study visits Must abstain from alcoholic beverages for at least 48 hrs prior to clinic visits and not increase alcohol consumption during the study Exclusion Criteria Clinically-significant abnormalities in medical history, screening laboratory results, physical examination that would render a subject unsuitable for inclusion. Including but not limited to: Platelet count < LLN INR > 1.4 aPTT > ULN FXI activity < 0.7 U/mL Treatment with another investigational drug, biological agent, or device within 1 month of Screening, or 5 half-lives of investigational agent, whichever is longer Any history of previous treatment with an oligonucleotide History of bleeding diathesis or coagulopathy Uncontrolled hypertension (BP > 160/100 mm Hg)

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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IONIS FXI-LRx<br>Ascending single and multiple doses of IONIS FXI-LRx by subcutaneous (SC) injection. | Drug: IONIS FXI-LRx<br>* Ascending single and multiple doses of IONIS FXI-LRx by subcutaneous (SC) injection<br>|
| Placebo Comparator: Placebo<br>Sterile Normal Saline (0.9% NaCl) calculated volume to match active comparator. | Drug: Placebo<br>* Sterile Normal Saline (0.9% NaCl) calculated volume to match active comparator<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability as Measured by the Number of Participants with Treatment-Emergent Adverse Events |  | Up to 232 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax: maximum observed drug concentration in plasma of IONIS FXI-LRx |  | Up to 232 Days | 
| Tmax: time taken to reach maximal concentration in plasma of IONIS FXI-LRx |  | Up to 232 Days | 
| AUC: area under the plasma concentration time curve for IONIS FXI-LRx |  | Up to 232 Days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IONIS FXI-L, Factor XI