Evaluate the Safety and Tolerability, as Well as the Pharmacokinetic and Pharmacodynamic Profiles of Single and Multiple Doses of Eplontersen Administered Subcutaneously to Healthy Volunteers and Patients With Hereditary Transthyretin-Mediated Amyloidosis (hATTR ).

Study Overview
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Brief Summary
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To evaluate the safety and tolerability, as well as the pharmacokinetic and pharmacodynamic profiles of single and multiple doses of Eplontersen administered subcutaneously to healthy volunteers and patients with Hereditary Transthyretin-Mediated Amyloidosis (hATTR ).

Detailed Description
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This will be a Phase 1/2, double-blind, randomized, placebo-controlled, dose-escalation study conducted at a single center for the healthy volunteer cohorts in up to 56 participants. It will consist of 1 single-dose cohort and 3 multiple-dose cohorts (n = 12 per cohort, 10 active:2 placebo). The open-label, hATTR patient cohort portion of the study will be conducted at multiple centers.

Official Title
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This Was a Phase 1/2, Double-blind, Randomized, Placebo-controlled, Dose-escalation Study Conducted at a Single Center for the Healthy Volunteer Cohorts in up to 56 Participants. It Consisted of 1 Single-dose Cohort and 3 Multiple-dose Cohorts (n = 12 Per Cohort, 10 Active:2 Placebo). The Open-label, hATTR Patient Cohort Portion of the Study Was Conducted at Multiple Centers.

Conditions
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Healthy Volunteers, hATTR Amyloidosis

Intervention / Treatment
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* Drug: ION-682884
* Drug: Placebo
* Dietary Supplement: Vitamin A


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for Healthy Volunteers (Cohorts A, B, C, and E) Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal Males must be surgically sterile or, abstinent or, if engaged in sexual relations with a woman of child-bearing potential, the subject or the subject's non-pregnant female partner must be using a highly effective contraceptive method Weight ≥ 50 kg and BMI < 32 kg/m^2 Exclusion Criteria for Healthy Volunteers (Cohorts A, B, C, and E) Clinically-significant (CS) abnormalities in medical history, screening laboratory results, physical or physical examination that would render a subject unsuitable for inclusion including abnormal safety labs Drug or alcohol dependency or abuse Treatment with another investigational drug, biological agent, or device within 1 month of Screening, or 5 half-lives of investigational agent, whichever is longer Blood donation within 28 days Have any other conditions, which, in the opinion of the Investigator or Sponsor would make the subject unsuitable for inclusion, or could interfere with the subject participating in or completing the Study Inclusion Criteria for hATTR Patients (Cohort D) Aged 18 to 82 years at the time of informed consent Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal Males must be surgically sterile or, abstinent or, if engaged in sexual relations with a woman of child-bearing potential, the subject or the subject's non-pregnant female partner must be using a highly effective contraceptive method Diagnosis of hereditary transthyretin-mediated polyneuropathy BMI > 16 kg/m2 Exclusion Criteria for hATTR Patients (Cohort D) Clinically-significant (CS) abnormalities in medical history, screening laboratory results, physical or physical examination that would render a subject unsuitable for inclusion, including but not limited to abnormal safety labs Karnofsky performance status ≤ 50 Other causes of sensorimotor or autonomic neuropathy (e.g., autoimmune disease), including uncontrolled diabetes Prior liver transplant or anticipated liver transplant within 1-yr of Screening New York Heart Association (NYHA) functional classification of ≥ 3 Acute coronary syndrome or major surgery within 3 months of Screening Other types of amyloidosis Have any other conditions, which, in the opinion of the Investigator or Sponsor would make the subject unsuitable for inclusion, or could interfere with the subject participating in or completing the Study

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 |
| --- | --- |
| Placebo Comparator: Multiple Dose Cohort: Placebo<br>Participants received ION-682884 matching placebo, subcutaneously (SC) once every 4 weeks [Q4W] (total of 4 doses) along with daily oral supplemental doses of the recommended daily allowance (RDA) of vitamin A during the 13-week Treatment Period. | Drug: Placebo<br>* Placebo comparator calculated volume to match ION-682884 administered SC<br>Dietary Supplement: Vitamin A<br>* Oral supplement<br>|
| Experimental: Multiple Dose Cohort A: ION-682884 45 mg<br>Participants received ION-682884, 45 milligrams (mg), SC, Q4W (total of 4 doses) along with daily oral supplemental doses of the RDA of vitamin A during the 13-week Treatment Period. | Drug: ION-682884<br>* ION-682884 administered SC<br>* Other names: IONIS-TTR-LRx;Dietary Supplement: Vitamin A<br>* Oral supplement<br>|
| Experimental: Multiple Dose Cohort E: ION-682884 60 mg<br>Participants received ION-682884, 60 mg, SC, Q4W (total of 4 doses) along with daily oral supplemental doses of the RDA of vitamin A during the 13-week Treatment Period. | Drug: ION-682884<br>* ION-682884 administered SC<br>* Other names: IONIS-TTR-LRx;Dietary Supplement: Vitamin A<br>* Oral supplement<br>|
| Experimental: Multiple Dose Cohort B: ION-682884 90 mg<br>Participants received ION-682884, 90 mg, SC, Q4W (total of 4 doses) along with daily oral supplemental doses of the RDA of vitamin A during the 13-week Treatment Period. | Drug: ION-682884<br>* ION-682884 administered SC<br>* Other names: IONIS-TTR-LRx;Dietary Supplement: Vitamin A<br>* Oral supplement<br>|
| Placebo Comparator: Single Dose Cohort: Placebo<br>Participants received single dose of ION-682884 matching placebo, SC along with daily oral supplemental doses of the RDA of vitamin A on Day 1. | Drug: Placebo<br>* Placebo comparator calculated volume to match ION-682884 administered SC<br>Dietary Supplement: Vitamin A<br>* Oral supplement<br>|
| Experimental: Single Dose Cohort C: ION-682884 120 mg<br>Participants received single dose of ION-682884, 120 mg, SC along with daily oral supplemental doses of the RDA of vitamin A on Day 1. | Drug: ION-682884<br>* ION-682884 administered SC<br>* Other names: IONIS-TTR-LRx;Dietary Supplement: Vitamin A<br>* Oral supplement<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With at Least One Treatment-Emergent Adverse Event (TEAE) | An adverse event (AE) is any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not the AE was considered related to the medicinal (investigational) product. An AE was to be regarded as a TEAE if it was present prior to receiving the first dose of study drug and subsequently worsened or was not present prior to receiving the first dose of study drug but subsequently appeared. | Up to Day 176 | 
| Percentage of Participants Using Concomitant Medications | A concomitant therapy was any non-protocol-specified drug or substance (including over-the-counter [OTC] medications, herbal medications, and vitamin supplements) administered between signing of informed consent and the last study visit. | Up to Day 176 | 
| Number of Participants With Clinically Significant Laboratory Values | Laboratory parameters included measurement of blood chemistry, hematology, coagulation, complement, or urinalysis parameters for the single-dose and multiple-dose cohorts. Number of participants with clinically significant values in laboratory based on Investigator's assessment are reported. Any value outside the normal range was to be flagged for the attention of the investigator was to assess whether or not a flagged value is of clinical significance. | Up to Day 176 | 
| Number of Participants With Clinically Significant Physical Examination Findings | Physical examination included measurement of height and weight for body mass index (BMI) determination. Number of participants with clinically significant findings in physical examination based on Investigator's assessment are reported. Any value outside the normal range was to be flagged for the attention of the investigator was to assess whether or not a flagged value is of clinical significance. | Up to Day 176 | 
| Number of Participants With Clinically Significant Electrocardiogram (ECG) Values | ECG measurements included assessment of ventricular rate (VR), PR interval, QR interval, QT interval, QT corrected using Fridericia's formula (QTcF), and QT corrected using Bazett's formula (QTcB). Number of participants with clinically significant values in electrocardiogram based on Investigator's assessment are reported. Any value outside the normal range was to be flagged for the attention of the investigator was to assess whether or not a flagged value is of clinical significance. | Up to Day 176 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax: Maximum Observed Plasma Drug Concentration of ION-TTR-LRx |  | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose on Days 1 and 85 | 
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of ION-TTR-LRx |  | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose on Days 1 and 85 | 
| AUCt: Area Under the Plasma Concentration-Time Curve From Time Zero to Time t for ION-TTR-LRx |  | From 0 to 672 hours post-dose on Day 85 for Cohorts A, B, and E; 0 hours to extrapolation to infinity post-dose on Day 1 for Cohort C | 
| CL/F: Apparent Total Clearance of ION-TTR-LRx |  | From 0 to 672 hours post-dose on Day 85 for Cohorts A, B, and E; 0 hours to extrapolation to infinity post-dose on Day 1 for Cohort C | 
| t1/2λz: Termination Half-Life of ION-TTR-LRx |  | Up to 92 hours; post-dose on Day 85 for Cohorts A, B, and E, and on Day 1 for Cohort C | 
| Ae0-24h: Amount of Administered Dose of ION-TTR-LRx Excreted in Urine Over a 24-Hour Period |  | From 0 to 24 hours post-dose on Days 1 and 85 | 
| Change From Baseline in Plasma Transthyretin (TTR) Levels Following Single and Multiple-dose Administration of ION-TTR-LRx |  | Baseline, Days 29 and 99 | 
| Change From Baseline in Plasma Retinol Binding Protein 4 (RBP4) Levels Following Single and Multiple-Dose Administration of ION-TTR-LRx |  | Baseline, Days 29 and 99 | 
| Percent Abundance of ION-682884 Antisense Oligonucleotide (ASO) Species (Metabolite) Following Administration of ION-682884 90 mg | As prespecified in the protocol, this outcome measure was planned to be analyzed only in the Multiple Dose Cohort B: 90 mg ION-682884. | 2 hours post-dose on Day 85 |