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.
Overview
- Phase
- Phase 1
- Intervention
- Placebo
- Conditions
- Healthy Volunteers
- Sponsor
- Ionis Pharmaceuticals, Inc.
- Enrollment
- 47
- Locations
- 1
- Primary Endpoint
- Number of Participants With at Least One Treatment-Emergent Adverse Event (TEAE)
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief Summary
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
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
Multiple Dose Cohort: Placebo
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.
Intervention: Placebo
Multiple Dose Cohort: Placebo
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.
Intervention: Vitamin A
Multiple Dose Cohort A: ION-682884 45 mg
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.
Intervention: ION-682884
Multiple Dose Cohort A: ION-682884 45 mg
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.
Intervention: Vitamin A
Multiple Dose Cohort E: ION-682884 60 mg
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.
Intervention: ION-682884
Multiple Dose Cohort E: ION-682884 60 mg
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.
Intervention: Vitamin A
Multiple Dose Cohort B: ION-682884 90 mg
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.
Intervention: ION-682884
Multiple Dose Cohort B: ION-682884 90 mg
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.
Intervention: Vitamin A
Single Dose Cohort: Placebo
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.
Intervention: Placebo
Single Dose Cohort: Placebo
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.
Intervention: Vitamin A
Single Dose Cohort C: ION-682884 120 mg
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.
Intervention: ION-682884
Single Dose Cohort C: ION-682884 120 mg
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.
Intervention: Vitamin A
Outcomes
Primary Outcomes
Number of Participants With at Least One Treatment-Emergent Adverse Event (TEAE)
Time Frame: Up to Day 176
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.
Percentage of Participants Using Concomitant Medications
Time Frame: Up to Day 176
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.
Number of Participants With Clinically Significant Laboratory Values
Time Frame: Up to Day 176
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.
Number of Participants With Clinically Significant Physical Examination Findings
Time Frame: Up to Day 176
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.
Number of Participants With Clinically Significant Electrocardiogram (ECG) Values
Time Frame: Up to Day 176
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.
Secondary Outcomes
- 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)
- 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(2 hours post-dose on Day 85)
- 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)
- 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)