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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 ).

Primary Purpose

Healthy Volunteers, hATTR Amyloidosis

Status

Completed

Phase

Phase 1

Locations

Canada

Study Type

Interventional

Intervention

ION-682884

Placebo

Vitamin A

About this trial

This is an interventional treatment trial for Healthy Volunteers

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

Bio Pharma Services, Inc.

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Placebo Comparator

Experimental

Placebo Comparator

Experimental

Arm Label

Multiple Dose Cohort: Placebo

Multiple Dose Cohort A: ION-682884 45 mg

Multiple Dose Cohort E: ION-682884 60 mg

Multiple Dose Cohort B: ION-682884 90 mg

Single Dose Cohort: Placebo

Single Dose Cohort C: ION-682884 120 mg

Arm Description

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.

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.

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.

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.

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.

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.

Outcomes

Primary Outcome Measures

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.

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.

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.

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.

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.

Secondary Outcome Measures

Cmax: Maximum Observed Plasma Drug Concentration of ION-TTR-LRx

Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of ION-TTR-LRx

AUCt: Area Under the Plasma Concentration-Time Curve From Time Zero to Time t for ION-TTR-LRx

CL/F: Apparent Total Clearance of ION-TTR-LRx

t1/2λz: Termination Half-Life of ION-TTR-LRx

Ae0-24h: Amount of Administered Dose of ION-TTR-LRx Excreted in Urine Over a 24-Hour Period

Change From Baseline in Plasma Transthyretin (TTR) Levels Following Single and Multiple-dose Administration of ION-TTR-LRx

Change From Baseline in Plasma Retinol Binding Protein 4 (RBP4) Levels Following Single and Multiple-Dose Administration of ION-TTR-LRx

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.

Full Information

NCT ID

NCT03728634

First Posted

October 31, 2018

Last Updated

November 23, 2022

Sponsor

Ionis Pharmaceuticals, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT03728634

Brief Title

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 ).

Official Title

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.

Study Type

Interventional

2. Study Status

Record Verification Date

November 2022

Overall Recruitment Status

Completed

Study Start Date

December 21, 2018 (Actual)

Primary Completion Date

February 20, 2020 (Actual)

Study Completion Date

February 20, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Ionis Pharmaceuticals, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Yes

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Healthy Volunteers, hATTR Amyloidosis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

47 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Multiple Dose Cohort: Placebo

Arm Type

Placebo Comparator

Arm Description

Arm Title

Multiple Dose Cohort A: ION-682884 45 mg

Arm Type

Experimental

Arm Description

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.

Arm Title

Multiple Dose Cohort E: ION-682884 60 mg

Arm Type

Experimental

Arm Description

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.

Arm Title

Multiple Dose Cohort B: ION-682884 90 mg

Arm Type

Experimental

Arm Description

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.

Arm Title

Single Dose Cohort: Placebo

Arm Type

Placebo Comparator

Arm Description

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.

Arm Title

Single Dose Cohort C: ION-682884 120 mg

Arm Type

Experimental

Arm Description

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 Type

Drug

Intervention Name(s)

ION-682884

Other Intervention Name(s)

Eplontersen, AKCEA-TTR-LRx, IONIS-TTR-LRx

Intervention Description

ION-682884 administered SC

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Placebo comparator calculated volume to match ION-682884 administered SC

Intervention Type

Dietary Supplement

Intervention Name(s)

Vitamin A

Intervention Description

Oral supplement

Primary Outcome Measure Information:

Title

Number of Participants With at Least One Treatment-Emergent Adverse Event (TEAE)

Description

Time Frame

Up to Day 176

Title

Percentage of Participants Using Concomitant Medications

Description

Time Frame

Up to Day 176

Title

Number of Participants With Clinically Significant Laboratory Values

Description

Time Frame

Up to Day 176

Title

Number of Participants With Clinically Significant Physical Examination Findings

Description

Time Frame

Up to Day 176

Title

Number of Participants With Clinically Significant Electrocardiogram (ECG) Values

Description

Time Frame

Up to Day 176

Secondary Outcome Measure Information:

Title

Cmax: Maximum Observed Plasma Drug Concentration of ION-TTR-LRx

Time Frame

Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose on Days 1 and 85

Title

Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of ION-TTR-LRx

Time Frame

Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose on Days 1 and 85

Title

AUCt: Area Under the Plasma Concentration-Time Curve From Time Zero to Time t for ION-TTR-LRx

Time Frame

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

Title

CL/F: Apparent Total Clearance of ION-TTR-LRx

Time Frame

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

Title

t1/2λz: Termination Half-Life of ION-TTR-LRx

Time Frame

Up to 92 hours; post-dose on Day 85 for Cohorts A, B, and E, and on Day 1 for Cohort C

Title

Ae0-24h: Amount of Administered Dose of ION-TTR-LRx Excreted in Urine Over a 24-Hour Period

Time Frame

From 0 to 24 hours post-dose on Days 1 and 85

Title

Change From Baseline in Plasma Transthyretin (TTR) Levels Following Single and Multiple-dose Administration of ION-TTR-LRx

Time Frame

Baseline, Days 29 and 99

Title

Change From Baseline in Plasma Retinol Binding Protein 4 (RBP4) Levels Following Single and Multiple-Dose Administration of ION-TTR-LRx

Time Frame

Baseline, Days 29 and 99

Title

Percent Abundance of ION-682884 Antisense Oligonucleotide (ASO) Species (Metabolite) Following Administration of ION-682884 90 mg

Description

As prespecified in the protocol, this outcome measure was planned to be analyzed only in the Multiple Dose Cohort B: 90 mg ION-682884.

Time Frame

2 hours post-dose on Day 85

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Facility Information:

Facility Name

Bio Pharma Services, Inc.

City

Toronto

State/Province

Ontario

ZIP/Postal Code

M9L 3A2

Country

Canada

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

35869634

Citation

Diep JK, Yu RZ, Viney NJ, Schneider E, Guo S, Henry S, Monia B, Geary R, Wang Y. Population pharmacokinetic/pharmacodynamic modelling of eplontersen, an antisense oligonucleotide in development for transthyretin amyloidosis. Br J Clin Pharmacol. 2022 Dec;88(12):5389-5398. doi: 10.1111/bcp.15468. Epub 2022 Aug 7.

Results Reference

derived

PubMed Identifier

33283485

Citation

Viney NJ, Guo S, Tai LJ, Baker BF, Aghajan M, Jung SW, Yu RZ, Booten S, Murray H, Machemer T, Burel S, Murray S, Buchele G, Tsimikas S, Schneider E, Geary RS, Benson MD, Monia BP. Ligand conjugated antisense oligonucleotide for the treatment of transthyretin amyloidosis: preclinical and phase 1 data. ESC Heart Fail. 2021 Feb;8(1):652-661. doi: 10.1002/ehf2.13154. Epub 2020 Dec 7.

Results Reference

derived

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