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 ).

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.

Status

Completed

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03728634

Enrollment

Registered

2018-11-02

Start date

2018-12-21

Completion date

2020-02-20

Last updated

2022-12-19

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

hATTR Amyloidosis, Healthy Volunteers

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.

Interventions

DRUGION-682884

ION-682884 administered SC

DRUGPlacebo

Placebo comparator calculated volume to match ION-682884 administered SC

DIETARY_SUPPLEMENTVitamin A

Oral supplement

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to 65 Years

Healthy volunteers

Yes

Inclusion criteria

for Healthy Volunteers (Cohorts A, B, C, and E) 1. Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal 2. 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 3. Weight ≥ 50 kg and BMI \< 32 kg/m\^2

Exclusion criteria

for Healthy Volunteers (Cohorts A, B, C, and E) 1. 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 2. Drug or alcohol dependency or abuse 3. Treatment with another investigational drug, biological agent, or device within 1 month of Screening, or 5 half-lives of investigational agent, whichever is longer 4. Blood donation within 28 days 5. 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) 1. Aged 18 to 82 years at the time of informed consent 2. Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal 3. 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 4. Diagnosis of hereditary transthyretin-mediated polyneuropathy 5. BMI \> 16 kg/m2

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With at Least One Treatment-Emergent Adverse Event (TEAE)	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	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	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	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	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

Measure	Time frame	Description
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	—
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	—
Percent Abundance of ION-682884 Antisense Oligonucleotide (ASO) Species (Metabolite) Following Administration of ION-682884 90 mg	2 hours post-dose on Day 85	As prespecified in the protocol, this outcome measure was planned to be analyzed only in the Multiple Dose Cohort B: 90 mg ION-682884.
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	—
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	—

Countries

Canada

Participant flow

Pre-assignment details

A total of 47 participants were enrolled, of which 36 were randomized in multiple-dose cohorts and 11 in single-dose cohorts. This study consisted of a single-dose on Day 1, and 13 weeks of Post-Treatment Follow-up for participants in Cohort C and a 12-week Treatment Period followed by 13-week Post Treatment Evaluation Period for participants in Cohorts A, B, and E. Due to limited number of suitable participants with hereditary transthyretin amyloidosis (hATTR), Cohort D was never initiated.

Participants by arm

Arm	Count
Multiple Dose Cohort: Placebo Participants received ION-682884 matching placebo, SC, Q4W (total of 4 doses) along with daily oral supplemental doses of the RDA of vitamin A during the 13-week Treatment Period.	6
Multiple Dose Cohort A: ION-682884 45 mg Participants received ION-682884, 45 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.	10
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.	10
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.	10
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.	2
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.	9
Total	47

Baseline characteristics

Characteristic	Single Dose Cohort C: ION-682884 120 mg	Total	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
Age, Continuous	43.4 years	49.84 years	49.2 years	51.6 years	51.6 years	51.1 years	57.0 years
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	9 Participants	47 Participants	6 Participants	10 Participants	10 Participants	10 Participants	2 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	3 Participants	11 Participants	1 Participants	1 Participants	3 Participants	3 Participants	0 Participants
Race (NIH/OMB) Black or African American	3 Participants	11 Participants	1 Participants	3 Participants	3 Participants	1 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	3 Participants	25 Participants	4 Participants	6 Participants	4 Participants	6 Participants	2 Participants
Sex: Female, Male Female	1 Participants	20 Participants	4 Participants	3 Participants	6 Participants	4 Participants	2 Participants
Sex: Female, Male Male	8 Participants	27 Participants	2 Participants	7 Participants	4 Participants	6 Participants	0 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk
deaths Total, all-cause mortality	0 / 6	0 / 10	0 / 10	0 / 10	0 / 2	0 / 9
other Total, other adverse events	3 / 6	1 / 10	3 / 10	7 / 10	1 / 2	4 / 9
serious Total, serious adverse events	0 / 6	0 / 10	0 / 10	0 / 10	0 / 2	0 / 9

Outcome results

Primary

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.

Time frame: Up to Day 176