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 ).

Healthy Volunteers Clinical Trial

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03728634
• Other study ID #: ION-682884-CS1
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: December 21, 2018
• Est. completion date: February 20, 2020

Study information

• Verified date: November 2022
• Source: Ionis Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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 ).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 47
• Est. completion date: February 20, 2020
• Est. primary completion date: February 20, 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Exclusion Criteria for hATTR Patients (Cohort D)

1. 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

2. Karnofsky performance status = 50

3. Other causes of sensorimotor or autonomic neuropathy (e.g., autoimmune disease), including uncontrolled diabetes

4. Prior liver transplant or anticipated liver transplant within 1-yr of Screening

5. New York Heart Association (NYHA) functional classification of = 3

6. Acute coronary syndrome or major surgery within 3 months of Screening

7. Other types of amyloidosis

8. 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

Related Conditions & MeSH terms

• Amyloidosis
• hATTR Amyloidosis
• Healthy Volunteers

Intervention

Drug:
• ION-682884
ION-682884 administered SC
• Placebo
Placebo comparator calculated volume to match ION-682884 administered SC

Dietary Supplement:
• Vitamin A
Oral supplement

Locations

Country	Name	City	State
Canada	Bio Pharma Services, Inc.	Toronto	Ontario

Sponsors (1)

Lead Sponsor	Collaborator
Ionis Pharmaceuticals, Inc.

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Up to Day 176
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	t1/2?z: 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
Secondary	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
Secondary	Change From Baseline in Plasma Transthyretin (TTR) Levels Following Single and Multiple-dose Administration of ION-TTR-LRx		Baseline, Days 29 and 99
Secondary	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
Secondary	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