Clinical trial NCT03728634: 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
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Healthy Volunteers
hATTR Amyloidosis
Lead sponsor: Ionis Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2018-11-02
Enrollment: 47
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants With at Least One Treatment-Emergent Adverse Event (TEAE)
timeFrame: Up to Day 176
measure: Percentage of Participants Using Concomitant Medications
timeFrame: Up to Day 176
measure: Number of Participants With Clinically Significant Laboratory Values
timeFrame: Up to Day 176
measure: Number of Participants With Clinically Significant Physical Examination Findings
timeFrame: Up to Day 176
measure: Number of Participants With Clinically Significant Electrocardiogram (ECG) Values
timeFrame: Up to Day 176
Secondary outcomes:
measure: Cmax: Maximum Observed Plasma Drug Concentration of ION-TTR-LRx
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose on Days 1 and 85
measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of ION-TTR-LRx
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose on Days 1 and 85
measure: AUCt: Area Under the Plasma Concentration-Time Curve From Time Zero to Time t for ION-TTR-LRx
timeFrame: 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
measure: CL/F: Apparent Total Clearance of ION-TTR-LRx
timeFrame: 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
measure: t1/2λz: Termination Half-Life of ION-TTR-LRx
timeFrame: Up to 92 hours; post-dose on Day 85 for Cohorts A, B, and E, and on Day 1 for Cohort C
measure: Ae0-24h: Amount of Administered Dose of ION-TTR-LRx Excreted in Urine Over a 24-Hour Period
timeFrame: From 0 to 24 hours post-dose on Days 1 and 85
measure: Change From Baseline in Plasma Transthyretin (TTR) Levels Following Single and Multiple-dose Administration of ION-TTR-LRx
timeFrame: Baseline, Days 29 and 99
measure: Change From Baseline in Plasma Retinol Binding Protein 4 (RBP4) Levels Following Single and Multiple-Dose Administration of ION-TTR-LRx
timeFrame: Baseline, Days 29 and 99
measure: Percent Abundance of ION-682884 Antisense Oligonucleotide (ASO) Species (Metabolite) Following Administration of ION-682884 90 mg
timeFrame: 2 hours post-dose on Day 85
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: Bio Pharma Services, Inc.
state: Ontario
Study officials:
References:
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.
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.