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 ).

NCT03728634 | Completed Phase 1 Results FDA Drug

• 1 other identifier: ION-682884-CS1
• Study Type: interventional
• Target: 47
• Locations: 1 country
• Sites: 1

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 ).

Conditions

Healthy Volunteers; hATTR Amyloidosis

Outcome Measures

Primary Outcomes (5)

• 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

• 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

• 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

• 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

• 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 Outcomes (9)

• 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

• 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

Study Arms (6)

Multiple Dose Cohort: Placebo

PLACEBO COMPARATOR

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.

Drug: Placebo; Dietary Supplement: Vitamin A

Multiple Dose Cohort A: ION-682884 45 mg

EXPERIMENTAL

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.

Drug: ION-682884; Dietary Supplement: Vitamin A

Multiple Dose Cohort E: ION-682884 60 mg

EXPERIMENTAL

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.

Drug: ION-682884; Dietary Supplement: Vitamin A

Multiple Dose Cohort B: ION-682884 90 mg

EXPERIMENTAL

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.

Drug: ION-682884; Dietary Supplement: Vitamin A

Single Dose Cohort: Placebo

PLACEBO COMPARATOR

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.

Drug: Placebo; Dietary Supplement: Vitamin A

Single Dose Cohort C: ION-682884 120 mg

EXPERIMENTAL

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.

Drug: ION-682884; Dietary Supplement: Vitamin A

Interventions

ION-682884 DRUG

ION-682884 administered SC

Also known as: Eplontersen, AKCEA-TTR-LRx, IONIS-TTR-LRx

Multiple Dose Cohort A: ION-682884 45 mg; Multiple Dose Cohort B: ION-682884 90 mg; Multiple Dose Cohort E: ION-682884 60 mg; Single Dose Cohort C: ION-682884 120 mg

Placebo DRUG

Placebo comparator calculated volume to match ION-682884 administered SC

Multiple Dose Cohort: Placebo; Single Dose Cohort: Placebo

Vitamin A DIETARY_SUPPLEMENT

Oral supplement

Multiple Dose Cohort A: ION-682884 45 mg; Multiple Dose Cohort B: ION-682884 90 mg; Multiple Dose Cohort E: ION-682884 60 mg; Multiple Dose Cohort: Placebo; Single Dose Cohort C: ION-682884 120 mg; Single Dose Cohort: Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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
• 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

Sponsors & Collaborators

• Ionis Pharmaceuticals, Inc.: lead

Study Sites (1)

Bio Pharma Services, Inc.

Toronto, Ontario, M9L 3A2, Canada

Location

Related Publications (2)

• 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.

  PMID: 35869634 DERIVED

• 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.

  PMID: 33283485 DERIVED

MeSH Terms

Interventions

eplontersen; Vitamin A

Intervention Hierarchy (Ancestors)

Retinoids; Carotenoids; Polyenes; Alkenes; Hydrocarbons, Acyclic; Hydrocarbons; Organic Chemicals; Cyclohexenes; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Diterpenes; Pigments, Biological; Biological Factors

Results Point of Contact

• Title: Ionis Pharmaceuticals, Inc.
• Organization: Ionis Pharmaceuticals, Inc.

patients@ionisph.com

800-679-4747

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 31, 2018
• First Posted: November 2, 2018
• Study Start: December 21, 2018
• Primary Completion: February 20, 2020
• Study Completion: February 20, 2020
• Last Updated: December 19, 2022
• Results First Posted: December 19, 2022

Record last verified: 2022-11

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)