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 ).

NCT ID: NCT03728634

Last Updated: 2022-12-19

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 47 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-12-21
• Study Completion Date: 2020-02-20

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.

Conditions

Healthy Volunteers; hATTR Amyloidosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Multiple Dose Cohort: Placebo

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo comparator calculated volume to match ION-682884 administered SC

Vitamin A

Intervention Type: DIETARY_SUPPLEMENT

Oral supplement

Multiple Dose Cohort A: ION-682884 45 mg

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.

Group Type: EXPERIMENTAL

ION-682884

Intervention Type: DRUG

ION-682884 administered SC

Vitamin A

Intervention Type: DIETARY_SUPPLEMENT

Oral supplement

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.

Group Type: EXPERIMENTAL

ION-682884

Intervention Type: DRUG

ION-682884 administered SC

Vitamin A

Intervention Type: DIETARY_SUPPLEMENT

Oral supplement

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.

Group Type: EXPERIMENTAL

ION-682884

Intervention Type: DRUG

ION-682884 administered SC

Vitamin A

Intervention Type: DIETARY_SUPPLEMENT

Oral supplement

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo comparator calculated volume to match ION-682884 administered SC

Vitamin A

Intervention Type: DIETARY_SUPPLEMENT

Oral supplement

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.

Group Type: EXPERIMENTAL

ION-682884

Intervention Type: DRUG

ION-682884 administered SC

Vitamin A

Intervention Type: DIETARY_SUPPLEMENT

Oral supplement

Interventions

ION-682884

ION-682884 administered SC

Intervention Type: DRUG

Placebo

Placebo comparator calculated volume to match ION-682884 administered SC

Intervention Type: DRUG

Vitamin A

Oral supplement

Intervention Type: DIETARY_SUPPLEMENT

Other Intervention Names

Eplontersen; AKCEA-TTR-LRx; IONIS-TTR-LRx

Eligibility Criteria

Inclusion Criteria

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

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

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

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Ionis Pharmaceuticals, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Bio Pharma Services, Inc.

Toronto, Ontario, Canada

Countries

Canada

References

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.

Reference Type: DERIVED

PMID: 35869634 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33283485 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

ION-682884-CS1

Identifier Type: -

Identifier Source: org_study_id