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 ).

Ionis Pharmaceuticals

Status and phase: Completed; Phase 2; Phase 1

Conditions: Healthy Volunteers; hATTR Amyloidosis

Treatments: Dietary Supplement: Vitamin A; Drug: ION-682884; Drug: Placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT03728634

ION-682884-CS1

Details and patient eligibility

About

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 ).

Full 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.

Enrollment: 47 patients

Sex: All

Ages: 18 to 65 years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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47 participants in 6 patient groups, including a placebo group

Multiple Dose Cohort: Placebo

Placebo Comparator group

Description:

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.

Treatment:

Dietary Supplement: Vitamin A

Drug: Placebo

Multiple Dose Cohort A: ION-682884 45 mg

Experimental group

Description:

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.

Treatment:

Dietary Supplement: Vitamin A

Drug: ION-682884

Multiple Dose Cohort E: ION-682884 60 mg

Experimental group

Description:

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.

Treatment:

Dietary Supplement: Vitamin A

Drug: ION-682884

Multiple Dose Cohort B: ION-682884 90 mg

Experimental group

Description:

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.

Treatment:

Dietary Supplement: Vitamin A

Drug: ION-682884

Single Dose Cohort: Placebo

Placebo Comparator group

Description:

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.

Treatment:

Dietary Supplement: Vitamin A

Drug: Placebo

Single Dose Cohort C: ION-682884 120 mg

Experimental group

Description:

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.

Treatment:

Dietary Supplement: Vitamin A

Drug: ION-682884