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 ).

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.

Inclusion criteria

for Healthy Volunteers (Cohorts A, B, C, and E)

• 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

Exclusion criteria

for Healthy Volunteers (Cohorts A, B, C, and E)

• 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
• 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
• 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)

• 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

Exclusion criteria

for hATTR Patients (Cohort D)

• 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
• 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
• 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