ION-682884 in Patients With TTR Amyloid Cardiomyopathy

Inclusion Criteria: 1\. Only patient who have completed 24 months of therapy in the open label clinical trial of inotersen, "A 24-month open-label study of the tolerability and efficacy of an antisense oligonucleotide (inotersen) in patients with transthyretin (TTR) amyloid cardiomyopathy" (Protocol #:2018-P001436) will be enrolled. All patients in that study had either wild-type transthyretin amyloidosis (ATTRwt) or mutant transthyretin amyloidosis (ATTRm) cardiac amyloidosis, defined by standard criteria. Additional criteria for the current study are as follows: 1. Patients should, in the opinion of the Investigator, be in a stable state in terms of New York Heart Association (NYHA) class. Class I-III patients will be recruited. 2. Age 65-85 years 3. Male, or non-pregnant, non-lactating females. If a male partners with a premenopausal woman, he must be willing to use the following methods of contraception: condoms, oral/hormonal contraception, Intrauterine Device, diaphragm, or abstinence (all patients are either male of post-menopausal) (NB: There will be no premenopausal women in the proposed study) 4. Written informed consent to be obtained prior to study treatment 5. Willingness to return to the treating center for follow-up 6. Willingness and ability to self-administer, or to have spouse administer subcutaneous injections of study drug every 4 weeks. 7. Willingness to take oral Vitamin A supplementation throughout the study and for 3 months thereafter. Exclusion Criteria: 1\. Acute coronary syndrome, unstable angina, stroke, transient ischemic attack,, coronary revascularization, cardiac device implantation, cardiac valve repair, or major surgery within 3 emergency room for worsening of HF with discharge date within 4 weeks prior to or during Screening 3. Uncontrolled hypertension (systolic blood pressure \[BP\] \> 160 or diastolic BP \> 100 mmHg) 4. Uncontrolled clinically significant cardiac arrhythmia, per Investigator's assessment (e.g., no pacemaker, although indicated) 5. Severe uncorrected cardiac valvular disease 6. Cardiomyopathy not primarily caused by amyloidosis, for example, cardiomyopathy due to hypertension, valvular heart disease, or ischemic heart disease 7. Screening laboratory results as follows, or any other clinically significant abnormalities in Screening laboratory values that would render a patient unsuitable for inclusion 1. Alanine aminotransferase/aspartate aminotransferase (ALT/AST) \> 2.0 × upper limit of normal (ULN) 2. Total bilirubin ≥ 1.5 × ULN (patients with total bilirubin ≥ 1.5 × ULN may be allowed on study if indirect bilirubin only is elevated, ALT/AST is not greater than the ULN and known to have Gilbert's disease) 3. Platelets \< 125 × 109/L 4. Urine protein creatinine ratio (UPCR) ≥ 750 mg/g. In the event of UPCR above this threshold ineligibility may be confirmed by a repeat random spot UPCR ≥ 750 mg/g 5. Positive test for blood (including trace) on urinalysis that is subsequently confirmed with urine microscopy showing \> 5 red blood cells per high power field and is related to glomerulopathies. In women, this exclusion criterion must be assessed outside of menstrual period. If in the opinion of the Investigator the hematuria is not considered related to glomerulopathies the patient may be considered eligible, pending proper follow-up and a discussion with the Medical Monitor. Patients with history of bladder cancer must have been treated with curative intent and have not presented recurrence within the prior 5 years 6. Estimated glomerular filtration rate (eGFR) \< 30 mL/min/1.73 m2 at Screening. If the eGFR is thought to be underestimated, the CKD-EPI creatinine-cystatin C equation can be used for confirmation. 7. Abnormal thyroid function tests with clinical significance per Investigator judgement 8. Hemoglobin A1c (HbA1c) \> 9.5% 8. Monoclonal gammopathy of undetermined significance (MGUS) and/or alterations in immunoglobulin free light chain (FLC) ratio, unless fat, bone marrow, or heart biopsy confirming the absence of light chain and the presence of TTR protein by mass spectrometry or immunoelectron microscopy. For patients with CKD and without presence of monoclonal protein in blood and urine, the acceptable FLC ratio is 0.26-2.25. 9\. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1 10. Known history of or positive test for human immunodeficiency virus (HIV) (as evidenced by positive tests for HIV antibody and HIV RNA), hepatitis C (as evidenced by positive tests for HCV antibody and HCV RNA) or hepatitis B (as evidenced by a positive test for hepatitis B surface antigen) 11. History of bleeding, diathesis or coagulopathy (e.g., liver cirrhosis, hematologic malignancy, antiphospholipid antibody syndrome, congenital disorders such as hemophilia A, B, and Von Willebrand disease) 12. If receiving oral anticoagulants (except vitamin K antagonists), the dose must have been stable for 4 weeks prior to the first dose of Study Drug and regular monitoring must be performed, per clinical practice during the study. If the patient is receiving vitamin K antagonists (e.g., warfarin) INR should be in therapeutic range, as established by the Investigator, for 4 weeks prior to the first dose 13. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin, melanoma in situ, prostate carcinoma grade group 1, breast ductal carcinoma in situ, or carcinoma in situ of the cervix successfully treated. Patients with a history of other malignancies who have been treated with curative intent and without recurrence within 5 years may also be eligible per Investigator judgment 14. Prior liver or heart transplant, and/or Left Ventricular Assist Device (LVAD) or anticipated liver transplant or LVAD within 1 year after randomization 15. Karnofsky performance status of ≤ 50% 16. Contraindication for immunosuppressive therapy, per Investigator's discretion 17. Known Light chain/Primary Amyloidosis (AL) 18. Known leptomeningeal amyloidos \-