Clinical Trials

Inclusion Criteria:

• Must have given written informed consent (signed and dated) and any authorizations required by local law and be able to comply with all study requirements.
• 18 to 90 years of age (inclusive).
• Females: must be non-pregnant and non-lactating and either:
  • surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy);
  • post-menopausal (defined as 12 months of spontaneous amenorrhea in females > 55 years of age or, in females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative medical cause and folliclestimulating hormone (FSH) levels in the post-menopausal range for the laboratory involved);
  • abstinent*; or
  • if of child-bearing potential and engaged in sexual relations, agree to use 1 highly effective contraceptive method from the time of signing the informed consent form until at least 24 weeks after the last dose of Study Drug (ION‑682884 or placebo).
• Males must be surgically sterile or abstinent*; if engaged in sexual relations with a female of child-bearing potential, the patient must be using an acceptable contraceptive method from the time of signing the informed consent form until at least 24 weeks after the last dose of Study Drug.

*Abstinence is only acceptable as true abstinence; i.e., when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of a trial and withdrawal are not acceptable methods of contraception.

• Willing to be genetically tested for mutations in the TTR gene during screening, if it was not done before.
• Amyloid deposits in cardiac or non-cardiac tissue confirmed by Congo Red (or equivalent) staining OR technetium scintigraphy (99mTc -3,3-diphosphono-1,2- propanodicarboxylic acid [DPD-Tc], 99m Tc-pyrophosphate [PYP-Tc], or 99mTc-hydroxymethylene-diphosphonate [HMDP-Tc]) with Grade 2 or 3 cardiac uptake in the absence of abnormal light chains ratio, centrally confirmed.
• End-diastolic interventricular septum thickness of > 12 mm on Screening echocardiogram.
• Medical history of HF secondary to hereditary or wild-type ATTR-CM with at least:
  • 1 prior hospitalization for HF, which may include hospitalization for arrhythmia or pacemaker/ICD (implantable cardioverter defibrillator) placement; OR
  • symptoms and signs of volume overload or elevated intracardiac pressure that either requires or required treatment with diuretics for clinical stabilization.
• Screening N-terminal prohormone of brain natriuretic peptide (NT-proBNP) ≥ 600 pg/mL by central lab. For patients in atrial fibrillation at Screening the eligibility NT-proBNP value is ≥ 1200 pg/mL.
• New York Heart Association (NYHA) class I-III.
• 6MWT ≥ 150 meters.
• If on medical treatment for HF, stable medication regimen for at least 2 weeks prior to randomization.
• Willingness to adhere to vitamin A supplementation per protocol.

Exclusion Criteria:

• Acute coronary syndrome, unstable angina, stroke, transient ischemic attack (TIA), coronary revascularization, cardiac device implantation, cardiac valve repair, or major surgery within 3 months of Screening.
• Hospitalization or urgent visit to emergency department/emergency room (ED/ER) for worsening of HF within 4 weeks prior to or during Screening.
• Uncontrolled hypertension (systolic blood pressure [BP] > 160 or diastolic BP > 100 mmHg).
• Uncontrolled clinically significant cardiac arrhythmia, per Investigator’s assessment (e.g., no pacemaker, although indicated).
• Severe, uncorrected, cardiac valvular disease.
• Cardiomyopathy not primarily caused by ATTR-CM, for example, cardiomyopathy due to hypertension, valvular heart disease, or ischemic heart disease.
• Screening laboratory results as follows, or any other clinically significant abnormalities in Screening laboratory values that would render a patient unsuitable for inclusion:
  • Alanine aminotransferase/aspartate aminotransferase (ALT/AST) > 2.0 × upper limit of normal (ULN);
  • 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);
  • Platelets < lower limit of normal (LLN; central laboratory);
  • 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;
  • Positive test (including trace) for blood on urinalysis. In the event of a positive test ineligibility may be confirmed with urine microscopy showing > 5 red blood cells per high power field in women, this exclusion criterion must be assessed outside of menstrual period;
  • Estimated glomerular filtration rate (eGFR) < 30 mL /min/1.73 m^2 at Screening [CKD-EPI formula; (Levey et al. 2009)]. If the eGFR is thought to be underestimated, the CKD-EPI creatinine-cystatin C equation can be used for confirmation (Inker et al. 2012);
  • Abnormal thyroid function tests with clinical significance per Investigator judgement;
  • Serum retinol level at Screening < LLN (this criterion does not apply to hATTR-CM patients with mutation at the position 84 [e.g., Ile84Ser]);
  • Hemoglobin A1c (HbA1c) > 9.5%.
• Monoclonal gammopathy of undetermined significance (MGUS) and/or immunoglobulin free light chain ratio < 0.26 and/or > 1.65, 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.
• Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1.
• 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).
• 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).
• 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.
• Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been 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.
• Karnofsky performance status of ≤ 50%.
• Contraindication for immunosuppressive therapy, per Investigator’s discretion.
• Known Light chain/Primary Amyloidosis (AL).
• Known leptomeningeal amyloidosis.
• Known history of multiple myeloma.
• Treatment with another investigational drug and/or biological agent within 1 month of Screening, or 5 half-lives of investigational agent, whichever is longer.
• Current or previous treatment with Tegsedi™ (inotersen) or Onpattro™ (patisiran) or other oligonucleotide or RNA therapeutic (including siRNA).
• Current treatment with diflunisal, doxycycline, non-dihydropyridine calcium-channel blocker (e.g., verapamil, diltiazem). Patients receiving any of these agents must respect a wash-out period of 14 days before randomization.
• Unwillingness or inability to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator.
• Other physical, social, or psychological conditions including illicit drug or alcohol use, which, in the opinion of the Investigator would make the patient unsuitable for inclusion, or could interfere with the patient participating in or completing the study.