CARDIO-TTRansform: A Study to Evaluate the Efficacy and Safety of Eplontersen (Formerly Known as ION-682884, IONIS-TTR-LRx and AKCEA-TTR-LRx) in Participants With Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR CM)

Inclusion Criteria:

• Females must be non-pregnant and non-lactating, and either surgically sterile orpost-menopausal or abstinent. If engaged in sexual relations of child-bearingpotential, agree to use 1 highly effective contraceptive method

• Males must be surgically sterile or, abstinent or, if engaged in sexual relationswith a woman of child-bearing potential, the participant or the participant'snon-pregnant female partner must be using a highly effective contraceptive method

• Amyloid deposits in cardiac or non-cardiac tissue confirmed by Congo Red (orequivalent) 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 theabsence of abnormal light chains ratio, centrally confirmed

• End-diastolic interventricular septum thickness of > 12 millimeters (mm) onScreening echocardiogram

• New York Heart Association (NYHA) class I-III

Exclusion Criteria:

• Acute coronary syndrome, unstable angina, stroke, transient ischemic attack (TIA),coronary revascularization, cardiac device implantation, cardiac valve repair, ormajor surgery within 3 months of Screening

• Cardiomyopathy not primarily caused by ATTR-CM, for example, cardiomyopathy due tohypertension, valvular heart disease, or ischemic heart disease

• Monoclonal gammopathy of undetermined significance (MGUS) and/or alterations inimmunoglobulin free light chain (FLC) ratio unless fat, bone marrow, or heart biopsyconfirming the absence of light chain and the presence of TTR protein by massspectrometry or immunoelectron microscopy. For participants with chronic kidneydisease (CKD) and without presence of monoclonal protein in blood and urine, theacceptable FLC ratio is 0.26-2.25. Results different from that may be discussed withlocal hematologist, Investigator and Medical Monitor if the risks associated withthe biopsy outweigh the benefits

• Prior liver or heart transplant, and/or Left Ventricular Assist Device (LVAD) oranticipated liver transplant or LVAD within 1 year after randomization

• Current or previous treatment with Tegsedi™ (inotersen) or Onpattro™ (patisiran) orother oligonucleotide or ribonucleic acid (RNA) therapeutic (including smallinterfering ribonucleic acid [siRNA]; does not apply to COVID-19 mitochondrial [mRNA] vaccinations)

• Current treatment with diflunisal, doxycycline, with or without ursodeoxycholicacid, and/or non-dihydropyridine calcium-channel blocker (e.g., verapamil,diltiazem). Participants receiving any of these agents must respect a wash-outperiod of 14 days before randomization.