A Study to Evaluate the Efficacy and Safety of Concomitant Use of Eplontersen and ALXN2220 Compared With Eplontersen and Placebo for Adults Participants With ATTR-CM

Exclusion Criteria22

• Known leptomeningeal amyloidosis.
• Known light chain (AL) or secondary (amyloid A) amyloidosis, or any other form of systemic amyloidosis.
• Cardiomyopathy not primarily caused by ATTR-CM, for example, cardiomyopathy primarily due to hypertension, valvular heart disease, or ischaemic heart disease per Investigator's assessment.
• Acute coronary syndrome, unstable angina, stroke, transient ischaemic attack, coronary revascularisation, cardiac device implantation, cardiac valve repair, or major surgery within 12 weeks of Screening.
• Uncontrolled hypertension (average resting SBP > 160 mmHg or DBP > 100 mmHg at Screening).
• Average resting SBP < 90 mmHg or symptomatic orthostatic hypotension, despite appropriate treatment, at Screening per Investigator's assessment.
• Uncontrolled ventricular clinically significant cardiac arrhythmia, per Investigator's assessment.
• Left ventricular ejection fraction < 30% on echocardiography measured locally at Screening.
• Severe pulmonary impairment (SpO₂ < 92%) defined as resting SpO₂ below 92% on room air, measured by pulse oximetry, indicative of severe lung disease. Participants requiring supplemental oxygen to maintain SpO₂ ≥ 92%.
• Participants with renal failure requiring dialysis.
• History of solid organ transplantation or ventricular assist device or listing for heart transplantation at Screening. Note: prior history of planned corneal transplant is not an exclusion criterion.
• Suspected or known intolerance/allergy to proteins or any components of the study intervention.
• Any of the following results conducted at screening:
• i) Haemoglobin <8g/dL for women or <9g/dL for men. ii) Platelet count <125 X10*9/L or other disorder associated with clinically significant thrombocytopenia.
• iii) ALT >2.0 X ULN iv) TBL >2.5 X ULN (participants with known Gilbert's syndrome can be included with TBL >2.5 X ULN as long as direct bilirubin is ≤ 1.5 X ULN) v) Serum retinol level < LLN vi) By CKD-EPI formula, eGFR <20 mL/min/1.73 m2 measured by the central laboratory at Screening.
• Current unstable liver or biliary disease per Investigator's assessment.
• Multiple myeloma, lymphoma, leukemia, or any malignancy or clonal stem cell disorder within the past 5 years (except basal cell or squamous epithelial carcinomas of the skin, melanoma in situ or cervical carcinoma in situ that have been curatively resected, Stage I cancer in remission, or adequately treated prostate cancer stage I, IIA, or IIB with Gleason score ≤ 3+4 and prostate-specific antigen < 20 ng/mL).
• Any prior treatment with an ATTR amyloid depleter or a TTR gene silencing agent approved or in clinical development.
• Participated in a structured exercise training programme within the 1 month prior to Screening or planned to start during the trial.
• Participation in another investigational clinical study or intake of another investigational drug within 30 calendar days or 5 half-lives of the IMP, whichever is longer before signing the ICF.
• Judgement by the Investigator that the participant should not participate in the study if the participant has a known medical or psychological condition or other risk factor that might interfere with the participant's full participation in the study, pose any additional risk for the participant, or confound the assessment of the participant or outcome of the study.
• Previous enrolment or randomisation in the present study.