The purpose of this randomised, double-blind, placebo-controlled, multicenter study is to evaluate the efficacy and safety of concomitant use of eplontersen and ALXN2220 compared with eplontersen and placebo in adult participants with Transthyretin-mediated amyloid cardiomyopathy (ATTR-CM).

This is a Phase IIb, multicenter, double-blind study in 326 participants, who will be randomized to receive either eplontersen and ALXN2220 or eplontersen and placebo once every four weeks. Participants will also receive daily supplemental doses of the recommended daily allowance of vitamin A.

Capable of giving informed consent.

Inclusion Criteria:

• Participant must be ≥ 18 years to ≤ 85 years at the time of signing the informed consent.

• Participants who have a diagnosis of ATTR-CM with either wild-type or variant TTR genotype based on 1 of the following:

  1. Endomyocardial biopsy with confirmatory TTR amyloid typing OR
  2. Grade 2 or 3 cardiac uptake on 99mTc scintigraphy in the absence of monoclonal gammopathy OR
  3. Grade 2 or 3 cardiac uptake on 99mTc scintigraphy AND confirmatory TTR amyloid typing in the presence of monoclonal gammopathy.

• NYHA Class I to III at Screening and life expectancy of ≥ 1 year as per the Investigator's judgement.

• End-diastolic IVST ≥ 12 mm on echocardiography.

• NT-proBNP ≥ 600pg/mL for participants without ongoing atrial fibrillation/flutter at Screening or NT-proBNP ≥ 1200pg/mL for participants with ongoing atrial fibrillation/flutter at Screening.

• Able to complete symptom-limited maximal CPET at Screening based on the following test criteria:

  1. Able to exercise to near exhaustion during CPET as exhibited by RER ≥ 1.0 during symptom-limited CPET conducted during screening.
  2. If participant does not achieve RER ≥1.0, the CPET may be repeated once, at least 48 hours but less than 2 weeks (but before randomization) after the initial test.

• Treated according to locally recognised guidelines on standard-of-care treatment for patients with HF. Therapy should have been individually optimised and stable for ≥ 4 weeks (except diuretics) and include, unless contraindicated or not tolerated, treatment of high BP (targeting SBP < 130 mmHg as suggested in 2022 American College of Cardiology/American Heart Association/Heart Failure Society of America HF guidelines), and ischaemic heart disease.

• Willingness to adhere to daily self-administered vitamin A supplementation (3000 IU).

Exclusion Criteria:

• 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.

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.