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Efficacy and safety of eplontersen sodium plus ALXN2220 in adults with transthyretin-mediated amyloid cardiomyopathy (ATTR-CM)

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What is this trial about?

A plain-language summary of the goals, design and what participants do

The study focuses on adults with Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR-CM), a rare condition where abnormal protein builds up in the heart muscle, making it stiff and less able to pump blood. The treatment being tested combines two medicines: a subcutaneous (under‑the‑skin) injection of eplontersen, which helps reduce the problematic protein, and an intravenous (through a vein) infusion of ALXN2220, a specially designed antibody that also targets the protein. Participants will receive either this combination or the same eplontersen injection together with a placebo, which looks like the real medicine but does not contain the active drug.

The purpose of the study is to determine whether adding ALXN2220 to eplontersen improves the ability to exercise compared with eplontersen plus placebo. To assess this, participants will perform a cardiopulmonary exercise test (CPET), a breathing and exercise test that measures the maximum amount of oxygen the body can use during intense activity. The test will be done at the start of the study and again after about a year of treatment.

During the trial, participants will visit the clinic regularly for the subcutaneous injections, the intravenous infusions, and safety checks such as blood tests and heart examinations. The study will continue for roughly 52 weeks, with scheduled appointments to monitor how the heart is working and to record any side effects. All procedures are designed to follow standard safety guidelines.

The research process

The trial runs in 6 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Baseline visit

    After joining the study you will attend a baseline visit where your health status is recorded.

    The visit includes a cardiopulmonary exercise test (cpet) to measure your peak oxygen consumption, blood tests, and a questionnaire about your symptoms.

  2. Step 2

    Randomisation

    Based on the information collected at the baseline visit you will be randomly assigned to receive either the combination of eplontersen and alxn2220 or eplontersen with a placebo.

    The assignment is made by the study system and you will not know which group you are in.

  3. Step 3

    Medication administration

    You will receive eplontersen as a solution for injection that is given subcutaneously using a pre‑filled pen.

    In addition you will receive either alxn2220, which is given intravenously as a solution for injection, or a matching placebo that is also given intravenously.

    The exact dose, frequency and duration are defined by the study protocol and will be administered for a total period of 52 weeks.

  4. Step 4

    Regular follow‑up visits

    Throughout the 52‑week treatment period you will attend scheduled follow‑up visits.

    At each visit safety assessments, blood tests, and questionnaires will be performed to monitor your condition.

    Periodic cpet tests may be repeated to track changes in your functional capacity.

  5. Step 5

    Final assessment

    At the end of the 52‑week period you will have a final visit that repeats the baseline assessments, including the cpet test, blood tests, and symptom questionnaire.

    The results will be used to evaluate the effect of the study medication on your heart function and overall health.

  6. Step 6

    Study completion

    After the final assessment you will stop receiving the study medication.

    You will be provided with information about any further care that may be needed.

Who can join the trial?

8 criteria

  • Be at least 18 years old and not older than 85 years when you sign the consent form.
  • Have a confirmed diagnosis of transthyretin‑mediated amyloid cardiomyopathy (ATTR‑CM) and have either the normal (wild‑type) or a changed (variant) version of the TTR gene.
  • Be classified as NYHA Class I‑III (a scale that measures how much heart disease limits everyday activities) at the screening visit and have a life expectancy of at least one year according to the doctor’s judgment.
  • Show an elevated NT‑proBNP level (a blood marker that rises when the heart is under stress) at screening.
  • Be able to safely finish a symptom‑limited maximal CPET (a breathing test that measures how much oxygen your body can use during intense exercise) during screening.
  • Be receiving standard heart‑failure medicines that have been stable for at least four weeks (except for diuretics), including treatment to keep blood pressure below 130 mmHg systolic and care for any blocked arteries (ischemic heart disease), unless you cannot tolerate them.
  • Be able to sign an informed consent form, showing that you understand the study and agree to take part.
  • Agree to take a daily vitamin A supplement of 3000 IU as instructed.

Who cannot join the trial?

14 criteria

  • Leptomeningeal amyloidosis – a rare disease affecting the lining of the brain and spinal cord, makes you ineligible.
  • If you have a known or suspected allergy or intolerance to proteins or any part of the study medicine, you cannot join.
  • You must not have taken part in another experimental study or used another experimental drug within the last 30 days (or longer, depending on how the drug leaves the body).
  • People who work on planning or running this study, such as staff from the sponsor or the study site, cannot be participants.
  • If the doctor believes you have a medical or mental health condition that could interfere with the study or increase your risk, you will be excluded.
  • If you have already been enrolled or randomly assigned in this same study before, you cannot take part again.
  • Having other types of amyloidosis, such as light‑chain (AL) amyloidosis, secondary (AA) amyloidosis, or any systemic amyloidosis, excludes you.
  • If your heart muscle disease (cardiomyopathy) is mainly caused by other problems like high blood pressure, valve disease, or blocked arteries, you are not eligible.
  • Recent serious heart or brain events (such as heart attack, unstable chest pain, stroke, brief loss of brain blood flow) or major surgery, heart‑device implantation, or heart‑valve repair within the past 12 weeks disqualify you.
  • Having an uncontrolled, significant irregular heart rhythm (ventricular arrhythmia) as judged by the investigator excludes you.
  • If an ultrasound of your heart (echocardiogram) shows a left‑ventricular ejection fraction (a measure of how well the heart pumps) less than 30%, you cannot participate.
  • Severe lung problems with a resting oxygen level (SpO₂) below 92% on room air, or needing extra oxygen to keep it at 92% or higher, are exclusion criteria.
  • Kidney failure that requires dialysis (a machine that cleans the blood) makes you ineligible.
  • A history of solid‑organ transplant, use of a ventricular assist device (a mechanical heart pump), or being listed for a heart transplant at the screening visit excludes you.
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Investigated drugs

  • Wainzua (eplontersen)

    is a medication given as a liquid that is injected just under the skin. It works by binding to a protein called transthyretin, which helps prevent this protein from forming the sticky clumps (amyloid) that can damage the heart in transthyretin amyloid cardiomyopathy. In the study, participants receive this drug to see if it can improve their ability to exercise and overall heart function.

  • ALXN2220

    is a specially designed antibody that is given through a vein. This antibody targets the same transthyretin protein and helps the body clear it more quickly, reducing the buildup of harmful amyloid deposits. In the trial, it is used together with Wainzua to test whether the combination works better than Wainzua alone in improving patients’ exercise capacity and heart health.

What is already known about the treatment

  • Placebo for ALXN2220

    This is an inactive solution given by intravenous infusion that contains no active drug, and it is used only as a control in the study. It has no therapeutic effect and serves to help compare the results of the active treatments. The placebo is not a marketed medication and is not described in medical literature. It is simply a non‑active comparator.

  • Wainzua 45 mg solution for injection in pre-filled pen

    This medication is a clear solution for injection that is administered subcutaneously using a pre‑filled pen. It is an investigational antisense oligonucleotide currently being studied in clinical trials for transthyretin‑mediated amyloid cardiomyopathy (ATTR‑CM). It works by attaching to the genetic instructions that produce transthyretin, lowering the amount of this protein and helping to prevent harmful amyloid deposits. It is classified as an antisense therapy.

  • Recombinant human anti‑ATTR immunoglobulin G1 (IgG1) monoclonal antibody (mAb)

    This drug is given as an intravenous infusion of a sterile solution. It is an experimental monoclonal antibody that has received orphan‑drug designation for the treatment of ATTR‑CM. It binds to the circulating transthyretin protein, marking it for removal by the immune system and reducing the formation of amyloid deposits in the heart. It belongs to the class of therapeutic monoclonal antibodies.

Investigated diseases

Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR-CM) - Transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) is a condition in which abnormal transthyretin protein forms amyloid deposits that accumulate in the heart muscle. These deposits cause the walls of the heart chambers to become thicker and less flexible. As the disease advances, the heart’s ability to fill and pump blood gradually declines. Patients may notice increasing shortness of breath, fatigue, and swelling in the legs as the heart struggles to meet the body’s needs. The progression is typically slow but steady, leading to worsening heart function over time.
Trial detailsLast updated 7 Oct 2026
Age18+ yearsPhasePhase IITrial ID2025-523908-75-00Protocol codeD8456C00001Estimated enrolment326 patientsSponsorAstraZeneca AB

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