CLEOPATTRA: Effects of NNC6019-0001 versus placebo on cardiovascular outcomes in participants with transthyretin amyloid cardiomyopathy (ATTR-CM).

The primary objective is to demonstrate superiority of NNC6019-0001 versus placebo, both added to standard of care, in reducing cardiovascular death and morbidity in participants with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) or variant transthyretin amyloid cardiomyopathy (ATTRv-CM). This objective addresses the critical need to reduce mortality and cardiovascular events in patients with transthyretin amyloid cardiomyopathy, a progressive and life-threatening condition characterized by amyloid deposition in cardiac tissue leading to restrictive cardiomyopathy and heart failure.

The secondary objectives are to demonstrate superiority of NNC6019-0001 versus placebo, both added to standard of care, in participants with ATTRv-CM or ATTRwt-CM on:

• Heart failure symptoms, physical functioning and quality of life
• Cardiovascular morbidity
• Cardiovascular death and all-cause death
• Kidney function

These secondary endpoints evaluate the broader clinical impact of treatment on functional status, organ function, and overall survival, which are essential measures of therapeutic benefit in this patient population.

This clinical trial enrolled a total of **735 participants** diagnosed with **transthyretin amyloid cardiomyopathy** (ATTR-CM), including both wild-type (ATTRwt) and variant (ATTRv) forms of the condition. The study population included both **male and female** adults aged **18 years and above**. Participants were required to have an established diagnosis of ATTR-CM confirmed through cardiac amyloid infiltration demonstrated by cardiac biopsy positive for TTR amyloid, or Grade 2 or 3 cardiac uptake on bone tracer scintigraphy combined with either extracardiac biopsy or specific laboratory findings. All participants exhibited increased **left ventricular wall thickness** of at least 12 mm as measured by interventricular septal wall thickness on echocardiography. The trial population consisted of individuals with chronic **heart failure** (New York Heart Association class I-IV) requiring ongoing treatment with a **loop diuretic**, with documented history of either hospitalization for heart failure or clinical manifestations of volume overload or elevated intracardiac pressures. Participants were expected to be on stable cardiovascular medical therapy, with the exception of diuretics, for at least 4 weeks prior to randomization. Eligibility also required specific **NT-proBNP concentration** thresholds at screening, with a subset cap for participants with intermediate levels. Functional capacity was assessed by requiring participants to complete more than 50 meters on the **6-minute walk test** at screening. The target recruitment included approximately 15% of participants with the variant form of the disease.

This is a Phase 3, randomized, double-blind, placebo-controlled clinical trial designed to evaluate the effects of coramitug (NNC6019-0001) versus placebo, both added to standard of care, in participants with transthyretin amyloid cardiomyopathy (ATTR-CM). The trial will investigate the superiority of coramitug in reducing cardiovascular death and morbidity in participants with wild-type or variant ATTR-CM. Coramitug is a humanised IgG1 monoclonal antibody against misfolded transthyretin, administered as a solution for infusion via intravenous route in a liquid dosage form. The product has been designated as an orphan drug (EU/3/24/2991). The maximum treatment period is 192 weeks.

The trial will enroll male and female participants aged 18 years or above with an established diagnosis of ATTR-CM, including either wild-type or variant forms (with approximately 15% target recruitment for variant ATTR). Eligible participants must demonstrate cardiac amyloid infiltration through cardiac biopsy positive for TTR amyloid, or Grade 2 or 3 cardiac uptake at bone tracer scintigraphy combined with either extracardiac biopsy positive for TTR amyloid or normal serum free light chain ratio with negative protein electrophoresis. Participants must have increased left ventricular wall thickness with interventricular septal wall thickness of at least 12 mm as assessed by centralized echocardiography review, and chronic heart failure (NYHA I-IV) requiring ongoing treatment with a loop diuretic. Additional inclusion criteria include at least one documented hospitalization for heart failure or history of heart failure with signs or symptoms of volume overload or elevated intracardiac pressures, stable cardiovascular medical therapy for 4 weeks prior to randomization (except diuretics), specified NT-proBNP concentration levels at screening, and completion of more than 50 meters on the 6-minute walk test at screening.

The primary endpoint is the number of occurrences of a composite endpoint consisting of cardiovascular death and recurrent cardiovascular events (cardiovascular hospitalization and urgent heart failure visits). Secondary endpoints include change in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), change in 6-minute walk distance, number of occurrences of cardiovascular events, time to occurrence of cardiovascular death, time to occurrence of all-cause death, time to first occurrence of composite chronic kidney disease endpoint (including cardiovascular death, persistent decline in eGFR of at least 30%, persistent eGFR below 15 mL/min/1.73m², or initiation of chronic kidney replacement therapy), and change in KCCQ Overall Summary Score.

The estimated recruitment start date is January 12, 2026, with an estimated end date of July 26, 2028, resulting in an overall trial duration of approximately 30 months. Participant involvement will extend up to the maximum treatment period of 192 weeks. The trial will include a screening visit to assess eligibility criteria, a randomization visit where participants will be assigned to receive either coramitug or placebo, regular follow-up visits throughout the treatment period to monitor efficacy and safety parameters, and an end-of-study visit. Early termination from the study may occur under conditions that compromise participant safety, protocol non-compliance, withdrawal of consent, or at the discretion of the investigator or sponsor when continuation is deemed not in the best interest of the participant.

The experimental treatment consists of **coramitug** (also known as **NNC6019-0001** or **PRX004**), a **humanised IgG1 monoclonal antibody** directed against **misfolded transthyretin**. Coramitug is formulated as a **solution for infusion** and is administered via the **intravenous** route. The investigational medicinal product is supplied in 20 mL vials with 11 mL extractable volume. The maximum treatment period is 192 weeks. Coramitug has been designated as an **orphan drug** under the designation number EU/3/24/2991. The active substance is classified as a protein of non-recombinant origin and is manufactured by Novo Nordisk A/S.

The control treatment consists of **placebo**, which is provided as a liquid dosage form in 20 mL vials with 11 mL extractable volume. The placebo is designed to match the appearance of the active investigational medicinal product to maintain blinding throughout the study.

Both the experimental treatment and placebo are administered in addition to **standard-of-care therapy** for participants with **transthyretin amyloid cardiomyopathy**, including both wild-type (ATTRwt-CM) and variant (ATTRv-CM) forms of the disease. The study design allows for the evaluation of coramitug versus placebo in reducing cardiovascular death and morbidity when added to existing therapeutic regimens.

The primary efficacy endpoint is the number of occurrences of a composite endpoint consisting of **cardiovascular death**, recurrent **cardiovascular events** including cardiovascular hospitalization, and urgent **heart failure** visits. Secondary confirmatory efficacy endpoints include change in **Kansas City Cardiomyopathy Questionnaire Clinical Summary Score** (KCCQ-CSS) and change in **6-minute walk distance** (6MWD). Additional secondary endpoints comprise the number of occurrences of cardiovascular events (cardiovascular hospitalization and urgent heart failure visits), time to occurrence of cardiovascular death, time to occurrence of all-cause death, time to first occurrence of a composite **chronic kidney disease** endpoint consisting of cardiovascular death, onset of persistent decline in **estimated glomerular filtration rate** (eGFR) ≥30%, onset of persistent eGFR <15 mL/min/1.73m², and initiation of chronic kidney replacement therapy (dialysis or kidney transplant), as well as change in **Kansas City Cardiomyopathy Questionnaire Overall Summary Score** (KCCQ-OSS). Participants are required to complete more than 50 meters on the **6-minute walk test** at screening to be eligible for enrollment.