A Randomized, Placebo‑Controlled Trial of Zenagamtide (NNC0487‑0111) in Obese Patients with HFpEF or HFmrEF to Reduce CV Death and HF Hospitalization

The primary objective is to determine whether once‑weekly subcutaneous administration of NNC0487‑0111, added to standard of care, reduces the risk of a composite outcome comprising cardiovascular death, heart‑failure hospitalization, or urgent heart‑failure visit in participants with heart failure with preserved ejection fraction or mildly reduced ejection fraction and obesity. This endpoint addresses clinically pivotal morbidity and mortality concerns in this high‑risk population. Secondary objectives assess the impact of NNC0487‑0111 versus placebo, also added to standard therapy, on additional cardiovascular and heart‑failure outcomes and overall mortality, as well as on functional status, symptom burden, renal function, and rates of hospitalization, thereby providing a broader evaluation of efficacy and safety parameters.

The trial enrolled 3,618 participants diagnosed with HFpEF or HFmrEF and obesity. Both female and male individuals were included, spanning the age categories denoted by codes 3 and 4. Enrollment required a body mass index of at least 30 kg/m² at screening and a diagnosis of heart failure classified as New York Heart Association class II–IV in a stable condition, as determined by the investigator. For participants with type 2 diabetes, a diagnosis of at least 30 days prior to screening was required. All subjects were required to be receiving standard of care therapy, to which the investigational agent or placebo was added. No additional lifestyle criteria such as specific diet or physical activity regimens were stipulated in the inclusion parameters.

The study is a Phase III, randomized, double‑blind, placebo-controlled trial evaluating once‑weekly subcutaneous administration of zenagamtide (NNC0487‑0111) versus placebo, both in addition to standard of care, in participants with HFpEF or HFmrEF and obesity. After an initial screening visit to confirm eligibility criteria (BMI ≥ 30 kg/m², NYHA class II–IV, stable condition, and, if applicable, type 2 diabetes diagnosed ≥30 days prior), participants undergo baseline assessments and are randomized in a 1:1 ratio to active drug or placebo. Subsequent study visits are scheduled at regular intervals (e.g., weeks 4, 12, 24, 36, 48, and 60) to administer the study medication, monitor safety parameters, assess efficacy endpoints (including the time to first composite of cardiovascular death, heart‑failure hospitalization, or urgent heart‑failure visit), and record concomitant therapy. The end‑of‑study visit occurs after the planned treatment period, at which final efficacy and safety data are collected. Participants are expected to remain in the trial for approximately 12 months of active treatment plus follow‑up. Early termination may occur if a participant experiences a serious adverse event related to the investigational product, fails to meet adherence requirements, withdraws consent, or is lost to follow‑up, as determined by the investigator.

The investigational product, identified as NNC0487-0111, comprises the active peptide zenagamtide supplied in a solution for injection contained within a pre‑filled pen. All test products (NNC0487-0111 B 10141 through B 10146) are administered subcutaneously once weekly at a dose prepared as a 0 unit/other‑unit solution, consistent across each batch.

The control arm receives a matching placebo (Placebo NNC0487-0111) formulated to be indistinguishable from the active solution and delivered by the same subcutaneous pre‑filled pen on an identical weekly schedule.

Both investigational and placebo injections are given in addition to standard‑of‑care therapy for participants with heart failure with preserved or mildly reduced ejection fraction and obesity. Dosing compliance is monitored through electronic administration logs, site‑based verification of pen usage, and participant‑maintained injection diaries reviewed at each study visit.

Efficacy will be evaluated primarily by the time to first occurrence of a composite HF endpoint comprising cardiovascular death, heart‑failure hospitalization, or urgent heart‑failure visit. Secondary efficacy assessments include the time to first occurrence of a composite heart‑failure and major adverse cardiovascular event (MACE) endpoint (cardiovascular death, heart‑failure hospitalization, urgent heart‑failure visit, non‑fatal myocardial infarction, non‑fatal stroke), change from baseline in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ‑CSS) for participants with a baseline score < 80 points, change from baseline in estimated glomerular filtration rate (eGFR) calculated with creatinine and cystatin C using the CKD‑EPI 2021 equation for participants with baseline eGFR < 60 mL/min/1.73 m², and time to all‑cause death.

Time‑to‑event outcomes will be analyzed using survival‑type methods (e.g., Kaplan‑Meier estimates and Cox proportional‑hazards models). Changes in KCCQ‑CSS will be derived from the validated KCCQ questionnaire administered at baseline and subsequent visits, while eGFR changes will be based on laboratory measurements of serum creatinine and cystatin C processed according to the CKD‑EPI 2021 formula. All efficacy parameters will be collected in accordance with the study protocol and analyzed as predefined in the statistical analysis plan.