Sponsor Decision

This was a multicenter, randomized, placebo- and active-controlled, parallel-group, 24-week trial to investigate the efficacy, safety, and tolerability of XXB750 in participants with HFrEF/HFmrEF.

Eligible participants were randomized to receive either subcutaneous (s.c.) XXB750 or placebo; or sacubitril/valsartan for 16 weeks, and then followed-up for 8 weeks.

The study planned to randomize adult participants with LVEF < 50% receiving ACEI/ARB/ARNI and guideline-recommended HF therapies for HFrEF or HFmrEF to three XXB750 target dose levels; a cohort of participants treated with ACEI/ARB before the study was randomized to be converted to open-label sacubitril/valsartan in place of their pre-study ACEI/ARB. A total of 720 participants were planned to be randomized in this study.

Due to safety concerns, in August 2024 the study was halted and dosing of all double-blind injectable medication of XXB750 and matching Placebo was suspended until further notice. All randomized participants actively involved in the study continued to attend study visits as per the study schedule and underwent all study procedures. This included safety, pharmacokinetic, antidrug antibody, and biomarker biological sample collections, physical examinations, and reporting of adverse events. As directed above, injectable study medication (i.e., XXB750 and its matching Placebo) was not administered. On 26-Sep-2024, Novartis made the decision to terminate the study due to safety findings and DMC recommendation.

Due to the early study termination, all participants who had been randomized to receive XXB750 or Placebo were followed up for 12 weeks after they received the last dose which is in accordance with the originally planned follow-up duration as per protocol. Participants who were randomized to the open-label treatment arm 5 and received sacubitril/valsartan as study medication were not further followed up after discontinuation of the open-label study medication. Sacubitril/valsartan is authorized in all participating countries and was, within this study, used as a comparator within the respective labels only. Hence, an additional follow-up for the safety of the participants was not performed; and the investigator could treat the participant with standard-of-care treatment (which includes sacubitril/valsartan) as per his/her clinical judgment.

To help guard the safety of study participants, randomization initially excluded the planned highest target dose of 240 mg XXB750 (i.e., arm 4). The study was terminated prematurely prior to the pre-planned early safety analysis due to an imbalance in worsening heart failure events among participants randomized to XXB750 60 mg and 120 mg. Thus, no participants were exposed to the planned highest target dose of 240 mg every 4 weeks.

Inclusion Criteria:

• Current symptom(s) of HF NYHA class II-III and LVEF < 50%
• Elevated NT-proBNP levels at screening.
• Receiving standard of care background HF therapy.

Exclusion Criteria:

• Current acute decompensated HF or hospitalization for HF within 3 months prior to screening.
• Current symptomatic hypotension (for example dizziness/presyncope).
• K+ > 5.4 mmol/L at screening
• eGFR < 30 mL/min/1.73m2 at screening

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Patients received either active XXB750 injection or a placebo injection that looks identical to the active injection. Sacubitril/valsartan was administered in an open-label fashion