Efficacy and Safety of REGN7544 in Sepsis-Induced Hypotension: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate the effect of **REGN7544** on vasopressor requirements in participants with **sepsis-induced hypotension**. This is clinically relevant as reducing vasopressor dependency can improve patient outcomes by stabilizing blood pressure and potentially reducing the duration of intensive care unit stays.

Secondary objectives include:

• To evaluate the safety and tolerability of REGN7544.
• To evaluate the acute effect of REGN7544 on blood pressure.
• To evaluate the effect of REGN7544 on the resolution of shock.
• To evaluate the effect of REGN7544 on blood volume regulation.
• To evaluate the pharmacokinetics (PK) of REGN7544 following a single intravenous administration in participants with sepsis-induced hypotension.
• To assess the immunogenicity of a single intravenous dose of REGN7544.

The clinical trial involves a total of **45 participants** diagnosed with **sepsis-induced hypotension**. The study population includes both male and female subjects, with an age range encompassing adults and older adults. Participants were selected based on specific criteria, including a proven or suspected infection requiring antibiotics and sepsis-induced hypotension unresponsive to intravenous fluids, necessitating the use of one or two vasopressors to maintain a Mean Arterial Pressure (MAP) of at least 65 mm Hg. The trial does not include a vulnerable population, and no specific lifestyle considerations such as diet or physical activity are highlighted. The selection process ensures that participants meet the defined inclusion criteria, focusing on the clinical condition and treatment requirements.

The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** study designed to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamic effects of **REGN7544**, an antagonist monoclonal antibody to NPR1, in patients with **sepsis-induced hypotension**. The trial aims to assess the effect of REGN7544 on vasopressor requirements. The study is expected to commence recruitment on December 9, 2024, and conclude by April 12, 2026. Participants will be randomly assigned to receive either REGN7544 or a matching placebo, administered as a solution for injection via intravenous infusion.

The trial will include several study visits, beginning with a screening visit to confirm eligibility based on criteria such as proven or suspected infection and sepsis-induced hypotension unresponsive to intravenous fluids. Participants must be receiving 1 or 2 vasopressors and maintain a mean arterial pressure (MAP) of ≥ 65 mm Hg for at least 2 consecutive hours prior to randomization. Following the screening, participants will undergo regular follow-up visits to monitor primary and secondary endpoints, including cumulative vasopressor dose, occurrence of treatment-emergent adverse events, changes in MAP, and concentrations of REGN7544 in serum.

The expected duration of participant involvement in the trial is contingent upon the study's timeline, with the maximum treatment period being one day. Conditions that may lead to early termination from the study include the occurrence of severe adverse events or failure to adhere to the study protocol. The end-of-study visit will involve a comprehensive assessment of the participant's health status and the collection of final data to evaluate the study's outcomes.

The clinical trial involves the administration of **REGN7544**, an experimental medication formulated as a **solution for injection**. This investigational drug is a monoclonal antibody antagonist targeting NPR1, developed by Regeneron Pharmaceuticals, Inc. The active substance, also named REGN7544, is derived from a protein of other origin. The medication is administered via **intravenous infusion**. The dosing regimen specifies a maximum daily dose of 200 mg, with the total dose not exceeding 200 mg over the treatment period. The maximum treatment duration is set at one day. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol.

In addition to the experimental treatment, the study includes the use of a **matching placebo**. The placebo is designed to mimic the appearance and administration route of REGN7544, ensuring the study remains double-blind. The placebo is administered as a solution for injection via intravenous infusion, similar to the experimental drug. This approach allows for a controlled comparison of the efficacy and safety of REGN7544 in patients with sepsis-induced hypotension. The placebo administration follows the same dosing schedule as the experimental treatment, with compliance monitoring in place to maintain the integrity of the trial data.

The efficacy of REGN7544 in the treatment of **sepsis-induced hypotension** will be assessed through a series of predefined endpoints. The primary endpoint is the cumulative vasopressor dose, measured as norepinephrine equivalent dose (NED) per body weight. This will provide a quantitative measure of the drug's effect on reducing the need for vasopressors in maintaining adequate blood pressure.

Secondary endpoints include several parameters to further evaluate the drug's efficacy and safety profile. These include the occurrence of Common Terminology Criteria for Adverse Events (CTCAE) grade 3 and higher treatment-emergent adverse events (TEAEs), time-weighted average mean arterial pressure (MAP) from baseline, and change from baseline in MAP. Additionally, the proportion of surviving participants free of vasopressors, cumulative net fluid balance, cumulative urine output, and cumulative fluid intake will be assessed. Pharmacokinetic and immunogenicity assessments will include concentrations of REGN7544 in serum and the incidence and titer of anti-drug antibodies (ADA) to REGN7544.

The collection and analysis of these endpoints will be conducted at specified timepoints throughout the trial, ensuring a comprehensive evaluation of the drug's efficacy in the target population. The study is designed as a randomized, double-blind, placebo-controlled trial, which will provide robust data on the efficacy of REGN7544 in patients with sepsis-induced hypotension.