FDA fast tracks enibarcimab for the treatment of septic shock

 It is believed that modulation of ADM pathway may improve outcomes in patients with septic shock.

The Food and Drug Administration has granted Fast Track designation to enibarcimab for management of septic shock. Enibarcimab is a first-in-class non-neutralizing monoclonal antibody that binds to adrenomedullin (ADM), a vasoprotective hormone.

AdrenoMed is now preparing a confirmatory Phase IIb/III clinical trial to confirm the reduced septic shock mortality under enibarcimab treatment employing a precision medicine approach.

AdrenoMed’s CEO Dr. Richard Jones commented: “We are very pleased that enibarcimab has received Fast Track designation from the FDA, recognizing its potential as an innovative biomarker-guided treatment against septic shock to fill the unmet medical need in this very serious condition with a high death toll. This is a great confirmation of AdrenoMed’s efforts to reduce patient heterogeneity and develop effective treatments by bringing precision medicine also to intensive care units.”

Enibarcimab is a non-blocking antibody binding to the vasoprotective hormone adrenomedullin. Applying AdrenoMed’s precision medicine approach, enibarcimab treatment of patients with septic shock resulted in improved organ dysfunction and a relevant reduction of day 28 all-cause mortality from 24% to 8% in the patient population defined by the two biomarkers adrenomedullin and DPP3 in the AdrenOSS-2 trial.

With a mortality rate of 20-30% for sepsis and 30%-50% for septic shock in developed countries, sepsis represents an enormous public health burden and is responsible for almost 20% of all deaths worldwide.

Fast Track is a process designed by the FDA to facilitate the development of promising drugs for the treatment of serious conditions that fill an unmet medical need and to accelerate review by the regulatory authority, aimed at getting important new drugs to the patient earlier. A drug that receives Fast Track designation is eligible for more frequent meetings with FDA to discuss development plans for the drug regarding collection of data needed to support its approval; more frequent communication about such things as the design of the proposed clinical trials and use of biomarkers; eligibility for Accelerated Approval and Priority Review, if relevant criteria are met; and Rolling Review.

Dr. Stephan Witte, CMO of AdrenoMed, said: “We are very confident that the use of enibarcimab in combination with two biomarkers, Adrenomedullin (bio-ADM) and circulating dipeptidyl peptidase 3 (cDPP3), holds the promise to become the first effective targeted treatment against septic shock. With AdrenoMed’s biomarker-guided approach it is possible to clearly define the patient population benefitting most from enibarcimab, resulting in a more pronounced treatment effect and leading to improved mortality in septic shock.”

This was the conclusion also drawn by Prof. Peter Pickkers from the Department of Intensive Care Medicine and Radboud Center for Infectious Diseases (RCI), Nijmegen, Netherlands, in a poster session during the recent ISICEM 2024, which took place in Brussels, Belgium, from March 19 – 22, 2024, where he presented previously unpublished data from a prespecified subgroup of the AdrenOSS-2 trial.

About AdrenOSS-2

The double-blind, randomized, placebo-controlled, biomarker-guided Phase II trial AdrenOSS-2 (n = 301) had included a prespecified analysis of the role of cDPP3 as a second biomarker (next to ADM) to exclude patients who are unlikely to respond to enibarcimab treatment.

DPP3 is a cytosolic enzyme involved in the degradation of various cardiovascular and endorphin mediators. High levels of cDPP3 indicate a high risk of organ dysfunction and mortality. This pathway is mechanistically independent from the loss of vascular integrity, which is known to be the main driver of mortality in septic shock and is indicated by elevated plasma levels of ADM (>70 pg/mL). Consequently, the aim of additional analyses was to investigate the impact of different cDPP3 levels on the treatment effect (28-day all-cause mortality) and to identify a suitable cut-off level.

It was shown that the effect of enibarcimab on mortality improves with lower cDPP3 values and that the patients with elevated ADM, but non-elevated baseline cDPP3 (below the upper normal range, ≤ 30-50 ng/mL), benefitted the most from enibarcimab treatment. At 28 days, this patient subgroup had a statistically significant >60% relative reduction in mortality compared to placebo.