12484 Safety And Pharmacokinetics Of Anti-ACTH Antibody Lu AG13909 In Patients With Classic Congenital Adrenal Hyperplasia: Phase 1 Open-label, Multiple-Ascending-Dose Trial Protocol

Abstract Disclosure: U. Srirangalingam: Advisory Board Member; Self; Lundbeck. Consulting Fee; Self; Diurnal. Research Investigator; Self; Neurocrine. A. Velusamy: Consulting Fee; Self; Novo Nordisk. M. Binderup: Employee; Self; H. Lundbeck A/S. B. Baker: Employee; Self; H. Lundbeck A/S. M. Folden Flensburg: Employee; Self; H. Lundbeck A/S. L. Pickering Boserup: Employee; Self; H. Lundbeck A/S. J. Luthman: Employee; Self; H. Lundbeck A/S. H. Benecke: Employee; Self; H. Lundbeck A/S. R.J. Auchus: Consulting Fee; Self; Neurocrine Biosciences, Diurnal, Corcept Therapeutics, Recordati Rare Diseases, Crinetics Pharmaceuticals, Quest Diagnostics, Xeris Pharmaceuticals, Novo Nordisk, H. Lundbeck A/S, Sparrow Pharmaceuticals. Research Investigator; Self; Adrenas Therapeutics, Spruce Biosciences, Neurocrine Biosciences, Diurnal, Corcept Therapeutics, Recordati Rare Diseases, Crinetics Pharmaceuticals. Introduction: Classic congenital adrenal hyperplasia (CAH) is a rare, autosomal recessive disorder characterized by cortisol and aldosterone deficiency, elevated adrenocorticotropic hormone (ACTH) and subsequent hyperandrogenemia, most commonly due to 21-hydroxylase deficiency. Balancing physiological glucocorticoid replacement and control of hyperandrogenism remains a challenge with the risk of long-term consequences of glucocorticoid overtreatment. Lu AG13909 is a novel, high-affinity, anti-ACTH monoclonal antibody that neutralizes ACTH-induced signaling. In preclinical models, Lu AG13909 dose-dependently and persistently reduced plasma corticosterone and cortisol concentrations. No adverse effects were observed after 6 months of intravenous dosing every 2 weeks in cynomolgus monkeys. Here, we describe the ongoing first-in-human trial of Lu AG13909, investigating the safety, tolerability, pharmacokinetic (PK) properties, and pharmacodynamic (PD) effects of Lu AG13909 in adults with classic CAH. Methods: This is a Phase 1, open-label, multiple-ascending-dose trial with intra-participant dose escalation (EUCT #2023-503711-15-00). The trial enrolls men and women with classic CAH aged between ≥18 and ≤70 years under stable glucocorticoid and mineralocorticoid dosing, with morning 17-hydroxyprogesterone >4 times the upper limit of normal. Each participant receives up to 6 doses of Lu AG13909 every 28-35 days at increasing dose levels. The trial consists of 2 parts: Part A has a 3+3 design, in which 3 participants are given a certain dose, and escalation to the next dose is based on a 28-day safety observation period. Part B explores the pharmacologically relevant Lu AG13909 doses identified in Part A in a larger number of participants. The aim is for a total of 12 participants to receive each of the dose levels identified as relevant. Outcomes The primary safety and tolerability endpoints include adverse events and clinical safety tests. PK endpoints include maximum observed exposure and area under the Lu AG13909 concentration-time curve in a dosing interval. The PD endpoints are the relative reductions in morning 17-hydroxyprogesterone, androstenedione, and unbound ACTH, from baseline to the day after each Lu AG13909 dose. Conclusions This innovative, multi-dose, intra-participant dose escalation trial design was developed specifically for the rare classic CAH population, who have a high unmet medical need due to the challenges with current glucocorticoid treatment. The aim of the trial is to gather safety, PK, and PD data while minimizing participant risk and burden. Data from this trial will reinforce the development of Lu AG13909 as a novel treatment strategy in conditions characterized by increased levels of ACTH, such as classic CAH and Cushing disease. Presentation: 6/3/2024