MON-468 A Novel Anti-ACTH Antibody Lu AG13909 in Clinical Development for Treatment of Classic Congenital Adrenal Hyperplasia: A Phase 1 Open-Label, Multiple-Ascending-Dose Study

Abstract Disclosure: G. Johannsson: AstraZeneca, Novo Nordisk, Pharmanovia, Pfizer, Inc., Takeda, Shire. A. Velusamy: Immunovant, Novo Nordisk, Samsung/Philips/Canon. A. Prete: Diurnal, Spruce, Recordati, Lundbeck. H. Falhammar: None. M.M. Binderup: None. K.G. Larsen: None. M. Folden Flensburg: None. J. Luthman: None. U. Srirangalingam: Crinetics Pharmaceuticals Inc, Diurnal, Lundbeck. Introduction: Classic congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency is a rare autosomal recessive disorder. The defect in cortisol biosynthesis leads to impaired negative feedback on the hypothalamus-pituitary-adrenal axis, elevated adrenocorticotropic hormone (ACTH), and consequent hyperandrogenemia. Supraphysiologic glucocorticoid (GC) dosing, often required to manage hyperandrogenemia, is associated with adverse long-term health outcomes. Lu AG13909 is a novel, high-affinity, anti-ACTH monoclonal antibody that inhibits ACTH-induced signaling. Nonclinical studies demonstrated that Lu AG13909 induces a significant and durable reduction of corticosterone and aldosterone in rats, and of cortisol and aldosterone in cynomolgus monkeys. Here, we present the results of a first-in-human trial investigating the safety, tolerability, and pharmacokinetic and pharmacodynamic properties of Lu AG13909 in adults with classic CAH. Methods: This was a phase 1, open-label, multiple-ascending-dose trial with intra-participant dose escalation (NCT05669950). Eligible participants were men and women, aged ≥18 to ≤70 years, with classic CAH and pre-GC morning 17-hydroxyprogesterone (17-OHP) concentrations >4 times the upper limit of normal. Each participant received up to 6 doses of Lu AG13909 every 28 to 35 days at increasing dose levels, with stable GC therapy and mineralocorticoid replacement if needed. The trial consisted of 2 parts: Part A had a 3+3 design, in which 3 participants were given a certain dose level, and escalation to the next dose level was based on a 28-day safety observation period. Part B explored the pharmacologically relevant Lu AG13909 doses identified in Part A in a larger number of participants. The primary endpoints included adverse events; clinical safety; maximum observed exposure and area under the Lu AG13909 concentration-time curve in a dosing interval; and the relative reductions in morning 17-OHP and androstenedione (A4) concentrations from baseline to the day after each Lu AG13909 dose. Results: In total, 11 participants were enrolled (4 men, 7 women), with a mean age of 37 years (range: 21-58 years). At the Baseline Visit the geometric means for the concentrations of morning 17-OHP and A4 were 274 nmol/L (range: 100-1033 nmol/L) and 11.0 nmol/L (range: 3.9-49.5 nmol/L), respectively. Preliminary data (N=11) demonstrated clear pharmacodynamic effects following up to 6 intravenous infusions of Lu AG13909 at increasing doses, with consistent reductions in morning 17-OHP and A4 concentrations observed at all dose levels. No safety concerns were raised. Conclusions: The preliminary results of this phase 1 study show that Lu AG13909 is well-tolerated and can reduce adrenal androgen production, reinforcing continued clinical development of Lu AG13909 as a novel anti-ACTH treatment strategy for classic CAH. Presentation: Monday, July 14, 2025