Abstract
Disclosure: U. Srirangalingam: Crinetics Pharmaceuticals Inc, Diurnal, Lundbeck. A. Prete: Spruce, Diurnal, Recordati, Lundbeck. T. Frederiksen: None. M.M. Binderup: None. M. Folden Flensburg: None. J. Luthman: None. R.J. Auchus: Neurocrine Biosciences/Neurocrine UK, LTD, Spruce Biosciences, Corcept Therapeutics, Crinetics Pharamceuticals, Recordati Rare Diseases, Adrenas Therapeutics, Mineralys Pharmaceuticals, Quest Diagnostics, Xeris Pharmaceuticals, Novo Nordisk, Sparrow Pharmaceuticals, Astellas Pharmaceuticals, Acerand Therapeutics, 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. A phase 1 trial (NCT05669950) in adults with classic CAH demonstrated that Lu AG13909 is well-tolerated and can reduce 17-hydroxyprogesterone (17-OHP) and androstenedione (A4) concentrations. Here, we describe the phase 2 trial design, evaluating the efficacy and safety of Lu AG13909 in adults with classic CAH. Methods: The open-label phase 1 trial was amended to contain a phase 2 component in an adaptive design. The phase 2 trial will enroll men and women, aged ≥18 to ≤70 years with classic CAH, under stable GC dosing. Participants are divided into 2 cohorts: cohort C1, including up to 18 participants with hyperandrogenemia, and cohort C2, including up to 12 participants with normal androgen concentrations but treated with supraphysiologic GC doses. There are 2 treatment periods: Period 1 (maintenance of stable baseline daily GC dose) and Period 2 (down-titration of daily GC dose using a predefined schedule). In Period 1, participants will receive 6 (cohort C1) or 2 (cohort C2) intravenous (IV) administrations of Lu AG13909 at 4- to 5-week intervals. The shorter treatment duration in cohort C2 is due to normal A4 baseline concentration. Cohort C1 is divided into 3 treatment groups receiving either a low, medium, or high Lu AG13909 dose. Cohort C2 all receive the medium dose of Lu AG13909. All participants with normalized A4 concentrations enter Period 2 and receive 3 IV administrations of Lu AG13909 at 4- to 5-week intervals, with GC dose down-titrated over 12 weeks. Participants may enter an optional open-label extension, where they receive 12 IV administrations of Lu AG13909 at 4- to 5-week intervals, with daily GC dose optimization based on individual androgen concentrations. Outcomes: The primary endpoint is biochemical response, defined as morning concentrations of A4 <upper limit of normal (pre-daily GC dosing) after 24 weeks of treatment in cohort C1. Other endpoints include relative reduction from baseline in morning concentrations of A4 and 17-OHP; relative reduction from baseline in GC daily dose; and the safety, tolerability, and PK profile of Lu AG13909. Conclusions: This trial will evaluate the efficacy and safety of Lu AG13909 for lowering androgen concentrations, and GC dosing in adults with classic CAH, reinforcing the development of Lu AG13909 as a novel anti-ACTH treatment strategy.
Presentation: Saturday, July 12, 2025