ORF28-07 - A Phase II, Open-Label, Dose-Titration Trial to Investigate the Safety, Tolerability, Pharmacokinetics, and Efficacy of the Novel Anti-ACTH Antibody Asedebart in Adults with Cushing's Disease

Introduction: Cushing’s disease (CD) is a severe endocrine disorder typically caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma, which leads to chronic hypercortisolism that is associated with increased morbidity and mortality. The first-line treatment, transsphenoidal surgery, is often inadequate, with persistent or recurrent disease in many patients. Current pharmacologic treatments are limited. Asedebart is a novel, humanized, anti-ACTH monoclonal antibody that inhibits ACTH-induced melanocortin signaling. Preclinical and preliminary findings in congenital adrenal hyperplasia (CAH) suggest that asedebart may reduce elevated ACTH signaling and thus cortisol levels. Here we present preliminary data from a Phase II trial of asedebart in adults with CD.

Methods: This ongoing, multi-site, open-label, titration trial (NCT06471829) is enrolling participants aged 18–70 years, diagnosed with ACTH-driven CD of pituitary origin. Part A comprises an intravenous (IV) titration period to identify the optimal dose of asedebart and a subcutaneous (SC) period. Part B comprises an SC titration period and a maintenance period. The optional extension period comprises 52 weeks of SC treatment and a safety follow-up after the last dose. Clinical assessments and cortisol levels guide dose adjustments throughout the titration periods. The primary endpoint is urinary free cortisol (UFC) complete response at the end of the IV and SC titration periods. Other endpoints include adverse events (AEs), pharmacokinetic parameters, immunogenicity, changes in UFC and late-night salivary cortisol, patient-reported outcomes, and patient experience.

Results: As of September 2025, 7 participants (female, mean age 43 years) had received IV and SC administrations. All 6 ongoing participants had reductions in mean UFC following individual titration with asedebart. Fifteen treatment-emergent AEs were reported in 5 participants. One death occurred, which was unrelated to the study treatment. Asedebart was well tolerated overall.

Conclusions: These Phase II preliminary data show that asedebart reduced UFC in adults with CD. Treatment was generally well tolerated, with AEs consistent with its mode of action. These findings suggest that asedebart may be a promising treatment approach for CD.