FDA Grants Orphan Drug Designation to Asedebart for Cushing’s Syndrome

Lundbeck’s investigational anti-ACTH antibody asedebart (Lu AG13909) has received U.S. FDA Orphan Drug Designation for endogenous Cushing’s syndrome, adding regulatory momentum to a program targeting the hormonal driver of ACTH-dependent disease. The Phase II BalanCeD study is evaluating asedebart in adults with Cushing’s disease, with preliminary data showing urinary free cortisol normalization in most evaluable patients.

FDA Designation Highlights ACTH-Driven Disease

Endogenous Cushing’s syndrome includes both ACTH-dependent and ACTH-independent forms. In ACTH-dependent disease, excess ACTH usually comes from a pituitary tumor, causing Cushing’s disease, or less commonly from an ectopic ACTH-secreting tumor. By contrast, ACTH-independent Cushing’s syndrome results from autonomous adrenal cortisol production.

That distinction is central to asedebart’s mechanism. The antibody is being developed specifically for ACTH-dependent disease, where excessive ACTH stimulates the adrenal glands to produce cortisol and other adrenal steroids. Chronic cortisol excess can cause substantial metabolic, cardiovascular and neuropsychiatric complications and is associated with increased morbidity and mortality.

Surgery to remove the source of excess ACTH remains the preferred treatment when feasible, but some patients are not candidates for surgery or fail to achieve durable remission. Medical treatment therefore remains important for persistent or recurrent disease.

Asedebart Takes an Upstream Approach

Asedebart is a humanized monoclonal antibody that binds ACTH and prevents it from activating the melanocortin 2 receptor on adrenal cells. This interrupts ACTH signaling and reduces production of glucocorticoids, mineralocorticoids and androgens.

Current pharmacological approaches generally act elsewhere in the pathway. Adrenal steroidogenesis inhibitors such as osilodrostat, ketoconazole and metyrapone reduce cortisol synthesis, while pasireotide and cabergoline can modulate pituitary ACTH secretion. Mifepristone instead blocks glucocorticoid receptor signaling.

Asedebart therefore represents a distinct strategy: neutralizing circulating ACTH itself rather than suppressing its secretion or blocking adrenal steroid production downstream.

Phase II BalanCeD Study Provides Early Clinical Signal

The ongoing BalanCeD trial is a Phase II, multicenter, open-label dose-titration study evaluating asedebart in adults with Cushing’s disease. The study assesses cortisol control, safety, tolerability and pharmacokinetics, with urinary free cortisol (UFC) serving as a key efficacy measure.

At ENDO 2026, Lundbeck reported preliminary Phase II Part A results from the ongoing program. Seven of eight evaluable patients who completed individualized intravenous dose titration achieved UFC normalization. The treatment was generally well tolerated, although treatment-emergent adverse events occurred in all 12 enrolled patients at the data cutoff; three serious adverse events were reported, including one unrelated death. Two participants experienced glucocorticoid-deficiency events that were managed with short-term hydrocortisone.

Part B is evaluating subcutaneous administration, including cortisol reduction, safety, pharmacokinetics and patient experience. The Phase II protocol also includes an optional 52-week extension.

Regulatory Momentum Builds

The FDA designation follows orphan designation in the European Union for endogenous Cushing’s syndrome, while asedebart has also received orphan designations for CAH in the United States and European Union and for CAH and Cushing’s disease in Japan.

FDA Orphan Drug Designation can provide incentives including tax credits for qualified clinical testing and exemption from certain application fees. If approved, an orphan-designated product may also receive seven years of U.S. market exclusivity for the designated indication.

For now, asedebart remains investigational and is not approved by any regulatory authority. The next major development milestones will be the maturation of Phase II data, evaluation of the subcutaneous formulation and determination of whether ACTH neutralization can deliver durable biochemical control with an acceptable safety profile.

If successful, the program could establish direct ACTH neutralization as a new pharmacological approach for ACTH-driven Cushing’s disease and potentially other rare disorders characterized by chronically elevated ACTH.

 Reference

The U.S. FDA grants orphan drug designation for Lundbeck’s investigational anti-ACTH monoclonal antibody asedebart for treatment of endogenous Cushing’s syndrome, Lundbeck, 11 September 2026