Lundbeck announced that its investigational monoclonal antibody Lu AG13909 has received orphan drug designation from both the US Food and Drug Administration (FDA) on May 12, 2025, and the European Medicines Agency (EMA) on June 20, 2025, for the treatment of congenital adrenal hyperplasia (CAH). The designation recognizes the significant unmet medical need for this rare genetic disorder that affects approximately 1 in 14,000-18,000 live births worldwide.
Novel Anti-ACTH Therapeutic Approach
Lu AG13909 represents a first-in-class humanized monoclonal antibody that specifically targets adrenocorticotropic hormone (ACTH) with high affinity. The drug works by blocking ACTH binding to the melanocortin 2 receptor in the adrenal glands, thereby inhibiting neurohormonal signaling and decreasing the secretion of glucocorticoids, mineralocorticoids, and androgens from the adrenal glands.
"CAH is a life-long condition, requiring constant management. Many existing treatments focus on controlling cortisol levels, however these options are often complicated by side effects. The orphan drug designation for Lu AG13909, our potential first in class anti-ACTH antibody, reflects the program's innovative approach, as well as the high medical need to find new treatments for CAH," said Johan Luthman, EVP and Head of Research and Development at Lundbeck.
Expanding Clinical Development Program
Lundbeck is currently expanding an ongoing Phase I/II clinical open-label trial to evaluate the efficacy and safety of Lu AG13909 in adults with classic CAH. The trial will open for enrollment in North America and seven countries across Europe, with the first sites opening in late June 2025.
The expanded trial will enroll men and women aged 18 to 70 years with classic CAH who are under stable glucocorticoid dosing. Participants will receive monthly intravenous administrations of Lu AG13909 and will be divided into two cohorts: the first will include participants with hyperandrogenemia, and the second will include participants with normal androgen levels but treated with supraphysiologic glucocorticoid doses. Participants may enter an optional open-label extension where they receive monthly Lu AG13909 administration over a period of 12 months.
Promising Preclinical Results
In animal studies, Lu AG13909 demonstrated significant and durable reductions of corticosterone/cortisol and aldosterone levels. Notably, no adverse effects were observed after six months of intravenous dosing, supporting the drug's safety profile for further clinical development.
Addressing Unmet Medical Need
Classic CAH is characterized by enzyme deficiency, most commonly 21-hydroxylase deficiency, affecting adrenal steroidogenesis and leading to cortisol and aldosterone deficiency. The condition is marked by impaired cortisol production and elevated ACTH levels, which lead to additional adrenal hormone imbalances, ultimately resulting in multiple developmental disturbances including central nervous system symptoms and long-term health concerns.
People with 21-hydroxylase deficiency face the risk of adrenal crisis, a life-threatening condition that contributes to increased mortality throughout life. Current treatment approaches focus on balancing physiological glucocorticoid replacement and controlling hyperandrogenism, but this remains challenging due to the risk of long-term consequences from glucocorticoid overtreatment.
ACTH plays a key role in the biosynthesis of adrenal steroids and is considered a promising therapeutic target in conditions characterized by elevated ACTH levels. Lu AG13909's novel mechanism of action may provide a new therapeutic approach for treating conditions associated with chronically elevated ACTH levels, potentially addressing the limitations of current treatment options.
