Lundbeck presents innovative first in human trial design of Lu AG13909 for potential treatment of congenital adrenal hyperplasia

Lundbeck is to showcase innovative trial design at ENDO 2024 of the first in human trial of Lu AG13909 for congenital adrenal hyperplasia (CAH), a rare debilitating disease with excess morbidity and mortality.

H. Lundbeck A/S (Lundbeck) will present the novel design of the first in human trial of Lu AG13909, a potential first-in-class treatment for CAH, at ENDO in Boston.

The presentation will take place on 3 June 2024, at 12:00 (noon) EDT.

The poster is to be presented by trial investigator Dr. Srirangalingam Umasuthan, University College London Hospitals, London, UK, who said:

“We are pleased to be the first team worldwide to explore this new investigational drug for participants with CAH as part of this trial. We now have the opportunity to evaluate if it is efficacious and generally well tolerated.”

Lu AG13909 is a first-in-class monoclonal antibody, where early proof of mechanism has been established. Lu AG13909 aligns with Lundbeck's objective of investigating novel therapies for rare neurohormonal disorders.

This addition reinforces Lundbeck's emphasis on the biology cluster focus within hormonal/neuropeptide signaling. Lu AG13909 is a humanized anti-adrenocorticotropic hormone (ACTH) monoclonal antibody (mAb) that specifically recognizes ACTH with high affinity and blocks the ACTH binding to the melanocortin 2 receptor in the adrenal glands and thereby neutralizes the ACTH signaling.^{1 2}

The ongoing trial is expected to be concluded by early 2025.

About the first in human trial
The trial is a phase 1, open-label, multiple-ascending-dose trial with intra-participant dose escalation. The trial enrolls men and women aged between ≥18 and ≤70 years with classic CAH. Each participant receives up to 6 doses of Lu AG13909 intra venously every 4-5 weeks at increasing dose levels.

The trial consists of 2 parts: Part A is designed to escalate the dosage of Lu AG13909 in a small number of participants (N=3–6) to determine which Lu AG13909 dose levels are tolerable and pharmacologically relevant to be explored in a larger number of participants.

Part B is dedicated to exploring only those doses that have been deemed pharmacologically relevant from the findings in Part A. This exploration will be conducted in a larger group of participants (N=6–9), utilizing pharmacokinetic (PK) and pharmacodynamic (PD) data to guide the investigation. This structured approach ensures a thorough and systematic evaluation of Lu AG13909’s potential therapeutic impact.

The considerations incorporated into the trial design will ensure that most participants receive doses that are pharmacologically significant. This approach aims to minimize the burden and risk associated with their participation in the trial.

The primary safety and tolerability endpoints include adverse events and clinical safety tests. Pharmacokinetic endpoints include maximum observed exposure and area under the Lu AG13909 concentration-time curve in a dosing interval. The pharmacodynamic endpoints are the relative reductions in morning 17-hydroxyprogesterone, androstenedione, and unbound ACTH, from baseline to the day after each Lu AG13909 dose.

This trial is expected to inform Lundbeck about the potential of AG13909 to advance into mid-stage clinical development, as a new therapeutic approach for conditions marked by elevated ACTH levels, such as CAH.

About Lu AG13909
Lu AG13909 is a humanized anti-ACTH mAb that specifically recognizes ACTH with high affinity. It blocks the binding of ACTH to the melanocortin 2 receptor in the adrenal glands and thereby neutralizes the neurohormonal signaling of ACTH. This blockage causes a decreased secretion of glucocorticoids, mineralocorticoids, and androgens from the adrenal glands.^{1 2}

ACTH plays a key role in the biosynthesis of adrenal steroids³ and is therefore considered a promising therapeutic target in conditions characterized by elevated ACTH levels.¹ In this context, Lu AG13909, a novel molecule, may provide a therapeutic approach for treating conditions associated with chronically elevated ACTH levels.

In animal studies, Lu AG13909 has shown significant and durable reductions of corticosterone/cortisol and aldosterone.¹ No adverse effects were observed after 6 months of intravenous dosing.

About congenital adrenal hyperplasia
Classic CAH is a rare, autosomal recessive disorder⁴ affecting 1 in 14,000–18,000 live births worldwide.⁵ Classic CAH is characterized by an enzyme deficiency, most commonly 21-hydroxylase deficiency, affecting the adrenal steroidogenesis leading to cortisol and aldosterone deficiency.

People with 21-hydroxylase deficiency are at risk of adrenal crisis, a life-threatening condition contributing to the increased mortality throughout life.⁶ Balancing physiological glucocorticoid replacement and control of hyperandrogenism remains a challenge with the risk of long-term consequences of glucocorticoid overtreatment.^7-9
 

Contacts

About H. Lundbeck A/S
Lundbeck is a biopharmaceutical company focused exclusively on neuroscience, with more than 70 years of experience in improving the lives of people with neurological and psychiatric diseases.

As a focused innovator, we strive for our research and development programs to tackle some of the most complex challenges. We develop transformative medicines targeting people for whom there are few, if any, treatment options.

Our goal is to create long term value and make a positive contribution to people and societies, everywhere we operate. We are committed to fighting stigma and discrimination, and we act to improve health equity for the people we serve and the communities we are part of. 

For additional information, we encourage you to visit our corporate site www.lundbeck.com and connect with us via LinkedIn.
 

1. Feldhaus AL, Anderson K, Dutzar B, et al. ALD1613, a Novel Long-Acting Monoclonal Antibody to Control ACTH-Driven Pharmacology. Endocrinology 2017;158(1):1-8. doi: 10.1210/en.2016-1455

2. Lundbeck. Data on file.

3. Xing Y, Edwards MA, Ahlem C, et al. The effects of ACTH on steroid metabolomic profiles in human adrenal cells. J Endocrinol 2011;209(3):327-35. doi: 10.1530/joe-10-0493 [published Online First: 2011/03/25]

4. Claahsen-van der Grinten HL, Speiser PW, Ahmed SF, et al. Congenital Adrenal Hyperplasia-Current Insights in Pathophysiology, Diagnostics, and Management. Endocr Rev 2022;43(1):91-159. doi: 10.1210/endrev/bnab016 [published Online First: 2021/05/08]

5. Merke DP, Auchus RJ. Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency. N Engl J Med 2020;383(13):1248-61. doi: 10.1056/NEJMra1909786 [published Online First: 2020/09/24]

6. Lousada LM, Mendonca BB, Bachega T. Adrenal crisis and mortality rate in adrenal insufficiency and congenital adrenal hyperplasia. Arch Endocrinol Metab 2021;65(4):488-94. doi: 10.20945/2359-3997000000392 [published Online First: 20210716]

7. Han TS, Walker BR, Arlt W, Ross RJ. Treatment and health outcomes in adults with congenital adrenal hyperplasia. Nat Rev Endocrinol 2014;10(2):115-24. doi: 10.1038/nrendo.2013.239 [published Online First: 20131217]

8. Pofi R, Ji X, Krone NP, Tomlinson JW. Long-term health consequences of congenital adrenal hyperplasia. Clin Endocrinol (Oxf) 2023 doi: 10.1111/cen.14967 [published Online First: 20230907]

9. Auchus RJ, Courtillot C, Dobs A, et al. Treatment patterns and unmet needs in adults with classic congenital adrenal hyperplasia: A modified Delphi consensus study. Front Endocrinol (Lausanne) 2022;13:1005963. doi: 10.3389/fendo.2022.1005963 [published Online First: 20221118]

H. Lundbeck A/S

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+45 3630 1311

info@lundbeck.com