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Neuroendocrinology and Pituitary

ORF28-08 - A First-in-Human Study of A Novel Growth Hormone Receptor Antagonist Antibody in Healthy Men Demonstrates Translational Potential for Acromegaly

Sunday, June 14, 2026
3:00 PM - 3:15 PM CT
Location: Room W183BC

Background
Acromegaly is a rare, chronic, progressive endocrine disorder caused by prolonged exposure to excess growth hormone (GH), most commonly due to a GH-secreting pituitary adenoma, resulting in elevated insulin-like growth factor-1 (IGF-1). GH receptor antagonists (GHRA) offer therapeutic advantages in acromegaly by directly blocking GH signaling, lowering IGF-1, and improving insulin sensitivity. However, the only approved GHRA, pegvisomant, requires daily administration, resulting in suboptimal patient adherence and reduced real-world efficacy. MAR002 is a novel, selective, half-life-extended, allosteric, human monoclonal GHRA antibody in development for the treatment of acromegaly. In non-human primates, MAR002 exhibited potent and sustained IGF-1 suppression. In a head-to-head comparison with pegvisomant, a single dose of MAR002 achieved similar maximum IGF-1 suppression, but with a considerably longer duration of effect. These preclinical findings strongly supported advancing MAR002 into clinical development.

Methods
This Phase 1, first-in-human trial (NCT07195175) evaluated the safety, tolerability, and pharmacokinetics of MAR002 administered subcutaneously (SC) in healthy men. Participants were randomized and blinded to receive single ascending doses of MAR002 or placebo. The primary objective was to assess safety and tolerability, including adverse events, clinical laboratory assessments, and vital signs. Secondary objectives included characterization of MAR002 pharmacokinetics, and exploratory objectives included assessment of changes in serum IGF-1 following MAR002 administration.

Results
Overall, 37 participants were randomized. MAR002 was generally safe and well-tolerated, with no serious adverse events or dose-limiting toxicities. Following a single SC dose, MAR002 produced dose-dependent suppression of serum IGF-1, with minimal change in placebo recipients. In the highest dose cohort, the mean maximum percent change (±SD) from baseline in IGF-1 was −54.2% ± 13%, with suppression greater than 50% sustained for 43 days. The observed IGF-1 suppression is comparable to reported effects of pegvisomant (80 mg single dose), but with substantially longer durability, and exceeds levels reported with somatostatin receptors ligands in recent development.

Conclusions
MAR002 was generally safe and well-tolerated and produced sustained, dose-dependent suppression of serum IGF-1 in healthy men. Based on established precedent with pegvisomant in healthy volunteers, the proof-of-mechanism observed with MAR002 is predictive of clinically meaningful IGF-1 normalization in patients with acromegaly and may enable substantially reduced dosing frequency compared with daily pegvisomant. These data support advancement of MAR002 into Phase 2 evaluation in acromegaly as a promising potential new therapy.