OR12-06 Development of a Novel Growth Hormone Receptor Antagonist Antibody for the Treatment of Acromegaly

Abstract Disclosure: K. Kurylo: Marea Therapeutics, Inc. W. Huynh: Marea Therapeutics, Inc. P.R. Bouchard: Marea Therapeutics, Inc. M.N. Milton: Marea Therapeutics, Inc. P.F. Moesta: Marea Therapeutics, Inc. L.E. Dichtel: Marea Therapeutics, Inc., Recordati, Lumos Pharma, Perspectum, Novo Nordisk, Third Rock Ventures, Merida Biosciences, Flare Therapeutics. J. Gromada: Marea Therapeutics, Inc. V. Ramanan: Marea Therapeutics, Inc. M.P. Joing: Marea Therapeutics, Inc. B.B. Cummings: Marea Therapeutics, Inc. E.J. Weiss: Marea Therapeutics, Inc.. Acromegaly is a rare disease characterized by excessive growth hormone (GH) production from a benign anterior pituitary adenoma. Elevated GH levels lead to increased production of IGF-1 from the liver, and acromegaly is linked to increased morbidity and mortality. GH receptor antagonists (GHRA) are an attractive therapeutic option, as they directly block GH action, lower IGF-1, and improve insulin sensitivity. However, the only currently available GHRA, pegvisomant, requires daily administration, resulting in low patient compliance and reduced real-world efficacy. Here, we report the development and characterization of MAR002, a novel half-life extended GHRA monoclonal antibody with the potential to enhance ease of use, improve efficacy, and elevate the quality of life for patients with acromegaly. In vitro, MAR002 had a significantly stronger binding affinity to GHR and resulted in more potent dose-dependent inhibition of GH-induced GHR signaling (IC50: 1 nM) vs. pegvisomant (IC50: 122nM). The greater potency of MAR002 was maintained when GH was pre-bound to GHR. MAR002 maintained stable GHR signaling suppression with supraphysiological GH levels (≥90% suppression), whereas such levels of GH outcompeted pegvisomant (no suppression). Epitope mapping revealed that unlike pegvisomant, MAR002 does not bind known GH binding sites on GHR, and additional binding assays confirmed MAR002 and GH can bind simultaneously to GHR. Together, these data demonstrate that MAR002 binds allosterically to inhibit GHR signaling; a novel GH-binding independent mechanism distinct from pegvisomant, which is an orthosteric inhibitor known to occupy the same binding site as GH. In cynomolgus monkeys, administration of equimolar doses of MAR002 and pegvisomant was well tolerated and demonstrated similar peak IGF-1 suppression (80% reduction, n=3 per group). MAR002 demonstrated a more favorable PK/PD profile, as it was detected in serum concentrations that resulted in ≥50% IGF-1 suppression for 36 days vs.15 days for pegvisomant. Of note, half-life extending mutations in monoclonal antibodies are reported to be up to 3x more durable in humans than in monkeys. This, in addition to the more favorable serum residence time of MAR002 predicts a substantially longer duration of IGF-1 lowering in humans compared to pegvisomant. In summary, we developed and characterized a novel half-life extended, allosteric, inhibitory GHR antibody with a mechanism distinct from pegvisomant. Stronger inhibitory activity of MAR002 against GHR in vitro, combined with a superior PK/PD profile in cynomolgus monkeys, should provide a prolonged therapeutic effect in patients, requiring less-frequent dosing vs. pegvisomant (e.g. potentially biweekly, monthly, or less frequent). This work enables continued MAR002 development to assess its safety, efficacy, and potential to improve the care for patients with acromegaly. Presentation: Sunday, July 13, 2025