SUN-463 - Development of A Quantitative Systems Pharmacology Model to Investigate the Influence of Melanocortin-2 Receptor Antagonist Residence Time in the Treatment of Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia (CAH) is characterized by impaired cortisol synthesis, causing a loss of the hypothalamic-pituitary adrenal axis feedback mechanisms required to maintain normal adrenocorticotrophic hormone (ACTH) secretion, resulting in aberrant and excess fluctuations of ACTH levels. Excess ACTH leads to adrenal hyperplasia and androgen accumulation. The melanocortin-2 receptor (MC2R) is the cognate receptor for ACTH and an MC2R antagonist represents an attractive therapeutic agent for CAH as demonstrated by Atumelnant, currently in clinical trials. We previously characterized a novel MC2R antagonist, OMS1620, which has a long residence time at MC2R (127 min at rat MC2R) and was highly efficacious in its blockade of ACTH-stimulated corticosterone in rats[1]. The effects of the kinetics of antagonist-target interaction, particularly compound residence time, have an increased importance under the non-equilibrium and high agonist concentrations found in CAH[2].

In this study, we developed a novel quantitative systems pharmacology rodent in silico model to investigate the effect of antagonist residence time at the MC2R on adrenal function, measured by corticosterone production. This model used experimentally-derived rat PK and PD values to build the model structure.

First, we simulated the effects of a single exogenous ACTH i.v. bolus on adrenal function to highlight the impact of the negative feedback loop of corticosterone on ACTH production. Next, the model was tested in the presence of a wide range of OMS1620 or Atumelnant doses. OMS1620 showed a strong suppression of the ACTH-stimulated corticosterone response, even at very low doses, due to its long residence time. Atumelnant demonstrated a plateau of ACTH inhibition due to its shorter residence. In silico modulation of the residence time of OMS1620 to shorter values (by 10-fold) showed a simulated response with a clear plateau of inhibition, accurately replicating in vivo experimental data of OMS1620 analogues with shorter residence times. This demonstrates the impact of compound residence time on the acute response to ACTH.

Finally, we simulated a range of different ACTH stimuli, such as the wide range seen in CAH. Here, increasing ACTH concentrations resulted in an increasingly robust corticosterone response. A single dose of OMS1620 was resistant to the challenge of all ACTH doses used, showing a minimal increase in measured response.

This model further highlights the ability of MC2R antagonists with a long residence time to treat all patients in CAH, including those with high ACTH levels. Importantly, we predict this will enable full down-titration of replacement glucocorticoids to physiological levels without the concern over rising ACTH levels and associated loss of efficacy.



References

[1] Malet Sanz et al., 2025, J Endocr Soc, 9 (Suppl 1), bvaf149.402

[2] Copeland et al., 2006, Nat Rev Drug Discov, 5, 730-9

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