MON-620 Sub-Chronic Dosing of a Non-peptide Somatostatin 2 Receptor Agonist Reduces IGF-1 and Acutely Impacts Glucose and Insulin Homeostasis in Dogs

Disclosure: A.P. Tovar: None. J.E. McMahon: None. J.L. Graves: None. P.A. Frankino: None. S. Markison: None. S.F. Betz: None. H.C. Chen: None. M. Peloquin: None. Agonism of the somatostatin 2 (SST2) receptor induces broad metabolic and hormonal actions by suppressing the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis as well as through effects in the pancreas. SST2 agonism, in addition to being developed for various human endocrine disorders, has a therapeutic potential for extending the lifespan of large-breed companion dogs, which have significantly decreased lifespan relative to smaller dogs. This disparity is associated with, and may be caused by, increased GH and IGF-1 levels and the effects in large dogs bear similarity to acromegaly in humans. Both octreotide and lanreotide are commonly used as SST2 agonists, however both are peptides with poor oral bioavailability (requiring injections), which have poor selectivity to somatostatin receptor subtypes (SST3, SST5) that may contribute to unwanted effects. LOY-003 is a novel, orally bioavailable non-peptide SST2 agonist. We investigated the pharmacokinetics (PK) and pharmacodynamic response to varying doses of LOY-003 in beagle dogs. LOY-003 was dosed daily via oral gavage at escalating dose levels to 40 beagle dogs (n = 4M + 4F/group). IGF-1 samples were collected serially in the days prior to dosing and on treatment days 8, 15, and 22. Fasting plasma glucose and insulin samples were collected after the first dose on day 1 at pre-treatment, 0.5, 1, and 2 hours post-dose. Plasma concentrations of LOY-003 were assessed at pre-treatment, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on days 1, 8, 15, 22, and 29. The PK profile of LOY-003 in dogs was shown to peak at day 8, reaching steady state by day 15 with no detectable exposure after a 1 week washout in any group. Significant reductions in IGF-1 were observed as early as day 8, in groups receiving 0.3 mg/kg (-41.07%, p<0.001), 1.0 mg/kg (-40.30%, p<0.001), and 3.0 mg/kg (-45.91%, p<0.001), with sustained reductions continuing to day 22. Fasting glucose decreased by 2 hours post-treatment on day 1 in dogs receiving 0.3 mg/kg (-7.42%, p = 0.006), 1.0 mg/kg (-12.43%, p < 0.001), and 3.0 mg/kg (-12.63%, p < 0.001) of LOY-003. Additionally, significant reductions to fasting insulin were observed immediately at 0.5 hours post-treatment in groups receiving 0.3 mg/kg (-54.27%, p < 0.001), 1.0 mg/kg (-60.85%, p < 0.001), and 3.0 mg/kg (-47.37%, p < 0.001) of LOY-003. These data demonstrate SST2 agonism results in meaningful and sustained reductions in IGF-1 levels, as well as enhanced glucose and insulin homeostasis. These data indicate LOY-003 improves markers of metabolic function, supporting further investigation of its effects on metabolic health and mortality in dogs. Presentation: Monday, July 14, 2025