SAT-408 Bioactivity of Long Acting PTH Fusion Molecules Tested in a Novel Non-Surgical Animal Model of Hypoparathyroidism

Abstract

Introduction: There is an unmet need for the development of long-acting PTH molecules to treat patients with hypoparathyroidism. We have established a novel non-surgical rodent model of hypoparathyroidism using oral Cinacalcet-HCl to test long acting analogues of PTH. Here we have tested the pharmacodynamics properties of two long acting PTH fusion molecules. Methods: PTH fusion molecules tested: Fusion-1 is PTH (1–34) linked to GHBP (residues 1–238), and Fusion-2 is a Hybrid PTH-PTHrP (1) linked to GHBP (residues 1–238). For in vivo studies, normal male wistar rats were gavaged with 30 mg/kg Cinacalcet-HCl, immediately followed by a subcutaneous dose of PTH Fusion at 20 nmol/kg. Control animals received PTH (1–34) and vehicle only. Serum samples were taken and analysed for ionised calcium (iCa). Results: Oral administration of Cinacalcet-HCl caused a reduction in iCa that was significantly different from vehicle controls at 2 to 24hrs post dose (ANOVA P < 0.0001). PTH 1–34 maintained iCa levels for 2 hours after administration above that of Cinacalcet-HCl (AUC±SD (mmol/L).hr from baseline, 0.076 ±0.047 and 0.168±0.0874, t-test P=0.0289) but then levels fell and recovered as for Cinacalcet-HCl alone. Subcutaneous doses of both fusions were able to abrogate the effects of Cinacalcet-HCl from 4hrs post dose onwards giving a prolonged response, with iCa levels quicker to return to baseline levels at 48hrs compared to Cinacalcet-HCl. The AUC±SD (mmol/L).hr from baseline for iCa over 72 hours was 3.93±1.4 for Fusion-1, 5.0±2.7 for Fusion-2 & 10±2.8 for Cinacaclet-HCl and were significantly reduced for both fusions compared to Cinacalcet-HCl alone (t-test P = 0.0028 & P = 0.019, respectively) and not significantly different from vehicle only. Conclusions: Cinacalcet-HCl behaved as expected in terms of iCa lowering (2). PTH maintained iCa but only for 2 hours. Both PTH fusion molecules showed a delayed and prolonged response and reduced the impact of Cinacalcet-HCl induced low iCa levels from 4hrs to 24hrs. These data provide proof of concept for long acting biological activity of these novel PTH fusion proteins.