Browse views: by Year, by Function, by GLF, by Subfunction, by Conference, by Journal

AXT914 a novel, orally-active parathyroid hormone-releasing drug in two early studies of healthy volunteers and postmenopausal women

John, Markus, Harfst, Eva, Loeffler, Juergen, Belleli, Rossella, Bruin, Gerardus, Seuwen, Klaus, Klickstein, Lloyd, Mindeholm, Linda, Widler, Leo and Kneissel, Michaela (2014) AXT914 a novel, orally-active parathyroid hormone-releasing drug in two early studies of healthy volunteers and postmenopausal women. Bone, 64. pp. 204-210. ISSN 8756-3282


Antagonism of the calcium-sensing receptor in the parathyroid gland leads to parathyroid hormone (PTH) release. Calcilytics are a new class of molecules designed to exploit this mechanism. In order to mimic the known bone-anabolic pharmacokinetic (PK) profile of s.c. administered PTH, such molecules must trigger sharp, transient and robust release of PTH. The results of two early clinical studies with the orally-active calcilytic AXT914, a quinazolin-2ne derivative are reported. These were GCP-compliant, single and multiple dose studies of PK/PD and tolerability in healthy volunteers and postmenopausal women.The first study, examined single ascending doses (4 to 120. mg) and limited multiple doses (60 or 120. mg. q.d. for 12. days) of AXT914. The second study was a randomized, double-blind, active- and placebo-controlled, 4-week repeat-dose parallel group study of healthy postmenopausal women (45 and 60. mg AXT914, placebo, 20. μg Forteo/teriparatide/PTH(1-34) fragment).AXT914 was well tolerated at all doses and reproducibly induced the desired PTH-release profiles. Yet, 4. weeks of 45 or 60. mg AXT914 did not result in the expected changes in circulating bone biomarkers seen with teriparatide. However total serum calcium levels increased above baseline in the 45 and 60. mg AXT914 treatment groups (8.0 % and 10.7%, respectively), compared to that in the teriparatide and placebo groups (1.3% and 1.0%, respectively). Thus the trial was terminated after a planned interim analysis due to lack of effect on bone formation biomarkers and dose-limiting effects on serum calcium.In conclusion, AXT914 was well tolerated but the observed transient and reproducible PTH-release after repeat oral administration of AXT914 which showed an exposure profile close to that of s c. PTH, did not translate into a bone anabolic response and was associated with a persistent dose-related increase in serum calcium concentrations. © 2014.

Item Type: Article
Keywords: Bone formation Calcilytics Osteoporosis Parathyroid hormone Teriparatide
Date Deposited: 25 Oct 2017 00:45
Last Modified: 25 Jan 2019 00:46


Email Alerts

Register with OAK to receive email alerts for saved searches.