- Email: [email protected]
Preclinical studies of calcilytic compounds
Abstracts / Bone 47 (2010) S15–S28
hypercalcaemia (FBH or FHH) and neonatal severe primary hyperparathyroidism (NSHPT). However, some individuals with loss-of-function CaSR mutations remain normocalcaemic. In addition, there is genetic heterogeneity amongst the forms of FHH. Thus, the majority of FHH patients have loss-of-function CaSR mutations, and this is referred to as FHH type 1. However, in one family, the causative gene for FHH is located on 19p13, referred to as FHH type 2, and in another family it is located on 19q13, referred to as FHH type 3. Gain-of-function CaSR mutations have been shown to result in autosomal dominant hypocalcaemia with hypercalciuria (ADHH) and Bartter's syndrome type V. CaSR auto-antibodies have been found in FHH patients who did not have loss-of-function CaSR mutations, and in patients with an acquired form (ie. autoimmune) of hypoparathyroidism. Thus, abnormalities of the CaSR are associated with 3 hypercalcaemic and 3 hypocalcaemic disorders. Disclosure of Interest: None declared Keywords: G-protein-coupled-receptor, hypercalcaemia, hypocalcaemia doi:10.1016/j.bone.2010.04.032
IS32 Preclinical studies of calcilytic compounds E.F. Nemeth⁎1 1 MetisMedica, Toronto, Canada Daily administration of exogenous parathyroid hormone (PTH) or peptides like teriparatide that activate the PTH receptor stimulate new bone formation and decrease the risk of fracture. Transient, daily increases in circulating levels of endogenous PTH might be expected to similarly achieve an anabolic effect on the skeleton. Calcilytics are calcium receptor antagonists that stimulate the secretion of PTH from parathyroid cells. Some calcilytics are orally bioavailable and elicit rapid, 2- to 3-fold increases in circulating levels of endogenous PTH which remain elevated for various times depending upon the pharmacokinetics of the particular compound. Short- or long-acting calcilytics have very different effects on the skeleton in rodent models of osteoporosis (ovariectomized (OVX) rat) that are related to the pattern of change in plasma levels of PTH. Treatment with a short-acting calcilytic, which causes a transient increase in plasma levels of PTH that returns to baseline within 2 to 3 hours, stimulates new bone formation at both cortical (femoral diaphysis) and trabecular (lumbar spine) sites and increases bone mineral density (BMD) in the lumbar spine. Some biomechanical estimates of bone strength are also increased in lumbar vertebrae and femoral mid-shaft following treatment with a short-acting calcilytic. In contrast, a long-acting calcilytic, which increases plasma levels of PTH for about 12 hours, stimulates both formation and resorption to similar extents so there is no net increase (or decrease) in BMD at skeletal sites. Calcilytic compounds stimulate the synthesis of PTH (by stabilizing PTH mRNA) but neither short- nor long-acting calcilytic compounds stimulate parathyroid cell proliferation in OVX rats following daily treatment for 3 months. Calcilytic compounds that elicit transient increases in circulating levels of endogenous PTH thus have a potential as novel, orally-active anabolic therapies for osteoporosis. In general, the effects of shortacting calcilytics on the skeletal parameters are similar to those produced by exogenously administered teriparatide. However, there are some quantitative and qualitative differences that might result from differences in the secretion of endogenous hormone when compared to exogenously administered peptide and/or actions of calcilytics on calcium receptors in tissues other than the parathyroid gland.
S25
Disclosure of Interest: None declared Keywords: None doi:10.1016/j.bone.2010.04.033
IS33 Translational and clinical studies on calcilytics M.R. John⁎1 1 Novartis, Basel, Switzerland Antagonism of the calcium-sensing receptor in parathyroid glands leads to parathyroid hormone (PTH) release via stimulation of an endogenous hormone-release mechanism. Calcilytics are a new class of molecules which aim to exploit this mechanism. In order to mimic the known bone-anabolic PK profile of s.c. administered PTH, a drug must release PTH transiently and robustly. Following a random screen, lead-identification and -optimization resulted in two potent development candidates, ATF936 and AXT914. They were characterized in preclinical in vivo models, including rat, dog and monkey and demonstrated shared and distinct pharmacokinetic (PK) and pharmacodynamic (PD) properties. In a two-part, dose-limited exploratory IND study, both compounds were tested for their ability to stimulate PTH-release. In part A, both compounds were administered in parallel to 12 healthy male volunteers (HMVs) in a randomized, within-subject dose-rising, double - blind, active comparator, placebo-controlled single dose study. Blood samples for safety, PK, and pharmacodynamic analyses were obtained frequently over each 24-h postdose period. For both compounds, elevations in plasma intact and bioactive PTH closely followed the linear PK profiles of either compound. AXT914 was selected for part B. In part B, a double - blind, active comparator, placebo-controlled multiple-dose study, AXT914 was administered daily for 12 days at either 60 mg or 120 mg to a population of 8 HMVs or 16 healthy postmenopausal females. AXT914 demonstrated a reproducible PK/PTHrelease profile. Early effects on biochemical markers of bone turnover were distinct from the expected profile following short-term administration of PTH, as both osteocalcin and CTX1 showed small increases under domiciled conditions. Both compounds were well tolerated at all doses and no serious adverse events were reported. Adverse event frequency, safety laboratory values, vital signs or 12-lead ECG intervals did not suggest any compound related adverse effects. AXT914 did demonstrate an asymptomatic increase in serum and ionized calcium following multiple dosing. In conclusion, the observed transient and reproducible PTH -release profiles were close to those observed with s.c. PTH. Interpretation of the very early biochemical marker response was inconclusive. Longer clinical studies are necessary to see if this promising class of compounds might yield a novel pharmaceutical approach for oral bone anabolic osteoporosis therapy. Disclosure of Interest: None declared Keywords: anabolic, calcilytic, PTH 1-84 doi:10.1016/j.bone.2010.04.034
IS34 MiRNA mechanism for repression of osteoclast differentiation E. Hornstein⁎1 1 Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel When stem cells and multipotent progenitors differentiate, they undergo fate restriction, enabling a single fate, and blocking differentiation
hypercalcaemia (FBH or FHH) and neonatal severe primary hyperparathyroidism (NSHPT). However, some individuals with loss-of-function CaSR mutations remain normocalcaemic. In addition, there is genetic heterogeneity amongst the forms of FHH. Thus, the majority of FHH patients have loss-of-function CaSR mutations, and this is referred to as FHH type 1. However, in one family, the causative gene for FHH is located on 19p13, referred to as FHH type 2, and in another family it is located on 19q13, referred to as FHH type 3. Gain-of-function CaSR mutations have been shown to result in autosomal dominant hypocalcaemia with hypercalciuria (ADHH) and Bartter's syndrome type V. CaSR auto-antibodies have been found in FHH patients who did not have loss-of-function CaSR mutations, and in patients with an acquired form (ie. autoimmune) of hypoparathyroidism. Thus, abnormalities of the CaSR are associated with 3 hypercalcaemic and 3 hypocalcaemic disorders. Disclosure of Interest: None declared Keywords: G-protein-coupled-receptor, hypercalcaemia, hypocalcaemia doi:10.1016/j.bone.2010.04.032
IS32 Preclinical studies of calcilytic compounds E.F. Nemeth⁎1 1 MetisMedica, Toronto, Canada Daily administration of exogenous parathyroid hormone (PTH) or peptides like teriparatide that activate the PTH receptor stimulate new bone formation and decrease the risk of fracture. Transient, daily increases in circulating levels of endogenous PTH might be expected to similarly achieve an anabolic effect on the skeleton. Calcilytics are calcium receptor antagonists that stimulate the secretion of PTH from parathyroid cells. Some calcilytics are orally bioavailable and elicit rapid, 2- to 3-fold increases in circulating levels of endogenous PTH which remain elevated for various times depending upon the pharmacokinetics of the particular compound. Short- or long-acting calcilytics have very different effects on the skeleton in rodent models of osteoporosis (ovariectomized (OVX) rat) that are related to the pattern of change in plasma levels of PTH. Treatment with a short-acting calcilytic, which causes a transient increase in plasma levels of PTH that returns to baseline within 2 to 3 hours, stimulates new bone formation at both cortical (femoral diaphysis) and trabecular (lumbar spine) sites and increases bone mineral density (BMD) in the lumbar spine. Some biomechanical estimates of bone strength are also increased in lumbar vertebrae and femoral mid-shaft following treatment with a short-acting calcilytic. In contrast, a long-acting calcilytic, which increases plasma levels of PTH for about 12 hours, stimulates both formation and resorption to similar extents so there is no net increase (or decrease) in BMD at skeletal sites. Calcilytic compounds stimulate the synthesis of PTH (by stabilizing PTH mRNA) but neither short- nor long-acting calcilytic compounds stimulate parathyroid cell proliferation in OVX rats following daily treatment for 3 months. Calcilytic compounds that elicit transient increases in circulating levels of endogenous PTH thus have a potential as novel, orally-active anabolic therapies for osteoporosis. In general, the effects of shortacting calcilytics on the skeletal parameters are similar to those produced by exogenously administered teriparatide. However, there are some quantitative and qualitative differences that might result from differences in the secretion of endogenous hormone when compared to exogenously administered peptide and/or actions of calcilytics on calcium receptors in tissues other than the parathyroid gland.
S25
Disclosure of Interest: None declared Keywords: None doi:10.1016/j.bone.2010.04.033
IS33 Translational and clinical studies on calcilytics M.R. John⁎1 1 Novartis, Basel, Switzerland Antagonism of the calcium-sensing receptor in parathyroid glands leads to parathyroid hormone (PTH) release via stimulation of an endogenous hormone-release mechanism. Calcilytics are a new class of molecules which aim to exploit this mechanism. In order to mimic the known bone-anabolic PK profile of s.c. administered PTH, a drug must release PTH transiently and robustly. Following a random screen, lead-identification and -optimization resulted in two potent development candidates, ATF936 and AXT914. They were characterized in preclinical in vivo models, including rat, dog and monkey and demonstrated shared and distinct pharmacokinetic (PK) and pharmacodynamic (PD) properties. In a two-part, dose-limited exploratory IND study, both compounds were tested for their ability to stimulate PTH-release. In part A, both compounds were administered in parallel to 12 healthy male volunteers (HMVs) in a randomized, within-subject dose-rising, double - blind, active comparator, placebo-controlled single dose study. Blood samples for safety, PK, and pharmacodynamic analyses were obtained frequently over each 24-h postdose period. For both compounds, elevations in plasma intact and bioactive PTH closely followed the linear PK profiles of either compound. AXT914 was selected for part B. In part B, a double - blind, active comparator, placebo-controlled multiple-dose study, AXT914 was administered daily for 12 days at either 60 mg or 120 mg to a population of 8 HMVs or 16 healthy postmenopausal females. AXT914 demonstrated a reproducible PK/PTHrelease profile. Early effects on biochemical markers of bone turnover were distinct from the expected profile following short-term administration of PTH, as both osteocalcin and CTX1 showed small increases under domiciled conditions. Both compounds were well tolerated at all doses and no serious adverse events were reported. Adverse event frequency, safety laboratory values, vital signs or 12-lead ECG intervals did not suggest any compound related adverse effects. AXT914 did demonstrate an asymptomatic increase in serum and ionized calcium following multiple dosing. In conclusion, the observed transient and reproducible PTH -release profiles were close to those observed with s.c. PTH. Interpretation of the very early biochemical marker response was inconclusive. Longer clinical studies are necessary to see if this promising class of compounds might yield a novel pharmaceutical approach for oral bone anabolic osteoporosis therapy. Disclosure of Interest: None declared Keywords: anabolic, calcilytic, PTH 1-84 doi:10.1016/j.bone.2010.04.034
IS34 MiRNA mechanism for repression of osteoclast differentiation E. Hornstein⁎1 1 Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel When stem cells and multipotent progenitors differentiate, they undergo fate restriction, enabling a single fate, and blocking differentiation