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The Calcimimetic AMG 073 Reduces Parathyroid Hormone and Calcium X Phosphorus in Secondary Hyperparathyroidism

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The Calcimimetic AMG 073 Reduces Parathyroid Hormone and Calcium X Phosphorus in Secondary Hyperparathyroidism Kidney International, Vol. 63 (2003), pp. 248–254 The calcimimetic AMG 073 reduces parathyroid hormone and calcium x phosphorus in secondary hyperparathyroidism JILL S. LINDBERG,SHARON M. MOE,WILLIAM G. GOODMAN,JACK W. COBURN, STUART M. SPRAGUE,WEI LIU,PETER W. BLAISDELL,ROBERT M. BRENNER, STEWART A. TURNER, and KEVIN J. MARTIN Ochsner Clinical Research Center, New Orleans, Louisiana, USA; Indiana University School of Medicine, Indianapolis, Indiana, USA; Department of Medicine, UCLA School of Medicine, Los Angeles; Veterans Administration Medical Center, Los Angeles, California, USA; Evanston Hospital, Evanston, Illinois, USA; Amgen, Thousand Oaks, California, USA; St. Louis University, St. Louis, Missouri, USA The calcimimetic AMG 073 reduces parathyroid hormone and Secondary hyperparathyroidism is characterized by calcium x phosphorus in secondary hyperparathyroidism. parathyroid gland hyperplasia and increased concentra- Background. A need exists for a therapy that lowers para- tions of parathyroid hormone (PTH) [1, 2]. Elevated PTH thyroid hormone (PTH) without increasing calcium x phospho- rus in patients with secondary hyperparathyroidism. The calci- levels may adversely affect a variety of organs, including mimetic AMG 073 increases the sensitivity of the parathyroid the central nervous system, cardiac and pulmonary func- calcium-sensing receptor to extracellular calcium, thereby re- tion [3–5]. Furthermore, Block et al found that elevated ducing PTH secretion. Consequently, AMG 073 may provide PTH levels are associated with an increase in the relative a novel therapy for secondary hyperparathyroidism. risk of mortality [6]. Abnormalities of bone and mineral Methods. Seventy-eight hemodialysis patients with second- metabolism are another important complication in these ary hyperparathyroidism were enrolled into this 18-week, dou- ble-blind, randomized, placebo-controlled, dose titration study. patients. Bone histology in these patients often reveals Daily oral AMG 073 doses were administered to determine the pathology of osteitis fibrosa cystica [7, 8]. the effect on PTH, serum calcium, phosphorus, and calcium x Current strategies for managing secondary hyperpara- phosphorus. thyroidism in patients with end-stage renal disease (ESRD) Results. The mean baseline PTH was similar in patients ad- utilize large oral doses of calcium or noncalcium-con- Ϯ Ϯ ministered AMG 073 or placebo (632 280.1 pg/mL vs. 637 taining phosphate-binding agents to control hyperphos- 455.9 pg/mL, respectively). PTH decreased by 26.0% in the AMG 073-treated group, compared with an increase of 22.0% phatemia while the vitamin D sterols, calcitriol, paricalci- in the placebo group (P Ͻ 0.001). A greater proportion in tol or doxercalciferol, are administered to lower PTH the AMG 073 group (38%) had a decrease in PTH Ն30%, levels [9–12]. Unfortunately, episodes of hypercalcemia compared with the placebo group (8%) (P ϭ 0.001). Decreases are common in patients treated with calcium-containing in PTH were independent of baseline vitamin D usage. Patients phosphate-binding agents and serum calcium and phos- receiving AMG 073 had an 11.9% decrease in calcium x phos- phorus levels often rise after the administration of su- phorus compared with a 10.9% increase in the placebo group praphysiological doses of vitamin D [13–15]. Both ther- (P Ͻ 0.001). Use of vitamin D sterols, as well as both calcium and noncalcium-containing phosphate binders. were similar apeutic interventions may contribute to vascular and between treatment groups. Administration of AMG 073 was soft-tissue calcification [16]. Moreover, neither treatment safe and well tolerated in this 18-week study. immediately decreases PTH synthesis and secretion. Conclusions. The calcimimetic AMG 073 decreases both Consequently, an unmet medical need exists for a ther- PTH and calcium x phosphorus levels in hemodialysis patients apy that can control PTH levels without raising serum with secondary hyperparathyroidism. calcium or phosphorus levels in patients with secondary hyperparathyroidism. AMG 073 represents a new class of compounds known Key words: calcimimetic, calcium-sensing receptor, parathyroid hor- mone, calcium x phosphorus, secondary hyperparathyroidism, end- as calcimimetics. These small molecules act on the para- stage renal disease. thyroid gland calcium-sensing receptor, increasing its sensitivity to extracellular calcium, thereby reducing Received for publication April 18, 2002 and in revised form July 22, 2002 PTH secretion [17, 18]. Calcimimetics have been shown Accepted for publication August 15, 2002 to inhibit PTH release from parathyroid cells both in 2003 by the International Society of Nephrology vitro and in vivo and have been proposed as a therapy for 248 Lindberg et al: Calcimimetic reduces parathyroid hormone 249 Fig. 1. Study schema. a, one patient withdrew consent before receiving study drug; b, three patients were on a dose of 10 mg at the end of the maintenance phase. hyperparathyroidism [19]. These agents reduce plasma care (phosphate binders and/or vitamin D sterols). Pa- PTH levels within 1 to 2 hours of oral administration in tients were eligible for this study if they met criteria, humans [20]. The rapid onset of the effects of calcimi- including age Ն18 years; serum calcium corrected for metic agents suggests that these compounds may permit serum albumin Ն8.8 mg/dL and Ͻ11.0 mg/dL; serum precise pharmacological control of PTH secretion in pa- phosphorus Ն2.5 mg/dL; and calcium x phosphorus tients with secondary hyperparathyroidism. Ͻ70 (mg/dL)2. Patients receiving vitamin D sterols were Single oral doses of AMG 073 have resulted in dose- required to be on a stable dose for at least 21 days before dependent decreases in PTH when administered to he- enrollment. Dialysate calcium concentration and calcium modialysis patients with secondary hyperparathyroid- supplements/oral phosphate binders dose could not be ism, while daily doses of 50 mg over 8 days reduced PTH changed during the 7 days before enrollment. Patients by 39% [20]. Importantly, decreases in serum calcium, were required to be medically stable with no evidence phosphorus, and the calcium x phosphorus product were of an active infection, malignant process, or disease also observed in this study. In the present 18-week study, known to cause hypercalcemia. Patients were also re- the efficacy and safety of AMG 073 were assessed in quired to have a hemoglobin Ͼ9.0 g/dL or a hematocrit reducing PTH without concomitant increases in cal- Ͼ27%, as well as liver transaminases and bilirubin levels cium x phosphorus in hemodialysis patients with second- no more than twice the upper limit of normal. ary hyperparathyroidism. Study design This was a placebo-controlled, double-blind, random- METHODS ized, multicenter study consisting of two phases: a 12-week Patients dose-titration phase, followed by a maintenance phase This study was approved by each study center’s Institu- in which the final dose from the end of the dose-titration tional Review Board or ethics committee and all patients phase was maintained for 6 weeks (Fig. 1). gave written informed consent before participation. The Patients were randomized 1:1 to receive AMG 073 or study was conducted at 23 centers in the United States placebo. Patients began on a once daily dose of 20 mg and two in Canada. These centers enrolled 78 patients which could then be titrated up to 30, 40, or 50 mg, or treated for at least 3 months with hemodialysis who had down to 10 mg, every 3 weeks until they had achieved PTH levels Ն300 pg/mL despite receiving standard of a reduction in PTH values of Ն30% from baseline and 250 Lindberg et al: Calcimimetic reduces parathyroid hormone to Յ250 pg/mL, unless the patient had symptoms of Table 1. Baseline characteristics of study patients hypocalcemia or the serum calcium was Ͻ7.8 mg/dL. Placebo AMG 073 Total The dose of study drug was reduced if patients experi- N ϭ 39 N ϭ 39 N ϭ 78 enced PTH values Ͻ100 pg/mL on two consecutive Gender number (%) Women 17 (44) 15 (38) 32 (41) weekly visits. Men 22 (56) 24 (62) 46 (59) Laboratory assessments were made at weekly visits Race number (%) throughout the study to determine the effect of AMG Black 29 (74) 26 (67) 55 (71) White 6 (15) 10 (26) 16 (21) 073 on PTH, serum calcium, serum phosphorus, and Asian 2 (5) 2 (5) 4 (5) calcium x phosphorus. These assessments were made Hispanic 2 (5) 1 (3) 3 (4) immediately before administering the daily oral dose of Age years Mean (SD) 48.8 (15.6) 52.7 (16.4) 50.8 (16.0) study medication (24 hours after the dose on the preced- Duration of dialysis months ing day). Number 39 38 77 Mean (SD) 69.7 (53.9) 60.3 (58.3) 65.1 (55.9) Efficacy was assessed by determining the proportion Range 5–277 3–241 3–277 of patients with reductions in PTH Ն30% between treat- Vitamin D use number (%) 24 (62) 26 (67) 50 (64) ment groups during the maintenance phase. The mean Phosphate binder use number (%) 34 (87) 34 (87) 68 (87) percent change from baseline for PTH, serum calcium, phosphorus, and calcium x phosphorus were also com- pared between treatment groups during the maintenance phase. Safety was assessed by monitoring adverse events, Statistical analysis laboratory variables (hematology and biochemistry), and All patients randomized into the study were included vital signs. in determining the proportion of patients with reductions in PTH Ն30% (drop outs before the maintenance phase Concomitant medication were considered not to have achieved this reduction). In addition to AMG 073 or placebo, patients continued The mean percent change from baseline through the to receive their prescribed therapy for secondary hyper- maintenance phase was determined for PTH, serum cal- parathyroidism (phosphate binders and vitamin D ste- cium, phosphorus, and calcium x phosphorus. All pa- rols) during the study. The study protocol provided guid- tients who received at least one dose of AMG 073 or ance on the use of vitamin D sterols.
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