Sclerostin, an osteocyte-secreted protein, negatively regulates osteoblasts and inhibits bone formation. In this first-in-human study, a sclerostin monoclonal antibody (AMG 785) was administered to healthy men and postmenopausal women. In this phase I, randomized, double-blind, placebo-controlled, ascending, single-dose study, 72 healthy subjects received AMG 785 or placebo (3:1) subcutaneously (0.1, 0.3, 1, 3, 5, or 10 mg/kg) or intravenously (1 or 5 mg/kg). Depending on dose, subjects were followed for up to 85 days. The effects of AMG 785 on safety and tolerability (primary objectives) and pharmacokinetics, bone turnover markers, and bone mineral density (secondary objectives) were evaluated. AMG 785 generally was well tolerated. One treatment-related serious adverse event of nonspecific hepatitis was reported and was resolved. No deaths or study discontinuations occurred. AMG 785 pharmacokinetics were nonlinear with dose. Dose-related increases in the bone-formation markers procollagen type 1 N-propeptide (P1NP), bone-specific alkaline phosphatase (BAP), and osteocalcin were observed, along with a dose-related decrease in the bone-resorption marker serum C-telopeptide (sCTx), resulting in a large anabolic window. In addition, statistically significant increases in bone mineral density of up to 5.3% at the lumbar spine and 2.8% at the total hip compared with placebo were observed on day 85. Six subjects in the higher-dose groups developed anti-AMG 785 antibodies, 2 of which were neutralizing, with no discernible effect on the pharmacokinetics or pharmacodynamics. In summary, single doses of AMG 785 generally were well tolerated, and the data support further clinical investigation of sclerostin inhibition as a potential therapeutic strategy for conditions that could benefit from increased bone formation. ß

This 16-week study evaluated pharmacokinetics and pharmacodynamics of denosumab in 55 subjects with renal function ranging from normal to dialysis-dependent kidney failure. Participants received a single 60-mg subcutaneous dose of denosumab. Kidney function groups were based on calculations using the Cockcroft-Gault equation and U.S. Food and Drug Administration (FDA) guidance in place when the study was designed. Renal function did not have a significant effect on denosumab pharmacokinetics or pharmacodynamics. These findings suggest denosumab dose adjustment based on glomerular filtration rate is not required. Rapid decreases in serum C-telopeptide in all groups were sustained throughout the study. The most common adverse events were hypocalcemia (15%), pain in extremity (15%), and nausea (11%). Most adverse events were mild to moderate in severity. Calcium and vitamin D supplementation was not initially required by the study protocol, but was added during the trial. No subject who received adequate calcium and vitamin D supplementation became hypocalcemic. Seven subjects had nadir serum calcium concentrations between 7.5 and <8.0 mg/dL (1.9 and <2.0 mmol/L), and 5 subjects (4 with advanced renal disease) had nadir serum calcium <7.5 mg/dL (<1.9 mmol/L). Two subjects (1 symptomatic, 1 asymptomatic) were hospitalized for intravenous calcium gluconate treatment. At the recommended dose, denosumab is a useful therapeutic option for patients with impaired renal function. Supplementation of calcium and vitamin D is strongly recommended when patients initiate denosumab therapy, particularly in patients with reduced renal function. © 2012 American Society for Bone and Mineral Research.

Romosozumab (formerly AMG 785/CDP7851) is a monoclonal antibody that blocks sclerostin from inhibiting osteoblast maturation and function. This double-blind, placebo-controlled, randomized, ascending multiple-dose study enrolled 32 postmenopausal women and 16 healthy men with low bone mass. Women received six doses of 1 or 2 mg/kg once every 2 weeks (Q2W) or three doses of 2 or 3 mg/kg once every 4 weeks (Q4W) or placebo; and men received 1 mg/kg Q2W or 3 mg/kg Q4W or placebo. Mean serum romosozumab exposures increased approximately dose-proportionally. Romosozumab increased serum type 1 aminoterminal propeptide (PINP) by 66-147%, decreased serum C-telopeptide (sCTX) by 15-50%, and increased lumbar spine bone mineral density by 4-7%. Two subjects developed neutralizing antibodies without discernable effects on pharmacokinetics, pharmacodynamics, or safety. Adverse event rates were balanced between groups without any significant safety findings. These data support continued investigation of sclerostin inhibition in disorders that could benefit from increased bone formation.

Cinacalcet hydrochloride (cinacalcet) is a calcimimetic approved for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease (CKD) receiving dialysis and for the treatment of hypercalcaemia in patients with parathyroid carcinoma. Following oral administration, peak plasma concentrations of cinacalcet occur within 2-6 hours. The absolute bioavailability is 20-25%, and administration of cinacalcet with low- or high-fat meals increases exposure (area under the plasma concentration-time curve from time zero to infinity [AUC(infinity)]) 1.5- to 1.8-fold. Cinacalcet has no significant interaction with calcium carbonate or sevelamer hydrochloride, phosphate binders commonly used in the treatment of patients with CKD receiving dialysis. The terminal elimination half-life is 30-40 hours, and steady-state concentrations are achieved within 7 days. The pharmacokinetics of cinacalcet are dose proportional over the dose range of 30-180 mg. The pharmacokinetic profile of cinacalcet is not notably affected by varying degrees of renal impairment. The pharmacokinetics of cinacalcet are comparable between healthy subjects, patients with primary hyperparathyroidism and patients with secondary hyperparathyroidism with reduced renal function (including those patients with secondary hyperparathyroidism receiving dialysis). Additionally, the pharmacokinetics of cinacalcet are similar in patients with secondary hyperparathyroidism receiving haemodialysis and patients with secondary hyperparathyroidism receiving peritoneal dialysis. Mild hepatic impairment does not affect the pharmacokinetics of cinacalcet, whereas moderate or severe hepatic impairment increases the exposure (AUC(infinity)) by approximately 2- and 4-fold, respectively. Age, sex, bodyweight and race do not notably affect the pharmacokinetics of cinacalcet. Cinacalcet is extensively metabolized by multiple hepatic cytochrome P450 (CYP) enzymes (primarily 3A4, 2D6 and 1A2) with <1% of the parent drug excreted in the urine. Dose adjustments of cinacalcet may be necessary, and parathyroid hormone (PTH) and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor (e.g. ketoconazole, erythromycin, itraconazole). Cinacalcet is a strong inhibitor of CYP2D6; therefore, dose adjustment of concomitant medications that are predominantly metabolized by CYP2D6 and have a narrow therapeutic index (e.g. flecainide, vinblastine, thioridazine and most tricyclic antidepressants) may be required. Cinacalcet does not appreciably inhibit or induce the activities of CYP3A4, 1A2, 2C9 or 2C19. An inverse relationship exists between plasma PTH and cinacalcet concentrations. PTH concentrations are greatest before dose administration when the cinacalcet concentration is lowest (24 hours after the previous day's dose). Nadir PTH levels occur approximately 2-3 hours after dosing.

Four weekly s.c. doses of AMG 745 were well tolerated and were associated with increased LBM and decreased fat in the men receiving ADT for nonmetastatic prostate cancer. RESULTS support further investigation of AMG 745 in clinical settings with muscle loss and atrophy.