Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody

Abstract

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

Inhibition of sclerostin by monoclonal antibody enhances bone healing and improves bone density and strength of nonfractured bones

“…(33,34) Although the mechanism by which Scl-Ab reduced osteoclastic resorption is unclear, similar evidence for an antiresorptive effect with Scl-Ab administration was observed in OVX rats (20) and in healthy men and postmenopausal women. (22) However, inconsistent with the changes in histologic resorption, serum CTX was significantly increased in the Scl-Ab group at the end of the study (3.2 AE 0.3 ng/mL versus 2.5 AE 0.1 ng/mL, p < .05). An increase in serum CTX with Scl-Ab was not observed previously in female nonhuman primates (21) and may have been related to increased bone turnover at the fracture site and the greater callus size in the Scl-Ab group.…”

“…(20) Similarly, treatment with a humanized Scl-Ab resulted in increased bone formation, bone mass, and bone strength in intact nonhuman primates (21) and increased biochemical markers of bone formation in healthy men and postmenopausal women. (22) This study investigated the effects of systemic administration of Scl-Ab in two models used previously to assess the effects of therapeutic agents on fracture healing: the rat closed femoral fracture model (23) and the cynomolgus monkey fibular osteotomy model. (24) We hypothesized that Scl-Ab would enhance fracture healing in these models by increasing bone formation, bone mass, and bone strength at the site of fracture, in addition to its anabolic effects at nonfractured sites.…”

Sclerostin: A gem from the genome leads to bone-building antibodies

“…(97) These encouraging first-in-human data have led to expanded clinical efforts, with phase 2 trials currently under way in fracture healing and postmenopausal osteoporosis.…”

Sclerostin antibody treatment enhances bone strength but does not prevent growth retardation in young mice treated with dexamethasone

“…Sclerostin has been reported to antagonize signaling in the bone morphogenetic protein pathway (17), but it is currently believed that inhibition of the Wnt pathway is more important for the activity of sclerostin on bone formation in vivo (18). Antibodies to sclerostin increase bone strength, bone formation, and bone healing in a range of animal models (19)(20)(21)(22), and a monoclonal antibody to sclerostin was recently evaluated for its clinical effects (23).…”