Single- and Multiple-Dose Randomized Studies of Blosozumab, a Monoclonal Antibody Against Sclerostin, in Healthy Postmenopausal Women

Abstract

Two clinical studies were conducted to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple doses (intravenous [iv] and subcutaneous [sc]) of blosozumab in postmenopausal women, including prior/current bisphosphonate (BP) users. In these phase 1, randomized, subject-and investigator-blind, placebo-controlled studies, subjects received escalating doses of blosozumab: single iv doses up to 750 mg, single sc doses of 150 mg, multiple iv doses up to 750 mg every 2 weeks (Q2W) for 8 weeks, multiple sc doses up to 270 mg Q2W for 8 weeks, or placebo. Six subjects were randomized to each dose in the single-dose study (12 to placebo) and up to 12 subjects to each arm in the multiple-dose study. Blosozumab was well tolerated with no safety concerns identified after single or multiple administrations up to 750 mg. Dose-dependent responses were observed in sclerostin, N-terminal propeptide of procollagen type 1, bone-specific alkaline phosphatase, osteocalcin, C-terminal fragment of type 1 collagen, and bone mineral density (BMD) after single and multiple (up to 5) administrations of blosozumab. There was up to a 3.41% (p ¼ 0.002) and up to a 7.71% (p < 0.001) change from baseline in lumbar spine BMD at day 85 after single or multiple administrations of blosozumab, respectively. Prior BP use did not appear to have a clear impact on the effects of single doses of blosozumab when considering bone biomarker and BMD responses. Antibodies to blosozumab were detected by a screening assay, but no patterns with regard to dose or route of administration and no clear impact on blosozumab exposure or PD responses were identified. In summary, blosozumab was well tolerated and exhibited anabolic effects on bone. These findings support further investigation of blosozumab as a potential anabolic therapy for osteoporosis.

Bone markers and osteoporosis therapy

“…The similarity in this kinetics could reflect levels of sclerostin predominantly bound to blosozumab. BTMs in the subset of patients with previous bisphosphonate exposure showed similar dose-dependent responses, although with a lower magnitude (56).…”

“…Another cohort received either blosozumab 150 mg or placebo SC. The other two cohorts with prior exposure to bisphosphonate received either 225 mg or 750 mg of IV blosozumab (56). The second phase I trial was a multiple-dose, multicenter, randomized, subject-and investigator blinded, placebo-controlled, parallel design study, in which 59 patients were randomized to either placebo or blosozumab SC (270 mg) or IV (750 mg) once every 2 weeks (Q2W), or blosozumab SC (180 or 270 mg) or IV 540 mg once every 4 weeks (Q4W ) for 8 weeks.…”

Inhibition of sclerostin in the management of osteoporosis: results of a phase 2 clinical trial meet expectations

“…Overall, romosozumab increased bone formation and decreased bone resorption consistent with the results of the phase 1 studies with this sclerostin inhibitor and with blosozumab. 5,6 The pattern of response was, however, intriguing, showing an early rapid increase in bone formation markers followed by a progressive decline with time (Figure 1), which was not due to the development of …”

“…4 Furthermore, in phase 1 human studies, increases in bone formation and decreases of bone resorption associated with significant increases in BMD were reported after administration of single doses of two different humanized antibodies, romosozumab (Amgen (Thousand Oaks, CA, USA), UCB (Brussels, Belgium)) and blosozumab (Eli Lilly, Indianapolis, IN, USA). 5,6 McClung et al 7 recently reported the results of a phase 2 clinical trial on the efficacy and tolerability of romosozumab in 419 postmenopausal women with low bone mass. This was a typical phase 2 study that compared different doses and dosing intervals of subcutaneous injections of romosozumab with placebo, oral alendronate, 70 mg weekly, and subcutaneous teriparatide, 20 mg daily.…”

“…Overall, romosozumab increased bone formation and decreased bone resorption consistent with the results of the phase 1 studies with this sclerostin inhibitor and with blosozumab. 5,6 The pattern of response was, however, intriguing, showing an early rapid increase in bone formation markers followed by a progressive decline with time ( Figure 1), which was not due to the development of An explanation of the pattern of changes of bone turnover markers with romosozumab treatment is not readily available. On the basis of studies of patients with genetically determined sclerostin deficiency, we hypothesized earlier that the long-term response to exogenously administered inhibitors of sclerostin may be more complex and different from that observed in shortterm studies of animals and humans.…”