BPS804 Anti-Sclerostin Antibody in Adults With Moderate Osteogenesis Imperfecta: Results of a Randomized Phase 2a Trial

Abstract

This 21-week, open-label, phase 2a trial aimed to evaluate the pharmacodynamics and safety of multiple, escalating infusions of BPS804, a neutralizing, anti-sclerostin antibody, in adults with moderate osteogenesis imperfecta (OI). Patients received BPS804 (three escalating doses each separated by 2 weeks [5, 10, and 20 mg/kg]) or no treatment (reference group). The primary efficacy endpoints were mean changes from baseline to day 43 in: procollagen type 1 N-terminal propeptide (P1NP), procollagen type 1 C-terminal propeptide (P1CP), bone-specific alkaline phosphatase (BSAP), osteocalcin (OC), and type 1 collagen cross-linked C-telopeptide (CTX-1). Mean change from baseline to day 141 in lumbar spine areal bone mineral density (aBMD) was also assessed. BPS804 safety and tolerability were assessed every 2 weeks. Overall, 14 adults were enrolled (BPS804 group: n ¼ 9, mean age 30.7 years, mean aBMD Z-score -2.6; reference group, n ¼ 5, mean age 27.4 years, mean aBMD Z-score -2.2). In the BPS804 group, P1NP, P1CP, BSAP, and OC were increased by 84% (p < 0.001), 53% (p ¼ 0.003), 59% (p < 0.001), and 44% (p ¼ 0.012), respectively, versus baseline (reference: P1NP, þ6%. BPS804 treatment downregulated CTX-1 by 44% from baseline (reference: -7%; significance was not tested for this biomarker), and increased aBMD by 4% (p ¼ 0.038; reference group: þ1%; p ¼ 0.138). BPS804 was generally well tolerated. There were 32 adverse events reported in nine patients; none was suspected to be treatment-related. There were no treatment-related fractures. BPS804 stimulates bone formation, reduces bone resorption, and increases lumbar spine aBMD in adults with moderate OI. This paves the way for a longerterm, phase 3 trial into the efficacy, safety, and tolerability of BPS804 in patients with OI.

SOST, an LNGFR target, inhibits the osteogenic differentiation of rat ectomesenchymal stem cells

“…40 Moreover, SOST antibodies increase osteoclast numbers and stimulate the bone formation rate in a mouse model of recessive osteogenesis imperfect (OI) and in adults with moderate OI from a randomized phase 2a trial. 41,42 In this study, we demonstrated that SOST negatively regulated osteogenesis in EMSCs, which are the progenitors of all tooth tissues, suggesting that targeting SOST may have great prospects in dental tissue regeneration and engineering.…”

“…SOST is a vital negative regulator of bone formation. It has recently been reported that SOST inhibition increases bone formation in several disorders . Delgado‐Calle et al have shown that SOST inhibition augmented osteoblast numbers, promoted new bone formation and decreased osteoclast number in multiple myeloma‐colonized bone .…”

“…It has recently been reported that SOST inhibition increases bone formation in several disorders. [38][39][40][41][42] Delgado-Calle et al have shown that SOST inhibition augmented osteoblast numbers, promoted new bone formation and decreased osteoclast number in multiple myeloma-colonized bone. 38 McDonald and his colleague have revealed that the SOST antibody prevented myeloma-induced bone loss, decreased osteolytic bone lesions and enhanced fracture resistance.…”

Sclerostin Antibody Treatment Stimulates Bone Formation to Normalize Bone Mass in Male Down Syndrome Mice

“…In this study, treatment with SclAb not only stimulated bone mass in WT and Ts65Dn DS mice but also returned bone mass and bone microarchitecture to normal age‐matched WT levels at multiple skeletal sites. The data suggest that the anabolic effect of SclAb treatment that is well documented in high bone turnover scenarios such as osteoporosis and osteogenesis imperfecta was able to enhance bone mass, bone quality, and bone formation in the face of low bone turnover. The microarchitectural changes in the trabecular and cortical compartments are entirely consistent with increased bone strength after SclAb treatment, although this was not specifically assessed.…”

“…However, unlike PTH, there is little data to suggest that SclAb therapy would be inappropriate for the treatment of low bone mass in people with DS. Indeed, there is data from a recent randomized phase 2a clinical trial in adults with moderate osteogenesis imperfecta that demonstrated safe and powerful anabolic effects in a younger adult population than previous SclAb clinical trials. In contrast, there is conflicting data in a preclinical murine model of severe osteogenesis imperfecta suggesting that SclAb treatment may be less effective in more severely affected osteogenesis imperfecta mice .…”