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BV-265, a BMP-2/BMP-6/activin A chimera, delivered in a composite matrix generates bone repair in nonhuman primates at lower concentrations than BMP-2. Building better bone: Bone morphogenetic protein (BMP) can promote superior bone growth compared to autograft, historically considered the "gold standard" for bone repair; however, supraphysiologic concentrations of BMP are typically required. Seeherman et al. developed chimeric BMPs with improved potency and an optimized carrier matrix. Chimeras based on BMP-2 were engineered to express BMP-6 and activin A receptor binding domains, which improved binding affinity and activated BMP target genes in cells and resulted in greater bone formation in rats. Complete bone healing was observed in nonhuman primate models of open fracture using composite carrier to deliver concentrations of chimeric BMP that were lower than those approved for clinical use. This study systematically identifies an optimized BMP chimera and carrier combination with promising potential for bone healing. Bone morphogenetic protein (BMP)/carriers approved for orthopedic procedures achieve efficacy superior or equivalent to autograft bone. However, required supraphysiological BMP concentrations have been associated with potential local and systemic adverse events. Suboptimal BMP/receptor binding and rapid BMP release from approved carriers may contribute to these outcomes. To address these issues and improve efficacy, we engineered chimeras with increased receptor binding by substituting BMP-6 and activin A receptor binding domains into BMP-2 and optimized a carrier for chimera retention and tissue ingrowth. BV-265, a BMP-2/BMP-6/activin A chimera, demonstrated increased binding affinity to BMP receptors, including activin-like kinase-2 (ALK2) critical for bone formation in people. BV-265 increased BMP intracellular signaling, osteogenic activity, and expression of bone-related genes in murine and human cells to a greater extent than BMP-2 and was not inhibited by BMP antagonist noggin or gremlin. BV-265 induced larger ectopic bone nodules in rats compared to BMP-2 and was superior to BMP-2, BMP-2/6, and other chimeras in nonhuman primate bone repair models. A composite matrix (CM) containing calcium-deficient hydroxyapatite granules suspended in a macroporous, fenestrated, polymer mesh–reinforced recombinant human type I collagen matrix demonstrated improved BV-265 retention, minimal inflammation, and enhanced handling. BV-265/CM was efficacious in nonhuman primate bone repair models at concentrations ranging from 1/10 to 1/30 of the BMP-2/absorbable collagen sponge (ACS) concentration approved for clinical use. Initial toxicology studies were negative. These results support evaluations of BV-265/CM as an alternative to BMP-2/ACS in clinical trials for orthopedic conditions requiring augmented healing. [ABSTRACT FROM AUTHOR]