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How VOXZOGO® works

In achondroplasia, the endogenous C-type natriuretic peptide (CNP) cannot adequately regulate the overactive fibroblast growth factor receptor 3 (FGFR3) signaling.1,2

This affects the proliferation and terminal differentiation of growth plate chondrocytes, resulting in impaired endochondral bone growth and linear growth.3 VOXZOGO®, a biological CNP analog, acts as a positive regulator of endochondral bone growth, targeting overactive FGFR3 signaling and promoting chondrocyte proliferation and differentiation.4

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VOXZOGO® Mechanism of Action

Understanding achondroplasia

Bone development occurs through two distinct processes5,6

INTRAMEMBRANOUS OSSIFICATION

  • Differentiation of embryonic mesenchymal cells into osteoblasts6
  • Flat bones of the skull6
  • Involved in the development of ~10% of the body’s bones7,8

ENDOCHONDRAL OSSIFICATION

  • Takes place in ~90% of the skeleton7,8
  • Replacement of a cartilage model by bone6
  • Regulated by the fibroblast growth factor receptor 3 (FGFR3) signaling9

Individuals with achondroplasia have overactive fibroblast growth factor receptor 3 (FGFR3) signaling1-3

Endogenous CNP levels cannot adequately regulate overactive FGFR3 signaling, resulting in impaired endochondral bone growth.1-2

CNP: C-type natriuretic peptide; FGFR3: fibroblast growth factor receptor 3; MAPK: mitogen-activated protein kinase; NPR-B: natriuretic peptide receptor-B; RAF: rapidly accelerated fibrosarcoma proto-oncogene, serine/threonine kinase; RAS: rat sarcoma virus kinase.

VOXZOGO®, a CNP analog, works to increase endochondral bone growth4

VOXZOGO® targets overactive FGFR3 signaling and promotes chondrocyte proliferation and differentiation.4

CNP: C-type natriuretic peptide; FGFR3: fibroblast growth factor receptor 3; MAPK: mitogen-activated protein kinase; NPR-B: natriuretic peptide receptor-B; RAF: rapidly accelerated fibrosarcoma proto-oncogene, serine/threonine kinase; RAS: rat sarcoma virus kinase.

References:

  1. Laederich MB, Horton WA. Achondroplasia: pathogenesis and implications for future treatment. Curr Opin Pediatr. 2010;22(4):516-523.
  2. Yasoda A, Komatsu Y, Chusho H, et al. Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway. Nat Med. 2004;10(1):80-86.
  3. Horton WA, Hall JG, Hecht JT. Achondroplasia. Lancet. 2007;370(9582):162-172.
  4. VOXZOGO® [package insert]. Novato, CA: BioMarin Pharmaceutical Inc; 2021.
  5. Xie Y, Zhou S, Chen H, et al. Recent research on the growth plate: advances in fibroblast growth factor signaling in growth plate development and disorders. J Mol Endocrinol. 2014;53(1):T11-T34.
  6. Mackie E, Tatarczuch L, Mirams M. The skeleton: a multi-functional complex organ: the growth plate chondrocyte and endochondral ossification. J Endocrinol. 2011;211(2):109-121.
  7. Berendsen AD, Olsen BR. Bone development. Bone. 2015;80:14-18.
  8. Clarke B. Normal bone anatomy and physiology. Clin J Am Soc Nephrol. 2008;3(suppl 3):S131-S139.
  9. Matsushita T, Wilcox WR, Chan YY, et al. FGFR3 promotes synchondrosis closure and fusion of ossification centers through the MAPK pathway. Hum Mol Genet. 2009;18(2):227-240.