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Endochondral bone growth is inhibited in achondroplasia1,2

Endochondral bone growth, in which cartilage is replaced by bone at open growth plates, requires a balance of cell signals—CNP (which promotes bone growth) and FGFR3 (which slows bone growth).1,3

Endochondral bones make up >90% of the bones in the body4-13

Overactive FGFR3 signaling relative to CNP signaling in growth plate cells is the underlying cause of inhibited bone growth in achondroplasia. Endogenous CNP levels cannot adequately regulate overactive FGFR3 signals.1

 

CNP, C-type natriuretic peptide; FGFR3, fibroblast growth factor receptor 3.

Inhibited bone growth throughout the body can affect different aspects of development1-4,23,24

Inhibited endochondral bone growth leads to distinct characteristic features such as reduced and disproportionate growth.1,2,23

Upper-to-lower body segment ratio is a common measure of body proportionality and is calculated by the length of the upper body divided by the length of the lower body.25-27

VOXZOGO is the only FDA-approved therapy indicated from birth that targets the underlying cause of achondroplasia1,2,28

VOXZOGO targets overactive FGFR3 signaling in achondroplasia by mimicking the body’s natural CNP to promote endochondral bone growth, but only while growth plates remain open.28

CNP, C-type natriuretic peptide; FGFR3, fibroblast growth factor receptor 3.

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Watch how VOXZOGO targets overactive FGFR3 signaling to promote bone growth28

Maximize time on treatment by starting early and continuing until growth plates close28,29

VOXZOGO promotes endochondral bone growth, but only while growth plates remain open.28

International consensus guidelines support early initiation of VOXZOGO29

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BioMarin provided funding for the International consensus guidelines on the implementation and monitoring of vosoritide therapy in individuals with achondroplasia, including honoraria to participants. BioMarin was not involved in the selection of the guidelines development group, defining the guidelines scope, the voting process, analysis of the results, or preparation of the submitted manuscript. Please see Acknowledgements section of publication for additional detail.29

References:

  1. Horton WA, Hall JG, Hecht JT. Achondroplasia. Lancet. 2007;370(9582):162-172.
  2. Savarirayan R, Ireland P, Irving M, et al. International Consensus Statement on the diagnosis, multidisciplinary management and lifelong care of individuals with achondroplasia. Nat Rev Endocrinol. 2022;18(3):173-189.
  3. Mackie EJ, 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.
  4. Clarke B. Normal bone anatomy and physiology. Clin J Am Soc Nephrol. 2008;3(suppl 3):S131-S139.
  5. Breeland G, Sinkler MA, Menezes RG. Embryology, bone ossification. In: StatPearls. StatPearls Publishing; 2023. Accessed April 23, 2025. https://www.ncbi.nlm.nih.gov/books/NBK539718/
  6. Berendsen AD, Olsen BR. Bone development. Bone. 2015;80:14-18.
  7. Cowan PT, Launico MV, Kahai P. Anatomy, bones. In: StatPearls. StatPearls Publishing; 2024. Accessed April 23, 2025. https://www.ncbi.nlm.nih.gov/books/NBK537199/
  8. Johns Hopkins Medicine. Anatomy of the bone. Accessed April 23, 2025. https://www.hopkinsmedicine.org/health/wellness-and-prevention/anatomy-of-the-bone
  9. Jin SW, Sim KB, Kim SD. Development and growth of the normal cranial vault: an embryologic review. J Korean Neurosurg Soc. 2016;59(3):192-196.
  10. Anderson BW, Kortz MW, Black AC, et al. Anatomy, head and neck, skull. In: StatPearls. StatPearls Publishing; 2023. Accessed April 23, 2025. https://www.ncbi.nlm.nih.gov/books/NBK499834/
  11. Encyclopaedia Britannica. Science & Tech. Skull. Accessed April 23, 2025. https://www.britannica.com/science/skull
  12. Hall R, Beals K, Neumann H, et al. Introduction to Human Osteology. Grand Valley State University; 2008.
  13. Encyclopaedia Britannica. Science & Tech. Clavicle. Accessed April 23, 2025. https://www.britannica.com/science/clavicle
  14. Baron J, Sävendahl L, De Luca F, et al. Short and tall stature: a new paradigm emerges. Nat Rev Endocrinol. 2015;11(12):735-746.
  15. Shahzad F. Pediatric mandible reconstruction: controversies and considerations. Plast Reconstr Surg Glob Open. 2020;8(12):e3285.
  16. Bartleby. Henry Gray (1825-1861). Anatomy of the Human Body. 1918. Fig. 237. Accessed May 7, 2025. https://www.bartleby.com/lit-hub/anatomy-of-the-human-body/fig-237/
  17. Encyclopaedia Britannica. Science & Tech. Pelvis. Accessed May 7, 2025. https://www.britannica.com/science/pelvis
  18. Mayo Clinic. Growth plate fracture. Accessed May 7, 2025. https://www.mayoclinic.org/diseases-conditions/growth-plate-fractures/multimedia/growth-plate-fracture/img-20005879
  19. International Center for Limb Lengthening. Growth arrest. Accessed June 10, 2025. https://www.limblength.org/conditions/growth-arrest/
  20. Hsieh YL, Wei X, Wang Y, et al. Chondrocyte Tsc1 controls cranial base bone development by restraining the premature differentiation of synchondroses. Bone. 2021;153:116142.
  21. Musculoskeletal Key. Cranial and pelvic “vertebrae” are they real vertebrae? Accessed June 10, 2025. https://musculoskeletalkey.com/cranial-and-pelvic-vertebrae-are-they-real-vertebrae/
  22. Young M, Selleri L, Capellini TD. Genetics of scapula and pelvis development: An evolutionary perspective. Curr Top Dev Biol. 2019;132:311-349.
  23. Witt S, Rohenkohl A, Bullinger M, et al. Understanding, assessing and improving health-related quality of life of young people with achondroplasia – a collaboration between a patient organization and academic medicine. Pediatr Endocrinol Rev. 2017;15(suppl 1):109-118.
  24. Hoover-Fong J, Cheung MS, Fano V, et al. Lifetime impact of achondroplasia: current evidence and perspectives on the natural history. Bone. 2021;146:115872.
  25. Hoover-Fong JE, Schulze KJ, McGready J, et al. Age-appropriate body mass index in children with achondroplasia: interpretation in relation to indexes of height. Am J Clin Nutr. 2008;88(2):364-371.
  26. Chilbule SK, Dutt V, Madhuri V. Limb lengthening in achondroplasia. Indian J Orthop. 2016;50(4):397-405.
  27. Nwosu BU, Lee MM. Evaluation of short and tall stature in children. Am Fam Physician. 2008;78(5):597-604.
  28. VOXZOGO [package insert]. Novato, CA: BioMarin Pharmaceutical Inc; 2024.
  29. Savarirayan R, Hoover-Fong J, Ozono K, et al. International consensus guidelines on the implementation and monitoring of vosoritide therapy in individuals with achondroplasia. Nat Rev Endocrinol. 2025;21(5):314-324.
  30. Kvist O, Dallora AL, Nilsson O, et al. A cross-sectional magnetic resonance imaging study of factors influencing growth plate closure in adolescents and young adults. Acta Paediatr. 2021;110(4):1249-1256.
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INDICATION AND IMPORTANT SAFETY INFORMATION

Warnings and Precautions for Risk of Low Blood Pressure

Transient decreases in blood pressure were observed in clinical studies. Patients with significant cardiac or vascular disease and patients on anti-hypertensive medicinal products were excluded from participation in VOXZOGO clinical trials. To reduce the risk of a decrease in blood pressure and associated symptoms (dizziness, fatigue, and/or nausea), patients should be well hydrated, have adequate food intake, and drink approximately 8-10 ounces of fluid in the hour prior to VOXZOGO administration.

In a 52-week, randomized, double-blind, placebo-controlled trial in 121 subjects with achondroplasia, subjects aged from 5.1 to 14.9 years, (Study 1) eight (13%) of 60 patients treated with VOXZOGO had a total of 11 events of transient decrease in blood pressure, compared to 3 (5%) of 61 patients on placebo, over a 52-week treatment period. The median time to onset from injection was 31 (18 to 120) minutes, with resolution within 31 (5 to 90) minutes in VOXZOGO-treated subjects. Two out of 60 (3%) VOXZOGO-treated patients each had one symptomatic episode of decreased blood pressure with vomiting and/or dizziness compared to 0 of 61 (0%) patients on placebo.

Adverse Reactions:
Adverse reactions that occurred in ≥5% of patients treated with VOXZOGO and at a rate greater than that of placebo in the phase 3 study are injection site reactions (including erythema, swelling, urticaria, pain, bruising, pruritus, hemorrhage, discoloration, and induration), vomiting, arthralgia, decrease in blood pressure, gastroenteritis, diarrhea, dizziness, ear pain, influenza, fatigue, seasonal allergy, and dry skin. VOXZOGO-treated patients had an increase in alkaline phosphatase levels (17%), and was noted as a laboratory abnormality.

Injection site reactions:In Study 1, injection site reactions occurred in 51 (85%) subjects receiving VOXZOGO and 50 (82%) subjects receiving placebo over a 52-week period of treatment. Patients receiving VOXZOGO experienced a total of 6983 events of injection site reactions, while patients receiving placebo experienced a total of 1776 events of injection site reactions, over a 52-week period, representing 120.4 events per patient/year exposure and 29.2 events per patient/year exposure, respectively. Two patients in the VOXZOGO arm discontinued treatment due to adverse events of pain and anxiety with injections.

Pediatric Patients 0 to <5 Years:The safety of VOXZOGO in pediatric patients 0 to <5 years with achondroplasia was evaluated in a 52-week randomized, double-blind, placebo-controlled study (Study 2). In this study, 64 patients from birth to <5 years of age were randomized to receive either a daily vosoritide dose with similar exposure to that characterized to be safe and effective in children with ACH aged ≥5 years old, or placebo. An additional 11 patients received open-label treatment as part of this study. The most common adverse reactions (>10%) reported in pediatric patients 0 to <5 years were injection site reactions (86%) and rash (28%). The overall safety profile of VOXZOGO in pediatric patients 0 to <5 years was similar to that seen in older pediatric patients.

Administration and Monitoring:
VOXZOGO is administered as a daily subcutaneous injection. Prior to use, instruct caregivers on proper preparation and administration of VOXZOGO, and ensure caregivers have demonstrated the ability to perform a subcutaneous injection.

Monitor and assess patient body weight, growth, and physical development regularly every 3-6 months. Adjust dosage according to the patient’s actual body weight. Permanently discontinue treatment with VOXZOGO upon confirmation of no further growth potential, indicated by closure of epiphyses.

Special Populations:

  • There are no available data on the use of VOXZOGO in pregnant women, or data on the presence of VOXZOGO in human milk, the effects on the breastfed infant, or the effects on milk production.
  • The influence of renal impairment on the pharmacokinetics of VOXZOGO has not been evaluated. No dosage adjustment is needed for patients with eGFR ≥60 mL/min/1.73 m2. VOXZOGO is not recommended for patients with eGFR <60 mL/min/1.73 m2.

You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to BioMarin at 1-866-906-6100.

Please see additional safety information in the full Prescribing Information.

VOXZOGO® (vosoritide) is indicated to increase linear growth in pediatric patients with achondroplasia and open growth plates.

  • This indication is approved under accelerated approval based on an improvement in annualized growth velocity. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).