Efficacy and Safety of Vosoritide for Achondroplasia: A Systematic Review and Dose- Related Meta-Analysis, 2024 Article type: Systematic review and Dose-related Meta-analysis

Efficacy and Safety of Vosoritide for Achondroplasia: A Systematic Review and Dose- Related Meta-Analysis, 2024 Article type: Systematic review and Dose-related Meta-analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Efficacy and Safety of Vosoritide for Achondroplasia: A Systematic Review and Dose- Related Meta-Analysis, 2024 Article type: Systematic review and Dose-related Meta-analysis Misha Khan, Syed Muhammad Muneeb Akhtar, Eeshal Zulfiqar, Hafsa Sabir, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4451136/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Achondroplasia, the most common form of dwarfism, poses significant medical and psychosocial challenges. Vosoritide, a new C-type natriuretic peptide analog, has shown promise in treating achondroplasia by helping bones grow. Therefore, we conducted this study to examine the effect of different vosoritide doses on height from baseline (z-score), annualized growth velocity (AGV), the upper-to-lower body segment ratio (ULBR), and side effects. changes in growth velocity and the frequency of adverse effects. Methods This systematic review and dose-related meta-analyses follow the PRISMA guidelines, which meticulously screen and extract randomized controlled trials (RCTs) from four databases until April 2024 involving 220 patients. We used pairwise meta-analyses and assessed quality using the Cochrane Risk of Bias Tool. Results Higher Vosoritide doses (15 µg/kg or 15–30 µg/kg) showed significantly greater improvements in height z-scores compared to lower doses (2.5 µg/kg or 7.5 µg/kg) or placebo. We observed similar trends for AGV. The 15 µg/kg dose displayed a significantly greater increase compared to both 2.5 µg/kg and 7.5 µg/kg. Interestingly, no significant difference was found between the 15 µg/kg and 30 µg/kg groups, suggesting a possible plateau effect at higher doses. Importantly, both the 15 µg/kg and 15–30 µg/kg groups demonstrated statistically significant improvements in growth velocity compared to placebo. While most comparisons showed no significant changes in ULBR, one study reported a small increase in ULBR with the 15 µg/kg dose compared to the 2.5 µg/kg dose. Adverse effects were mild to moderate across all studies, with no severe effects reported. Conclusion Vosoritide improves achondroplasia growth in a dose-dependent manner. Higher doses (15 µg/kg or 15–30 µg/kg) significantly increased height and growth velocity compared to lower doses or placebo. All adverse effects were mild to moderate. However, the impact on the ULBR and adverse effects require further investigation. Achondroplasia Vosoritide Height Annualised growth velocity Upper-to-lower Body segment ratio Dose-related meta-analyses Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1- Introduction Achondroplasia (ACH), is a skeletal dysplasia disorder with an incidence of one in every 10,000 to 30,000 births, globally affecting over 250,000 individuals [ 1 ]. Clinical manifestations include a range of medical and psychosocial difficulties throughout life, such as disproportionately short stature, rhizomelic shortened limbs, deformities of the lower extremity, characteristic facial configuration (relatively large cranium size, forehead protrusion, flat nasal bridge, midface hypoplasia, and relative mandible protrusion), macrocephaly, narrow foramen magnum, ventricular enlargement, upper airway stenosis, otitis media, a narrow thorax, vertebral hyperlordosis, spinal kyphosis, and potential complications like hypotonia, hearing deficit, spinal canal stenosis, sleep apnea, and sudden infant death [ 2 – 4 ]. ACH is an autosomal dominant genetic disease caused by a mutation in Fibroblast Growth Factor Receptor 3 (FGFR3). Chondrocytes and mature osteoblasts express FGFR3, which regulates linear bone growth. A gain-of-function mutation in the FGFR3 gene, which is a negative regulator of endochondral ossification, sets off a signalling cascade that includes the receptor becoming more stable, dimerization becoming stronger, and tyrosine kinase activity becoming stronger. These events happen too quickly and stop bones from growing normally [ 1 , 5 , 6 ]. Despite the limited therapeutic options (growth hormone and surgical lengthening) to increase ACH height, both had limited effects and complications, and neither of them addressed the underlying ACH pathophysiology [ 7 ]. Therefore, a promising treatment option for ACH is to counteract FGFR3's negative effects on chondrocytes. The endogenous C-type natriuretic peptide (CNP) and its natriuretic peptide receptor 2 (NPR2) can stop FGFR3 signaling, which can cause endochondral ossification and promote endochondral bone growth. [ 8 , 9 ]. Vosoritide, a modified human recombinant CNP analog, binds to the receptor to raise the level of cyclic guanosine monophosphate (cGMP) inside cells, stopping the FGFR3 signalling cascade [ 10 ]. The European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) approved Vosoritide in 2021 for the treatment of ACH children with open epiphyses who are ≥ 5 years old in the United States of America (USA), ≥ 2 years old in the European Union (EU), Brazil, and Australia, and from birth in Japan [ 11 ]. Vosoritide expanded the previously restricted range of ACH treatment options. Although vosoritide's side effects are mostly mild and easy to handle, patients may discontinue it if they cannot tolerate daily injections and manage injection-site reactions, including pain. Moreover, although it greatly speeds up the annualized growth velocity (AGV), the response to vosoritide can vary across regions and institutions and vary in both magnitude and timing depending on the dose, duration, and timing of these assessments. Providers must inform patients and their families about the data from the vosoritide clinical trial. International consensus guidance is required to support the use of vosoritide in clinical practice [ 11 – 13 ]. Although its first approved medications in 2021 have efficacy and safety, there's a shortage of practical guidance. Due to the rarity of ACH, there are only a limited number of patients. Therefore, it is crucial to investigate the different aspects of utilizing vosoritide in clinical settings and share the knowledge acquired from early experiences in the published clinical trials. Therefore we conducted this systematic review and dose-related meta-analysis aim to provide a more robust understanding of the potential benefits and risks associated with vosoritide and comprehensively evaluating their efficacy and safety through the following objectives: systematically analyzing data from relevant randomized controlled trials (RCTs) until April 2024 to examine the effect of different vosoritide doses on height from baseline (represented as z-scores), annualized growth velocity (AGV), the upper-to-lower body segment ratio (ULBR), changes in growth velocity (a measure of linear growth over time), and safety profiles (the frequency of adverse effects) 2- Methodology The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [ 14 ] guided the performance of this systematic review and dose-related meta-analysis. 2 − 1: Search strategy The following search strategy was created by combining boolean words, MeSH terms, and keywords: vosoritide" OR "BMN 111" OR "Voxzogo" OR "natriuretic peptide, c type") AND "Achondroplasia". Without implementing any filters, we used this thorough search approach to find relevant articles across electronic databases such as PubMed, Cochrane CENTRAL, Clinicaltrials.gov, and Science Direct from inception to April 2024. We also screened the bibliographies of the included articles. Detailed Search Strategy Supplementary Table 1 2–2: Inclusion and Exclusion Criteria (Study Selection) The inclusion criteria consisted of randomized controlled trials (RCTs) on Vosoritide OR BMN 111 OR Voxzogo OR Natriuretic Peptide, C-Type, AND Achondroplasia. We excluded articles that did not meet the eligibility criteria, including editorials, observational studies, review articles, animal studies, conference abstracts, and studies unavailable in English. 2–3: Data screening The search results were imported into Rayyan software for screening the articles [ 15 ]. Two authors independently screened the titles and abstracts initially. Then the full text of all the included studies was retrieved and reviewed. Any discrepancies between the authors during the screening process were resolved with a senior author. 2–4: Data extraction We extracted data from a Microsoft Excel spreadsheet, which included basic information about studies (author name, study name, publication year, country, publication type, sample size), baseline characteristics (height z-score, annualized growth velocity (AGV), and upper-to-lower body segment ratio (ULBR), changes in baseline characteristics (height z-score, AGV, ULRB), and adverse effects. ‘The total number of patients or events’ for categorical variables, whereas for continuous variables,' means'' and standard deviations (SD)’ were extracted. 2–5: Quality Assessment The quality assessment of the included trials was conducted with the Cochrane Risk of Bias Tool for Randomized Controlled Trials (RoB 2. O), which assesses the randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of reported results in RCTs [ 16 ]. The Cochrane Risk of Bias Tool classified the studies as either low or high risk of bias or raised certain concerns. Robvis, a visualization tool, generated risk-of-bias graphs and figures [ 17 ]. A group discussion sorted out any discrepancies during the screening process. 2–6 : Statistical Analysis All statistical analyses were performed using the 'R Programming Language', version 4.1.2 [ 18 ]. Pairwise meta-analyses were conducted to assess the comparative efficacy of individual vosoritide doses against both placebo and each other, focusing on changes from baseline in height z-scores, AGV, and the ULBR. Mean differences (MD) with corresponding 95% confidence intervals (CIs) were estimated using a random-effects model with the inverse variance method. For adverse effects, we calculated risk ratios (RR) with a 95% CI. This statistic tells us how much more likely (or less likely) someone in one group was to experience an adverse effect compared to the other group. The meta-analysis findings were visually evaluated using a forest plot, with statistical significance determined at a threshold of p < 0.05. 3- Results 3.1: Study Selection Using a specific search strategy, we performed a detailed search across multiple electronic databases—PubMed, Google Scholar, Cochrane Library, and Elsevier’s ScienceDirect. This initial search produced 89 articles. After eliminating 9 duplicates, we assessed the titles and abstracts of 80 articles. We excluded 72 of these articles because they did not meet the predefined inclusion and exclusion criteria. After a thorough review of the full texts, only three clinical trials met the criteria for inclusion in this review. The PRISMA Flow Diagram illustrates the selection process, presented in Fig. 1 . 3.2: Baseline Characteristics From 2019 to 2024, the USA, Japan, Australia, the UK, and France conducted the selected studies. These studies collectively involved 220 patients diagnosed with achondroplasia, whose ages ranged from 3 months to 18 years. Table 1 summarizes the details of each study. 3.3: Quality Assessment and Publication Bias The risk of bias was consistently low, with all studies being of high quality [ 19 – 21 ]. Savarirayan R et al. 2019 [ 19 ] was an open-label trial, so it did not involve randomization, the allocation concealment process, or the blinding of the participants and personnel. Figure 1 provides a quality assessment. 3.4: Outcomes The following summarizes the effects of various Vosoritide doses on height Z-scores, AGV, and ULBR, as well as the side effects in all studies. 3.4.1: The effect of different doses of vosoritide on the Height Z-Score Overall, higher doses of Vosoritide tend to have a greater positive effect on height Z-scores than lower doses or placebos. Figure 2 Compared to different doses regarding height Z-scores , Savarirayan R et al. 2019 [ 19 ] showed a negligible difference between Vosoritide 15 µg/kg vs. Vosoritide 2.5 µg/kg (MD = 0.05, SE = 0.44, 95% CI = -0.81; 0.91). While it is much better at raising the height Z score by comparing Vosoritide 15 µg/kg to 7.5 µg/kg (MD = 0.54, SE = 0.27, 95% CI = 0.01; 1.07), Vosoritide 7.5 µg/kg is considerably more effective than 2.5 µg/kg (MD = 0.49, SE = 0.45, 95% CI = -0.39; 1.37). In terms of height, Z-scores Compared to the placebo , Savarirayan R. et al. 2020 [ 22 ] found that Vosoritide 15 µg/kg had a slightly stronger positive effect than the placebo (MD = 0.28, SE = 0.07, 95% CI = 0.15; 0.41); Savarirayan R. et al. 2024 [ 23 ] found that Vosoritide 15–30 µg/kg had a higher positive effect than the placebo (MD = 0.25, SE = 0.14, 95% CI = -0.02; 0.52). 3.4.2: The effect of Vosoritide on annualized growth velocity (AGV) Different doses of vosoritide have varying effects on AGV; higher doses generally show a more pronounced positive effect. Figure 3 Compared to different doses regarding AGV , the 2019 study by Savarirayan R et al. [ 19 ] found that the vosoritide 15 µg/kg had a much stronger positive effect than the vosoritide 2.5 µg/kg (MD = 2.38, SE = 0.87, 95% CI = 0.67; 4.09) and then the vosoritide 7.5 µg/kg (MD = 0.73, SE = 0.81, 95% CI = -0.86; 2.32). However, other comparisons yielded no significant results; there was no significant difference between Vosoritide 15 µg/kg and Vosoritide 30 µg/kg (MD = -0.07, SE = 0.99, 95% CI = -2.00; 1.86), and the dose of 30 µg/kg for AGV (MD = 0.80, SE = 0.91, 95% CI = -0.99; 2.59). vs. Vosoritide, 7.5 µg/kg. Compared to the placebo regarding AGV , it had a higher positive effect with more, e.g., Vosoritide (15 µg/kg) (MD = 1.58, SE = 0.22, 95% CI = 1.15; 2.01) and Vosoritide 15–30 µg/kg (MD = 0.78, SE = 0.38, 95% CI = 0.04; 1.52) [ 20 ]. While Savarirayan R et al. 2024 [ 21 ] found that Vosoritide 15–30 µg/kg had a greater effect on AGV (MD = 0.78, SE = 0.38, 95% CI = 0.04; 1.52) than the placebo group. 3.4.3 The effect of Vosoritide on the upper-to-lower body segment ratio (ULBR) Compared to different doses, S avarirayan R et al. [ 19 ] discovered that the ULBR was slightly higher for the higher dose of Vosoritide (15 g/kg vs. 2.5 g/kg) (MD = 0.12, SE = 0.05, 95% CI = 0.02; 0.22). Other comparisons did not show any significant results. Compared to placebo , in terms of ULBR, Savarirayan R et al. [ 20 , 22 ] found that Vosoritide 15 µg/kg and Vosoritide 15–30 µg/kg had almost no difference (MD = -0.01, SE = 0.02, 95% CI = -0.05; 0.03) and (MD = -0.07, SE = 0.05, 95% CI = -0.17; 0.03) respectively compared to the placebo. Overall, Savarirayan R et al. 2019 [ 19 ] noted a small increase in the ULBR when comparing different doses of Vosoritide to placebo or each other. Figure 4 3.4.4. Vosoritide Adverse Effect All the included studies show that ACH patients on Vosoritide only experience mild to moderate treatment-emergent adverse effects, such as reactions at the injection site (such as erythema, swelling, and urticaria), pyrexia, coughing, headaches, and vomiting, in descending order, without any severe side effects [ 19 , 20 , 21 ] 5- Discussion This systematic review and dose-related meta-analysis, which statistically combines three RCTs with a total of 220 patients, consolidates the existing research on the safety and dose-related effects of vosoritide in achondroplasia. Our analysis of patients with achondroplasia revealed a clear dose-dependent effect of vosoritide on height Z-scores and annualized growth velocity, as well as mild to moderate treatment-emergent adverse effects. 5.1: The effect of vosoritide in different doses on height Z-score In this network meta-analysis, RCTs reported that Vosoritide 15 µg/kg had a better effect on height Z-Score than Vosoritide 7.5 µg/kg and Vosoritide 2.5 µg/kg [ 19 ]. Vosoritide 15 µg/kg and Vosoritide 15–30 µg/kg had a better effect than the placebo [ 20 – 21 ]. A height Z-score is an accurate and widespread measure to monitor children's growth by quantifying the number of standard deviations by which a child's height deviates from the mean height for their age and gender [ 23 ]. As a result, the vosoritide treatment has improved the baseline height and is a good treatment for ACH, a genetic disorder that affects bone growth. The recombinant human CNP analogue, possessing a modified N-terminal domain and resembling CNP in its pharmacological action as an endogenous positive regulator of endochondral bone formation, explains this. It has the capability to obstruct the downstream signaling of the constitutively active FGFR3, thereby reinstating chondrocyte differentiation, enhancing bone growth, and enhancing growth outcomes [ 11 , 24 – 25 ]. 100% of panel experts agreed that starting vosoritide treatment earlier and for longer-term results in a greater final height compared to those starting later [ 22 ]. Furthermore, this meta-analysis indicates that in ACP treatment, higher doses of Vosoritide (15 µg/kg) improved height Z-Score more than Vosoritide 7.5 µg/kg and Vosoritide 2.5 µg/kg. This may be due to its pharmacokinetic, pharmacodynamic, and dose-response relationships [ 24 ]. 5.2: The effect of vosoritide on annualized growth velocity (AGV) Vosoritide significantly raises the AGV compared to the placebo because it works in a new way to mimic the growth-promoting effects of CNP (which raises the baseline height) and CXM (which shows collagen X marker endochondral bone growth) [ 24 , 26 ]. Moreover, vosoritide at a dose of 15 µg/kg increased AGV significantly more than at lower doses of 2.5 µg/kg or 7.5 µg/kg [ 21 ]. showed dose-dependent changes between 2.5 and 30 µg/kg. According to exposure-response analyses, AGV, and CXM peaked at 15 µg/kg. The results support the idea that the exposure-response relationship for changes in both reached a peak at Vosoritide 15 µg/kg [ 24 , 27 ]. This clarifies what was interesting, there was no difference between the dose groups of 15 µg/kg and 30 µg/kg, pointing to a potential plateau effect at higher doses. The exposures at these dose levels appear to have induced a maximum and saturated response, as there were no significant increases in AGV at 30 µg/kg as opposed to 15 µg/kg. At 15 µg/kg, the AGV change from the beginning point had reached the peak of the exposure-response curve. [ 24 , 28 ]. 5.3 The effect of vosoritide on upper-to-lower body segment ratio (ULBR) In this, meta-analysis vosoritide effect on ULBR showed that there was no significant difference compared to a placebo [ 20 , 21 ]. This may be attributed to that ULBR as an outcome can affected by some factors like sample size, treatment duration, and endpoints measured, [ 24 ] However, when compared to different doses, there was no significant difference except between 15 g/kg and 2.5 g/kg, where the effect was slightly higher [ 19 ]. Inconsistency with what was reported by an 85% panel of experts suggests a more optimistic outlook, as long-term Vosoritide treatment is likely to lead to clinically meaningful improvements in ULBR, particularly for patients who begin treatment between 2 years old and puberty [ 22 ]. Therefore, the effect of Vosoritide on ULBR remains inconclusive. 5.4: Vosoritide Adverse Effect All of the included RCT studies show that ACH patients on Vosoritide experience only mild to moderate treatment-emergent adverse effects. In descending order, the reported adverse effects were these reactions at the injection site (such as erythema, swelling, and urticaria); pyrexia, coughing, headaches, and vomiting did not cause any severe side effects. In agreement with a generally mild side-effect profile, injection site effects and asymptomatic hypotension are the most commonly observed adverse effects [ 30 ]. Other studies have reported weak positive correlations between the maximum increase in doses from the predose heart rate and no correlation between the exposure to vosoritide plasma and a decrease in either systolic or diastolic blood pressure [ 30 ]. This is attributed to the fact that Concentrations below 15 have a limited effect on chondrocytes. A higher exposure range of 30 µg/kg has systemic pharmacological activity at its peak, and it affects NPR-B in many organs, including the lungs, heart, brain, liver, and fat cells [ 24 ]. However, a study examining parents' experiences with Vosoritide identified some key challenges that may be considered its effects and adverse effects, such as the care provider-patient relationship that depends on the environment, as home administering injections required a significant learning curve. Secondly, publicly funded home care nurses and parents reported that parents substantially reduced the burden of managing the treatment regimen. Finally, maintaining a consistent dosing schedule proved difficult, especially for families who travel or have active older children. This difficulty is likely due to the need for cool storage and potential challenges with the injection device [ 18 ]. These findings emphasise the need for improved support systems and potentially more user-friendly administration methods to optimise the use of Vosoritide for children with achondroplasia [31 = 32]. 4.6 Strength Since this dose-dependent meta-analysis only includes a well-critically appraised study design (RCT), including a large sample size (220 ACP cases) across a wider age range of rare diseases1 in 20,000–30,000 live births, and the study comparing different vosoritide dosages was well-designed and adequately powered, the results are more reliable and would strengthen the generalizability of the findings about the promising evidence for the efficacy of vosoritide in ACH. 4.7 Limitations Only three studies were limited to their location Moreover, one of the included studies [ 18 ] was an open-label trial, potentially introducing bias. The studies reviewed encompassed a limited treatment duration. There are limitations to consider for future research directions. 6- Conclusively Compared to placebo, vosoritide significantly increases the annual growth velocity and height Z-score. Vosoritide has an exposure-response property, as higher doses had a significant improvement at the AGV and height Z-score compared to lower doses until its plateau at dose groups of 15 µg/kg. In terms of its effect on ULBR, there was no significant difference compared to a placebo. However, when compared to different doses, there was no significant difference except between 15 g/kg and 2.5 g/kg, where the effect was slightly higher. Vosoritide appears to be well-tolerated and efficacious for ACH. 7- Recommendations Optimizing treatment strategies for Achondroplasia requires further investigation. Head-to-head comparisons between Vosoritide and other existing treatments, such as growth hormone therapy, could provide valuable insights for clinicians. By addressing these limitations and pursuing these future research directions, we can gain a more comprehensive understanding of Vosoritide's long-term effects and potential as a treatment for Achondroplasia. When monitoring heart rate, systolic blood pressure, and diastolic blood pressure in the clinic, Further studies with larger sample sizes and longer follow-ups are necessary to definitively determine the long-term effects of Vosoritide on ULBR body proportions in patients with Achondroplasia. Further research with long-term follow-up is necessary to assess the sustained effects of Vosoritide on growth, skeletal development, and potential side effects beyond the initial treatment period. Future studies with consistent double-blinding would minimize potential bias and strengthen the evidence base. 8- List of Abbreviations Achondroplasia (ACH) Fibroblast growth factor receptor 3 (FGFR3) C-type natriuretic peptide (CNP) confidence intervals (CI) Mean differences (MD) Randomized controlled trials (RCTs) The annualized growth velocity (AGV) Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) The European Medicines Agency (EMA) Food and Drug Administration (FDA) The United States of America (USA) Declarations 9.1 Acknowledgement We would like to thank all the contributor authors for their great efforts in this systematic review. 9.2 Conflict of interest No conflict of interest. 9.3 Consent to participate. We obtained informed consent from patients included in the study. 9.4 Consent to publish. Patients signed informed consent regarding publishing their data and photographs. 9.5 Funding No funding for this project. 9.6 Competing interests. The authors declare no conflict of interest. 9.7 Previous publication We declare that this research paper has not been published elsewhere in any other academic journal or platform. 9.8 Generative AI in scientific writing We declare that we have not used AI in writing any part of this manuscript. 9.9 Author contribution Conception: M.Kh Methods: M.Kh , S.M, Validation: I.A, M.B, E.S, H.S Data curation, and extraction: I.A, M.B, E.S, H.S Formal analysis: M.Kh Writing the original draft: M.Kh , S.M, H.S and S.A manuscript revision and editing: All authors Supervision: M.Kh Visualization: S.A 9.9 Data availability statement The data available when on reasonable request from the corresponding author ( [email protected] ) References Shiang, R., Thompson, L. M., Zhu, Y. Z., Church, D. M., Fielder, T. J., Bocian, M., Winokur, S. T., & Wasmuth, J. J. (1994). Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. 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Drugs, 81(17), 2057–2062. https://doi.org/10.1007/s40265-021-01623-w Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, Chou R, Glanville J, Grimshaw JM, Hróbjartsson A, Lalu MM, Li T, Loder EW, Mayo-Wilson E, McDonald S, McGuinness LA, Stewart LA, Thomas J, Tricco AC, Welch VA, Whiting P, Moher D. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021 Mar 29;372: n71. doi: 10.1136/bmj. n71. Mourad Ouzzani, Hossam Hammady, Zbys Fedorowicz, and Ahmed Elmagarmid. Rayyan - a web and mobile app for systematic reviews. Systematic Reviews (2016) 5:210, DOI: 10.1186/s13643-016-0384-4. Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA; Cochrane Bias Methods Group; Cochrane Statistical Methods Group. The Cochrane Collaboration's tool for assessing risk of bias in randomized trials. BMJ. 2011 Oct 18;343:d5928. doi: 10.1136/bmj.d5928. 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E., Ginebreda, I., Mohnike, K., Charrow, J., Hoernschemeyer, D., Ozono, K., Alanay, Y., Arundel, P., Kagami, S., Yasui, N., … Day, J. (2020). Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial. Lancet (London, England) , 396 (10252), 684–692. https://doi.org/10.1016/S0140-6736(20)31541-5 Savarirayan, R., Wilcox, W. R., Harmatz, P., Phillips, J., 3rd, Polgreen, L. E., Tofts, L., Ozono, K., Arundel, P., Irving, M., Bacino, C. A., Basel, D., Bober, M. B., Charrow, J., Mochizuki, H., Kotani, Y., Saal, H. M., Army, C., Jeha, G., Qi, Y., Han, L., … Day, J. (2024). Vosoritide therapy in children with achondroplasia aged 3-59 months: a multinational, randomised, double-blind, placebo-controlled, phase 2 trial. The Lancet. Child & adolescent health , 8 (1), 40–50. https://doi.org/10.1016/S2352-4642(23)00265-1 Savarirayan R, Baratela W, Butt T, et al. Literature review and expert opinion on the impact of achondroplasia on medical complications and health-related quality of life and expectations for long-term impact of vosoritide: a modified Delphi study. Orphanet J Rare Dis . 2022;17(1):224. Published 2022 Jun 13. doi:10.1186/s13023-022-02372-z Martinez-Millana A, Hulst JM, Boon M, Witters P, Fernandez-Llatas C, Asseiceira I, Calvo-Lerma J, Basagoiti I, Traver V, De Boeck K, Ribes-Koninckx C. Optimisation of children z-score calculation based on new statistical techniques. PLoS One. 2018 Dec 20;13(12):e0208362. doi: 10.1371/journal.pone.0208362. PMID: 30571681; PMCID: PMC6301782. Chan, M. L., Qi, Y., Larimore, K., Cherukuri, A., Seid, L., Jayaram, K., Jeha, G., Fisheleva, E., Day, J., Huntsman-Labed, A., Savarirayan, R., Irving, M., Bacino, C. A., Hoover-Fong, J., Ozono, K., Mohnike, K., Wilcox, W. R., Horton, W. A., & Henshaw, J. (2022). Pharmacokinetics and Exposure-Response of Vosoritide in Children with Achondroplasia. Clinical pharmacokinetics , 61 (2), 263–280. https://doi.org/10.1007/s40262-021-01059-1 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. Kubota T, Adachi M, Kitaoka T, Hasegawa K, Ohata Y, et al. (2020) Clinical practice guidelines for achondroplasia. Clin Pediatr Endocrinol 29: 25–42. Potter LR, Yoder AR, Flora DR, Antos LK, Dickey DM. Natriuretic peptides: Their structures, receptors, physiologic functions and therapeutic applications. Handb Exp Pharmacol. 2009;191:341–366 Santhekadur PK, Kumar DP, Seneshaw M, Mirshahi F, Sanyal AJ. The multifaceted role of natriuretic peptides in metabolic syndrome. Biomed Pharmacother. 2017;92:826–835. Foreman PK, van Kessel F, van Hoorn R, van den Bosch J, Shediac R, et al. (2020) Birth prevalence of achondroplasia: a systematic literature review and meta-analysis. Am J Med Genet A 182: 2297–2316. Harada D, Namba N, Hanioka Y, Ueyama K, Sakamoto N, et al. (2017) Final adult height in long-term growth hormone-treated achondroplasia patients. Eur J Pediatr 176: 873–879 Hunter AG, Bankier A, Rogers JG, Sillence D, Scott CI. Medical complications of achondroplasia: a multicentre patient review. J Med Genet. 1998;35(9):705–12. NiMhurchadha S, Butler K, Argent R, et al. Parents' Experience of Administering Vosoritide: A Daily Injectable for Children with Achondroplasia. Adv Ther . 2023;40(5):2457-2470. doi:10.1007/s12325-023-02496-z Franconi F, Campesi I. Pharmacogenomics, pharmacokinetics and pharmacodynamics: interaction with biological differences between men and women. Br J Pharmacol . 2014;171(3):580-594. doi:10.1111/bph.12362 Tables Table 1: Summary of Baseline Characteristics Author Country Group Drug Doses Sample Size Duration Age; Mean (SD) Male; n (%) Female; n (%) Height Z-scores; Mean (SD) Annualized Growth Velocity (AGV); Mean (SD) Upper-to-lower body segment ratio; Mean (SD) Savarirayan R et al. 2019 USA, Australia, France, UK Vosoritide 2.5 μg/kg 8 42 months 7.3±1.6 3 (38) 5 (62) -5.69 (1.190) 3.90 (1.108) 2.06 (0.140) 7.5 μg/kg 8 8.3±2.2 5 (62) 3 (38) -5.14 (0.853) 2.89 (1.392) 2.03 (0.179) 15.0 μg/kg 10 8.0±1.6 4 (40) 6 (60) -4.61 (1.136) 4.04 (2.275) 1.91 (0.229) 30.0 μg/kg 9 6.9±1.2 4 (44) 5 (56) -5.17 (0.703) 4.39 (1.150) 1.99 (0.188) Savarirayan R et al. 2020 Australia, Germany, Japan, Spain, Turkey, the USA, and the UK Vosoritide 15·0 µg/kg 60 52 weeks 8·35 (2·43) 31 (52) 29 (48) −5·13 (1·11) 4·26 (1·53) 1·98 (0·20) Placebo - 61 9·06 (2·47) 33 (54) 28 (46) −5·14 (1·07) 4·06 (1·20) 2·01 (0·21) Savarirayan R et al. 2024 USA, Japan, Australia, UK Vosoritide 15 µg/kg in Cohort 1; 30 µg/kg in Cohort 2 and 3 32 52 weeks 24·39 (16·83) 17 (53) 15 (47) −3·79 (0·97) 11·06 (7·57) 2·60 (0·41) Placebo - 32 27·82 (19·25) 13 (41) 19 (59) −4·28 (1·48) 9·60 (7·74) 2·52 (0·36) Table 2: Summary of Outcomes Author Group Drug Doses Change from Baseline in Annualized Growth Velocity (AGV)(cm/year), LS mean, n [95% CI] Change from Baseline in height Z-score, n, LS mean [95% CI] Change from baseline in upper-to-lower body segment ratio Any TEAs; n (%) Serious TEAs; n (%) Treatment related TEAEs; n (%) Savarirayan R et al. 2019 Vosoritide 2.5 μg/kg 1.24 (1.125) 0.98 (0.985) -0.15 (0.079) 35(100) 4(11) - 7.5 μg/kg 1.63 (1.010) 0.49 (0.491) -0.13 (0.106) 15.0 μg/kg 1.55 (1.885) 1.03 (0.570) -0.03 (0.132) 30.0 μg/kg NA (NA) NA (NA) NA (NA) Savarirayan R et al. 2020 Vosoritide 15·0 µg/kg 1·71 (1·40 to 2·01) 0·27 (0·18 to 0·36) −0·03 (−0·06 to 0·00) 59 (98%) 3 (5%) 53 Placebo - 0·13 (−0·18 to 0·45) −0·01 (−0·10 to 0·09) −0·02 (−0·05 to 0·01 60 (98%) 4 (7%) 51 Savarirayan R et al. 2024 Vosoritide 15 µg/kg in Cohort 1; 30 µg/kg in Cohort 2 and 3 -2.17, n = 32 [-2.76 to -1.58] n = 32, -0.06(-0.26 to 0.15) -0.20(-0.28 to -0.13) 32 (100%) 3 (9.4%) 29 (90.6) Placebo - -2.95, n = 32 (-3.45 to -2.45) n = 32, -0.31(-0.48 to -0.13) -0.13(-0.21 to -0.06) - 6 (18.8%) 17 (53.1) Additional Declarations No competing interests reported. Supplementary Files PRISMA2020checklist1.docx SupplementaryFileAchondroplasia.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4451136","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":319507535,"identity":"bfd0775e-d962-4d24-a5f8-70433ce88a48","order_by":0,"name":"Misha Khan","email":"","orcid":"","institution":"Liaquat National Hospital and Medical College","correspondingAuthor":false,"prefix":"","firstName":"Misha","middleName":"","lastName":"Khan","suffix":""},{"id":319507537,"identity":"1ff69d16-ee87-4964-9291-51ddb139b6f1","order_by":1,"name":"Syed Muhammad Muneeb Akhtar","email":"","orcid":"","institution":"Dow University of Health Sciences","correspondingAuthor":false,"prefix":"","firstName":"Syed","middleName":"Muhammad Muneeb","lastName":"Akhtar","suffix":""},{"id":319507538,"identity":"7491dcb8-6925-4489-ab11-e9c3c5e9c584","order_by":2,"name":"Eeshal Zulfiqar","email":"","orcid":"","institution":"Dow University of Health Sciences","correspondingAuthor":false,"prefix":"","firstName":"Eeshal","middleName":"","lastName":"Zulfiqar","suffix":""},{"id":319507541,"identity":"72f3c7a5-1b01-4c59-95c5-95da55b0f887","order_by":3,"name":"Hafsa Sabir","email":"","orcid":"","institution":"Liaquat National Hospital and Medical College","correspondingAuthor":false,"prefix":"","firstName":"Hafsa","middleName":"","lastName":"Sabir","suffix":""},{"id":319507543,"identity":"d6e029f9-a9a2-4aac-a2cb-6ed38ee65d4e","order_by":4,"name":"Samar A. 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19:20:35","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":403583,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePreferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA\u003c/strong\u003e)\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4451136/v1/0c65e3bd237cbb1458339f43.png"},{"id":59608557,"identity":"6e4e5243-dd24-4a47-88d8-5680afcc7f0a","added_by":"auto","created_at":"2024-07-03 19:12:35","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":590834,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eChange in Height Z-scores Pairwise Meta-analysis\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-4451136/v1/69626d96f1dd964741b70cfc.png"},{"id":59607171,"identity":"5801f03b-c194-4830-b40e-ff42114d48e3","added_by":"auto","created_at":"2024-07-03 19:04:35","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":823967,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eChange in Annualized Growth Velocity Pairwise Meta-analysis\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-4451136/v1/a16d27d6e75637bc9716b30c.png"},{"id":59607177,"identity":"8461124f-5319-4200-82a1-5ab818e9ae97","added_by":"auto","created_at":"2024-07-03 19:04:35","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":599455,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eChange in Upper-to-Lower Body Ratio Pairwise Meta-analysis\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-4451136/v1/81ee32a68429b502c8ddb4c2.png"},{"id":59607176,"identity":"10c78af5-be94-4adf-812f-d1c0e430c996","added_by":"auto","created_at":"2024-07-03 19:04:35","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":464377,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSummary of Adverse Effects\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-4451136/v1/59ccf8246cb92a49a8ea59df.png"},{"id":67600667,"identity":"d3dc8ace-fedf-49f6-800e-5597c2706d0e","added_by":"auto","created_at":"2024-10-28 03:09:05","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3969286,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4451136/v1/dda8cfe1-cfa9-43f7-85c5-e86c56ac4f65.pdf"},{"id":59608555,"identity":"323ee662-64e6-4399-b74b-2acc12e4f10d","added_by":"auto","created_at":"2024-07-03 19:12:35","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":22414,"visible":true,"origin":"","legend":"","description":"","filename":"PRISMA2020checklist1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4451136/v1/579c015b1f411f43739b42e4.docx"},{"id":59607178,"identity":"7c092775-9d5c-41db-ac05-264fd5c1215b","added_by":"auto","created_at":"2024-07-03 19:04:35","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":305303,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFileAchondroplasia.docx","url":"https://assets-eu.researchsquare.com/files/rs-4451136/v1/fcd8c6055cd577803f6e20f0.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy and Safety of Vosoritide for Achondroplasia: A Systematic Review and Dose- Related Meta-Analysis, 2024 Article type: Systematic review and Dose-related Meta-analysis","fulltext":[{"header":"1- Introduction","content":"\u003cp\u003eAchondroplasia (ACH), is a skeletal dysplasia disorder with an incidence of one in every 10,000 to 30,000 births, globally affecting over 250,000 individuals [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Clinical manifestations include a range of medical and psychosocial difficulties throughout life, such as disproportionately short stature, rhizomelic shortened limbs, deformities of the lower extremity, characteristic facial configuration (relatively large cranium size, forehead protrusion, flat nasal bridge, midface hypoplasia, and relative mandible protrusion), macrocephaly, narrow foramen magnum, ventricular enlargement, upper airway stenosis, otitis media, a narrow thorax, vertebral hyperlordosis, spinal kyphosis, and potential complications like hypotonia, hearing deficit, spinal canal stenosis, sleep apnea, and sudden infant death [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eACH is an autosomal dominant genetic disease caused by a mutation in Fibroblast Growth Factor Receptor 3 (FGFR3). Chondrocytes and mature osteoblasts express FGFR3, which regulates linear bone growth. A gain-of-function mutation in the FGFR3 gene, which is a negative regulator of endochondral ossification, sets off a signalling cascade that includes the receptor becoming more stable, dimerization becoming stronger, and tyrosine kinase activity becoming stronger. These events happen too quickly and stop bones from growing normally [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDespite the limited therapeutic options (growth hormone and surgical lengthening) to increase ACH height, both had limited effects and complications, and neither of them addressed the underlying ACH pathophysiology [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Therefore, a promising treatment option for ACH is to counteract FGFR3's negative effects on chondrocytes. The endogenous C-type natriuretic peptide (CNP) and its natriuretic peptide receptor 2 (NPR2) can stop FGFR3 signaling, which can cause endochondral ossification and promote endochondral bone growth. [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eVosoritide, a modified human recombinant CNP analog, binds to the receptor to raise the level of cyclic guanosine monophosphate (cGMP) inside cells, stopping the FGFR3 signalling cascade [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) approved Vosoritide in 2021 for the treatment of ACH children with open epiphyses who are \u0026ge;\u0026thinsp;5 years old in the United States of America (USA),\u0026thinsp;\u0026ge;\u0026thinsp;2 years old in the European Union (EU), Brazil, and Australia, and from birth in Japan [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Vosoritide expanded the previously restricted range of ACH treatment options.\u003c/p\u003e \u003cp\u003eAlthough vosoritide's side effects are mostly mild and easy to handle, patients may discontinue it if they cannot tolerate daily injections and manage injection-site reactions, including pain. Moreover, although it greatly speeds up the annualized growth velocity (AGV), the response to vosoritide can vary across regions and institutions and vary in both magnitude and timing depending on the dose, duration, and timing of these assessments. Providers must inform patients and their families about the data from the vosoritide clinical trial. International consensus guidance is required to support the use of vosoritide in clinical practice [\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough its first approved medications in 2021 have efficacy and safety, there's a shortage of practical guidance. Due to the rarity of ACH, there are only a limited number of patients. Therefore, it is crucial to investigate the different aspects of utilizing vosoritide in clinical settings and share the knowledge acquired from early experiences in the published clinical trials.\u003c/p\u003e \u003cp\u003eTherefore we conducted this systematic review and dose-related meta-analysis aim to provide a more robust understanding of the potential benefits and risks associated with vosoritide and comprehensively evaluating their efficacy and safety through the following objectives: systematically analyzing data from relevant randomized controlled trials (RCTs) until April 2024 to examine the effect of different vosoritide doses on height from baseline (represented as z-scores), annualized growth velocity (AGV), the upper-to-lower body segment ratio (ULBR), changes in growth velocity (a measure of linear growth over time), and safety profiles (the frequency of adverse effects)\u003c/p\u003e"},{"header":"2- Methodology","content":"\u003cp\u003eThe Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] guided the performance of this systematic review and dose-related meta-analysis.\u003c/p\u003e\n\u003ch3\u003e2 − 1: Search strategy\u003c/h3\u003e\n\u003cp\u003eThe following search strategy was created by combining boolean words, MeSH terms, and keywords: vosoritide\" OR \"BMN 111\" OR \"Voxzogo\" OR \"natriuretic peptide, c type\") AND \"Achondroplasia\". Without implementing any filters, we used this thorough search approach to find relevant articles across electronic databases such as PubMed, Cochrane CENTRAL, Clinicaltrials.gov, and Science Direct from inception to April 2024. We also screened the bibliographies of the included articles. Detailed Search Strategy \u003cb\u003eSupplementary Table\u0026nbsp;1\u003c/b\u003e\u003c/p\u003e\n\u003ch3\u003e2–2: Inclusion and Exclusion Criteria (Study Selection)\u003c/h3\u003e\n\u003cp\u003eThe inclusion criteria consisted of randomized controlled trials (RCTs) on Vosoritide OR BMN 111 OR Voxzogo OR Natriuretic Peptide, C-Type, AND Achondroplasia. We excluded articles that did not meet the eligibility criteria, including editorials, observational studies, review articles, animal studies, conference abstracts, and studies unavailable in English.\u003c/p\u003e\n\u003ch3\u003e2–3: Data screening\u003c/h3\u003e\n\u003cp\u003eThe search results were imported into Rayyan software for screening the articles [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Two authors independently screened the titles and abstracts initially. Then the full text of all the included studies was retrieved and reviewed. Any discrepancies between the authors during the screening process were resolved with a senior author.\u003c/p\u003e\n\u003ch3\u003e2–4: Data extraction\u003c/h3\u003e\n\u003cp\u003eWe extracted data from a Microsoft Excel spreadsheet, which included basic information about studies (author name, study name, publication year, country, publication type, sample size), baseline characteristics (height z-score, annualized growth velocity (AGV), and upper-to-lower body segment ratio (ULBR), changes in baseline characteristics (height z-score, AGV, ULRB), and adverse effects. \u0026lsquo;The total number of patients or events\u0026rsquo; for categorical variables, whereas for continuous variables,' means'' and standard deviations (SD)\u0026rsquo; were extracted.\u003c/p\u003e\n\u003ch3\u003e2–5: Quality Assessment\u003c/h3\u003e\n\u003cp\u003eThe quality assessment of the included trials was conducted with the Cochrane Risk of Bias Tool for Randomized Controlled Trials (RoB 2. O), which assesses the randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of reported results in RCTs [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The Cochrane Risk of Bias Tool classified the studies as either low or high risk of bias or raised certain concerns. Robvis, a visualization tool, generated risk-of-bias graphs and figures [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. A group discussion sorted out any discrepancies during the screening process.\u003c/p\u003e\n\u003ch3\u003e2–6 : Statistical Analysis\u003c/h3\u003e\n\u003cp\u003eAll statistical analyses were performed using the 'R Programming Language', version 4.1.2 [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Pairwise meta-analyses were conducted to assess the comparative efficacy of individual vosoritide doses against both placebo and each other, focusing on changes from baseline in height z-scores, AGV, and the ULBR. Mean differences (MD) with corresponding 95% confidence intervals (CIs) were estimated using a random-effects model with the inverse variance method. For adverse effects, we calculated risk ratios (RR) with a 95% CI. This statistic tells us how much more likely (or less likely) someone in one group was to experience an adverse effect compared to the other group. The meta-analysis findings were visually evaluated using a forest plot, with statistical significance determined at a threshold of \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e"},{"header":"3- Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.1: Study Selection\u003c/h2\u003e \u003cp\u003eUsing a specific search strategy, we performed a detailed search across multiple electronic databases\u0026mdash;PubMed, Google Scholar, Cochrane Library, and Elsevier\u0026rsquo;s ScienceDirect. This initial search produced 89 articles. After eliminating 9 duplicates, we assessed the titles and abstracts of 80 articles. We excluded 72 of these articles because they did not meet the predefined inclusion and exclusion criteria. After a thorough review of the full texts, only three clinical trials met the criteria for inclusion in this review. The PRISMA Flow Diagram illustrates the selection process, presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.2: Baseline Characteristics\u003c/h2\u003e \u003cp\u003eFrom 2019 to 2024, the USA, Japan, Australia, the UK, and France conducted the selected studies. These studies collectively involved 220 patients diagnosed with achondroplasia, whose ages ranged from 3 months to 18 years. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e summarizes the details of each study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.3: Quality Assessment and Publication Bias\u003c/h2\u003e \u003cp\u003eThe risk of bias was consistently low, with all studies being of high quality [\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Savarirayan R et al. 2019 [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] was an open-label trial, so it did not involve randomization, the allocation concealment process, or the blinding of the participants and personnel. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e provides a quality assessment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.4: Outcomes\u003c/h2\u003e \u003cp\u003eThe following summarizes the effects of various Vosoritide doses on height Z-scores, AGV, and ULBR, as well as the side effects in all studies.\u003c/p\u003e \u003cdiv id=\"Sec14\" class=\"Section3\"\u003e \u003ch2\u003e3.4.1: The effect of different doses of vosoritide on the Height Z-Score\u003c/h2\u003e \u003cp\u003eOverall, higher doses of Vosoritide tend to have a greater positive effect on height Z-scores than lower doses or placebos. Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eCompared to different doses regarding height Z-scores\u003c/b\u003e, Savarirayan R et al. 2019 [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] showed a negligible difference between Vosoritide 15 \u0026micro;g/kg vs. Vosoritide 2.5 \u0026micro;g/kg (MD\u0026thinsp;=\u0026thinsp;0.05, SE\u0026thinsp;=\u0026thinsp;0.44, 95% CI = -0.81; 0.91). While it is much better at raising the height Z score by comparing Vosoritide 15 \u0026micro;g/kg to 7.5 \u0026micro;g/kg (MD\u0026thinsp;=\u0026thinsp;0.54, SE\u0026thinsp;=\u0026thinsp;0.27, 95% CI\u0026thinsp;=\u0026thinsp;0.01; 1.07), Vosoritide 7.5 \u0026micro;g/kg is considerably more effective than 2.5 \u0026micro;g/kg (MD\u0026thinsp;=\u0026thinsp;0.49, SE\u0026thinsp;=\u0026thinsp;0.45, 95% CI = -0.39; 1.37).\u003c/p\u003e \u003cp\u003e \u003cb\u003eIn terms of height, Z-scores Compared to the placebo\u003c/b\u003e, Savarirayan R. et al. 2020 [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] found that Vosoritide 15 \u0026micro;g/kg had a slightly stronger positive effect than the placebo (MD\u0026thinsp;=\u0026thinsp;0.28, SE\u0026thinsp;=\u0026thinsp;0.07, 95% CI\u0026thinsp;=\u0026thinsp;0.15; 0.41); Savarirayan R. et al. 2024 [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] found that Vosoritide 15\u0026ndash;30 \u0026micro;g/kg had a higher positive effect than the placebo (MD\u0026thinsp;=\u0026thinsp;0.25, SE\u0026thinsp;=\u0026thinsp;0.14, 95% CI = -0.02; 0.52).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section3\"\u003e \u003ch2\u003e3.4.2: The effect of Vosoritide on annualized growth velocity (AGV)\u003c/h2\u003e \u003cp\u003eDifferent doses of vosoritide have varying effects on AGV; higher doses generally show a more pronounced positive effect. Figure\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eCompared to different doses regarding AGV\u003c/b\u003e, the 2019 study by Savarirayan R et al. [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] found that the vosoritide 15 \u0026micro;g/kg had a much stronger positive effect than the vosoritide 2.5 \u0026micro;g/kg (MD\u0026thinsp;=\u0026thinsp;2.38, SE\u0026thinsp;=\u0026thinsp;0.87, 95% CI\u0026thinsp;=\u0026thinsp;0.67; 4.09) and then the vosoritide 7.5 \u0026micro;g/kg (MD\u0026thinsp;=\u0026thinsp;0.73, SE\u0026thinsp;=\u0026thinsp;0.81, 95% CI = -0.86; 2.32). However, other comparisons yielded no significant results; there was no significant difference between Vosoritide 15 \u0026micro;g/kg and Vosoritide 30 \u0026micro;g/kg (MD = -0.07, SE\u0026thinsp;=\u0026thinsp;0.99, 95% CI = -2.00; 1.86), and the dose of 30 \u0026micro;g/kg for AGV (MD\u0026thinsp;=\u0026thinsp;0.80, SE\u0026thinsp;=\u0026thinsp;0.91, 95% CI = -0.99; 2.59). vs. Vosoritide, 7.5 \u0026micro;g/kg.\u003c/p\u003e \u003cp\u003e \u003cb\u003eCompared to the placebo regarding AGV\u003c/b\u003e, it had a higher positive effect with more, e.g., Vosoritide (15 \u0026micro;g/kg) (MD\u0026thinsp;=\u0026thinsp;1.58, SE\u0026thinsp;=\u0026thinsp;0.22, 95% CI\u0026thinsp;=\u0026thinsp;1.15; 2.01) and Vosoritide 15\u0026ndash;30 \u0026micro;g/kg (MD\u0026thinsp;=\u0026thinsp;0.78, SE\u0026thinsp;=\u0026thinsp;0.38, 95% CI\u0026thinsp;=\u0026thinsp;0.04; 1.52) [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. While Savarirayan R et al. 2024 [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] found that Vosoritide 15\u0026ndash;30 \u0026micro;g/kg had a greater effect on AGV (MD\u0026thinsp;=\u0026thinsp;0.78, SE\u0026thinsp;=\u0026thinsp;0.38, 95% CI\u0026thinsp;=\u0026thinsp;0.04; 1.52) than the placebo group.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section3\"\u003e \u003ch2\u003e3.4.3 The effect of Vosoritide on the upper-to-lower body segment ratio (ULBR)\u003c/h2\u003e \u003cp\u003e \u003cb\u003eCompared to different doses, S\u003c/b\u003eavarirayan R et al. [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] discovered that the ULBR was slightly higher for the higher dose of Vosoritide (15 g/kg vs. 2.5 g/kg) (MD\u0026thinsp;=\u0026thinsp;0.12, SE\u0026thinsp;=\u0026thinsp;0.05, 95% CI\u0026thinsp;=\u0026thinsp;0.02; 0.22). Other comparisons did not show any significant results.\u003c/p\u003e \u003cp\u003e \u003cb\u003eCompared to placebo\u003c/b\u003e, in terms of ULBR, Savarirayan R et al. [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] found that Vosoritide 15 \u0026micro;g/kg and Vosoritide 15\u0026ndash;30 \u0026micro;g/kg had almost no difference (MD = -0.01, SE\u0026thinsp;=\u0026thinsp;0.02, 95% CI = -0.05; 0.03) and (MD = -0.07, SE\u0026thinsp;=\u0026thinsp;0.05, 95% CI = -0.17; 0.03) respectively compared to the placebo.\u003c/p\u003e \u003cp\u003eOverall, Savarirayan R et al. 2019 [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] noted a small increase in the ULBR when comparing different doses of Vosoritide to placebo or each other. Figure\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section3\"\u003e \u003ch2\u003e3.4.4. Vosoritide Adverse Effect\u003c/h2\u003e \u003cp\u003eAll the included studies show that ACH patients on Vosoritide only experience mild to moderate treatment-emergent adverse effects, such as reactions at the injection site (such as erythema, swelling, and urticaria), pyrexia, coughing, headaches, and vomiting, in descending order, without any severe side effects [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"5- Discussion","content":"\u003cp\u003eThis systematic review and dose-related meta-analysis, which statistically combines three RCTs with a total of 220 patients, consolidates the existing research on the safety and dose-related effects of vosoritide in achondroplasia. Our analysis of patients with achondroplasia revealed a clear dose-dependent effect of vosoritide on height Z-scores and annualized growth velocity, as well as mild to moderate treatment-emergent adverse effects.\u003c/p\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003e\u003cb\u003e5.1: The effect of vosoritide in different doses on height Z-score\u003c/b\u003e\u003c/h2\u003e \u003cp\u003eIn this network meta-analysis, RCTs reported that Vosoritide 15 \u0026micro;g/kg had a better effect on height Z-Score than Vosoritide 7.5 \u0026micro;g/kg and Vosoritide 2.5 \u0026micro;g/kg [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Vosoritide 15 \u0026micro;g/kg and Vosoritide 15\u0026ndash;30 \u0026micro;g/kg had a better effect than the placebo [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. A height Z-score is an accurate and widespread measure to monitor children's growth by quantifying the number of standard deviations by which a child's height deviates from the mean height for their age and gender [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAs a result, the vosoritide treatment has improved the baseline height and is a good treatment for ACH, a genetic disorder that affects bone growth. The recombinant human CNP analogue, possessing a modified N-terminal domain and resembling CNP in its pharmacological action as an endogenous positive regulator of endochondral bone formation, explains this. It has the capability to obstruct the downstream signaling of the constitutively active FGFR3, thereby reinstating chondrocyte differentiation, enhancing bone growth, and enhancing growth outcomes [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. 100% of panel experts agreed that starting vosoritide treatment earlier and for longer-term results in a greater final height compared to those starting later [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFurthermore, this meta-analysis indicates that in ACP treatment, higher doses of Vosoritide (15 \u0026micro;g/kg) improved height Z-Score more than Vosoritide 7.5 \u0026micro;g/kg and Vosoritide 2.5 \u0026micro;g/kg. This may be due to its pharmacokinetic, pharmacodynamic, and dose-response relationships [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003e5.2: The effect of vosoritide on annualized growth velocity (AGV)\u003c/h2\u003e \u003cp\u003eVosoritide significantly raises the AGV compared to the placebo because it works in a new way to mimic the growth-promoting effects of CNP (which raises the baseline height) and CXM (which shows collagen X marker endochondral bone growth) [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Moreover, vosoritide at a dose of 15 \u0026micro;g/kg increased AGV significantly more than at lower doses of 2.5 \u0026micro;g/kg or 7.5 \u0026micro;g/kg [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. showed dose-dependent changes between 2.5 and 30 \u0026micro;g/kg.\u003c/p\u003e \u003cp\u003eAccording to exposure-response analyses, AGV, and CXM peaked at 15 \u0026micro;g/kg. The results support the idea that the exposure-response relationship for changes in both reached a peak at Vosoritide 15 \u0026micro;g/kg [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. This clarifies what was interesting, there was no difference between the dose groups of 15 \u0026micro;g/kg and 30 \u0026micro;g/kg, pointing to a potential plateau effect at higher doses. The exposures at these dose levels appear to have induced a maximum and saturated response, as there were no significant increases in AGV at 30 \u0026micro;g/kg as opposed to 15 \u0026micro;g/kg. At 15 \u0026micro;g/kg, the AGV change from the beginning point had reached the peak of the exposure-response curve. [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003e5.3 The effect of vosoritide on upper-to-lower body segment ratio (ULBR)\u003c/h2\u003e \u003cp\u003eIn this, meta-analysis \u003cb\u003evosoritide\u003c/b\u003e effect on ULBR showed that there was no significant difference compared to a placebo [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. This may be attributed to that ULBR as an outcome can affected by some factors like sample size, treatment duration, and endpoints measured, [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eHowever, when compared to different doses, there was no significant difference except between 15 g/kg and 2.5 g/kg, where the effect was slightly higher [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Inconsistency with what was reported by an 85% panel of experts suggests a more optimistic outlook, as long-term Vosoritide treatment is likely to lead to clinically meaningful improvements in ULBR, particularly for patients who begin treatment between 2 years old and puberty [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Therefore, the effect of Vosoritide on ULBR remains inconclusive.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003e5.4: Vosoritide Adverse Effect\u003c/h2\u003e \u003cp\u003eAll of the included RCT studies show that ACH patients on Vosoritide experience only mild to moderate treatment-emergent adverse effects. In descending order, the reported adverse effects were these reactions at the injection site (such as erythema, swelling, and urticaria); pyrexia, coughing, headaches, and vomiting did not cause any severe side effects. In agreement with a generally mild side-effect profile, injection site effects and asymptomatic hypotension are the most commonly observed adverse effects [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Other studies have reported weak positive correlations between the maximum increase in doses from the predose heart rate and no correlation between the exposure to vosoritide plasma and a decrease in either systolic or diastolic blood pressure [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis is attributed to the fact that Concentrations below 15 have a limited effect on chondrocytes. A higher exposure range of 30 \u0026micro;g/kg has systemic pharmacological activity at its peak, and it affects NPR-B in many organs, including the lungs, heart, brain, liver, and fat cells [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHowever, a study examining parents' experiences with Vosoritide identified some key challenges that may be considered its effects and adverse effects, such as the care provider-patient relationship that depends on the environment, as home administering injections required a significant learning curve. Secondly, publicly funded home care nurses and parents reported that parents substantially reduced the burden of managing the treatment regimen. Finally, maintaining a consistent dosing schedule proved difficult, especially for families who travel or have active older children. This difficulty is likely due to the need for cool storage and potential challenges with the injection device [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. These findings emphasise the need for improved support systems and potentially more user-friendly administration methods to optimise the use of Vosoritide for children with achondroplasia [31\u0026thinsp;=\u0026thinsp;32].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec23\" class=\"Section2\"\u003e \u003ch2\u003e4.6 Strength\u003c/h2\u003e \u003cp\u003eSince this dose-dependent meta-analysis only includes a well-critically appraised study design (RCT), including a large sample size (220 ACP cases) across a wider age range of rare diseases1 in 20,000\u0026ndash;30,000 live births, and the study comparing different vosoritide dosages was well-designed and adequately powered, the results are more reliable and would strengthen the generalizability of the findings about the promising evidence for the efficacy of vosoritide in ACH.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section2\"\u003e \u003ch2\u003e4.7 Limitations\u003c/h2\u003e \u003cp\u003eOnly three studies were limited to their location Moreover, one of the included studies [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] was an open-label trial, potentially introducing bias. The studies reviewed encompassed a limited treatment duration. There are limitations to consider for future research directions.\u003c/p\u003e \u003c/div\u003e"},{"header":"6- Conclusively","content":"\u003cp\u003eCompared to placebo, vosoritide significantly increases the annual growth velocity and height Z-score. Vosoritide has an exposure-response property, as higher doses had a significant improvement at the AGV and height Z-score compared to lower doses until its plateau at dose groups of 15 \u0026micro;g/kg.\u003c/p\u003e \u003cp\u003eIn terms of its effect on ULBR, there was no significant difference compared to a placebo. However, when compared to different doses, there was no significant difference except between 15 g/kg and 2.5 g/kg, where the effect was slightly higher. Vosoritide appears to be well-tolerated and efficacious for ACH.\u003c/p\u003e"},{"header":"7- Recommendations","content":"\u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eOptimizing treatment strategies for Achondroplasia requires further investigation. Head-to-head comparisons between Vosoritide and other existing treatments, such as growth hormone therapy, could provide valuable insights for clinicians. By addressing these limitations and pursuing these future research directions, we can gain a more comprehensive understanding of Vosoritide's long-term effects and potential as a treatment for Achondroplasia.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eWhen monitoring heart rate, systolic blood pressure, and diastolic blood pressure in the clinic,\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eFurther studies with larger sample sizes and longer follow-ups are necessary to definitively determine the long-term effects of Vosoritide on ULBR body proportions in patients with Achondroplasia.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eFurther research with long-term follow-up is necessary to assess the sustained effects of Vosoritide on growth, skeletal development, and potential side effects beyond the initial treatment period. Future studies with consistent double-blinding would minimize potential bias and strengthen the evidence base.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e"},{"header":"8- List of Abbreviations","content":"\u003cp\u003eAchondroplasia (ACH)\u003c/p\u003e \u003cp\u003eFibroblast growth factor receptor 3 (FGFR3)\u003c/p\u003e \u003cp\u003eC-type natriuretic peptide (CNP)\u003c/p\u003e \u003cp\u003econfidence intervals (CI)\u003c/p\u003e \u003cp\u003eMean differences (MD)\u003c/p\u003e \u003cp\u003eRandomized controlled trials (RCTs)\u003c/p\u003e \u003cp\u003eThe annualized growth velocity (AGV)\u003c/p\u003e \u003cp\u003ePreferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)\u003c/p\u003e \u003cp\u003eThe European Medicines Agency (EMA)\u003c/p\u003e \u003cp\u003eFood and Drug Administration (FDA)\u003c/p\u003e \u003cp\u003eThe United States of America (USA)\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e9.1\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eWe would like to thank all the contributor authors for their great efforts in this systematic review.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e9.2\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e9.3 Consent to participate.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe obtained informed consent from patients included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e9.4 Consent to publish.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients signed informed consent regarding publishing their data and photographs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e9.5 Funding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;No funding for this project.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e9.6 Competing interests.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe\u0026nbsp;authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e9.7\u0026nbsp;Previous publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;We declare that this research paper has not been published elsewhere in any other academic journal or platform.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e9.8\u0026nbsp;Generative AI in scientific writing\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;We declare that we have not used AI in writing any part of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e9.9 Author contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConception: M.Kh\u003c/p\u003e\n\u003cp\u003eMethods: M.Kh , S.M,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eValidation: \u0026nbsp;I.A, M.B, E.S, H.S\u003c/p\u003e\n\u003cp\u003eData curation, and extraction: \u0026nbsp;I.A, M.B, E.S, H.S\u003c/p\u003e\n\u003cp\u003eFormal analysis: M.Kh\u003c/p\u003e\n\u003cp\u003eWriting the original draft: \u0026nbsp;M.Kh , S.M, H.S and S.A\u003c/p\u003e\n\u003cp\u003emanuscript revision and editing: All authors\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSupervision: M.Kh\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eVisualization: \u0026nbsp;S.A\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e9.9\u0026nbsp;Data availability statement\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data available when on reasonable request from the corresponding author ([email protected])\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eShiang, R., Thompson, L. 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The multifaceted role of natriuretic peptides in metabolic syndrome. \u003cem\u003eBiomed Pharmacother. \u003c/em\u003e2017;92:826\u0026ndash;835.\u003c/li\u003e\n\u003cli\u003eForeman PK, van Kessel F, van Hoorn R, van den Bosch J, Shediac R, et al. (2020) Birth prevalence of achondroplasia: a systematic literature review and meta-analysis. Am J Med Genet A 182: 2297\u0026ndash;2316.\u003c/li\u003e\n\u003cli\u003eHarada D, Namba N, Hanioka Y, Ueyama K, Sakamoto N, et al. (2017) Final adult height in long-term growth hormone-treated achondroplasia patients. Eur J Pediatr 176: 873\u0026ndash;879\u003c/li\u003e\n\u003cli\u003eHunter AG, Bankier A, Rogers JG, Sillence D, Scott CI. Medical complications of achondroplasia: a multicentre patient review. J Med Genet. 1998;35(9):705\u0026ndash;12.\u003c/li\u003e\n\u003cli\u003eNiMhurchadha S, Butler K, Argent R, et al. Parents\u0026apos; Experience of Administering Vosoritide: A Daily Injectable for Children with Achondroplasia. \u003cem\u003eAdv Ther\u003c/em\u003e. 2023;40(5):2457-2470. doi:10.1007/s12325-023-02496-z\u003c/li\u003e\n\u003cli\u003eFranconi F, Campesi I. Pharmacogenomics, pharmacokinetics and pharmacodynamics: interaction with biological differences between men and women. \u003cem\u003eBr J Pharmacol\u003c/em\u003e. 2014;171(3):580-594. doi:10.1111/bph.12362\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1: Summary of Baseline Characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"1029\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.968901846452867%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eAuthor\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.997084548104956%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eCountry\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.122448979591836%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eGroup\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.037900874635568%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eDrug Doses\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.899902818270165%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eSample Size\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.41399416909621%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eDuration\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.288629737609329%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge; Mean (SD)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.608357628765792%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eMale; n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.608357628765792%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eFemale; n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.26044703595724%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eHeight Z-scores; Mean (SD)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.577259475218659%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eAnnualized Growth Velocity (AGV); Mean (SD)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.216715257531584%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eUpper-to-lower body\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003esegment ratio; Mean (SD)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.968901846452867%\" rowspan=\"4\" valign=\"bottom\"\u003e\n \u003cp\u003eSavarirayan R et al. 2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.997084548104956%\" rowspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eUSA, Australia, France,\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eUK\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.122448979591836%\" rowspan=\"4\" valign=\"bottom\"\u003e\n \u003cp\u003eVosoritide\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.037900874635568%\" valign=\"bottom\"\u003e\n \u003cp\u003e2.5 \u0026mu;g/kg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.899902818270165%\" valign=\"bottom\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.41399416909621%\" rowspan=\"4\" valign=\"bottom\"\u003e\n \u003cp\u003e42 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.288629737609329%\" valign=\"bottom\"\u003e\n \u003cp\u003e7.3\u0026plusmn;1.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.608357628765792%\" valign=\"bottom\"\u003e\n \u003cp\u003e3 (38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.608357628765792%\" valign=\"bottom\"\u003e\n \u003cp\u003e5 (62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.26044703595724%\" valign=\"bottom\"\u003e\n \u003cp\u003e-5.69 (1.190)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.577259475218659%\" valign=\"bottom\"\u003e\n \u003cp\u003e3.90 (1.108)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.216715257531584%\" valign=\"bottom\"\u003e\n \u003cp\u003e2.06 (0.140)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.466487935656836%\" valign=\"bottom\"\u003e\n \u003cp\u003e7.5 \u0026mu;g/kg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.517426273458446%\" valign=\"bottom\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.05361930294906%\" valign=\"bottom\"\u003e\n \u003cp\u003e8.3\u0026plusmn;2.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.115281501340483%\" valign=\"bottom\"\u003e\n \u003cp\u003e5 (62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.115281501340483%\" valign=\"bottom\"\u003e\n \u003cp\u003e3 (38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.394101876675602%\" valign=\"bottom\"\u003e\n \u003cp\u003e-5.14 (0.853)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.10723860589812%\" valign=\"bottom\"\u003e\n \u003cp\u003e2.89 (1.392)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.230563002680967%\" valign=\"bottom\"\u003e\n \u003cp\u003e2.03 (0.179)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.466487935656836%\" valign=\"bottom\"\u003e\n \u003cp\u003e15.0 \u0026mu;g/kg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.517426273458446%\" valign=\"bottom\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.05361930294906%\" valign=\"bottom\"\u003e\n \u003cp\u003e8.0\u0026plusmn;1.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.115281501340483%\" valign=\"bottom\"\u003e\n \u003cp\u003e4 (40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.115281501340483%\" valign=\"bottom\"\u003e\n \u003cp\u003e6 (60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.394101876675602%\" valign=\"bottom\"\u003e\n \u003cp\u003e-4.61 (1.136)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.10723860589812%\" valign=\"bottom\"\u003e\n \u003cp\u003e4.04 (2.275)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.230563002680967%\" valign=\"bottom\"\u003e\n \u003cp\u003e1.91 (0.229)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.466487935656836%\" valign=\"bottom\"\u003e\n \u003cp\u003e30.0 \u0026mu;g/kg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.517426273458446%\" valign=\"bottom\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.05361930294906%\" valign=\"bottom\"\u003e\n \u003cp\u003e6.9\u0026plusmn;1.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.115281501340483%\" valign=\"bottom\"\u003e\n \u003cp\u003e4 (44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.115281501340483%\" valign=\"bottom\"\u003e\n \u003cp\u003e5 (56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.394101876675602%\" valign=\"bottom\"\u003e\n \u003cp\u003e-5.17 (0.703)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.10723860589812%\" valign=\"bottom\"\u003e\n \u003cp\u003e4.39 (1.150)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.230563002680967%\" valign=\"bottom\"\u003e\n \u003cp\u003e1.99 (0.188)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.968901846452867%\" rowspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003eSavarirayan R et al. 2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.997084548104956%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eAustralia, Germany, Japan, Spain, Turkey, the USA, and the UK\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.122448979591836%\" valign=\"bottom\"\u003e\n \u003cp\u003eVosoritide\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.037900874635568%\" valign=\"bottom\"\u003e\n \u003cp\u003e15\u0026middot;0 \u0026micro;g/kg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.899902818270165%\" valign=\"bottom\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.41399416909621%\" rowspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003e52 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.288629737609329%\" valign=\"bottom\"\u003e\n \u003cp\u003e8\u0026middot;35 (2\u0026middot;43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.608357628765792%\" valign=\"bottom\"\u003e\n \u003cp\u003e31 (52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.608357628765792%\" valign=\"bottom\"\u003e\n \u003cp\u003e29 (48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.26044703595724%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026minus;5\u0026middot;13 (1\u0026middot;11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.577259475218659%\" valign=\"bottom\"\u003e\n \u003cp\u003e4\u0026middot;26 (1\u0026middot;53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.216715257531584%\" valign=\"bottom\"\u003e\n \u003cp\u003e1\u0026middot;98 (0\u0026middot;20)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.787391841779975%\" valign=\"bottom\"\u003e\n \u003cp\u003ePlacebo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.495673671199011%\" valign=\"bottom\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.776266996291719%\" valign=\"bottom\"\u003e\n \u003cp\u003e61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.27070457354759%\" valign=\"bottom\"\u003e\n \u003cp\u003e9\u0026middot;06 (2\u0026middot;47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.405438813349814%\" valign=\"bottom\"\u003e\n \u003cp\u003e33 (54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.405438813349814%\" valign=\"top\"\u003e\n \u003cp\u003e28 (46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.506798516687269%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026minus;5\u0026middot;14 (1\u0026middot;07)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.54140914709518%\" valign=\"bottom\"\u003e\n \u003cp\u003e4\u0026middot;06 (1\u0026middot;20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.81087762669963%\" valign=\"bottom\"\u003e\n \u003cp\u003e2\u0026middot;01 (0\u0026middot;21)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.968901846452867%\" rowspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003eSavarirayan R et al. 2024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.997084548104956%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eUSA, Japan, Australia, UK\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.122448979591836%\" valign=\"bottom\"\u003e\n \u003cp\u003eVosoritide\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.037900874635568%\" valign=\"bottom\"\u003e\n \u003cp\u003e15 \u0026micro;g/kg in Cohort 1; 30 \u0026micro;g/kg in Cohort 2 and 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.899902818270165%\" valign=\"bottom\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.41399416909621%\" rowspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003e52 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.288629737609329%\" valign=\"bottom\"\u003e\n \u003cp\u003e24\u0026middot;39 (16\u0026middot;83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.608357628765792%\" valign=\"bottom\"\u003e\n \u003cp\u003e17 (53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.608357628765792%\" valign=\"bottom\"\u003e\n \u003cp\u003e15 (47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.26044703595724%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026minus;3\u0026middot;79 (0\u0026middot;97)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.577259475218659%\" valign=\"bottom\"\u003e\n \u003cp\u003e11\u0026middot;06 (7\u0026middot;57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.216715257531584%\" valign=\"bottom\"\u003e\n \u003cp\u003e2\u0026middot;60 (0\u0026middot;41)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.787391841779975%\" valign=\"bottom\"\u003e\n \u003cp\u003ePlacebo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.495673671199011%\" valign=\"bottom\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.776266996291719%\" valign=\"bottom\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.27070457354759%\" valign=\"bottom\"\u003e\n \u003cp\u003e27\u0026middot;82 (19\u0026middot;25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.405438813349814%\" valign=\"bottom\"\u003e\n \u003cp\u003e13 (41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.405438813349814%\" valign=\"bottom\"\u003e\n \u003cp\u003e19 (59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.506798516687269%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026minus;4\u0026middot;28 (1\u0026middot;48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.54140914709518%\" valign=\"bottom\"\u003e\n \u003cp\u003e9\u0026middot;60 (7\u0026middot;74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.81087762669963%\" valign=\"bottom\"\u003e\n \u003cp\u003e2\u0026middot;52 (0\u0026middot;36)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2: Summary of Outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"974\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.342915811088295%\" valign=\"bottom\" style=\"width: 9.7222%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAuthor\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.084188911704312%\" valign=\"bottom\" style=\"width: 8.3333%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGroup\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.240246406570842%\" valign=\"bottom\" style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDrug Doses\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.632443531827516%\" valign=\"bottom\" style=\"width: 19.697%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eChange from Baseline in Annualized Growth Velocity (AGV)(cm/year),\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eLS mean, n [95% CI]\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.605749486652977%\" valign=\"bottom\" style=\"width: 18.4343%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eChange from Baseline in height Z-score, n,\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eLS mean [95% CI]\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.529774127310063%\" valign=\"bottom\" style=\"width: 10.3535%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eChange from baseline in upper-to-lower body segment ratio\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.673511293634497%\" valign=\"bottom\" style=\"width: 6.5657%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAny TEAs; n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.11088295687885%\" valign=\"bottom\" style=\"width: 6.6919%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSerious TEAs; n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.780287474332649%\" valign=\"bottom\" style=\"width: 9.0909%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment related TEAEs; n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.342915811088295%\" rowspan=\"4\" valign=\"bottom\" style=\"width: 9.7222%;\"\u003e\n \u003cp\u003eSavarirayan R et al. 2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.084188911704312%\" rowspan=\"4\" valign=\"bottom\" style=\"width: 8.3333%;\"\u003e\n \u003cp\u003eVosoritide\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.240246406570842%\" valign=\"bottom\" style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e2.5 \u0026mu;g/kg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.632443531827516%\" valign=\"bottom\" style=\"width: 19.697%;\"\u003e\n \u003cp\u003e1.24 (1.125)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.605749486652977%\" valign=\"bottom\" style=\"width: 18.4343%;\"\u003e\n \u003cp\u003e0.98 (0.985)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.529774127310063%\" valign=\"bottom\" style=\"width: 10.3535%;\"\u003e\n \u003cp\u003e-0.15 (0.079)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.673511293634497%\" rowspan=\"4\" valign=\"bottom\" style=\"width: 6.5657%;\"\u003e\n \u003cp\u003e35(100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.11088295687885%\" rowspan=\"4\" valign=\"bottom\" style=\"width: 6.6919%;\"\u003e\n \u003cp\u003e4(11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.780287474332649%\" rowspan=\"4\" valign=\"bottom\" style=\"width: 9.0909%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.929203539823009%\" valign=\"bottom\" style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e7.5 \u0026mu;g/kg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.672566371681416%\" valign=\"bottom\" style=\"width: 19.697%;\"\u003e\n \u003cp\u003e1.63 (1.010)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.902654867256636%\" valign=\"bottom\" style=\"width: 18.4343%;\"\u003e\n \u003cp\u003e0.49 (0.491)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.495575221238937%\" valign=\"bottom\" style=\"width: 10.3535%;\"\u003e\n \u003cp\u003e-0.13 (0.106)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.929203539823009%\" valign=\"bottom\" style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e15.0 \u0026mu;g/kg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.672566371681416%\" valign=\"bottom\" style=\"width: 19.697%;\"\u003e\n \u003cp\u003e1.55 (1.885)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.902654867256636%\" valign=\"bottom\" style=\"width: 18.4343%;\"\u003e\n \u003cp\u003e1.03 (0.570)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.495575221238937%\" valign=\"bottom\" style=\"width: 10.3535%;\"\u003e\n \u003cp\u003e-0.03 (0.132)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.929203539823009%\" valign=\"bottom\" style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e30.0 \u0026mu;g/kg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.672566371681416%\" valign=\"bottom\" style=\"width: 19.697%;\"\u003e\n \u003cp\u003eNA (NA)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.902654867256636%\" valign=\"bottom\" style=\"width: 18.4343%;\"\u003e\n \u003cp\u003eNA (NA)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.495575221238937%\" valign=\"bottom\" style=\"width: 10.3535%;\"\u003e\n \u003cp\u003eNA (NA)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.342915811088295%\" rowspan=\"2\" valign=\"bottom\" style=\"width: 9.7222%;\"\u003e\n \u003cp\u003eSavarirayan R et al. 2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.084188911704312%\" valign=\"bottom\" style=\"width: 8.3333%;\"\u003e\n \u003cp\u003eVosoritide\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.240246406570842%\" valign=\"bottom\" style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e15\u0026middot;0 \u0026micro;g/kg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.632443531827516%\" valign=\"bottom\" style=\"width: 19.697%;\"\u003e\n \u003cp\u003e1\u0026middot;71 (1\u0026middot;40 to 2\u0026middot;01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.605749486652977%\" valign=\"bottom\" style=\"width: 18.4343%;\"\u003e\n \u003cp\u003e0\u0026middot;27 (0\u0026middot;18 to 0\u0026middot;36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.529774127310063%\" valign=\"bottom\" style=\"width: 10.3535%;\"\u003e\n \u003cp\u003e\u0026minus;0\u0026middot;03 (\u0026minus;0\u0026middot;06 to 0\u0026middot;00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.673511293634497%\" valign=\"bottom\" style=\"width: 6.5657%;\"\u003e\n \u003cp\u003e59 (98%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.11088295687885%\" valign=\"bottom\" style=\"width: 6.6919%;\"\u003e\n \u003cp\u003e3 (5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.780287474332649%\" valign=\"bottom\" style=\"width: 9.0909%;\"\u003e\n \u003cp\u003e53\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.814269535673839%\" valign=\"bottom\" style=\"width: 8.3333%;\"\u003e\n \u003cp\u003ePlacebo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.192525481313703%\" valign=\"bottom\" style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.346545866364664%\" valign=\"bottom\" style=\"width: 19.697%;\"\u003e\n \u003cp\u003e0\u0026middot;13 (\u0026minus;0\u0026middot;18 to 0\u0026middot;45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.214043035107586%\" valign=\"bottom\" style=\"width: 18.4343%;\"\u003e\n \u003cp\u003e\u0026minus;0\u0026middot;01 (\u0026minus;0\u0026middot;10 to 0\u0026middot;09)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.23329558323896%\" valign=\"bottom\" style=\"width: 10.3535%;\"\u003e\n \u003cp\u003e\u0026minus;0\u0026middot;02 (\u0026minus;0\u0026middot;05 to 0\u0026middot;01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.361268403171008%\" valign=\"bottom\" style=\"width: 6.5657%;\"\u003e\n \u003cp\u003e60 (98%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.946772366930917%\" valign=\"bottom\" style=\"width: 6.6919%;\"\u003e\n \u003cp\u003e4 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.89127972819932%\" valign=\"bottom\" style=\"width: 9.0909%;\"\u003e\n \u003cp\u003e51\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.342915811088295%\" rowspan=\"2\" valign=\"bottom\" style=\"width: 9.7222%;\"\u003e\n \u003cp\u003eSavarirayan R et al. 2024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.084188911704312%\" valign=\"bottom\" style=\"width: 8.3333%;\"\u003e\n \u003cp\u003eVosoritide\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.240246406570842%\" valign=\"bottom\" style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e15 \u0026micro;g/kg in Cohort 1; 30 \u0026micro;g/kg in Cohort 2 and 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.632443531827516%\" valign=\"bottom\" style=\"width: 19.697%;\"\u003e\n \u003cp\u003e-2.17, n = 32 [-2.76 to -1.58]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.605749486652977%\" valign=\"bottom\" style=\"width: 18.4343%;\"\u003e\n \u003cp\u003en = 32, -0.06(-0.26 to 0.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.529774127310063%\" valign=\"bottom\" style=\"width: 10.3535%;\"\u003e\n \u003cp\u003e-0.20(-0.28 to -0.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.673511293634497%\" valign=\"bottom\" style=\"width: 6.5657%;\"\u003e\n \u003cp\u003e32 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.11088295687885%\" valign=\"bottom\" style=\"width: 6.6919%;\"\u003e\n \u003cp\u003e3 (9.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.780287474332649%\" valign=\"bottom\" style=\"width: 9.0909%;\"\u003e\n \u003cp\u003e29 (90.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.814269535673839%\" valign=\"bottom\" style=\"width: 8.3333%;\"\u003e\n \u003cp\u003ePlacebo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.192525481313703%\" valign=\"bottom\" style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.346545866364664%\" valign=\"bottom\" style=\"width: 19.697%;\"\u003e\n \u003cp\u003e-2.95, n = 32 (-3.45 to -2.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.214043035107586%\" valign=\"bottom\" style=\"width: 18.4343%;\"\u003e\n \u003cp\u003en = 32, -0.31(-0.48 to -0.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.23329558323896%\" valign=\"bottom\" style=\"width: 10.3535%;\"\u003e\n \u003cp\u003e-0.13(-0.21 to -0.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.361268403171008%\" valign=\"bottom\" style=\"width: 6.5657%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.946772366930917%\" valign=\"bottom\" style=\"width: 6.6919%;\"\u003e\n \u003cp\u003e6 (18.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.89127972819932%\" valign=\"bottom\" style=\"width: 9.0909%;\"\u003e\n \u003cp\u003e17 (53.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Achondroplasia, Vosoritide, Height, Annualised growth velocity, Upper-to-lower Body segment ratio, Dose-related meta-analyses","lastPublishedDoi":"10.21203/rs.3.rs-4451136/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4451136/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eAchondroplasia, the most common form of dwarfism, poses significant medical and psychosocial challenges. Vosoritide, a new C-type natriuretic peptide analog, has shown promise in treating achondroplasia by helping bones grow. Therefore, we conducted this study to examine the effect of different vosoritide doses on height from baseline (z-score), annualized growth velocity (AGV), the upper-to-lower body segment ratio (ULBR), and side effects. changes in growth velocity and the frequency of adverse effects.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis systematic review and dose-related meta-analyses follow the PRISMA guidelines, which meticulously screen and extract randomized controlled trials (RCTs) from four databases until April 2024 involving 220 patients. We used pairwise meta-analyses and assessed quality using the Cochrane Risk of Bias Tool.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eHigher Vosoritide doses (15 \u0026micro;g/kg or 15\u0026ndash;30 \u0026micro;g/kg) showed significantly greater improvements in height z-scores compared to lower doses (2.5 \u0026micro;g/kg or 7.5 \u0026micro;g/kg) or placebo. We observed similar trends for AGV. The 15 \u0026micro;g/kg dose displayed a significantly greater increase compared to both 2.5 \u0026micro;g/kg and 7.5 \u0026micro;g/kg. Interestingly, no significant difference was found between the 15 \u0026micro;g/kg and 30 \u0026micro;g/kg groups, suggesting a possible plateau effect at higher doses. Importantly, both the 15 \u0026micro;g/kg and 15\u0026ndash;30 \u0026micro;g/kg groups demonstrated statistically significant improvements in growth velocity compared to placebo. While most comparisons showed no significant changes in ULBR, one study reported a small increase in ULBR with the 15 \u0026micro;g/kg dose compared to the 2.5 \u0026micro;g/kg dose. Adverse effects were mild to moderate across all studies, with no severe effects reported.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eVosoritide improves achondroplasia growth in a dose-dependent manner. Higher doses (15 \u0026micro;g/kg or 15\u0026ndash;30 \u0026micro;g/kg) significantly increased height and growth velocity compared to lower doses or placebo. All adverse effects were mild to moderate. However, the impact on the ULBR and adverse effects require further investigation.\u003c/p\u003e","manuscriptTitle":"Efficacy and Safety of Vosoritide for Achondroplasia: A Systematic Review and Dose- Related Meta-Analysis, 2024 Article type: Systematic review and Dose-related Meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-03 19:04:30","doi":"10.21203/rs.3.rs-4451136/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9f920ed0-6579-4e32-9006-fa4b1de9ad9f","owner":[],"postedDate":"July 3rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-10-28T03:08:24+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-03 19:04:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4451136","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4451136","identity":"rs-4451136","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}