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Introduction: Achondroplasia is a heritable disorder of the skeleton that affects approximately 300,000 individuals worldwide. Until recently, treatment for this condition has been purely symptomatic. Efficacious treatment options for children are now approved or are in clinical trials. Areas covered: This review discusses key advances in the therapeutic management of children with achondroplasia, including vosoritide, the first approved drug, and other emerging precision therapies. These include navepegritide, a long-acting form of C-type natriuretic peptide, and infigratinib, a tyrosine kinase receptor inhibitor, summarizing trial outcomes to date. Expert opinion: The advent of the first approved precision therapy for achondroplasia in vosoritide has been a paradigm shifting advance for children affected by this condition. In addition to changing their natural growth history, it is hoped that it will decrease their medical complications and enhance functionality. These new treatment options highlight the importance of prompt prenatal identification and subsequent testing of a suspected fetus with achondroplasia and counseling of families. It is hoped that, in the near future, families will have the option to consider a range of effective targeted therapies that best suit their child with achondroplasia, starting from birth should they choose. [ABSTRACT FROM AUTHOR]

Introduction: Vosoritide is a C-type natriuretic peptide (CNP) analog that binds its receptor on chondrocytes, promoting growth by inhibiting the ERK1/2-MAPK pathway. We previously reported the results of a phase II study in children with hypochondroplasia. Vosoritide led to an average increase in annualized height velocity (AHV) of 1.81 cm/year and gain of 0.36 in height standard deviation (SD) over 12 months. We present here the pharmacokinetic/pharmacodynamic (PK/PD) data from this study and examine the correlations between these parameters and growth outcomes. Methods: We conducted a phase II trial of daily subcutaneous vosoritide (15 μg/kg/day) in 24 prepubertal subjects with hypochondroplasia (12 females, mean age 5.9 ± 2.3 years, mean height −3.29 + 0.68 SD). Plasma vosoritide levels were assayed using an electrochemiluminescence assay. PD markers including serum collagen X biomarker (CXM) and urine cyclic guanosine monophosphate (cGMP) production were measured at day 1, month 6, and month 12 visits. Pearson correlations and regression analyses were performed between PK and PD parameters and growth outcomes. Results: Vosoritide PK parameters were similar to those previously reported in patients with achondroplasia. CXM levels increased from a baseline mean of 22.5 ± 6.5 to 41.6 ± 15.9 ng/mL after 12 months of treatment (p < 0.0001). Urine cGMP increased within 1 h and peaked at 2 h after injection. The mean AUC for cGMP production was not significantly different at each study visit. The maximum change in cGMP AUC correlated with PK AUC (r = 0.46, p = 0.0001). However, drug exposure, as measured by average PK AUC, did not correlate with any growth outcome. CXM levels correlated with the prior 6-month interval height velocity (partial correlation coefficient = 0.40, p = 0.0048). However, change in CXM did not correlate with change in height velocity or change in height SD during treatment. Conclusions: Vosoritide treatment showed improvement in AHV and height SD in children with hypochondroplasia. PK analysis indicates that drug exposure was correlated to global CNP activity as measured by urine cGMP but did not correlate with growth outcomes. More studies are needed to identify specific patient characteristics that can predict response to therapy and clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: Achondroplasia is the most common form of skeletal disorder with disproportionate short stature. Vosoritide is the first disease-specific, precision pharmacotherapy to increase growth velocity in children with achondroplasia. Limb surgery is a standard approach to increase height and arm span, improve proportionality and functionality, as well as correcting deformities. The aim of this study was to gain expert opinion on the combined use of vosoritide and limb surgery in children and adolescents with achondroplasia. Methods: An international expert panel of 17 clinicians and orthopaedic surgeons was convened, and a modified Delphi process undertaken. The panel reviewed 120 statements for wording, removed any unnecessary statements, and added any that they felt were missing. There were 26 statements identified as facts that were not included in subsequent rounds of voting. A total of 97 statements were rated on a ten-point scale where 1 was 'Completely disagree' and 10 'Completely agree'. A score of ≥ 7 was identified as agreement, and ≤ 4 as disagreement. All experts who scored a statement ≤ 4 were invited to provide comments. Results: There was 100% agreement with several statements including, "Achieve a target height, arm span or upper limb length to improve daily activities" (mean level of agreement [LoA] 9.47, range 8–10), the "Involvement of a multidisciplinary team in a specialist centre to follow up the patient" (mean LoA 9.67, range 7–10), "Planning a treatment strategy based on age and pubertal stage" (mean LoA 9.60, range 8–10), and "Identification of short- and long-term goals, based on individualised treatment planning" (mean LoA 9.27, range 7–10), among others. The sequence of a combined approach and potential impact on the physes caused disagreement, largely due to a lack of available data. Conclusions: It is clear from the range of responses that this modified Delphi process is only the beginning of new considerations, now that a medical therapy for achondroplasia is available. Until data on a combined treatment approach are available, sharing expert opinion is a vital way of providing support and guidance to the clinical community. [ABSTRACT FROM AUTHOR]

Background: Achondroplasia, the most prevalent skeletal dysplasia, stems from a functional mutation in the fibroblast growth factor receptor 3 gene, leading to growth impairment. This condition presents multifaceted medical, functional and psychosocial challenges throughout childhood, adolescence and adulthood. Current management strategies aim to minimise medical complications, optimise functional capabilities and provide comprehensive supportive care. Vosoritide (trade name: VOXZOGO®, BioMarin Pharmaceuticals) is the first disease-modifying pharmaceutical treatment approved for the management of patients with achondroplasia and became available in Australia in May 2023. Methods: Standardised clinical guidelines for its optimal use are not yet widely available. To address this gap, a multidisciplinary Australian Vosoritide Working Group, comprising 12 experts with experience in achondroplasia management from across Australia, developed recommendations to guide the use of vosoritide in clinical practice. Results: The recommendations, which are expert opinions of the Australian Vosoritide Working Group, aim to (i) standardise the use of vosoritide across Australia, (ii) support the safe clinical rollout of vosoritide and (iii) support universal access. Conclusions: These recommendations have been developed for healthcare professionals and institutions that are engaged in using vosoritide in the management of achondroplasia and will be revised using a formal framework for clinical guideline development once more evidence is available. [ABSTRACT FROM AUTHOR]

As we continue to understand more about the complex mechanism of growth, a plethora of novel therapies have recently been developed that aim to address barriers and optimize efficacy. This review aims to explore these novel therapies and provide a succinct review based on the latest clinical studies in order to introduce clinicians to therapies that will soon constitute the future in the field of short stature. Conclusion: The review focuses on long-acting growth hormone formulations, a novel growth hormone oral secretagogue, novel treatments for children with achondroplasia, and targeted therapies for rare forms of skeletal dysplasias. What is Known: • Recombinant human growth hormone has been the mainstay of treatment for children with short stature for years. • Such therapy is not always effective based on the underlying diagnosis (e.g achondroplasia, Turner syndrome). Compliance with daily injections is challenging and can directly affect efficacy. What is New: • Recent development of long-acting growth hormone regimens and oral secretagogues can overcome some of these barriers, however several limitations need to be taken into consideration. • Newer therapies for achondroplasia, and other rare forms of skeletal dysplasias introduce us to a new era of targeted therapies for children with short stature. Clinicians ought to be aware of pitfalls and caveats before introducing these novel therapies to every day practice. [ABSTRACT FROM AUTHOR]

Introduction: Vosoritide is the first precision medical therapy approved to increase growth velocity in children with achondroplasia. Sharing early prescribing experiences across different regions could provide a framework for developing practical guidance for the real-world use of vosoritide. Methods: Two meetings were held to gather insight and early experience from experts in Europe, the Middle East, and the USA. The group comprised geneticists, pediatric endocrinologists, pediatricians, and orthopedic surgeons. Current practices and considerations for vosoritide were discussed, including administration practicalities, assessments, and how to manage expectations. Results: A crucial step in the management of achondroplasia is to determine if adequate multidisciplinary support is in place. Training for families is essential, including practical information on administration of vosoritide, and how to recognize and manage injection-site reactions. Advocated techniques include establishing a routine, empowering patients by allowing them to choose injection sites, and managing pain. Patients may discontinue vosoritide if they cannot tolerate daily injections or are invited to participate in a clinical trial. Clinicians in Europe and the Middle East emphasized the importance of assessing adherence to daily injections, as non-adherence may impact response and reimbursement. Protocols for monitoring patients receiving vosoritide may be influenced by regional differences in reimbursement and healthcare systems. Core assessments may include pubertal staging, anthropometry, radiography to confirm open physes, the review of adverse events, and discussion of concomitant or new medications—but timing of these assessments may also differ regionally and vary across institutions. Patients and families should be informed that response to vosoritide can vary in both magnitude and timing. Keeping families informed regarding vosoritide clinical trial data is encouraged. Conclusion: The early real-world experience with vosoritide is generally positive. Sharing these insights is important to increase understanding of the practicalities of treatment with vosoritide in the clinical setting. [ABSTRACT FROM AUTHOR]

Background: Several novel treatment options have recently become available in childhood bone diseases. The purpose of this article is to provide an update on some of the therapeutic agents used in the treatment of pediatric osteoporosis, X-linked hypophosphatemic rickets, and achondroplasia (ACH). Summary: Vitamin D3 and Ca supplementation remains the basis of childhood osteoporosis treatment. Bisphosphonate (BP) therapy is the main antiresorptive therapeutic option, while denosumab, a human monoclonal IgG2 antibody with high affinity and specificity for a primary regulator of bone resorption – RANKL, represents a possible alternative. Its potent inhibition of bone resorption and turnover process leads to continuous increase of bone mineral density throughout the treatment also in the pediatric population. With a half-life much shorter than BPs, its effects are rapidly reversible upon discontinuation. Safety and dosing concerns in children remain. Novel treatment options have recently become available in two rare bone diseases. Burosumab, a monoclonal antibody against FGF-23, has been approved for the treatment of children with X-linked hypophosphatemic rickets older than 1 year. It presents an effective, more etiology-based treatment for rickets compared to conventional therapy, without the need for multiple daily oral phosphate supplementation. Its long-term efficacy and safety are currently being investigated. After years of anticipation, a novel treatment option for ACH has become available. C-type natriuretic peptide analog vosoritide effectively increases proportional growth and has a reasonable safety profile in children >2 years. Its effect on other features of the disease and the final height is yet to be determined. Several other treatment options for ACH exploring different therapeutic approaches are currently being investigated. Key Messages: Denosumab is effective in the treatment of childhood-onset osteoporosis; however, further studies are necessary to determine the optimal treatment protocol. Burosumab is more etiology-based and convenient in comparison to conventional treatment of X-linked hypophospha--temic rickets in children and adults. Vosoritide importantly changes the natural course of achondroplasia, at least in the short term. [ABSTRACT FROM AUTHOR]

Background: Achondroplasia, the most prevalent skeletal dysplasia, stems from a functional mutation in the fibroblast growth factor receptor 3 gene, leading to growth impairment. This condition presents multifaceted medical, functional and psychosocial challenges throughout childhood, adolescence and adulthood. Current management strategies aim to minimise medical complications, optimise functional capabilities and provide comprehensive supportive care. Vosoritide (trade name: VOXZOGO®, BioMarin Pharmaceuticals) is the first disease-modifying pharmaceutical treatment approved for the management of patients with achondroplasia and became available in Australia in May 2023. Methods: Standardised clinical guidelines for its optimal use are not yet widely available. To address this gap, a multidisciplinary Australian Vosoritide Working Group, comprising 12 experts with experience in achondroplasia management from across Australia, developed recommendations to guide the use of vosoritide in clinical practice. Results: The recommendations, which are expert opinions of the Australian Vosoritide Working Group, aim to (i) standardise the use of vosoritide across Australia, (ii) support the safe clinical rollout of vosoritide and (iii) support universal access. Conclusions: These recommendations have been developed for healthcare professionals and institutions that are engaged in using vosoritide in the management of achondroplasia and will be revised using a formal framework for clinical guideline development once more evidence is available.

Background: Achondroplasia is the most common form of skeletal dysplasia. Recent advances in therapeutic options have highlighted the need for understanding the burden and treatment landscape of the condition. This systematic literature review (SLR) aimed to identify health-related quality of life (HRQoL)/utilities, healthcare resource use (HCRU), costs, efficacy, safety and economic evaluation data in achondroplasia and to identify gaps in the research. Methods: Searches of MEDLINE, Embase, the University of York Centre for Reviews and Dissemination (CRD), the Cochrane Library and grey literature were performed. Articles were screened against pre-specified eligibility criteria by two individuals and study quality was assessed using published checklists. Additional targeted searches were conducted to identify management guidelines. Results: Fifty-nine unique studies were included. Results demonstrated a substantial HRQoL and HCRU/cost-related burden of achondroplasia on affected individuals and their families throughout their lifetimes, particularly in emotional wellbeing and hospitalisation costs and resource use. Vosoritide, growth hormone (GH) and limb lengthening all conferred benefits for height or growth velocity; however, the long-term effects of GH therapy were unclear, data for vosoritide were from a limited number of studies, and limb lengthening was associated with complications. Included management guidelines varied widely in their scope, with the first global effort to standardise achondroplasia management represented by the International Achondroplasia Consensus Statement published at the end of 2021. Current evidence gaps include a lack of utility and cost-effectiveness data for achondroplasia and its treatments. Conclusions: This SLR provides a comprehensive overview of the current burden and treatment landscape for achondroplasia, along with areas where evidence is lacking. This review should be updated as new evidence becomes available on emerging therapies. [ABSTRACT FROM AUTHOR]

Introduction: Vosoritide is the first approved pharmacological treatment for achondroplasia and is indicated for at-home injectable administration by a trained caregiver. This research aimed to explore parents' and children's experience of initiating vosoritide and administering this treatment at home. Methods: Qualitative telephone interviews were conducted with parents of children being treated with vosoritide in France and Germany. Interviews were transcribed and analysed using thematic analysis. Results: Fifteen parents participated in telephone interviews in September and October 2022. The median age of children in this sample was 8 years old (range 3–13 years) and children had been taking treatment from 6 weeks to 13 months. Four themes document families' experience with vosoritide: (1) awareness of vosoritide treatment, uncovering that parents first heard of vosoritide through their own research, patient advocacy groups, or through their physicians; (2) treatment understanding and decision-making, which found that their decision to take treatment is based on a desire to relieve future medical complications and increase height for improved independence, and they consider the extent to which the treatment has severe side effects; (3) training and initiation, which showed that the hospital initiation and training sessions varied considerably both across and within countries, with different treatment centres taking different approaches; and (4) managing treatment at home brings psychological and practical challenges, which are ultimately overcome with perseverance and available support. Conclusions: Parents and children are resilient to challenges posed by a daily injectable treatment and highly motivated to improve their quality of life. Parents are prepared to overcome short-term treatment challenges for future gains in terms of health and functional independence for their children. Greater support could ensure they have the right information to initiate treatment and manage treatment at home, which will improve parents' and children's experience. [ABSTRACT FROM AUTHOR]

Background: Achondroplasia, due to a specific pathogenic variant in FGFR3, is the most common viable skeletal dysplasia and the diagnosis is mostly done in the prenatal period. Since 2021, the use of Vosoritide, a specific treatment for achondroplasia, validated in phase 3 placebo-controlled trials, has been recommended to significantly increase the height of children and infants. In the light of these new therapeutic prospects, a complete understanding of the pathophysiology of skeletal damages occurring from foetal life is required., Objectives: To describe foetal imaging and the antenatal and postnatal management of pregnancies complicated by a diagnosis of foetal achondroplasia., Methods: A retrospective and descriptive study, including all pregnant women with a prenatal diagnosis of achondroplasia, was conducted in the prenatal unit of Necker Hospital (Paris, France) between 2009 and 2022. Maternal and obstetric characteristics and foetal imaging (ultrasound and bone CT) were collected. Pregnancy outcomes, paediatric follow-up in the case of live births, and post-mortem examination (PME) data in the case of termination of pregnancy were reported. In addition, we have prospectively developed a specific research protocol using foetal brain MRI to assess the anatomy of the foramen magnum, following the same approach currently recommended in the postnatal period., Results: 29 cases of achondroplasia were included. Median gestational age at referral was 31 +2 weeks', about 1 week after the suspected diagnosis on routine ultrasound. Shortening of the femoral length and of all the other long bones, macrocephaly, facial abnormalities, increased metaphyseal-diaphyseal angle and tapering of the proximal femoral bone were the five most prevalent ultrasound signs. Foetal diagnosis was done by the identification of the foetal FGFR3 mutation and/or by CT scans (n = 15) where specific abnormalities of the long bones, platyspondyly and abnormal profile have been described in 100 % of cases. PME revealed: i) on external examinations (n = 7) that all fetuses had very short long bones, moderate platyspondyly, small iliac wings with internal spines, macrocrania, and narrow thorax, ii) on internal examination (n = 5) all had severe abnormalities in the growth plate and particularities in the temporal cortex and hippocampal region. One foetal MRI was performed at 33 weeks' and revealed tight stenosis of the foramen magnum and compression of the spinal cord. Of the live-born infants for whom follow-up was known (n = 6), 2/6 (including the case who had a foetal MRI) required neurosurgical intervention in the first few months of life for spinal cord compression due to severe stenosis of the foramen magnum., Conclusion: A complete mapping of the skeletal features present in foetuses with achondroplasia is reported here, providing a better understanding of the pathophysiology of this condition. New tools such as foetal MRI, to assess the risk of postnatal severe neurological complications, could help improve the care pathway of the affected neonates., Competing Interests: Declaration of competing interest The authors have no competing interests inside this work to declare, (Copyright © 2024. Published by Elsevier Masson SAS.)

Introduction: Patients with achondroplasia present, in addition to disproportionate short stature, multiple manifestations that require a comprehensive approach. The present consensus of experts in Spain responds to the need to establish clear guidelines for the management of achondroplasia with the introduction of a new treatment, vosoritide., Material and Methods: A panel of six experts in achondroplasia participated in the development of the consensus. They developed a narrative review of the recommendations on achondroplasia and vosoritide treatment, which were agreed upon and adapted to the Spanish context in two subsequent meetings with a structured discussion format., Results: This protocol underscores that achondroplasia requires specialised and multidisciplinary management involving expert paediatricians and specialists in paediatric endocrinology or medical genetics, in collaboration with specialists in neurology, neurosurgery, pneumology, otorhinolaryngology, rehabilitation, and orthopaedics or psychology, among others, with adequate coordination of care. This interdisciplinary team should be involved in the planning of vosoritide treatment (including the education of patients and caregivers, with management of their expectations, and their training in the practical aspects of vosoritide administration), treatment initiation and close monitoring with regular assessment of anthropometric, biochemical, functional or patient-reported variables., Conclusions: This protocol for the administration of vosoritide will allow standardised implementation and optimization of treatment outcomes. It also offers an opportunity to improve the management of achondroplasia in Spain through a comprehensive and interdisciplinary approach., (Copyright © 2024. Published by Elsevier España, S.L.U.)

Purpose: Evaluate the impact of vosoritide on health-related quality of life in children with achondroplasia., Methods: Participants received vosoritide (15 μg/kg/day) in an extension trial (NCT03424018) after having participated in a placebo-controlled trial (NCT03197766)., Results: The population comprised 119 participants (mean [SD] age 9.7 [2.6] years). Mean treatment duration was 4 (0.78) years. At year 3, the largest mean (SD) changes were observed in the Quality of Life of Short Stature Youth physical score (5.99 [19.41], caregiver reported; 6.32 [20.15], self-reported) and social score (2.85 [8.29] and 6.76 [22.64], respectively). Changes were greatest in participants with ≥1 SD increase in height z-score (physical: 11.36 [19.51], caregiver-reported [n = 38]; 8.48 [21.83], self-reported [n = 28]) (social: 5.84 [15.45] and 9.79 [22.80], respectively). To determine how domain scores may change with age in untreated persons, models were produced using observational/untreated-person data. A 1-year increase in age was associated with a change of 0.16 (SE, 0.55) and 0.16 (0.50), for caregiver-reported physical and social domain scores, respectively. Self-reported scores changed by 1.45 (0.71) and 1.92 (0.77), respectively., Conclusion: These data suggest that after 3 years of treatment, vosoritide demonstrates a positive effect on physical and social functioning among children with achondroplasia, particularly in children with a more pronounced change in height z-score., Competing Interests: Conflict of Interest All authors were investigators in this clinical trial except for Richard Rowell, Andrea Low, Ian Sabir, Alice Huntsman-Labed, and Jonathan Day, who are employees of the funder (BioMarin). Antonio Leiva-Gea has received consulting fees from BioMarin, has participated as a clinical trial investigator for BioMarin and QED Therapeutics, has received speaker fees from BioMarin, MBA, and EAF, and has received travel support from BioMarin and MBA. Carlos A. Bacino has received consulting fees from BioMarin and has participated as clinical trial investigator for Roche, BioMarin and Ascendis. Carlos E. Prada has received consulting fees from BioMarin, Sanofi, and Takeda, has participated as a clinical trial investigator for BioMarin, Sanofi, Hemoshear, and Prevail, and has received speaker payments from Sanofi. Julie E. Hoover-Fong has received consulting fees from BioMarin, Ascendis, QED Therapeutics, Innoskel, and Tyra, has received research grants from Alexion, has participated as a clinical trial investigator for BioMarin, QED Therapeutics, and Pfizer/Therachon, has received speaker fees from Medscape, and has received travel support from BioMarin, QED Therapeutics, and Tyra. Klaus Mohnike has received consulting payments from BioMarin, QED Therapeutics and Novo Nordisk, has participated as a clinical trial investigator for BioMarin, and has received speaker fees and travel support from BioMarin and Novo Nordisk. Lynda E. Polgreen has received consulting fees from BioMarin, Lysogene, and Denali, has participated as a clinical trial investigator for BioMarin, Pfizer, and Takeda, and has received travel support from BioMarin. Melita Irving has received consulting fees from BioMarin, QED Therapeutics/Bridge Bio, Ascendis, Sanofi, and Tyra, has participated as a clinical trial investigator for BioMarin, QED Therapeutics/Bridge Bio, and Ascendis, has received speaker fees from BioMarin, QED Therapeutics/Bridge Bio, Ascendis, Ipsen, and Sandoz, and has received travel support from BioMarin, QED Therapeutics/Bridge Bio, and Ascendis. Paul Harmatz has received consultancy fees from Grace Science, Rallybio, Neurogene, Novel Pharma, and Orchard Therapeutics, has received speaker fees, travel support, and travel grants from BioMarin, has received research funding from Adrenas, Amicus, Ascendis, ASPA, Azafaros, BioMarin, Calcilytics, Denali, Homology, JCR Pharmaceuticals, Orphazyme, QED Therapeutics, RegenXbio, Sangamo, Takeda, Idorsia, Prevail,and Allievex, and has participated as a clinical trial investigator for BioMarin. Ravi Savarirayan has received consulting fees and travel support from BioMarin, QED Therapeutics, and Ascendis, and has participated as a clinical trial investigator for BioMarin, QED Therapeutics, Ascendis, and Sanofi. Takuo Kubota has received speaker payments from BioMarin and Novo Nordisk and research grants from Eli Lilly. William R. Wilcox has received consulting fees from BioMarin and has participated as a clinical trial investigator for BioMarin. All other authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

In recent years, new therapies for the treatment of rare pediatric bone disorders have emerged, guided by an increasing understanding of the genetic and molecular etiology of these diseases. Herein, we review three such disorders, impacted by debilitating deficits in bone mineralization or cartilage ossification, as well as the novel disease-modifying drugs that are now available to treat these conditions. Specifically, we discuss asfotase alfa, burosumab-twza, and vosoritide, for the treatment of hypophosphatasia, X-linked hypophosphatemia and achondroplasia, respectively. For each skeletal disorder, an overview of the clinical phenotype and natural history of disease is provided, along with a discussion of the clinical pharmacology, mechanism of action and FDA indication for the relevant medication. In each case, a brief review of clinical trial data supporting drug development for each medication is provided. Additionally, guidance as to drug dosing and long-term monitoring of adverse events and pediatric efficacy is presented, to aid the clinician seeking to utilize these novel therapies in their practice, or to become familiar with the healthcare expectations for children receiving these medications through specialized multidisciplinary clinics. The availability of these targeted therapies now significantly augments treatment options for conditions in which past therapy has relied upon less specific, symptomatic medical and orthopedic care.

Introduction Achondroplasia (ACP) is a common skeletal dysplasia. Vozoritide is the first drug that has an effect on the pathogenesis of impaired enchondral growth in achondroplasia. Clinical trials of the second and third phases have shown its effectiveness according to the latest literature data presented. After providing scientifically grounded information, a questionnaire was completed by parents of children with ACP to have their opinion before the introduction of the drug into medical practice. Materials and methods The survey was conducted on June 21-24, 2021 at the Ilizarov Center supported by the patient’s organization Small People Support Center for Patients with Achondroplasia and Other Bone Dysplasias and Their Families. The questionnaire included 5 questions, compiled by the first author of this study. 65 completed questionnaires were received for the analysis. Results and discussion The overwhelming majority of parents have confidence in the use of vozoritide as a means of achieving targeted growth which may allow to avoid surgical treatment. However, the parallel use of this drug and surgical treatment for incomplete growth of a child is not excluded if the growth graphs show that the required parameters have not been achieved by the time the growth zones are closed. Despite the fact that at present only the influence of vozoritide on the growth of a child with ACP has been reliably proven, parents feel confident with the information about the possible effect of the drug on other problems associated with impaired enchondral growth, and are ready to start therapy at an earlier age and for a longer period. Parents do not oppose the pharmacological treatment to surgical treatment. Vozoritide is seen as the main component of treatment, and surgery as a complementary one that follows (if necessary). This reasonable combination increases the parents' confidence in the predicted favorable treatment outcome.

Background: Achondroplasia is associated with disproportionate short stature and significant and potentially severe medical complications. Vosoritide is the first medicine to treat the underlying cause of achondroplasia and data from phase 3 and phase 2 extension studies showed effects on growth and body proportions. However, there are currently no long-term data available on the direct impact on endpoints such as medical complications and health-related quality of life (HRQoL). This study explored the perceived impact of achondroplasia on medical complications, HRQoL, healthcare resource use and mortality, and potential modifying effects of vosoritide, based on published evidence and expert opinion. Structured expert opinion was obtained by an international modified Delphi study among 14 experts in managing achondroplasia performed on a virtual platform and consisting of an explorative phase followed by an anonymous individual rating round.Results: Overall, the panelists expect that in individuals starting long-term treatment between 2 years of age and puberty, growth velocity increases observed in the clinical trials will be maintained until final height is reached (92% agreement) and will likely result in clinically meaningful improvements in upper-to-lower body segment ratio (85%). Earlier treatment initiation will likely result in a greater final height (100%) and more likely improve proportionality (92%) than later treatment. Although current data are limited, ≥ 75% of panelists find it conceivable that the earlier long-term treatment is started, the greater the probability of a positive effect on the lifetime incidence of symptomatic spinal stenosis, kyphosis, obstructive sleep apnea, and foramen magnum stenosis. These are among the most clinically important complications of achondroplasia because of their high impact on comorbidity, mortality, and/or HRQoL. A positive effect of vosoritide on the incidence of surgeries through lifetime was considered more likely with earlier long-term treatment (90%).Conclusions: This explorative study, based on international expert opinion, provides further insight into the medical and functional impacts of achondroplasia and how these might be modified through long-term use of vosoritide. The results can be used to guide the direction and design of future research to validate the assumptions and to discuss potential treatment outcomes with disease modifying therapies with families and clinicians. [ABSTRACT FROM AUTHOR]

Activating mutations in the FGFR3 receptor tyrosine kinase lead to most prevalent form of genetic dwarfism in humans, the achondroplasia. Many features of the complex function of FGFR3 in growing skeleton were characterized, which facilitated identification of therapy targets, and drove progress toward treatment. In August 2021, the vosoritide was approved for treatment of achondroplasia, which is based on a stable variant of the C-natriuretic peptide. Other drugs may soon follow, as several conceptually different inhibitors of FGFR3 signaling progress through clinical trials. Here, we review the current achondroplasia therapeutics, describe their mechanisms, and illuminate motivations leading to their development. We also discuss perspectives of curing achondroplasia, and options for repurposing achondroplasia drugs for dwarfing conditions unrelated to FGFR3. [ABSTRACT FROM AUTHOR]

Not available [JBCGenetics 2022; 5(2.000): 059-060]

Short stature is one of the most common reasons for referral to pediatric endocrinologists. The vast majority of short children do not have growth hormone (GH) deficiency or another pathologic process that is interfering with normal growth. While GH has been approved in the US for several etiologies of non-GH deficient short stature, its high cost and need for daily injections represent barriers for many families. Alternative agents for the management of short stature include the use of gonadotropin releasing hormone analogs (GnRHas) to delay puberty, and aromatase inhibitors (AIs) in boys to postpone epiphyseal fusion. The results of studies employing GnRHas as either monotherapy or combined with GH are mixed, and there is a dearth of rigorously designed clinical trials that have followed patients to adult height. While AIs have been found to result in modest increases in adult height in some studies, important questions about their long-term safety exist. The C-type natriuretic peptide analog vosoritide is an experimental agent that is emerging as a potential treatment for a few specific conditions including achondroplasia, although its efficacy in attenuating disproportionality is as yet unproven. While each of these therapeutic strategies holds promise, none are currently considered standard of care and several important questions remain. These include the impact of these interventions on quality of life as well as long-term outcomes. [ABSTRACT FROM AUTHOR]

Achondroplasia, characterized by short stature and skeletal abnormalities, is caused by a gain-of-function variant in the fibroblast growth factor receptor 3 gene. Vosoritide, a C-type natriuretic peptide analog, is an emerging treatment for achondroplasia that functions by promoting endochondral ossification. Vosoritide was approved for the treatment of achondroplasia in Europe and the United States in 2021, and in Japan, the following year. However, vosoritide is associated with a risk of hypotension and vomiting after subcutaneous injection due to its vasodilating effect. Herein, we present two cases of cardiovascular adverse events in infants following vosoritide injection. Case 1 involved a one-month-old female infant with achondroplasia who received the first subcutaneous injection of vosoritide 30 minutes after her last formula intake. Following injection, she developed transient symptomatic hypotension accompanied by vomiting. Although established guidelines recommend that injections be administered after approximately 30 minutes (Europe/Japan) or within one hour (USA) following the last feeding, an extended interval of 1.5 to two hours was required to prevent hypotension-associated vomiting. Case 2 involved a three-month-old female infant with achondroplasia. The first subcutaneous vosoritide injection was administered four hours after the last formula intake, and she subsequently developed prolonged compensated shock with marked tachycardia requiring intervention, including repetitive bolus saline injection. These cases indicate the need to monitor patients for cardiovascular adverse events following subcutaneous injection of vosoritide in early infancy., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Nishioka et al.)

Background: Hypochondroplasia is a rare autosomal dominant skeletal dysplasia due to activating variants in FGFR3 . It presents with disproportionate short stature with a wide range of clinical severity. There are currently no approved medications to treat short stature in children with hypochondroplasia. Vosoritide is a C-type natriuretic peptide analog that was recently approved for improving growth in children with achondroplasia. We aimed to evaluate the safety and efficacy of vosoritide in children with hypochondroplasia., Methods: We conducted a single-arm, phase 2, open-label trial at a single centre in the USA and enrolled 26 children with hypochondroplasia. The trial consists of a 6-month observation period to establish a baseline annualized growth velocity followed by a 12-month intervention period during which vosoritide is administered daily via subcutaneous injection at a dose of 15 μg/kg/day. The trial's co-primary endpoints included the incidence of adverse events and the change from baseline in age-sex standardized annualized growth velocity and height standardized deviation score (SDS) after 12 months of treatment. This trial is registered with ClinicalTrials.gov (NCT04219007)., Findings: Twenty-four participants with a mean age of 5.86 years received vosoritide therapy. The first participant was enrolled on August 4, 2020, and the final participant completed the 18-month trial on September 8, 2023. Vosoritide was well tolerated with no treatment-related serious adverse events. Injection site reactions occurred in 83.3% of participants. No participants discontinued therapy due to an adverse event. Annualized growth velocity increased by 2.26 standard deviations (SD) and height SDS increased by 0.36 SD during the treatment period versus the observation period. Hypochondroplasia specific height SDS increased by 0.38 SD. There was a 1.81 cm/year increase in absolute annualized growth velocity., Interpretation: Vosoritide was safe and effective in increasing growth velocity in children with hypochondroplasia. Efficacy was similar to what has been reported in children with achondroplasia., Funding: This study was supported by an investigator-initiated grant from BioMarin Pharmaceutical., Competing Interests: AD and NM have served as consultants for BioMarin, but all compensation has been paid to Children's National Hospital and neither author has received any personal compensation from BioMarin. AD received an investigator-initiated grant from BioMarin to fund the current study. RKS has received an investigator-initiated grant from BioMarin to fund a study of vosoritide in girls with Turner syndrome. The remaining authors have nothing to disclose., (© 2024 The Author(s).)

Dwarfism is a rare condition characterized by small stature. Achondroplasia is predominantly considered the leading cause of dwarfism. Although the condition is not life-threatening, it dramatically impacts the social life of the patient. The United States Food and Drug Administration (US FDA) first approved the drug Voxzogo (vosoritide) for achondroplasia. The drug also received approval from the European Medicines Agency (EMA) via the centralized procedure. The drug is associated with a decrease in blood pressure, a severe adverse event. However, this adverse event/risk has been overcome by benefits, i.e . fulfilling of unmet medical need. In the United States, the drug received accelerated approval as it satisfied the criteria of rare pediatric disease. This review includes a detailed orphan drug approval process with particular reference to vosoritide, which is considered a milestone for the treatment of achondroplasia., Competing Interests: The authors have no conflicts of interest to disclose., (2023, International Research and Cooperation Association for Bio & Socio - Sciences Advancement.)

Competing Interests: The authors declare no conflicts of interest.

In recent years, new therapies for the treatment of rare pediatric bone disorders have emerged, guided by an increasing understanding of the genetic and molecular etiology of these diseases. Herein, we review three such disorders, impacted by debilitating deficits in bone mineralization or cartilage ossification, as well as the novel disease-modifying drugs that are now available to treat these conditions. Specifically, we discuss asfotase alfa, burosumab-twza, and vosoritide, for the treatment of hypophosphatasia, X-linked hypophosphatemia and achondroplasia, respectively. For each skeletal disorder, an overview of the clinical phenotype and natural history of disease is provided, along with a discussion of the clinical pharmacology, mechanism of action and FDA indication for the relevant medication. In each case, a brief review of clinical trial data supporting drug development for each medication is provided. Additionally, guidance as to drug dosing and long-term monitoring of adverse events and pediatric efficacy is presented, to aid the clinician seeking to utilize these novel therapies in their practice, or to become familiar with the healthcare expectations for children receiving these medications through specialized multidisciplinary clinics. The availability of these targeted therapies now significantly augments treatment options for conditions in which past therapy has relied upon less specific, symptomatic medical and orthopedic care., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Thrailkill, Kalaitzoglou and Fowlkes.)

Achondroplasia is the commonest form of dwarfism and results from a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene on chromosome 4p16.3. The mutation is at nucleotide 1138 resulting in a G-to-A transition (134934.0001). This condition is characterized by full penetration meaning that everyone with this genetic mutation will exhibit the phenotypic characteristics of achondroplasia. It is a gain-of function mutation that causes increased inhibition of cartilage formation. C-type natriuretic peptide (CNP) acts on the growth plate through the natriuretic peptide receptor-B (NPR-B) causing the transformation of guanosine 5'-triphosphate into cyclic guanosine monophosphate. However, CNP cannot be used in the treatment of achondroplasia because it is rapidly degraded by neutral endopeptidase. Vosoritide is a modified recombinant human CNP and has a half-life 10 times that of CNP. Clinical trials have demonstrated that vosoritide is effective in significantly increasing the annualized growth velocity in children with achondroplasia before the fusion of the epiphyses., (Copyright 2022 Clarivate.)

From the medical, pharmaceutical, and social perspectives, 2021 has been a year dominated by the COVID-19 pandemic. However, despite this global health crisis, the pharmaceutical industry has continued its endeavors, and 2021 could be considered an excellent year in terms of the drugs accepted by the US Food and Drug Administration (FDA). Thus, during this year, the FDA has approved 50 novel drugs, of which 36 are new chemical entities and 14 biologics. It has also authorized 10 TIDES (8 peptides, 2 oligonucleotides), in addition to 2 antibody-drug conjugates (ADCs) whose structures contain peptides. Thus, TIDES have accounted for about 24% of the approvals in the various drug categories. Importantly, this percentage has surpassed the figure in 2020 (10%), thus reflecting the remarkable success of TIDES. In this review, the approved TIDE-based drugs are analyzed on the basis of their chemical structure, medical target, mode of action, administration route, and adverse effects.