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Genes Oct 2022Hereditary metabolic bone diseases are characterized by genetic abnormalities in skeletal homeostasis and encompass one of the most diverse groups among rare diseases.... (Review)
Review
Hereditary metabolic bone diseases are characterized by genetic abnormalities in skeletal homeostasis and encompass one of the most diverse groups among rare diseases. In this review, we examine 25 selected hereditary metabolic bone diseases and recognized genetic variations of 78 genes that represent each of the three groups, including sclerosing bone disorders, disorders of defective bone mineralization and disorder of bone matrix and cartilage formation. We also review pathophysiology, manifestation and treatment for each disease. Advances in molecular genetics and basic sciences has led to accurate genetic diagnosis and novel effective therapeutic strategies for some diseases. For other diseases, the genetic basis and pathophysiology remain unclear. Further researches are therefore crucial to innovate ways to overcome diagnostic challenges and develop effective treatment options for these orphan diseases.
Topics: Humans; Bone Diseases, Metabolic; Rare Diseases
PubMed: 36292765
DOI: 10.3390/genes13101880 -
Clinical Pharmacokinetics Feb 2022Vosoritide, an analog of C-type natriuretic peptide, has been developed for the treatment of children with achondroplasia. The pharmacokinetics of vosoritide and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND OBJECTIVE
Vosoritide, an analog of C-type natriuretic peptide, has been developed for the treatment of children with achondroplasia. The pharmacokinetics of vosoritide and relationships between plasma exposure and efficacy, biomarkers, and safety endpoints were evaluated in a phase II, open-label, dose-escalation study (N = 35 patients aged 5-14 years who received daily subcutaneous injections for 24 months) and a phase III, double-blind, placebo-controlled study (N = 60 patients aged 5-18 years randomized to receive daily subcutaneous injections for 52 weeks).
METHODS
Pharmacokinetic parameters for both studies were obtained from non-compartmental analysis. Potential correlations between vosoritide exposure and changes in annualized growth velocity, collagen type X marker (CXM; a biomarker of endochondral ossification), cyclic guanosine monophosphate (cGMP; a biomarker of pharmacological activity), heart rate, and systolic and diastolic blood pressures were then evaluated.
RESULTS
The exposure-response relationships for changes in both annualized growth velocity and the CXM biomarker saturated at 15 μg/kg, while systemic pharmacological activity, as measured by urinary cGMP, was near maximal or saturated at exposures obtained at the highest dose studied (i.e. 30 μg/kg). This suggested that the additional bioactivity was likely in tissues not related to endochondral bone formation. In the phase III study, following subcutaneous administration at the recommended dose of 15 μg/kg to patients with achondroplasia aged 5-18 years, vosoritide was rapidly absorbed with a median time to maximal plasma concentration (C) of 15 minutes, and cleared with a mean half-life of 27.9 minutes after 52 weeks of treatment. Vosoritide exposure (C and area under the concentration-time curve [AUC]) was consistent across visits. No evidence of accumulation with once-daily dosing was observed. Total anti-vosoritide antibody (TAb) responses were detected in the serum of 25 of 60 (42%) treated patients in the phase III study, with no apparent impact of TAb development noted on annualized growth velocity or vosoritide exposure. Across the exposure range obtained with 15 µg/kg in the phase III study, no meaningful correlations between vosoritide plasma exposure and changes in annualized growth velocity or CXM, or changes from predose heart rate, and systolic or diastolic blood pressures were observed.
CONCLUSIONS
The results support the recommended dose of vosoritide 15 µg/kg for once-daily subcutaneous administration in patients with achondroplasia aged ≥ 5 years whose epiphyses are not closed.
CLINICAL TRIALS REGISTRATION
NCT02055157, NCT03197766, and NCT01603095.
Topics: Achondroplasia; Adolescent; Area Under Curve; Biomarkers; Child; Child, Preschool; Double-Blind Method; Humans; Injections, Subcutaneous; Natriuretic Peptide, C-Type
PubMed: 34431071
DOI: 10.1007/s40262-021-01059-1 -
Lancet (London, England) Sep 2020There are no effective therapies for achondroplasia. An open-label study suggested that vosoritide administration might increase growth velocity in children with... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
There are no effective therapies for achondroplasia. An open-label study suggested that vosoritide administration might increase growth velocity in children with achondroplasia. This phase 3 trial was designed to further assess these preliminary findings.
METHODS
This randomised, double-blind, phase 3, placebo-controlled, multicentre trial compared once-daily subcutaneous administration of vosoritide with placebo in children with achondroplasia. The trial was done in hospitals at 24 sites in seven countries (Australia, Germany, Japan, Spain, Turkey, the USA, and the UK). Eligible patients had a clinical diagnosis of achondroplasia, were ambulatory, had participated for 6 months in a baseline growth study and were aged 5 to less than 18 years at enrolment. Randomisation was done by means of a voice or web-response system, stratified according to sex and Tanner stage. Participants, investigators, and trial sponsor were masked to group assignment. Participants received either vosoritide 15·0 μg/kg or placebo, as allocated, for the duration of the 52-week treatment period administered by daily subcutaneous injections in their homes by trained caregivers. The primary endpoint was change from baseline in mean annualised growth velocity at 52 weeks in treated patients as compared with controls. All randomly assigned patients were included in the efficacy analyses (n=121). All patients who received one dose of vosoritide or placebo (n=121) were included in the safety analyses. The trial is complete and is registered, with EudraCT, number, 2015-003836-11.
FINDINGS
All participants were recruited from Dec 12, 2016, to Nov 7, 2018, with 60 assigned to receive vosoritide and 61 to receive placebo. Of 124 patients screened for eligibility, 121 patients were randomly assigned, and 119 patients completed the 52-week trial. The adjusted mean difference in annualised growth velocity between patients in the vosoritide group and placebo group was 1·57 cm/year in favour of vosoritide (95% CI [1·22-1·93]; two-sided p<0·0001). A total of 119 patients had at least one adverse event; vosoritide group, 59 (98%), and placebo group, 60 (98%). None of the serious adverse events were considered to be treatment related and no deaths occurred.
INTERPRETATION
Vosoritide is an effective treatment to increase growth in children with achondroplasia. It is not known whether final adult height will be increased, or what the harms of long-term therapy might be.
FUNDING
BioMarin Pharmaceutical.
Topics: Absorptiometry, Photon; Achondroplasia; Adolescent; Biomarkers; Body Height; Bone Density; Child; Child, Preschool; Collagen Type X; Double-Blind Method; Female; Humans; Injection Site Reaction; Injections, Subcutaneous; Male; Natriuretic Peptide, C-Type; Osteogenesis
PubMed: 32891212
DOI: 10.1016/S0140-6736(20)31541-5 -
Genetics in Medicine : Official Journal... Dec 2021Achondroplasia is caused by pathogenic variants in the fibroblast growth factor receptor 3 gene that lead to impaired endochondral ossification. Vosoritide, an analog of... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Achondroplasia is caused by pathogenic variants in the fibroblast growth factor receptor 3 gene that lead to impaired endochondral ossification. Vosoritide, an analog of C-type natriuretic peptide, stimulates endochondral bone growth and is in development for the treatment of achondroplasia. This phase 3 extension study was conducted to document the efficacy and safety of continuous, daily vosoritide treatment in children with achondroplasia, and the two-year results are reported.
METHODS
After completing at least six months of a baseline observational growth study, and 52 weeks in a double-blind, placebo-controlled study, participants were eligible to continue treatment in an open-label extension study, where all participants received vosoritide at a dose of 15.0 μg/kg/day.
RESULTS
In children randomized to vosoritide, annualized growth velocity increased from 4.26 cm/year at baseline to 5.39 cm/year at 52 weeks and 5.52 cm/year at week 104. In children who crossed over from placebo to vosoritide in the extension study, annualized growth velocity increased from 3.81 cm/year at week 52 to 5.43 cm/year at week 104. No new adverse effects of vosoritide were detected.
CONCLUSION
Vosoritide treatment has safe and persistent growth-promoting effects in children with achondroplasia treated daily for two years.
Topics: Achondroplasia; Child; Double-Blind Method; Humans; Natriuretic Peptide, C-Type; Treatment Outcome
PubMed: 34341520
DOI: 10.1038/s41436-021-01287-7 -
Genetics in Medicine : Official Journal... Dec 2022This study was undertaken to collect baseline growth parameters in children with achondroplasia who might enroll in interventional trials of vosoritide, and to establish... (Observational Study)
Observational Study
PURPOSE
This study was undertaken to collect baseline growth parameters in children with achondroplasia who might enroll in interventional trials of vosoritide, and to establish a historical control.
METHODS
In this prospective, observational study, participants (≤17 years) underwent a detailed medical history and physical examination and were followed every 3 months until they finished participating in the study by enrolling in an interventional trial or withdrawing.
RESULTS
A total of 363 children were enrolled (28 centers, 8 countries). Mean (SD) follow up was 20.4 (15.0) months. In participants <1 year, mean annualized growth velocity (AGV) was 11.6 cm/year for girls and 14.6 cm/year for boys. By age 1 year, mean AGV decreased to 7.4 cm/year in girls and 7.1 cm/year in boys. By age 10 years, mean AGV decreased to 3.6 cm/year for both sexes. Mean height z-score in participants <1 year was -2.5 for girls and -3.2 for boys and decreased up to the age 5 years (-5.3 for girls; -4.6 for boys). Girls and boys had a disproportionate upper-to-lower body segment ratio. Mean ratio was highest in participants aged <1 year (2.9 for girls; 2.8 for boys) and decreased gradually to approximately 2 in both sexes from 4 years of age onward.
CONCLUSION
This study represents one of the largest datasets of prospectively collected medical and longitudinal growth data in children with achondroplasia. It serves as a robust historical control to measure therapeutic interventions against and to further delineate the natural history of this condition.
Topics: Child; Male; Female; Humans; Child, Preschool; Prospective Studies; Achondroplasia; Body Height
PubMed: 36107167
DOI: 10.1016/j.gim.2022.08.015 -
The Lancet. Child & Adolescent Health Apr 2024Achondroplasia is the most common form of dwarfism in humans, caused by a common pathogenic variant in the gene encoding fibroblast growth factor receptor 3, FGFR3,... (Review)
Review
Achondroplasia is the most common form of dwarfism in humans, caused by a common pathogenic variant in the gene encoding fibroblast growth factor receptor 3, FGFR3, which impairs the process of endochondral ossification of the growing skeleton. In this Review, we outline the clinical and genetic hallmarks of achondroplasia and related FGFR3 conditions, the natural history and impact of achondroplasia over a patient's lifespan, and diagnosis and management options. We then focus on the new and emerging drug therapies that target the underlying pathogenesis of this condition. These new options are changing the natural growth patterns of achondroplasia, with the prospect of better long-term health outcomes for patients.
Topics: Child; Humans; Achondroplasia
PubMed: 38485412
DOI: 10.1016/S2352-4642(23)00310-3 -
The Lancet. Child & Adolescent Health Jan 2024Vosoritide is a recombinant C-type natriuretic peptide analogue that increases annualised growth velocity in children with achondroplasia aged 5-18 years. We aimed to... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Vosoritide is a recombinant C-type natriuretic peptide analogue that increases annualised growth velocity in children with achondroplasia aged 5-18 years. We aimed to assess the safety and efficacy of vosoritide in infants and children younger than 5 years.
METHODS
This double-blind, randomised, placebo-controlled, phase 2 trial was done in 16 hospitals across Australia, Japan, the UK, and the USA. Children younger than 60 months with a clinical diagnosis of achondroplasia confirmed by genetic testing and who had completed a baseline growth study or observation period were enrolled into one of three sequential cohorts based on age at screening: 24-59 months (cohort 1); 6-23 months (cohort 2); and 0-5 months (cohort 3). Each cohort included sentinels who received vosoritide to determine appropriate daily drug dose, with the remainder randomly assigned (1:1) within each age stratum (except in Japan, where participants were randomly assigned within each cohort) to receive daily subcutaneous injections of vosoritide (30·0 μg/kg for infants aged 0-23 months; 15·0 μg/kg for children aged 24-59 months) or placebo for 52 weeks. Participants, caregivers, investigators, and the sponsor were masked to treatment assignment. The first primary outcome was safety and tolerability, assessed in all participants who received at least one study dose. The second primary outcome was change in height Z score at 52 weeks from baseline, analysed in all randomly assigned participants. This trial is registered with EudraCT, 2016-003826-18, and ClinicalTrials.gov, NCT03583697.
FINDINGS
Between May 13, 2018, and March 1, 2021, 75 participants were recruited (37 [49%] females). 11 were assigned as sentinels, whereas 32 were randomly assigned to receive vosoritide and 32 placebo. Two participants discontinued treatment and the study: one in the vosoritide group (death) and one in the placebo group (withdrawal). Adverse events occurred in all 75 (100%) participants (annual rate 204·5 adverse events per patient in the vosoritide group and 73·6 per patient in the placebo group), most of which were transient injection-site reactions and injection-site erythema. Serious adverse events occurred in three (7%) participants in the vosoritide group (decreased oxygen saturation, respiratory syncytial virus bronchiolitis and sudden infant death syndrome, and pneumonia) and six (19%) participants in the placebo group (petit mal epilepsy, autism, gastroenteritis, vomiting and parainfluenza virus infection, respiratory distress, and skull fracture and otitis media). The least-squares mean difference for change from baseline in height Z score between the vosoritide and placebo groups was 0·25 (95% CI -0·02 to 0·53).
INTERPRETATION
Children with achondroplasia aged 3-59 months receiving vosoritide for 52 weeks had a mild adverse event profile and gain in the change in height Z score from baseline.
FUNDING
BioMarin Pharmaceutical.
Topics: Female; Humans; Infant; Male; Achondroplasia; Double-Blind Method; Gastroenteritis; Natriuretic Peptide, C-Type; Child, Preschool
PubMed: 37984383
DOI: 10.1016/S2352-4642(23)00265-1 -
European Journal of Pediatrics Mar 2024As 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... (Review)
Review
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.
Topics: Child; Humans; Growth Disorders; Human Growth Hormone; Growth Hormone; Turner Syndrome; Achondroplasia
PubMed: 37831302
DOI: 10.1007/s00431-023-05239-y