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EClinicalMedicine Nov 2023TransCon CNP (navepegritide) is an investigational prodrug of C-type natriuretic peptide (CNP) designed to allow for continuous CNP exposure with once-weekly dosing....
Once-weekly TransCon CNP (navepegritide) in children with achondroplasia (ACcomplisH): a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-escalation trial.
BACKGROUND
TransCon CNP (navepegritide) is an investigational prodrug of C-type natriuretic peptide (CNP) designed to allow for continuous CNP exposure with once-weekly dosing. This 52-week phase 2 (ACcomplisH) trial assessed the safety and efficacy of TransCon CNP in children with achondroplasia.
METHODS
ACcomplisH is a global, randomised, double-blind, placebo-controlled, dose-escalation trial. Study participants were recruited between June 10, 2020, and September 24, 2021. Eligible participants were prepubertal, aged 2-10 years, with genetically confirmed achondroplasia, and randomised 3:1 to once-weekly subcutaneous injections of TransCon CNP (6, 20, 50, or 100 μg CNP/kg/week) or placebo for 52 weeks. Primary objectives were safety and annualised growth velocity (AGV). ACcomplisH is registered with ClinicalTrials.gov (NCT04085523) and Eudra (CT 2019-002754-22).
FINDINGS
Forty-two participants received TransCon CNP at doses of 6 μg (n = 10; 7 female), 20 μg (n = 11; 3 female), 50 μg (n = 10; 3 female), or 100 μg (n = 11; 6 female) CNP/kg/week, with 15 receiving placebo (5 female). Treatment-emergent adverse events (TEAEs) were mild or moderate with no grade 3/4 events reported. There were 2 serious TEAEs that were assessed as not related to TransCon CNP. Eleven injection site reactions occurred in 8 participants receiving TransCon CNP and no symptomatic hypotension occurred. TransCon CNP demonstrated a dose-dependent improvement in AGV. At 52 weeks, TransCon CNP 100 μg CNP/kg/week significantly improved AGV vs placebo (least squares mean [95% CI] 5.42 [4.74-6.11] vs 4.35 [3.75-4.94] cm/year; p = 0.0218), and improved achondroplasia-specific height SDS from baseline (least squares mean [95% CI] 0.22 [0.02-0·41] vs -0·08 [-0.25 to 0.10]; p = 0.0283). All participants completed the randomised period and continued in the ongoing open-label extension period receiving TransCon CNP 100 μg CNP/kg/week.
INTERPRETATION
This phase 2 trial suggests that TransCon CNP is effective, safe, with low injection site reaction frequency, and may provide a novel, once-weekly treatment option for children with achondroplasia. These results support TransCon CNP at 100 μg CNP/kg/week in the ongoing pivotal trial.
FUNDING
Ascendis Pharma, A/S.
PubMed: 37823031
DOI: 10.1016/j.eclinm.2023.102258 -
Orphanet Journal of Rare Diseases Oct 2023Achondroplasia is an autosomal dominant disorder mainly affecting bony growth, typically resulting in markedly short stature. From a neurosurgical viewpoint, patients...
BACKGROUND
Achondroplasia is an autosomal dominant disorder mainly affecting bony growth, typically resulting in markedly short stature. From a neurosurgical viewpoint, patients sometimes develop spinal cord compression at the narrowed foramen magnum and hydrocephalus. This study aims to construct growth references for height, weight, and head circumference (HC) of young achondroplasia patients in Korea and to evaluate the predictability of the necessity and timing of neurosurgical procedures through growth patterns.
METHODS
Growth data were collected from achondroplasia patients who visited our institution between January 2002 and August 2022. First, we constructed percentile growth curves of height, weight, and HC for the patients under 3 years of age with the generalized additive model for location, scale, and shape (GAMLSS). Second, the growth patterns of the patients with hydrocephalus who underwent neurosurgical procedures such as foramen magnum decompression (FMD) and ventriculoperitoneal (VP) shunt were analyzed.
RESULTS
There were 125 achondroplasia patients, including 67 males and 58 females. Among 125 patients, 46 underwent FMD, and 5 underwent VP shunt. As short stature and macrocephaly were typical characteristics of achondroplasia, the height of achondroplasia was lower than that of the general population, and HC in achondroplasia showed accelerated growth postnatally. There were no significant changes in HC in hydrocephalus patients before they underwent neurosurgical procedures. The influence of hydrocephalus on the growth patterns of HC in achondroplasia seemed insignificant.
CONCLUSION
Growth references for height, weight, and HC in young achondroplasia patients were constructed. It is the first report of growth patterns of achondroplasia in Korea. Unlike other pediatric patients, the diagnosis of hydrocephalus and the necessity of neurosurgical procedures are hard to be predicted with HC in achondroplasia. Neuroimaging should be considered for achondroplasia patients with neurological symptoms.
Topics: Male; Female; Child; Humans; Infant; Decompression, Surgical; Neurosurgical Procedures; Hydrocephalus; Achondroplasia; Republic of Korea
PubMed: 37798741
DOI: 10.1186/s13023-023-02929-6 -
Diagnostics (Basel, Switzerland) Sep 2023This paper presents a rare case of fetal hydrops detected at just 23 weeks of gestation in a 22-year-old woman's first pregnancy. The fetal ultrasound revealed severe...
This paper presents a rare case of fetal hydrops detected at just 23 weeks of gestation in a 22-year-old woman's first pregnancy. The fetal ultrasound revealed severe skeletal anomalies, craniofacial deformities, and thoracic abnormalities, suggesting a complex and severe skeletal dysplasia, potentially type IA Achondrogenesis-a lethal autosomal recessive condition marked by ossification delay. This case highlights the significance of advanced genetic testing, such as next-generation sequencing (NGS) and whole-genome sequencing (WGS), in diagnosing and understanding skeletal dysplasias. Skeletal dysplasias represent a group of genetic disorders that affect osteogenesis. The prevalence of this condition is 1 in 4000 births. Sadly, 25% of affected infants are stillborn, and around 30% do not survive the neonatal period. There is a wide range of rare skeletal dysplasias, each with its own specific recurrence risk, dysmorphic expression, and implications for neonatal survival and quality of life. When skeletal dysplasia is incidentally discovered during routine ultrasound screening in a pregnancy not known to be at risk of a specific syndrome, a systematic examination of the limbs, head, thorax, and spine is necessary to reach the correct diagnosis. Prenatal diagnosis of skeletal dysplasia is crucial for providing accurate counselling to future parents and facilitating the proper management of affected pregnancies. An accurate diagnosis can be a real challenge due to the wide spectrum of clinical presentations of skeletal dysplasia but advances in imaging technologies and molecular genetics have improved accuracy. Additionally, some of these skeletal dysplasias may present clinical overlap, making it especially difficult to distinguish. After the 11th revision of genetic skeletal disorder nosology, there are 771 entities associated with 552 gene mutations. The most common types of skeletal dysplasia are thanatophoric dysplasia, osteogenesis imperfect, achondroplasia, achondrogenesis, and asphyxiating thoracic dystrophy.
PubMed: 37761271
DOI: 10.3390/diagnostics13182905 -
European Journal of Medical Genetics Nov 2023The clinical features of achondroplasia can cause acute self-limited pain that can evolve into chronic pain. Pain causes a low quality of life, in terms of physical,...
The clinical features of achondroplasia can cause acute self-limited pain that can evolve into chronic pain. Pain causes a low quality of life, in terms of physical, emotional, social, and school functioning in both adult and children with achondroplasia. We conducted a systematic review according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement to describe prevalence, assessment tools, causes and management strategies of pain in this rare disease. We found that shoulder and knee pain is typically referred during infancy, while knee pain is generally referred around 5-6 years of age. The prevalence of general pain in adolescence can be as high as 90%. Chronic pain in the achondroplasia population increases with age, with up to 70% of adults reporting general pain and back pain. Recognizing the multiple determinants of acute and chronic pain in patients with achondroplasia may enable physicians to better understand and manage this burden, particularly with the advent of new drugs that may modify some of the striking features of achondroplasia.
Topics: Adolescent; Humans; Child; Adult; Quality of Life; Chronic Pain; Achondroplasia
PubMed: 37758167
DOI: 10.1016/j.ejmg.2023.104850 -
Hong Kong Medical Journal = Xianggang... Oct 2023
Topics: Humans; Scoliosis; Anesthesia, Spinal; Achondroplasia; Ultrasonography, Interventional
PubMed: 37723609
DOI: 10.12809/hkmj2210169 -
Orphanet Journal of Rare Diseases Sep 2023Skeletal dysplasias are a diverse group of rare disorders in the chondro-osseous tissue that can have a significant impact on patient's functionality. The worldwide...
BACKGROUND
Skeletal dysplasias are a diverse group of rare disorders in the chondro-osseous tissue that can have a significant impact on patient's functionality. The worldwide prevalence of skeletal dysplasias at birth is approximately 1:5000 births. To date, disease burden and trends of skeletal dysplasias in the Sri Lankan population have not been described in any epidemiological study. Our aim was to evaluate the burden and the current trends in hospital admissions for skeletal dysplasias in the Sri Lankan population. A retrospective evaluation of hospital admissions for skeletal dysplasia during 2017-2020 was performed using population-based data from the eIMMR database which covers government hospitals in the entire country. The trends in hospital admissions for skeletal dysplasias by calendar year, age, and types of skeletal dysplasia were described using appropriate summary statistics.
RESULTS
Respective crude admission rates of skeletal dysplasias in the years 2017, 2018, 2019 and 2020 were 5.2, 8.1, 8.0, and 6.5 per million population. A female predominance (1.4:1) was noted during the studied period. Of all reported cases the majority (n = 268; 44.2%) were children less than 4 years. Each year, 0-4 years age group represented 40-47% of the total hospital admissions. More than half of the cases were reported from Colombo (28.1%) and Kandy (25.4%) districts combined. 60% of cases were diagnosed as osteogenesis imperfecta (OI). Rising trends were observed in the hospital admissions for osteogenesis imperfecta, achondroplasia and osteopetrosis, while other skeletal dysplasia types collectively showed a relatively stable trend.
CONCLUSION
This preliminary study revealed a female predominance of skeletal dysplasias and a relatively high admission rate of osteogenesis imperfecta in the Sri Lankan population. A distinct trend was not visible in the studied years probably due to the impact on hospital services due to COVID- Pandemic. Future research on the healthcare burden on families affected by skeletal dysplasia is required to better understand the overall cost of care and identify therapies that reduce admission rates. This study highlights the value of analysing population-based data on rare diseases to improve healthcare in low-resource countries.
Topics: Infant, Newborn; Child; Female; Humans; Male; Osteogenesis Imperfecta; Sri Lanka; Retrospective Studies; COVID-19; Osteochondrodysplasias; Hospitals
PubMed: 37684696
DOI: 10.1186/s13023-023-02884-2 -
Frontiers in Pediatrics 2023Children with skeletal dysplasia are frequently referred to pediatric endocrinologists due to short stature. These children may present with disproportionate growth or... (Review)
Review
Children with skeletal dysplasia are frequently referred to pediatric endocrinologists due to short stature. These children may present with disproportionate growth or medical histories that point to a skeletal dysplasia. This primer will discuss when to be concerned about skeletal dysplasia, the initial steps in evaluation for a skeletal dysplasia, and new therapies that are either recently approved or in development.
PubMed: 37675393
DOI: 10.3389/fped.2023.1229666 -
International Journal of Molecular... Aug 2023Human patients with mutations within or genes (encoding C-type natriuretic peptide (CNP) and guanylyl cyclase-B (GC-B), respectively) display clinical signs associated...
Human patients with mutations within or genes (encoding C-type natriuretic peptide (CNP) and guanylyl cyclase-B (GC-B), respectively) display clinical signs associated with skeletal abnormalities, such as overgrowth or short stature. Mice with induced models of or deletion display profound achondroplasia, dwarfism and early death. Recent pharmacological therapies to treat short stature are utilizing long-acting CNP analogues, but the effects of manipulating CNP expression during development remain unknown. Here, we use (zebrafish) as a model for vertebrate development, employing both pharmacological and reverse genetics approaches to alter expression of genes encoding CNP in zebrafish. Four orthologues of CNP were identified in zebrafish, and spatiotemporal expression profiling confirmed their presence during development. Bioinformatic analyses suggested that is the most likely the orthologue of mammalian CNP. Exogenous CNP treatment of developing zebrafish embryos resulted in impaired growth characteristics, such as body length, head width and eye diameter. This reduced growth was potentially caused by increased apoptosis following CNP treatment. Expression of endogenous was downregulated in these CNP-treated embryos, suggesting that negative feedback of the CNP system might influence growth during development. CRISPR knock-down of endogenous in developing zebrafish embryos also resulted in impaired growth characteristics. Collectively, these data suggest that CNP in zebrafish is crucial for normal embryonic development, specifically with regard to growth.
Topics: Female; Pregnancy; Humans; Animals; Mice; Natriuretic Peptide, C-Type; Zebrafish; Growth Disorders; Achondroplasia; Mammals
PubMed: 37629102
DOI: 10.3390/ijms241612921 -
Human Reproduction (Oxford, England) Oct 2023In modern post-transition societies, we are reproducing later and living longer. While the impact of age on female reproductive function has been well studied, much less...
In modern post-transition societies, we are reproducing later and living longer. While the impact of age on female reproductive function has been well studied, much less is known about the intersection of age and male reproduction. Our current understanding is that advancing age brings forth a progressive decline in male fertility accompanied by a reduction in circulating testosterone levels and the appearance of age-dependent reproductive pathologies including benign prostatic hypertrophy and erectile dysfunction. Paternal ageing is also associated with a profound increase in sperm DNA damage, the appearance of multiple epigenetic changes in the germ line and an elevated mutational load in the offspring. The net result of such changes is an increase in the disease burden carried by the progeny of ageing males, including dominant genetic diseases such as Apert syndrome and achondroplasia, as well as neuropsychiatric conditions including autism and spontaneous schizophrenia. The genetic basis of these age-related effects appears to involve two fundamental mechanisms. The first is a positive selection mechanism whereby stem cells containing mutations in a mitogen-activated protein kinase pathway gain a selective advantage over their non-mutant counterparts and exhibit significant clonal expansion with the passage of time. The second is dependent on an age-dependent increase in oxidative stress which impairs the steroidogenic capacity of the Leydig cells, disrupts the ability of Sertoli cells to support the normal differentiation of germ cells, and disrupts the functional and genetic integrity of spermatozoa. Given the central importance of oxidative stress in defining the impact of chronological age on male reproduction, there may be a role for antioxidants in the clinical management of this process. While animal studies are supportive of this strategy, carefully designed clinical trials are now needed if we are to realize the therapeutic potential of this approach in a clinical context.
Topics: Animals; Male; Female; Semen; Reproduction; Aging; Spermatozoa; Mutation
PubMed: 37568254
DOI: 10.1093/humrep/dead157