Vosoritide Therapy in Children with Achondroplasia: Early Experience and Practical Considerations for Clinical Practice.

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.

Vosoritide therapy in children with achondroplasia aged 3-59 months: a multinational, randomised, double-blind, placebo-controlled, phase 2 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.

Parents' Experience of Administering Vosoritide: A Daily Injectable for Children with Achondroplasia.

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.

Vosoritide para acondroplasia con epífisis abierta / Vosoritide for achondroplasia with epiphysis open

INTRODUCCIÓN: La acondroplasia es la causa más común de baja estatura desproporcionada. Es causada por una mutación patogénica en el gen del receptor 3 del factor de crecimiento de fibroblastos (FGFR3, siglas del inglés Fibroblast Growth Factor Receptor 3), que codifica un receptor transmembrana importante en la regulación del crecimiento lineal de los huesos largos. Esto resulta en una alteración de la osificación endocondral, provocando un crecimiento desproporcionado, donde el crecimiento del tronco no se ve tan gravemente afectado como el de las extremidades y el cráneo. En el 80% de los casos es producida por una mutación genética de novo, siendo de herencia autosómica dominante. Cuando ambos padres tienen acondroplasia, la probabilidad de que cada uno de sus futuros hijos pueda tener una estatura promedio es del 25%, tener acondroplasia es del 50% y finalmente tener acondroplasia homocigota (que suele ser letal) es del 25%. La acondroplasia afecta el crecimiento de casi todos los huesos del cuerpo, incluidos el cráneo, la columna vertebral, los brazos y las piernas, lo que da como resultado una estatura muy baja con una apariencia característica: acortamiento predominantemente proximal (humero, fémur) de los huesos largos de las extremidades (rizomelia); de los dedos de las manos secundario a huesos metacarpianos cortos (braquidactilia), cifosis (deformidad convexa de la unión torácica-lumbar), compresión cervicomedular (debido al estrechamiento en la parte superior de la columna secundario al estrechamiento del foramen magnum); macrocefalia y rasgos faciales caracterizado por prominencia frontal y retrusión del tercio medio facial. Las personas afectadas pueden sufrir alguna de las complicaciones adicionales: hidrocefalia; estenosis del canal vertebral (pacientes después de su segunda o tercera década de vida); obstrucción de la vía aérea superior/apnea obstructiva del sueño (secundario a la reducción del espacio de las vías respiratorias por la retrusión de la parte media de la cara junto con el agrandamiento de adenoides y amígdalas); deformidades óseas (genu varum: desviación hacia afuera debido al arqueamiento); malformación de Arnold-Chiari; microftalmos, y disfunción del oído medio, obesidad, hipertensión arterial, problemas de movilidad, dolor crónico y baja actividad física. OBJETIVO: El objetivo del presente informe es evaluar la evidencia disponible acerca de la eficacia, seguridad, aspectos económicos, recomendaciones de sociedades científicas y las políticas de cobertura (PC) para el uso del vosoritide para personas con acondroplasia y epífisis abierta. DESCRIPCIÓN DE LA TECNOLOGÍA: El vosoritide (BMN 111) es un péptido natriurético humano tipo C recombinante modificado que es producido en células de Escherichia coli mediante tecnología de ADN recombinante. En los pacientes con acondroplasia, el gen FGFR3 que regula el crecimiento está "activado" permanentemente, impidiendo el crecimiento normal de los huesos por lo que terminan siendo más cortos de lo habitual.33 Vosoritide actúa uniéndose a un receptor denominado receptor del péptido natriurético tipo B, que reduce la actividad de FGFR3, y esto, promueve la proliferación y diferenciación de condrocitos y el crecimiento óseo endocondral. MÉTODOS: Las búsquedas se llevaron a cabo en las principales bases de datos bibliográficas: PUBMED, CRD (Centre for Reviews and Dissemination), Cochrane, TRIPdatabase (TRIP: Turning Research Into Practice), Epistemonikos, BRISA (Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas), LILACS (Literatura Latinoamericana y del Caribe en Ciencias de la Salud), INAHTA (International Network of Agencies for Health Technology Assessment), PROSPERO (International Prospective Register Of Systematic Reviews), en buscadores genéricos de internet y en sitios web de financiadores de salud. Se realizó una búsqueda sistemática de información publicada con fecha límite hasta el 29 de junio sobre el uso del vosoritide en pacientes con Acondroplasia y epífisis abierta. Se priorizó para la búsqueda inicial, la identificación de Revisiones Sistemáticas (RS) y Metaanálisis (MA), Evaluaciones de Tecnologías Sanitarias (ETS), Evaluaciones Económicas (EE), Guías de Práctica Clínica (GPC), políticas de cobertura (PC) de diferentes sistemas de salud y ensayos clínicos aleatorizados (ECA), se realizó una búsqueda con los filtros metodológicos correspondientes. RESULTADOS: Como resultado de la búsqueda bibliográfica, se recuperaron 12 estudios: ocho en curso, cuatro finalizados (estudio 111-101 [NCT01590446], estudio 111-202 [NCT02055157], Savarirayan y cols. 2020 [111-301, NCT03197766] y Savarirayan y cols. 2021 [111-302, NCT03424018]; tres Evaluaciones de Tecnologías Sanitarias (ETS); una revisión sistemática en curso; cinco Guías de Práctica Clínica (GPC) / Consensos / Recomendaciones. No se han hallado estudios primarios con comparación "cabeza-cabeza" entre el vosoritide versus cirugía de alargamiento u hormona de crecimiento. CONCLUSIONES: Al momento, no está autorizada su comercialización en Argentina, pero está en evaluación por el Registro de Especialidades Médicas. No se han encontrado estudios primarios con comparación "cabeza-cabeza" entre el vosoritide versus cirugía de alargamiento u hormona de crecimiento. No se recuperó evidencia relacionado con la tasa de complicaciones graves como: estrechez de la unión cérvico-medular; macrocefalia/hidrocefalia; estenosis del canal vertebral; obstrucción de la vía aérea superior; deformidades óseas; malformación de Arnold-Chiari; microftalmos. No hubo diferencias clínicamente significativas en la calidad de vida relacionada con la salud, ni tampoco en la independencia funcional para vosoritide frente a placebo en personas de 5 a 18 años de edad con acondroplasia y epífisis abierta (certeza alta ⨁⨁⨁⨁). Aumenta la velocidad de crecimiento anualizada (1,57 cm/año más alto), aunque se desconoce si se sostiene en el tiempo para vosoritide frente a placebo en personas de 5 a 18 años de edad con acondroplasia y epífisis abierta (certeza alta ⨁⨁⨁⨁). Aumenta la puntuación Z a 52 semanas de seguimiento (cambio medio de mínimos cuadrados 0.28 más alto), aunque se desconoce si se sostiene en el tiempo, para vosoritide frente a placebo en personas de 5 a 18 años de edad con acondroplasia y epífisis abierta (certeza alta ⨁⨁⨁⨁). No hay diferencias en la proporción de segmentos corporales superiores e inferiores entre el inicio y el final de seguimiento, para vosoritide frente a placebo en personas de 5 a 18 años de edad con acondroplasia y epífisis abierta (certeza alta ⨁⨁⨁⨁). Si bien probablemente no aumente el riesgo de eventos adversos serios, y aumenta el riesgo de cualquier evento adverso (certeza alta ⨁⨁⨁⨁). No se recuperaron Guías de Práctica Clínica que recomienden su utilización y la mayoría de las políticas de cobertura relevadas no la mencionan en la indicación evaluada. Si bien no existen evaluaciones económicas locales, se estima que podría ser NO costoefectiva en Argentina. Se estimó que el impacto en términos de costo de oportunidad requeriría sumar 32.870 gastos en salud per cápita por año, o limitaría el pago de 1.232 haberes jubilatorios mínimos anuales.

Efficacy of vosoritide in the treatment of achondroplasia.

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.

Pharmacokinetics and Exposure-Response of Vosoritide in Children with Achondroplasia.

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 (Cmax) of 15 minutes, and cleared with a mean half-life of 27.9 minutes after 52 weeks of treatment. Vosoritide exposure (Cmax 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.

Vosoritide: First Approval.

Vosoritide (VOXZOGO®) is a modified recombinant human C-type natriuretic peptide (CNP) analogue, being developed by BioMarin Pharmaceutical for the treatment of achondroplasia. Achondroplasia is caused by a gain-of-function mutation in the fibroblast growth factor receptor 3 gene (FGFR3), which is a negative regulator of bone growth. Vosoritide acts to restore chondrogenesis through its binding to natriuretic peptide receptor B (NPR-B), resulting in the inhibition of downstream signalling pathways of the overactive FGFR3 gene. Vosoritide was approved in August 2021 in the EU for the treatment of achondroplasia in patients aged ≥ 2 years whose epiphyses are not closed; the diagnosis of achondroplasia should be confirmed by appropriate genetic testing. The drug is also under regulatory review in the USA for the treatment of achondroplasia and clinical development is underway in several countries. This article summarizes the milestones in the development of vosoritide leading to this first approval for achondroplasia in patients aged ≥ 2 years whose epiphyses are not closed.

Safe and persistent growth-promoting effects of vosoritide in children with achondroplasia: 2-year results from an open-label, phase 3 extension study.

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.

Advantages and Disadvantages of Different Treatment Methods in Achondroplasia: A Review.

Achondroplasia (ACH) is a disease caused by a missense mutation in the FGFR3 (fibroblast growth factor receptor 3) gene, which is the most common cause of short stature in humans. The treatment of ACH is necessary and urgent because untreated achondroplasia has many complications, both orthopedic and neurological, which ultimately lead to disability. This review presents the current and potential pharmacological treatments for achondroplasia, highlighting the advantages and disadvantages of all the drugs that have been demonstrated in human and animal studies in different stages of clinical trials. The article includes the potential impacts of drugs on achondroplasia symptoms other than short stature, including their effects on spinal canal stenosis, the narrowing of the foramen magnum and the proportionality of body structure. Addressing these effects could significantly improve the quality of life of patients, possibly reducing the frequency and necessity of hospitalization and painful surgical procedures, which are currently the only therapeutic options used. The criteria for a good drug for achondroplasia are best met by recombinant human growth hormone at present and will potentially be met by vosoritide in the future, while the rest of the drugs are in the early stages of clinical trials.

Rationale, design, and methods of a randomized, controlled, open-label clinical trial with open-label extension to investigate the safety of vosoritide in infants, and young children with achondroplasia at risk of requiring cervicomedullary decompression surgery.

Achondroplasia causes narrowing of the foramen magnum and the spinal canal leading to increased mortality due to cervicomedullary compression in infants and significant morbidity due to spinal stenosis later in adulthood. Vosoritide is a C-natriuretic peptide analogue that has been shown to improve endochondral ossification in children with achondroplasia. The objective of this trial is to evaluate the safety of vosoritide and whether vosoritide can improve the growth of the foramen magnum and spinal canal in children that may require decompression surgery. An Achondroplasia Foramen Magnum Score will be used to identify infants at risk of requiring decompression surgery. This is a 2-year open label randomized controlled trial of vosoritide in infants with achondroplasia ages 0 to ≤12 months. Approximately 20 infants will be randomized 1:1 to either open label once daily subcutaneous vosoritide combined with standard of care or standard of care alone. The primary and secondary aims of the study are to evaluate the safety and efficacy of vosoritide in children with cervicomedullary compression at risk of requiring decompression surgery. The trial will be carried out in specialized skeletal dysplasia treatment centers with well established multidisciplinary care pathways and standardized approaches to the neurosurgical management of cervicomedually compression. After 2 years, infants randomized to standard of care alone will be eligible to switch to vosoritide plus standard of care for an additional 3 years. This pioneering trial hopes to address the important question as to whether treatment with vosoritide at an early age in infants at risk of requiring cervicomedullary decompression surgery is safe, and can improve growth at the foramen magnum and spinal canal alleviating stenosis. This in turn may reduce compression of surrounding structures including the neuraxis and spinal cord, which could alleviate future morbidity and mortality.Trial registrations: ClinicalTrials.gov, NCT04554940; EudraCT number, 2020-001055-40.

Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre 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.

C-Type Natriuretic Peptide Restores Growth Impairment Under Enzyme Replacement in Mice With Mucopolysaccharidosis VII.

Growth impairment in mucopolysaccharidoses (MPSs) is an unresolved issue as it is resistant to enzyme replacement therapy (ERT) and growth hormone therapy. C-type natriuretic peptide (CNP) is a promising agent that has growth-promoting effects. Here we investigate the effects of CNP on growth impairment of MPSs using Gusbmps-2J mice, a model for MPS type VII, with combination therapy of CNP and ERT by hydrodynamic gene delivery. Although monotherapies were not sufficient to restore short statures of treated mice, combination therapy resulted in successful restoration. The synergistic effects of CNP and ERT were not only observed in skeletal growth but also in growth plates. ERT reduced cell swelling in the resting zone and increased cell number by accelerating proliferation or inhibiting apoptosis. CNP thickened the proliferative and hypertrophic zones. Regarding changes in the bone, ERT restored bone sclerosis through decreased bone formation and increased bone resorption, and CNP did not adversely affect this process. In addition, improvement of joint deformation by ERT was suggested by analyses of joint spaces and articular cartilage. CNP additively provided restoration of the short stature of MPS VII mice in combination with ERT, which improved abnormalities of growth plates and bone metabolism.

C-Type Natriuretic Peptide Analogue Therapy in Children with Achondroplasia.

BACKGROUND: Achondroplasia is a genetic disorder that inhibits endochondral ossification, resulting in disproportionate short stature and clinically significant medical complications. Vosoritide is a biologic analogue of C-type natriuretic peptide, a potent stimulator of endochondral ossification. METHODS: In a multinational, phase 2, dose-finding study and extension study, we evaluated the safety and side-effect profile of vosoritide in children (5 to 14 years of age) with achondroplasia. A total of 35 children were enrolled in four sequential cohorts to receive vosoritide at a once-daily subcutaneous dose of 2.5 µg per kilogram of body weight (8 patients in cohort 1), 7.5 µg per kilogram (8 patients in cohort 2), 15.0 µg per kilogram (10 patients in cohort 3), or 30.0 µg per kilogram (9 patients in cohort 4). After 6 months, the dose in cohort 1 was increased to 7.5 µg per kilogram and then to 15.0 µg per kilogram, and in cohort 2, the dose was increased to 15.0 µg per kilogram; the patients in cohorts 3 and 4 continued to receive their initial doses. At the time of data cutoff, the 24-month dose-finding study had been completed, and 30 patients had been enrolled in an ongoing long-term extension study; the median duration of follow-up across both studies was 42 months. RESULTS: During the treatment periods in the dose-finding and extension studies, adverse events occurred in 35 of 35 patients (100%), and serious adverse events occurred in 4 of 35 patients (11%). Therapy was discontinued in 6 patients (in 1 because of an adverse event). During the first 6 months of treatment, a dose-dependent increase in the annualized growth velocity was observed with vosoritide up to a dose of 15.0 µg per kilogram, and a sustained increase in the annualized growth velocity was observed at doses of 15.0 and 30.0 µg per kilogram for up to 42 months. CONCLUSIONS: In children with achondroplasia, once-daily subcutaneous administration of vosoritide was associated with a side-effect profile that appeared generally mild. Treatment resulted in a sustained increase in the annualized growth velocity for up to 42 months. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov numbers, NCT01603095, NCT02055157, and NCT02724228.).

Chronic treatment with C-type natriuretic peptide impacts differently in the aorta of normotensive and hypertensive rats.

The aim of this study was to determine whether exogenous administration of C-type natriuretic peptide (CNP) induces functional and morphological vascular changes in spontaneously hypertensive rats (SHR) compared with normotensive rats. Male 12-week-old normotensive Wistar and SHR were administered with saline (NaCl 0.9%) or CNP (0.75 µg/h/100 g) for 14 days (subcutaneous micro-osmotic pumps). Systolic blood pressure (SBP) was measured in awake animals and renal parameters were evaluated. After decapitation, the aorta was removed, and vascular morphology, profibrotic markers, and vascular reactivity were measured. In addition, nitric oxide (NO) system and oxidative stress were evaluated. After 14-days of treatment, CNP effectively reduced SBP in SHR without changes in renal function. CNP attenuated vascular remodeling in hypertensive rats, diminishing both profibrotic and pro-inflammatory cytokines. Also, CNP activated the vascular NO system and exerted an antioxidant effect in aortic tissue of both groups, diminishing superoxide production and thiobarbituric acid-reactive substances, and increasing glutathione content. These results show that chronic treatment with CNP attenuates the vascular damage development in a model of essential hypertension, inducing changes in fibrotic, inflammatory, oxidative, and NO pathways that could contribute to beneficial long-term effects on vascular morphology, extracellular matrix composition, and function. The knowledge of these effects of CNP could lead to improved therapeutic strategies to not only control BP but also reduce vascular damage, primarily responsible for the risk of cardiovascular events.

Foramen magnum stenosis and midface hypoplasia in C-type natriuretic peptide-deficient rats and restoration by the administration of human C-type natriuretic peptide with 53 amino acids.

C-type natriuretic peptide (CNP)-knockout (KO) rats exhibit impaired skeletal growth, with long bones shorter than those in wild-type (WT) rats. This study compared craniofacial morphology in the CNP-KO rat with that in the Spontaneous Dwarf Rat (SDR), a growth hormone (GH)-deficient model. The effects of subcutaneous administration of human CNP with 53 amino acids (CNP-53) from 5 weeks of age for 4 weeks on craniofacial morphology in CNP-KO rats were also investigated. Skulls of CNP-KO rats at 9 weeks of age were longitudinally shorter and the foramen magnum was smaller than WT rats. There were no differences in foramen magnum stenosis and midface hypoplasia between CNP-KO rats at 9 and 33 weeks of age. These morphological features were the same as those observed in CNP-KO mice and activated fibroblast growth factor receptor 3 achondroplasia-phenotype mice. In contrast, SDR did not exhibit foramen magnum stenosis and midface hypoplasia, despite shorter stature than in control rats. After administration of exogenous CNP-53, the longitudinal skull length and foramen magnum size in CNP-KO rats were significantly greater, and full or partial rescue was confirmed. The synchondrosis at the cranial base in CNP-KO rats is closed at 9 weeks, but not at 4 weeks of age. In contrast, synchondrosis closure in CNP-KO rats treated with CNP-53 was incomplete at 9 weeks of age. Administration of exogenous CNP-53 accelerated craniofacial skeletogenesis, leading to improvement in craniofacial morphology. As these findings in CNP-KO rats are similar to those in patients with achondroplasia, treatment with CNP-53 or a CNP analog may be able to restore craniofacial morphology and foramen magnum size as well as short stature.

C-type natriuretic peptide analog treatment of craniosynostosis in a Crouzon syndrome mouse model.

Activating mutations of fibroblast growth factor receptors (FGFRs) are a major cause of skeletal dysplasias, and thus they are potential targets for pharmaceutical intervention. BMN 111, a C-type natriuretic peptide analog, inhibits FGFR signaling at the level of the RAF1 kinase through natriuretic peptide receptor 2 (NPR2) and has been shown to lengthen the long bones and improve skull morphology in the Fgfr3Y367C/+ thanatophoric dysplasia mouse model. Here we report the effects of BMN 111 in treating craniosynostosis and aberrant skull morphology in the Fgfr2cC342Y/+ Crouzon syndrome mouse model. We first demonstrated that NPR2 is expressed in the murine coronal suture and spheno-occipital synchondrosis in the newborn period. We then gave Fgfr2cC342Y/+ and Fgfr2c+/+ (WT) mice once-daily injections of either vehicle or reported therapeutic levels of BMN 111 between post-natal days 3 and 31. Changes in skeletal morphology, including suture patency, skull dimensions, and long bone length, were assessed by micro-computed tomography. Although BMN 111 treatment significantly increased long bone growth in both WT and mutant mice, skull dimensions and suture patency generally were not significantly affected. A small but significant increase in the relative length of the anterior cranial base was observed. Our results indicate that the differential effects of BMN 111 in treating various skeletal dysplasias may depend on the process of bone formation targeted (endochondral or intramembranous), the specific FGFR mutated, and/or the specific signaling pathway changes due to a given mutation.

Skeletal Dysplasias: What Every Bone Health Clinician Needs to Know.

PURPOSE OF REVIEW: This review highlights how skeletal dysplasias are diagnosed and how our understanding of some of these conditions has now translated to treatment options. RECENT FINDINGS: The use of multigene panels, using next-generation sequence technology, has improved our ability to quickly identify the genetic etiology, which can impact management. There are successes with the use of growth hormone in individuals with SHOX deficiencies, asfotase alfa in hypophosphatasia, and some promising data for c-type natriuretic peptide for those with achondroplasia. One needs to consider that a patient with short stature has a skeletal dysplasia as options for management may be available.

B-type natriuretic peptide and acute heart failure: Fluid homeostasis, biomarker and therapeutics / Péptido natriurético de tipo B e insuficiencia cardiaca aguda: homeostasis de fluidos, biomarcadores y terapéutica

Natriuretic peptides are a family of peptides with similar structures, but are genetically distinct with diverse actions in cardiovascular, renal and fluid homeostasis. The family consists of an atrial natriuretic peptide (ANP) and a brain natriuretic peptide (BNP) of myocardial cell origin, a C-type natriuretic peptide (CNP) of endothelial origin, and a urodilatin (Uro) which is processed from a prohormone ANP in the kidney. Nesiritide, a human recombinant BNP, was approved by the Federal Drug Administration (FDA) for the management of acute heart failure (AHF) in 2001. Human recombinant ANP (Carperitide) was approved for the same clinical indication in Japan in 1995, and human recombinant Urodilatin (Ularitide) is currently undergoing phase III clinical trial (TRUE AHF). This review will provide an update on important issues regarding the role of BNP in fluid hemostasis as a biomarker and therapeutics in AHF (AU)

Los péptidos natriuréticos son una familia de péptidos con estructura semejante, pero distintos genéticamente, con múltiples acciones en la homeostasis cardiovascular, renal y de fluidos. Esta familia está formada por un péptido natriurético auricular y un péptido natriurético cerebral que se originan en las células miocárdicas, un péptido natriurético de tipo C de origen endotelial y una urodilatina que se procesa de una prohormona del péptido natriurético auricular en el riñón. La nesitirida, un péptido natriurético cerebral recombinante humano, fue aprobada por la Administración de Medicamentos y Alimentos (FDA) en el año 2001 para el tratamiento de la insuficiencia cardiaca aguda. El péptido natriurético auricular recombinante humano (carperitida) fue aprobado con las mismas indicaciones clínicas en Japón en el año 1995, y la urodilatina recombinante humana (ularitida) forma parte ahora mismo de un ensayo de fase iii (TRUE-AHF). Esta revisión permitirá actualizar aspectos importantes relativos al papel que desempeña el péptido natriurético cerebral en la homeostasis de fluidos como biomarcador y fármaco para las insuficiencias cardiacas agudas (AU)

C-type natriuretic peptide restores impaired skeletal growth in a murine model of glucocorticoid-induced growth retardation.

Glucocorticoids are widely used for treating autoimmune conditions or inflammatory disorders. Long-term use of glucocorticoids causes impaired skeletal growth, a serious side effect when they are used in children. We have previously demonstrated that C-type natriuretic peptide (CNP) is a potent stimulator of endochondral bone growth. In this study, we investigated the effect of CNP on impaired bone growth caused by glucocorticoids by using a transgenic mouse model with an increased circulating CNP level. Daily administration of a high dose of dexamethasone (DEX) to 4-week-old male wild-type mice for 4weeks significantly shortened their naso-anal length, which was restored completely in DEX-treated CNP transgenic mice. Impaired growth of the long bones and vertebrae by DEX was restored to a large extent in the CNP transgenic background, with recovery in the narrowed growth plate by increased cell volume, whereas the decreased proliferation and increased apoptosis of the growth plate chondrocytes were unaffected. Trabecular bone volume was not changed by DEX treatment, but decreased significantly in a CNP transgenic background. In young male rats, the administration of high doses of DEX greatly decreased N-terminal proCNP concentrations, a marker of CNP production. In organ culture experiments using fetal wild-type murine tibias, longitudinal growth of tibial explants was inhibited by DEX but reversed by CNP. These findings now warrant further study of the therapeutic potency of CNP in glucocorticoid-induced bone growth impairment.

C-Type Natriuretic Peptide Improves Left Ventricular Functional Performance at Rest and Restores Normal Exercise Responses after Heart Failure.

In heart failure (HF), the impaired left ventricular (LV) arterial coupling and diastolic dysfunction present at rest are exacerbated during exercise. C-type natriuretic peptide (CNP) is elevated in HF; however, its functional effects are unclear. We tested the hypotheses that CNP with vasodilating, natriuretic, and positive inotropic and lusitropic actions may prevent this abnormal exercise response after HF. We determined the effects of CNP (2 µg/kg plus 0.4 µg/kg per minute, i.v., 20 minutes) on plasma levels of cGMP before and after HF and assessed LV dynamics during exercise in 10 chronically instrumented dogs with pacing-induced HF. Compared with the levels before HF, CNP infusion caused significantly greater increases in cGMP levels after HF. After HF, at rest, CNP administration significantly reduced LV end-systolic pressure (PES), arterial elastance (EA), and end-diastolic pressure. The peak mitral flow (dV/dtmax) was also increased owing to decreased minimum LVP (LVPmin) and the time constant of LV relaxation (τ) (P < 0.05). In addition, LV contractility (EES) was increased. The LV-arterial coupling (EES/EA) was improved. The beneficial effects persisted during exercise. Compared with exercise in HF preparation, treatment with CNP caused significantly less important increases in PES but significantly decreased τ (34.2 vs. 42.6 ms) and minimum left ventricular pressure with further augmented dV/dtmax Both EES, EES/EA (0.87 vs. 0.32) were increased. LV mechanical efficiency improved from 0.38 to 0.57 (P < 0.05). After HF, exogenous CNP produces arterial vasodilatation and augments LV contraction, relaxation, diastolic filling, and LV arterial coupling, thus improving LV performance at rest and restoring normal exercise responses after HF.