Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Savarirayan R

PROVIDER: S-EPMC8327889 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Savarirayan Ravi R Tofts Louise L Irving Melita M Wilcox William R WR Bacino Carlos A CA Hoover-Fong Julie J Font Rosendo Ullot RU Harmatz Paul P Rutsch Frank F Bober Michael B MB Polgreen Lynda E LE Ginebreda Ignacio I Mohnike Klaus K Charrow Joel J Hoernschemeyer Daniel D Ozono Keiichi K Alanay Yasemin Y Arundel Paul P Kotani Yumiko Y Yasui Natsuo N White Klane K KK Saal Howard M HM Leiva-Gea Antonio A Luna-González Felipe F Mochizuki Hiroshi H Basel Donald D Porco Dania M DM Jayaram Kala K Fisheleva Elena E Huntsman-Labed Alice A Day Jonathan R S JRS

Genetics in medicine : official journal of the American College of Medical Genetics 20210802 12

<h4>Purpose</h4>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 ...[more]

PMID: 34341520

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Project description: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.

Project description:BackgroundCardiomyopathy is a leading cause of morbidity and mortality in boys with Duchenne muscular dystrophy (DMD). We recently showed in a 12-month double-blind randomized controlled trial that adding eplerenone to background medical therapy was cardioprotective in this population. The objective of this study was to evaluate the safety and efficacy of longer-term eplerenone therapy in boys with DMD.ResultsEleven subjects (phase 1 baseline median [range] age: 13 [7 - 25] years) from the original 12-month trial at a single participating center were enrolled. Importantly, those who entered the extension study who had been on eplerenone previously were significantly older than those who had originally been on placebo (median age 10.5 vs. 18.0 years, p = 0.045). During an additional 24-month open-label extension study, all boys received eplerenone 25 mg orally once daily to treat preclinical DMD cardiomyopathy, defined as evident myocardial damage by late gadolinium enhancement cardiac magnetic resonance (LGE) with preserved ejection fraction (EF). The threshold for potassium level, the primary safety measure, was not exceeded in any non-hemolyzed blood sample. Over 24 months, left ventricular (LV) systolic strain, a more sensitive marker whose more negative values indicate greater contractility significantly improved (median change -4.4%, IQR -5.8 to -0.9%) in younger subjects whereas older subjects' strain remained stable without significant worsening or improvement (median change 0.2%, IQR -1.1 to 4.3%). EF and extent of myocardial damage by LGE remained stable in both groups over 2 years.ConclusionsEplerenone offers effective and safe cardioprotection for boys with DMD, particularly when started at a younger age. Eplerenone is a useful clinical therapeutic option, particularly if treatment is initiated earlier in life when cardiac damage is minimal.Trial registrationhttp://ClinicalTrials.gov identifier NCT01521546. Registered 26 January 2012.

Project description:Background and objectiveVosoritide, 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).MethodsPharmacokinetic 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.ResultsThe 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.ConclusionsThe 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 registrationNCT02055157, NCT03197766, and NCT01603095.

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Project description:IntroductionVosoritide 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.MethodsQualitative telephone interviews were conducted with parents of children being treated with vosoritide in France and Germany. Interviews were transcribed and analysed using thematic analysis.ResultsFifteen 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.ConclusionsParents 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.

Dataset Information

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

Purpose

Methods

Results

Conclusion

Publications

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

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