New developments in the management of achondroplasia

Högler, Wolfgang; Ward, Leanne M.

doi:10.1007/s10354-020-00741-6

Cited by 19 publications

(16 citation statements)

References 47 publications

(48 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Establishing the natural history of the condition is essential in rare diseases to avoid uncertainty regarding the optimal timing of intervention, incorrectly attributing side effects to the study drug rather than as disease-related complications (or vice versa ), and misunderstanding which are the best outcome measures. 18 Specifically, by establishing AHV in PROPEL, each child’s change in AHV in PROPEL 2 following infigratinib treatment can be compared with PROPEL data, allowing each child to act as their own control. Therefore, natural history observational studies, such as PROPEL, facilitate the assessment of outcomes of greatest relevance to individuals with a specific condition and rigorous assessment of safety data.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Infigratinib in children with achondroplasia: the PROPEL and PROPEL 2 studies

Savarirayan

Bergua

Arundel

et al. 2022

Therapeutic Advances in Musculoskeletal

View full text Add to dashboard Cite

Background: Achondroplasia is the most common short-limbed skeletal dysplasia resulting from gain-of-function pathogenic variants in fibroblast growth factor receptor 3 ( FGFR3) gene, a negative regulator of endochondral bone formation. Most treatment options are symptomatic, targeting medical complications. Infigratinib is an orally bioavailable, FGFR1–3 selective tyrosine kinase inhibitor being investigated as a direct therapeutic strategy to counteract FGFR3 overactivity in achondroplasia. Objectives: The main objective of PROPEL is to collect baseline data of children with achondroplasia being considered for future enrollment in interventional studies sponsored by QED Therapeutics. The objectives of PROPEL 2 are to obtain preliminary evidence of safety and efficacy of oral infigratinib in children with achondroplasia, to identify the infigratinib dose to be explored in future studies, and to characterize the pharmacokinetic (PK) profile of infigratinib and major metabolites. Design: PROPEL (NCT04035811) is a prospective, noninterventional clinical study designed to characterize the natural history and collect baseline data of children with achondroplasia over 6−24 months. PROPEL 2 (NCT04265651), a prospective, phase II, open-label study of infigratinib in children with achondroplasia, consists of a dose-escalation, dose-finding, and dose-expansion phase to confirm the selected dose, and a PK substudy. Methods and analysis: Children aged 3−11 years with achondroplasia who completed ⩾6 months in PROPEL are eligible for PROPEL 2. Primary endpoints include treatment-emergent adverse events and change from baseline in annualized height velocity. Four cohorts at ascending dose levels are planned for dose escalation. The selected dose will be confirmed in the dose-expansion phase. Ethics: PROPEL and PROPEL 2 are being conducted in accordance with the International Conference on Harmonization Good Clinical Practice guidelines, principles of the Declaration of Helsinki, and relevant human clinical research and data privacy regulations. Protocols have been approved by local health authorities, ethics committees, and institutions as applicable. Parents/legally authorized representatives are required to provide signed informed consent; signed informed assent by the child is also required, where applicable. Discussion: PROPEL and PROPEL 2 will provide preliminary evidence of the safety and efficacy of infigratinib as precision treatment of children with achondroplasia and will inform the design of future studies of FGFR-targeted agents in achondroplasia. Registration: ClinicalTrials.gov: NCT04035811; NCT04265651.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Therefore, natural history observational studies, such as PROPEL, facilitate the assessment of outcomes of greatest relevance to individuals with a specific condition and rigorous assessment of safety data. 18 …”

Section: Discussionmentioning

confidence: 99%

Infigratinib in children with achondroplasia: the PROPEL and PROPEL 2 studies

Savarirayan

Bergua

Arundel

et al. 2022

Therapeutic Advances in Musculoskeletal

View full text Add to dashboard Cite

show abstract

“…As novel pharmacological therapies emerge, early and complete diagnosis of achondroplasia in the childhood population will facilitate earlier access to treatment and provide potential benefits for the growth of the base of the skull and spinal canal in particular, which are both impacted by early synchondrosis closure in this condition (Högler & Ward, 2020). We are hopeful this may avoid early craniocervical surgery and some of the more burdensome spinal symptoms experienced by our current patients.…”

Section: Discussionmentioning

confidence: 99%

Childhood prevalence of achondroplasia in New South Wales and the Australian Capital Territory, Australia

Tofts

Armstrong

Pacey

2021

American J of Med Genetics Pt A

View full text Add to dashboard Cite

The aim of this study was to estimate the childhood prevalence of achondroplasia, trends over time in birth prevalence, and age at diagnosis in Australia. Children born between 1990 and 2019 with a clinical and radiological and/or molecular diagnosis of achondroplasia were identified from a tertiary hospital servicing New South Wales (NSW) and the Australian Capital Territory (ACT) and compared with population data from the Australian Bureau of Statistics. Childhood prevalence of achondroplasia, based on children ≤19 years of age and resident in NSW/ACT on June 30, 2019 (n = 109), was 5.2 per 100,000. A total of 127 individuals with achondroplasia were born in 1990–2019 in NSW/ACT. Birth prevalence rates increased across birth decades, from 3.3 per 100,000 live births in 1990–1999 to 5.3 per 100,000 in 2010–2019 (p < 0.0001). Median age at diagnosis decreased to 17 days in 2010–2019 compared with 30 days in 1990–1999 (p = 0.035), although the overall decreasing trend across consecutive decades did not reach statistical significance. This is the first study to show a rising birth prevalence rate for achondroplasia in Australia with a concurrent decreasing age at diagnosis, both of which were statistically significant after 2 decades.

show abstract

“…Authors reported that RBM-007 rescued the impaired differentiation and maturation of chondrocytes and restored defective skeletal growth in a mouse model of achondroplasia [ 89 , 90 ]. RBM-007 is in a Phase 1 study to evaluate its safety, tolerability and pharmacokinetics (JapicCTI-205345).…”

Section: Methods Of Treatmentmentioning

confidence: 99%

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

Wrobel

Pach

Beń‐Skowronek

2021

IJMS

View full text Add to dashboard Cite

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.

show abstract

New developments in the management of achondroplasia

Cited by 19 publications

References 47 publications

Infigratinib in children with achondroplasia: the PROPEL and PROPEL 2 studies

Infigratinib in children with achondroplasia: the PROPEL and PROPEL 2 studies

Childhood prevalence of achondroplasia in New South Wales and the Australian Capital Territory, Australia

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

Contact Info

Product

Resources

About