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research achondroplasia

This recent study1 by Dr. Wiktoria Wrobel (Medical University of Lublin, Poland) brings together the different pharmacological treatments for achondroplasia, both current and potential, highlighting the advantages and disadvantages of each, making it a great comprehensive review.

The many complications of achondroplasia, both orthopaedic and neurological, make its treatment necessary and urgent in order to minimise and prevent disability. Searching for a medicinal approach to reduce the impact of this condition has been the focus of many research centres around the world, and different approaches are being tried as we speak (see table 1). At the moment, the most advanced investigations involve growth hormone therapy (rhGH) and vosoritide (analog of C-type Natriuretic Peptide from Biomarin).


Table 1 - Classification of Drugs According to the Target of Action
Target of Action Drug Name
FGFR3 sFGFR3 (recifercept)
Inhibitors of HMG-CoA (statins)
Tyrosine kinase inhibitor (infigratinib)
FGFR 1–4 inhibitor (ASP5878)
FGFR3 antibody (vofatamab)
NPR-B CNP analogue (vosoritide)
Sustained-release CNP (TransCon CNP)
MAPK pathway Meclizine
Chondrocyte nucleus rhGH
PTH/PTHrP
Abbreviations: CNP - C-type natriuretic peptide; FGFR - fibroblast growth factor receptor; HMG-CoA - 3-hydroxy-3-methylglutaryl-coenzyme A reductase; NPR-B - natriuretic peptide receptor B; MAPK - mitogen-activated protein kinase; PTH - parathyroid hormone; PTHrP - parathyroid hormone-related peptide; rhGH - recombinant human growth hormone; sFGFR3—soluble fibroblast growth factor 3 receptor. Source: Wrobel W. Advantages and Disadvantages of Different Treatment Methods in Achondroplasia: A Review. Int J Mol Sci. 2021;22(11):5573. Published 2021 May 25. doi:10.3390/ijms22115573


Benefits and drawbacks of different drug therapies in achondroplasia

This study includes the potential impacts (see tables 2 and 3) 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 people's quality of life, possibly reducing the frequency and necessity of hospitalisation 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.
 
Table 2 - Benefits of different drug therapies in achondroplasia
Drug NameBenefits for PeopleBenefits for Animals
 Clinically used drugs 
Recombinant human growth hormone (rhGH)
  • Possibly better growth pattern in children with achondroplasia, especially in combination with l-thyroxine and surgical elongation of tibia and/or femur
  • Possibly better growth velocity with variable rather than continuous drug administration
 Drugs in different phases of clinical trials 
C-type natriuretic peptide (CNP) analog: vosoritide
  • Treatment targets underlying molecular pathogenesis, increasing growth velocity and height Z-score
  • More proportional growth
  • Resistance to natural endopeptidase
  • No serious side effects
  • Increase in axial and appendicular skeleton growth
  • Increase in the hypertrophic zone in tibial growth plates
  • Widening of lumbar vertebral openings
C-type natriuretic peptide prolonged-released: TransCon CNP
  • Long half-life, about 90 h
  • Resistance to natural endopeptidase
  • Prevents adverse cardiovascular effects because of long-release form
  • Phase II of research in progress NCT04085523
  • Increase in body and tail length in monkeys
  • No adverse effect on bone quality
  • Increase in the width of the proliferative zones in the proximal tibia
Infigratinib
(NVP-BGJ398)
  • No data
  • Phase II of research in progress NCT04265651
  • Increases the growth of long bones, axial and craniofacial skeleton
  • Increases the size of foramen magnum
  • Correction of spinal stenosis
  • Ameliorates the defective differentiation of the chondrocyte
Soluble recombinant human fibroblast growth factor receptor 3 (soluble FGFR3): recifercept
  • No data
  • Phase II of research in progress NCT04638153
  • Reduces mortality
  • Restores skeletal bone growth
  • Increases cortical bone thickness
  • Decreases spinal and skull deformities
  • Enlargement of pelvic bone
  • Corrects metabolic alteration (helps with atypical obesity)
Vofatamab (monoclonal antibody specific for FGFR3)
  • No data
  • No data
Meclizine
  • Administered orally
  • No data
  • Increases the growth of long bones, axial and skull lengths
  • Ameliorates short stature
  • Increases trabecular thickness
Statin
  • Ambiguous data
  • Ambiguous data
ASP5878
  • Administered orally
  • Increases the growth of long bones
  • Elongates the length of the cranial base
  • Increases thickness of growth plate cartilage
Parathyroid hormone (PTH)
  • Causes proper development of cartilage tissue
  • Increases proliferation and differentiation of chondrocytes and mesenchymal cells, extracellular matrix synthesis
  • Positive effect on growth velocity, similar body length to the rest of the healthy litter
  • Retardation of premature fusion of the skull synchondrosis
  • Inhibition of FGFR3 activation

Source: Wrobel W. Advantages and Disadvantages of Different Treatment Methods in Achondroplasia: A Review. Int J Mol Sci. 2021;22(11):5573. Published 2021 May 25. doi:10.3390/ijms22115573


Table 3 - Drawbacks of different drug therapies in achondroplasia
Drug NameDrawbacks for PeopleDrawbacks for Animals
Clinically used drugs
Recombinant human growth hormone (rhGH)
  • Theoretical possibility of the appearance of acromegaly signs, increase in foramen magnum narrowing and spinal cord compression, but no conclusive evidence
  • Ineffective in the case of deformation of the limbs and spine
  • Requires daily subcutaneous injections
  • Increases body mass
Drugs in different phases of clinical trials
C-type natriuretic peptide (CNP) analogue: vosoritide
  • Mild side effects: transient changes in blood pressure
  • Requires daily subcutaneous injections
  • Transient, mild hemodynamic effects
C-type natriuretic peptide prolonged-released: TransCon CNP
  • No data
  • Phase II of research in progress NCT04085523
  • Dose-dependent lowering of blood pressure in mice but not in monkeys
Infigratinib
(NVP-BGJ398)
  • Administered in injections
  • No data
  • Phase II of research in progress NCT04265651
  • No effect on the defect in the structure of long bones
  • Not found
Soluble recombinant human fibroblast growth factor receptor 3 (soluble FGFR3): recifercept
  • Administered in injections
  • No data
  • Phase II of research in progress NCT04638153
  • No effect on the trabecular bone
  • Effects are mediated only through FGF-dependent pathway
  • No signs of toxicity
  • Preserved fertility
Vofatamab (monoclonal antibody specific for FGFR3)
  • No data
  • No data
Meclizine
  • Phase I completed: no signs of toxicity were found
  • No effect on the area of foramen magnum or lumbar spinal canal
  • Cumulative effect of 20 mg/kg—toxicity: ineffective bone growth
Statin
  • Ambiguous data
  • Ambiguous data
ASP5878
  • Hyperphosphatemia
  • Retinal detachment
  • Diarrhoea
  • Elevated alanine transaminase
  • Slight atrophy of the corneal epithelium
Parathyroid hormone (PTH)
  • Unknown long-term effects, need for further studies on the safety profile
  • No data

Source: Wrobel W. Advantages and Disadvantages of Different Treatment Methods in Achondroplasia: A Review. Int J Mol Sci. 2021;22(11):5573. Published 2021 May 25. doi:10.3390/ijms22115573


Conclusions


This study demonstrates the commitment of various research centres in developing treatments for achondroplasia, however, even if these treatments are cleared for widespread use, they will not improve all the symptoms associated with achondroplasia. Although they provide the benefit of increasing bone length, their effects on important aspects, such as disproportionality, the axial skeleton (the part of the skeleton that consists of the bones of the head and trunk) and the foramen magnum, have unfortunately not been confirmed. Each of these aspects entails further complications that leave their mark on the daily lives of patients with achondroplasia.

The author also concludes that the ideal drug for achondroplasia should be small in size to readily penetrate the growth plate; specific for FGFR3 and effectively inhibit its signaling pathway. As a long term therapy, its production costs should be as low as possible, and the form of drug administration should be easy and acceptable for children. In addition, side effects should be minimised to the level of dose tolerance.


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.

Visit this page for achondroplasia's drug Research and Development (R&D) table (in Portuguese).

Read the full article here.

Sources:
1. Wrobel W, Pach E, Ben-Skowronek I. Advantages and Disadvantages of Different Treatment Methods in Achondroplasia: A Review. Int J Mol Sci. 2021;22(11):5573. Published 2021 May 25. doi:10.3390/ijms22115573
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