Advantages and Disadvantages of Different Treatment Methods in Achondroplasia

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Advantages and Disadvantages of Different Treatment Methods in Achondroplasia

Who conducted the study?

The study was conducted by Wiktoria Wrobel, Emilia Pach and Iwona Ben-Skowronek from the Metabolic Laboratory, Department of Paediatric Endocrinology and Diabetology with Endocrine, Medical University in Lublin, Poland.

What was the purpose of the study?

The aim of this study was to analyze the pharmacological therapeutic methods in achondroplasia, including the advantages and disadvantages of all drugs, both those currently used and those in different phases of clinical trials that have been demonstrated in human and animal studies.

This 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.

Methods of treatment analyzed:

The methods for treating achondroplasia can be grouped into surgical and pharmacological therapies. Surgical intervention consists of lengthening the lower limbs using an Ilizarov apparatus or monolateral external fixator and entails multiple procedures and possible serious complications.

C-Type Natriuretic Peptide in Achondroplasia Treatment
C-Type Natriuretic Peptide Analog: Vosoritide (BMN-111)
Prodrug, Prolonged-Release C-Type Natriuretic Peptide: TransCon CNP
Recombinant Human Growth Hormone (rhGH)
Tyrosine Kinase Inhibitor (TKI): Infigratinib
Soluble FGFR3 (TA-46): Recifercept
Vofatamab (B-701)
Meclizine
Statins
Parathyroid Hormone (PTH) and Parathyroid Hormone-Related Peptide (PTHrP
FGFR Inhibitor: ASP5878
Aptamer RBM-007

Results

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)
NPR-B	Sustained-release CNP prodrug (TransCon CNP)
MAPK pathway	Meclizine
Chondrocyte nucleus	rhGH
Chondrocyte nucleus	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.

Table 2. Benefits of different drug therapies in achondroplasia

Drug Name	Benefits for People	Benefits 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

Table 3. Drawbacks of different drug therapies in achondroplasia

Drug Name	Drawbacks for People	Drawbacks 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 Diarrhea 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

Figure 1. Current and potential treatments for achondroplasia.

In the normal growth plate, FGF acts on FGFR3, causing the activation of RAS and the MAPK pathway (RAF, ERK and MEK), resulting in the inhibition of chondrocyte proliferation and differentiation and a reduction in extracellular matrix synthesis. Drugs for achondroplasia include preparations that influence the function of the FGFR3 receptor and MAPK pathways and directly act on chondrocytes. The first group includes, among others, drugs that inhibit the receptor (ASP5878, which is an inhibitor of FGFR3, and vofatamab, an anti-FGFR3 antibody), as well as drugs that reduce the concentration of FGFR3 (infigratinib, which inhibits receptor phosphorylation, or statins, potentially causing proteasomal degradation of this molecule). The drug that competes with FGFR3 for a ligand is sFGFR3, a soluble receptor that, by binding to FGF, reduces its effect on the growth plate. Drugs that inhibit the MAPK pathway are CNP analogs, which inhibits RAF-1, and meclizine, which inhibits ERK. By acting on FGFR3 or MAPK, all of these drugs consequently increase the proliferation and differentiation of chondrocytes, improving bone elongation growth. RhGH and PTH or PTHrP have a direct stimulating effect on the proliferation and differentiation of chondrocytes.

Conclusions

Current data shows that finding a cure for achondroplasia is the subject of very intensive research by teams across the globe. For now, rhGH and vosoritide studies are more advanced. However, even if these treatments reach widespread use, they will not cure all the symptoms associated with achondroplasia. They can provide the benefit of increasing bone length, but their effects on disproportionality, the axial skeleton and the foramen magnum, have not been confirmed. Each of these entails further complications that leave their mark on the daily lives of people with achondroplasia.

The ideal drug for achondroplasia should be:

small in size, to readily penetrate the growth plate
be specific for FGFR3 and effectively inhibit its signaling pathway
as the therapy is long term, its production costs should be as low as possible, and the form of drug administration should be easy and acceptable for a pediatric patient
side effects should be minimized 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.

Read the full review here.