Achondroplasia is the most common skeletal dysplasia associated with disproportionate short stature, with an estimated prevalence of 4.6 per 100 000 births. It is caused by a pathogenic variant in the gene encoding fibroblast growth factor receptor 3 (FGFR3), which disrupts endochondral ossification of the growing skeleton.
ObjectiveTo provide an updated overview of the therapeutic approach to achondroplasia, including currently approved treatments and those under investigation.
ContentThe approval of vosoritide in 2021 has brought a major shift in the management of these patients. Updated follow-up guidelines have been published, along with initial outcomes in treated patients, with the aim of determining not only the impact on growth and final height but also on associated comorbidities, such as foramen magnum stenosis, and body proportions. We also review other emerging therapeutic strategies currently under development.
ConclusionsThe availability of targeted therapies has modified the traditional approach to the management of achondroplasia, which makes ongoing updates on approved and investigational treatments essential.
La acondroplasia constituye la displasia ósea que asocia talla baja disarmónica más frecuente. Tiene una prevalencia de 4.6 por cada 100.000 nacimientos. Está causada por una variante patogénica en el gen que codifica el receptor 3 del factor de crecimiento de fibroblastos, que altera el proceso de osificación endocondral del esqueleto en crecimiento.
ObjetivoActualizar el abordaje terapéutico de la acondroplasia, incluyendo los tratamientos actualmente autorizados y aquellos en investigación.
ContenidoLa aprobación de Vosoritide en 2021 ha supuesto un cambio en el manejo de estos pacientes, publicándose guías actualizadas de seguimiento, así como primeros resultados en pacientes tratados, intentando dar respuesta no solo al impacto sobre la talla sino sobre el resto de comorbilidades como la estenosis del foramen magnum y la proporcionalidad. Asimismo, se revisan otras estrategias terapéuticas en desarrollo.
ConclusionesLa disponibilidad de terapias dirigidas ha modificado el enfoque tradicional de la acondroplasia, siendo necesario una actualización continua en los tratamientos aprobados y en investigación.
Achondroplasia is the most common skeletal dysplasia associated with disproportionate short stature. It affects more than 300 000 people worldwide and is associated with numerous medical, surgical, and psychosocial comorbidities.
It is caused by a pathogenic variant in the gene that encodes fibroblast growth factor receptor 3 (FGFR3).1 Its incidence is estimated at 1–30 cases per 10 000 live births, and 80% of cases are de novo. The variant most frequently involved in achondroplasia is a single-nucleotide substitution of adenine or cytosine for guanine at nucleotide 1138 in FGFR3, leading to a glycine-to-arginine substitution in the transmembrane domain of the FGFR3 protein (p.Gly380Arg). This is a gain-of-function variant, and, since FGFR3 is a negative regulator of chondrocyte proliferation and maturation, it results in impaired endochondral ossification of the long bones and synchondrosis at the base of the skull.2 The impairment in synchondrosis and endochondral ossification explains the characteristic phenotype of achondroplasia, which includes rhizomelic short stature, relative macrocephaly, prominent forehead, flat nasal bridge, midface hypoplasia, short limbs and trident hand. The final height tends to be around 124 cm in female patients and 132 cm in male patients.3 Medical and surgical complications start manifesting in infancy and early childhood, including foramen magnum stenosis with cervical spinal cord compression, hydrocephalus, and central sleep apnea, in addition to an increased risk of sudden death. Chronic otitis media is common, as is obstructive apnea with enlargement of the adenoid glands and tonsils that frequently requires surgery. Throughout childhood, patients exhibit delays in motor milestones, hypotonia with spinal thoracolumbar kyphosis (usually transient), lumbar hyperlordosis, genu varum, and limited elbow extension. In adults, complications arise from lumbar spinal stenosis, osteoarthritis, and restricted range of motion in the elbow, causing pain and disability that result in a second surgical burden peak.4
Atypical obesity is a frequent complication, and it is associated with increased cardiovascular risk and reduced life expectancy.5
Until recently, treatments were only available to manage complications and comorbidities, whether medical (obesity and cardiovascular disorders) or surgical (foramen magnum decompression, spinal fusion, adenoidectomy and tonsillectomy, maxillary expansion, and limb lengthening). In recent years, novel drugs that may be disease-modifying have been developed, all of which target the FGFR3 signaling pathway.6
Between 1997 and 2021, growth hormone was the only treatment approved for individuals with achondroplasia, and only in Japan.7,8 Subsequent studies showed that its effectiveness is temporary and that it could have a negative impact on common comorbidities (foramen magnum stenosis and obstructive sleep apnea).9
The improved understanding of the natural history of achondroplasia and the involved signaling pathways has ushered in a new era. Current therapeutic approaches are diverse and include strategies that target the effects of the FGFR3 gain-of-function by blocking its activation, inhibiting its intracellular signaling, or antagonizing downstream signaling pathways.10,11 This article offers an update on the main drugs that are currently available and those under investigation (Table 1 and Fig. 1).
FGFR3-targeted therapies for achondroplasia: mechanism of action, phase of development, and route of administration FGFR3-targeted therapies for achondroplasia: mechanism of action, current phase of development, and route of administration.
| Mechanism of action | Phase of development | Administration | |
|---|---|---|---|
| Vosoritide (BioMarin®) | CNP analog, inhibits FGFR3 gain-of-function via RAF1 | Approved | SC daily |
| Navepegritide (Ascendis®) | Long-acting CNP analog | Fase 2 | SC weekly |
| Infigratinib (QED®) | Tyrosine kinase inhibitor (FGFR1-3) | Phase 3 | PO daily |
| TYRA-300 (TYRA Biosciences®) | Selective FGFR3 inhibitor | Phase 2 | PO daily |
| Meclizine | H1 histamine receptor antagonist that inhibits FGFR3 via MAPK | Phase 1a | PO daily |
| RBM-007 (Ribomic®) | RNA aptamer that acts as a ligand trap and inhibits FGFR2 | Phase 1 | SC weekly |
| Recifercept (Pfizer®) | Soluble recombinant FGFR acting as a decoy that intercepts FGFR ligands | Discontinued after phase 2 | SC weekly |
| SAR-442501 (Sanofi®) | Monoclonal anti-FGFR3 antibody | Discontinued after phase | SC twice a week |
Abbreviations: CNP, C-type natriuretic peptide; FGFR, fibroblast growth factor receptor; MAPK, mitogen-activated protein kinase; PO, oral; RAF1, RAF1 serine/threonine protein kinase; RNA, ribonucleic acid; SC, subcutaneous.
Mechanisms of action of the different drugs for achondroplasia. In the normal growth plate, FGF is involved in the downstream activation of RAS and the MAPK pathway (RAF, ERK, and MEK), resulting in inhibition of chondrocyte proliferation. In achondroplasia, the gene variant results in the activation of this receptor with inhibitory function. Drugs for achondroplasia aim to inhibit this receptor by targeting the pathways shown in this illustration.
Vosoritide: CNP analog that inhibits the RAF pathway. Navepegritide: long-acting CNP analog. Infigratinib: tyrosine kinase inhibitor (FGFR1-3). TYRA-300: selective FGFR3 inhibitor. Meclizine: histamine H1 receptor antagonist that inhibits the activity of FGFR3 via the MAPK pathway. RBM-007: RNA aptamer that acts as a ligand trap and inhibits FGFR2.
Vosoritide is a modified C-type natriuretic peptide (CNP) analog and was the first drug approved for medical treatment of achondroplasia. It binds natriuretic peptide receptor B (NPR-B), whose activation suppresses downstream signals in FGFR3 pathways through the inhibition of the MAPK pathway at the level of RAF1, promoting chondrocyte differentiation and increasing extracellular matrix synthesis.12 Early animal models showed that continuous administration of vosoritide improved the skeletal growth impairment.13
The first study in humans was the pivotal phase 2 trial conducted by BioMarin (BMN-111-202; with extension studies 111-205; NCT01603095, NCT02055157 and NCT02724228) in 35 children with achondroplasia aged 5–14 years, who had previously participated in a 6-month observational baseline growth study (111-901; NCT01603095).
The dose-finding study found that administration of doses of 25–30 μg/kg/day was safe, with evidence of a dose-dependent increase in the annualized growth velocity with a dose of 15 μg/kg/day. The study found a sustained increase in the annualized growth velocity of 1.5 cm/year relative to baseline for up to 42 months in children who received 15 μg/kg/day of vosoritide.14
The development process continued with a randomized, double-blind, placebo-controlled phase 3 trial (111-301; EudraCT 2015-003836-11) conducted in 121 children with achondroplasia aged 5–18 years to evaluate the efficacy and safety of vosoritide, which was administered at a dose of 15 μg/kg/day over 52 weeks (60 participants assigned to vosoritide and 61 to placebo). The study found an increase in growth velocity of 1.57 cm/year in children treated with vosoritide compared to those who received placebo (95% CI, 1.22–1.93).15 There were no changes in body segment proportionality nor bone age acceleration in children treated with vosoritide.
The open-label extension study that followed (111-302; NCT03424018) included 119 children, all of whom received 15 μg/kg/day of vosoritide, so that children who had been assigned to vosoritide in the initial study completed up to 2 years of treatment. At two years of follow-up, the annualized growth velocity was 5.52 cm (1.7 cm/year) in patients assigned to vosoritide from the beginning, and 5.43 cm (2.03 cm/year) in patients who crossed over from placebo to vosoritide. A direct comparison of the treated and untreated groups revealed similar changes in height in the first year of treatment (1.73 cm) and the second year of treatment (1.79 cm). The additional height gain over the two-year treatment period was 3.52 cm more than the untreated children, leading to the conclusion that the effect of treatment was sustained over time, with a height z score of +0.44 at week 104.16
These outcomes, combined with the preliminary trial data for children aged 2–5 years provided to regulatory agencies, led to the approval of vosoritide by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) in 2021 for the treatment of achondroplasia in children, from age 2 years in the European Union and from age 5 years in the United States, until the closure of the growth plates.
The extension study, which included patients with up to 6 years of follow-up, was published in 2024 and evinced a sustained, long-term growth-promoting effect. The mean difference in annualized growth velocity was 1.84 cm/year for male participants and 1.44 cm/year for female participants. Comparisons between treated and untreated children at the 3-year timepoint showed an additional height gain of 5.75 cm (95% CI, 4.93–6.57). There was significant improvement in the upper-to-lower body segment proportions at 3 years of treatment.17
Later trials investigated the use of vosoritide in children aged less than 5 years (111-206 and extension study 111-208; NCT03583697). The phase 2 trial included 75 children aged less than 60 months in three cohorts (cohort 1: 24–59 months; cohort 2: 6–23 months; cohort 3: 0–5 months). Cohorts 2 and 3 (age < 2 years) received 30 μg/kg/day of vosoritide. In these cohorts, the dose was increased after observing that the initial dose of 15 μg/kg/day achieved lower drug concentrations than described in previous studies. Upon reaching age 2 years, the dose was once again lowered to 15 μg/kg/day, which is the standard dose used in children aged 24–59 months and children older than 5 years.
One of the secondary objectives of the trial was to assess the change from baseline in the height z score in the vosoritide and placebo groups, finding a mean difference of +0.25 in the treated group (95% CI, −0.02 to 0.53).18 Another was to assess the changes in skull and brain morphology through MRI, which showed increases in facial volume and the area of the foramen magnum in cohort 3 (age < 6 months).
Since October 2023, vosoritide is approved by the FDA for all children with achondroplasia from birth and by the EMA from age 4 months until the closure of the growth plates. The postmarketing real-world evidence on vosoritide is still limited.
In a French cohort, at 12 months of treatment, participants (n = 22) exhibited an absolute gain in height of 6.2 cm/year, with an absolute increase in the height z score of +0.38.19 Data for 164 patients from Portugal, Australia, and Germany obtained through the CrescNet Registry Achondroplasia Module show an increase in the height z score of 0.45 in 85 treated patients after 1.23 years. In a German cohort (n = 34), there was a significant mean increase in the height z score of +0.38 (SD, 0.44).20
Regarding the safety profile of vosoritide, phase 2 trials have reported injection site reactions (generally mild and transient) and transient decreases in blood pressure. Evidence from phase 3 trials shows that most adverse events are mild and injection site reactions are the most common adverse effect. Blood pressure was monitored, and there were no clinically significant cardiovascular changes (only one patient experienced an episode of symptomatic hypotension upon standing up quickly; which was transient and did not require medical intervention).15 Administration of the first dose in a health care facility is recommended, ensuring that the patient is adequately hydrated (intake of approximately 240−300 mL of fluids in the hour preceding injection). Real-world studies have not reported any episodes of hypotension associated with its administration. On the other hand, they have confirmed that injection site reactions are the most frequent type of adverse event.19,20
The use of vosoritide is not recommended in patients with renal or hepatic impairment, or in patients with significant cardiovascular disease or on anti-hypertensive medication, special populations that were excluded from clinical trials. Vosoritide is contraindicated in patients with hypersensitivity to any of the active substances or excipients contained in the drug.
Drugs under developmentNavepegritideNavepegritide (TransCon CNP) is a long-acting C-type natriuretic peptide prodrug that is administered once a week. The phase 1 trial in 45 adults demonstrated that it was well tolerated with a pharmacokinetic profile supporting a once-weekly dosing regimen.21 The phase 2 trial assessed the safety and efficacy of escalating doses of navepegritide in 42 patients aged 2–10 years over a period of 52 weeks, and found a dose-dependent improvement in annualized growth velocity. At 52 weeks, the 100 μg/kg/week dose achieved an improvement in growth velocity compared to placebo (5.42 cm/year vs 4.35 cm/year) and an increase in the height z score of +0.22 (95% CI, 0.02−0.41).22
Following the promising results of the phase 2 trial, a pivotal, double-blind, randomized controlled trial of navepegritide (ClinicalTrials.gov Identifier: NCT05598320) is currently underway in children with achondroplasia aged 2–11 years (dose of 100 μg/kg/week).
InfigratinibThe fibroblast growth factor receptor (FGFR) family comprises four transmembrane tyrosine kinase receptors (1–4). Infigratinib is a selective FGFR1-3 tyrosine kinase receptor inhibitor that is orally bioavailable and is under development for treatment of FGFR-related diseases, such as cholangiocarcinomas and bladder cancers involving FGFR2 and FGFR3 variants.23 It inhibits FGFR3 phosphorylation, and, as a result, its downstream signaling pathways. Preclinical murine models showed that daily treatment with infigratinib at a dose of 2 mg/kg achieved a significant increase in bone growth.24 A subsequent study investigated its activity at lower doses with an intermittent dosing regimen (3 murine cohorts, treated with 0.2 mg/kg/day, 0.5 mg/kg/day or 1 mg/kg once every 3 days, and a control group). At 15 days of treatment, there was evidence of a progressive and dose-dependent increase in the length of the upper and lower extremities compared to the control group. Macroscopic analyses showed enlargement of the foramen magnum area at the skull base in the animals treated with 0. 5 mg/kg/day and 1 mg/kg/72 h.25
The PROPEL study (NCT04035811) was a prospective, noninterventional study conducted to characterize the natural history of achondroplasia in children through the collection of serial assessments over periods lasting 6–24 months. The PROPEL 2 study (NCT04265651) was a phase 2 dose-finding trial that assessed the safety and efficacy of infigratinib in 72 children aged 2.5–10 years with achondroplasia.26 Participants were divided into five cohorts, and the study included a dose-escalation phase lasting 6 months followed by a dose-expansion phase lasting 12 months during which the dose could be escalated in cohorts 1 and 2 (n = 58).
Linear growth increased the most in cohort 5 (0.25 mg/kg) with a mean change from baseline in the annualized height velocity of +2.51 cm/year at 18 months (95% CI, 1.22–3.79). The mean increase in the height z score relative to baseline was 0.54 (95% CI, 0.35−0.72). The mean change in upper-to-lower body segment ratio was −0.12 (95% CI, −0.18 to –0.06), evincing improvement in body proportions.27 Trials are currently underway to evaluate the long-term safety and efficacy of infigratinib: PROPEL OLE (open-label extension; NCT05145010) and PROPEL 3 (phase 3 randomized, double-blind and placebo-controlled; NCT06164951), with approximate sample sizes of 280 and 110 patients, respectively.
TYRA-300TYRA-300 is an oral, selective, and direct FGFR3 tyrosine kinase inhibitor. Compared to infigratinib, one of its key advantages is its high selectivity for FGFR3, as cross-inhibition of other receptors in the same family (FGFR1, FGFR2, and FGFR4) can cause significant side effects. On account of this selectivity, TYRA-300 is being investigated with the aim of minimizing these undesirable effects and offering a more favorable safety profile.
In murine models, treatment with TYRA-300 has been found to improve chondrocyte proliferation, arrangement, and differentiation, resulting in an increase in the dimensions and morphology of the foramen magnum and the length of the long bones.28
At present, TYRA-300 is being investigated in a phase 2 dose-escalation trial (BEACH301; NCT06842355) conducted in children with achondroplasia aged 3–10 years; its main objectives are to assess the safety and identify effective dose levels of TYRA-300, and to evaluate changes in growth velocity and body proportions. There are two cohorts in the trial: one of children naïve to growth-accelerating treatment, and another of children who have received some form of growth-accelerating treatment with an unsatisfactory response.
MeclizineMeclizine is an antihistamine approved for treatment of vertigo. It inhibits FGFR3 signaling through the MAPK pathway (inhibiting phosphorylation of ERK downstream from FGFR3). It has been found to increase length in transgenic mice with achondroplasia when administered orally 5 days a week for two weeks. The histological analyses showed restoration of the growth plate, with a reduction in the incidence of paraplegia attributed to the amelioration of spinal canal stenosis.29 In another murine model, meclizine was administered to pregnant females to determine whether it could prevent foramen magnum stenosis in the pups by measuring the foramen magnum area post birth. The study did not find significant differences, and the authors noted that it was probably due to low placental transmission of the drug.30
A phase 1b open-label study (jRCT2041200114) was conducted to assess the safety and pharmacokinetics of meclizine in 12 children with achondroplasia. There were two cohorts that received meclizine at doses of 12.5 mg/day (<20 kg) and 25 mg/day (>20 kg) for 14 days, and the outcomes of interest were the incidence of adverse events and pharmacokinetic parameters. This trial showed that a 14-day repeated dose of meclizine was well tolerated and achieved adequate pharmacokinetic profiles in children with achondroplasia aged 5–10 years in both cohorts.31
RBM-007It is an RNA aptamer that specifically binds FGF2, one of the ligands for FGFR3, blocking their interaction. It acts as a “ligand trap”, sequestering FGF2. In cultured rat chondrocytes, RBM-007 rescued the proliferation arrest and the degradation of the cartilaginous extracellular matrix. This drug could delineate a potential therapeutic approach for achondroplasia and other FGFR3-related skeletal dysplasias.32
ReciferceptIs a soluble recombinant form of FGFR3 that acts as a “decoy” receptor that competes for FGF ligands, intercepting FGFs in the vicinity and preventing their fixation to the mutant receptors. In the preclinical murine model (NCT04638153), administration of recifercept twice a week restored growth plate maturation.33 Phase 2 trials found no beneficial effects on growth, leading to discontinuation of the development process.34
SAR-442501It is a humanized monoclonal antibody that targets FGFR3, which was administered subcutaneously twice a week to children with achondroplasia from birth through age 12 years. Phase 2 studies found no beneficial effects on growth, so trials were discontinued.
DiscussionA deeper understanding of the pathophysiological basis of the disease has led to the development of new therapies that act through the inhibition of FGFR3 receptor signaling.2,6 At present, vosoritide is the only approved treatment for achondroplasia. Initial studies focused on the increase in annualized growth velocity and in height z scores. These studies found an increase in growth velocity of approximately 1.5 cm/year that was sustained at different ages.15 There was a slightly greater increase in growth velocity in male subjects (1.84 cm/year vs 1.44 cm/year) and increases in height z scores ranging from 0.25 to 0.45. Improvements in body proportions were observed starting at 3 years of treatment.16 However, the influence of other independent variables on growth acceleration (parental heights, baseline anthropometric values, etc) remains to be determined. Early identification of potential nonresponders is necessary, as is an assessment of the impact on other clinical outcomes during childhood, such as foramen magnum stenosis, or adulthood, such as spinal canal stenosis.35
The most widely used guidelines1,36,37 have yet to be updated concerning the follow-up after initiation of treatment with vosoritide or ongoing clinical trials. Some countries, like Australia or Spain, have developed expert consensus guidelines for the follow-up of patients treated with vosoritide that highlight the importance of a comprehensive interdisciplinary management approach with active surveillance for the potential medical and surgical complications of achondroplasia, which will generate evidence on the potential impact of vosoritide on outcomes of interest.37,38
There is controversy regarding the safety and potential efficacy of combining vosoritide with surgical limb lengthening, the conventional approach to treatment that has been used in a substantial percentage of patients in Spain. A panel of international experts highlighted the lack of evidence on the use of vosoritide versus limb lengthening in patients with achondroplasia, and in particular the absence of data on their combined use, although there are also no data contraindicating the combined approach.39 A multicenter study published in 2025 analyzed the integration of vosoritide therapy and surgical limb lengthening and found that the two approaches could be complementary, with no evidence of the two ossification processes interfering with one another or a negative impact on bone healing. However, these data are preliminary and were obtained in real-world practice, not controlled trials.40
There is a need for real-world evidence on the outcomes achieved with current and upcoming therapeutic approaches, which may include concomitant or sequential combination therapies. Since achondroplasia is a rare condition, national and international registries must be established to generate evidence as fast as possible to allow the evaluation of therapies (alone and in combination) that have a significant economic impact for which there is limited postmarketing data.
The boom in research in this field in recent years has sparked growing interest among professionals and patients at the prospect of future therapies that may not require subcutaneous administration and have a longer half-life, which may have a positive impact not only on growth, but also on other clinical outcomes.
The growing demand for information on therapies under investigation in clinical trials, which patients may turn to in their search for solutions they cannot find in approved therapies, calls for an update on these investigational drugs, which we covered in this review.
FundingThis research did not receive any external funding.
The authors have no conflicts of interest to declare.
