New treatments for children with achondroplasia

It is often lethal in the perinatal period due to a small chest wall, lung hypoplasia, and respiratory insufficiency figure 1C.13Natural historyAchondroplasia is unique compared with oth

New treatments for children with achondroplasia

Ravi Savarirayan, Julie Hoover-Fong, Patrick Yap, Svein O Fredwall

Achondroplasia is the most common form of dwarfism in humans, caused by a common pathogenic variant in the

gene encoding fibroblast growth factor receptor 3, FGFR3, which impairs the process of endochondral ossification of

the growing skeleton In this Review, we outline the clinical and genetic hallmarks of achondroplasia and related

FGFR3 conditions, the natural history and impact of achondroplasia over a patient’s lifespan, and diagnosis and

management options We then focus on the new and emerging drug therapies that target the underlying pathogenesis of this condition These new options are changing the natural growth patterns of achondroplasia, with the prospect of better long-term health outcomes for patients.

Achondroplasia is the most common form of heritable skeletal dysplasia with an estimated prevalence of 4–6 per 100 000 births.1 The clinical phenotype is characterised by relative macrocephaly, frontal bossing, depressed nasal bridge, midface hypoplasia, disproportionate short limbs, stature, and hands, shortening of the long bones, and a long trunk These features can be present from the third trimester of pregnancy, allowing clinical diagnosis and planned management in late pregnancy or shortly after birth.1,2 The typical radiographic features in a newborn are shown in figure 1A.

From early infancy, medical complications such as severe foramen magnum stenosis with cervico-medullary compression and sleep-disordered breathing can increase the risk of sudden death, which warrants a low threshold for investigations and prompt management.1,3,4 During infancy, hypotonia with associated thoracolumbar kyphosis, which usually improves with age without treatment, and gross motor delay are common By contrast, exaggerated lumbar lordosis, progressive genu varum, and restricted extension of the elbows persist and can cause long-term morbidity, including pain and disability such as impaired mobility and activities of daily life.1,5,6

Genetics and related FGFR3 conditions

Achondroplasia is caused by a gain-of-function mutation in the gene encoding fibroblast growth factor receptor 3,

FGFR3, which is inherited as an autosomal dominant

trait.7 This activation of FGFR3 and its inhibitory

downstream signalling pathways results in slowing of endochondral ossification Almost all individuals affected by achondroplasia have a 1138G→A (Gly380Arg) or 1138G→C (Gly380Arg) pathogenic variant within the

transmembrane-encoding region of FGFR3.7,8 The delineation of the downstream pathways and understanding the consequences of these pathogenic variants over the past 20 years has laid the foundation for targeted therapies (figure 2).8,9

Other conditions related to FGFR3 pathogenic variants

include hypochondroplasia, severe achondroplasia with developmental delay and acanthosis nigricans, and thanatophoric dysplasia.7,10,11 Hypochondroplasia is a milder form of achondroplasia, and children typically present with large heads, short stature, joint laxity, and

genu varum from early childhood, and sometimes they have a family history of short stature.12 Most children with hypochondroplasia do not have complications such as spinal cord compression; however, epilepsy, mild intellectual disability, and learning difficulties are more prevalent compared with children with achondroplasia The radiographic skeletal features are more subtle than those observed in achondroplasia and are often missed by radiologists without specialist training (figure 1B)

Thanatophoric dysplasia is the most severe of the

FGFR3-related skeletal dysplasia It is often lethal in the perinatal period due to a small chest wall, lung hypoplasia, and respiratory insufficiency (figure 1C).13

Natural history

Achondroplasia is unique compared with other genetic skeletal dysplasia causing short stature: 99% of all affected individuals have the same nucleotide change in

FGFR3, with 100% penetrance.1,7 The gain-of-function variant in achondroplasia is responsible for the most characteristic feature—short stature, with final adult height typically between 124 cm for women and 132 cm for men.6 Despite this genetic similarity, there is large phenotypic diversity in other disease manifestations

Lancet Child Adolesc Health

2024; 8: 301–10

Murdoch Children’s Research Institute, Parkville, VIC, Australia

(Prof R Savarirayan MD); University of Melbourne, Melbourne, VIC, Australia (Prof R Savarirayan); Johns Hopkins University School of Medicine, Baltimore, MD, USA (Prof J Hoover-Fong MD); Genetic Health Services New Zealand, Auckland, New Zealand (P Yap MD); TRS National Resource Centre for Rare Disorders, Oslo, Norway

(S O Fredwall MD)Correspondence to: Prof Ravi Savarirayan, Murdoch Children’s Research Institute, Parkville, VIC 3052, Australia

Key messages

• Achondroplasia is the most common form of human

dwarfism, caused by a FGFR3 mutation that activates

an inhibitory bone growth pathway, affecting approximately 300 000 individuals worldwide

• Children and adults with achondroplasia can have several medical challenges across the lifespan that affect their health and requires regular monitoring to detect and manage

• Several precision-based therapies have emerged that target the pathogenetic source

• Vosoritide, a C-type natriuretic peptide analogue, is the first of these treatments to be approved for use in children with achondroplasia to increase linear growth

• Whether vosoritide or the other drugs in clinical development for children with achondroplasia will improve health outcomes and quality of life needs longer-term studies

and their severity among affected individuals For example, one young child with achondroplasia might have multiple complications, including foramen magnum stenosis requiring surgical decompression, chronic middle-ear fluid requiring placement of pressure-equalising tubes, obstructive sleep apnoea treated with adenotonsillectomy, and genu varum managed by surgical guided growth, whereas another patient might have reached adulthood without any of these complications Although the genetic modifiers that contribute to this diversity are unclear, environmental and lifestyle factors related to weight management, exercise, and access to and compliance with health-care recommendations are likely to be key contributors Health-care workers and individuals with achondroplasia and their families need to be aware of the potential complications of achondroplasia to ensure careful monitoring and prompt treatment.

The natural history of achondroplasia has been well established in the medical literature, driven by the advent of potential therapies.6,14,15 From population studies, birth length, weight, and head circumference of newborn infants with achondroplasia overlap with those of infants with average stature However, within the first 6 months of life, the linear growth of those with achondroplasia clearly diverges, heading toward 4–6 SD below average, while their weight overlaps with the lower quartile of their average stature peers, and their head circumference overlaps with the upper boundary for average statured children.16,17 Early motor milestones are delayed for infants with achondroplasia due to macrocephaly, short-limbed short stature, and a degree of central hypotonia.1,6 Unlike other children, this motor delay is not correlated with global developmental delay or cognitive impairment Achondroplasia-specific developmental charts should

therefore be used for longitudinal care to allow accurate advice and management to be provided to families by paediatricians and other health-care workers.18

Achondroplasia is a multisystemic condition with a high prevalence of medical complications, which have variable frequencies and risks across the lifespan (figure 3),6,14,15,36 resulting in a high surgical burden in childhood and adulthood (table 1).23,32 In the largest published cohort of 1374 patients with achondroplasia, 80% had at least one achondroplasia-related surgery and many required repeated procedures over their lifespan.23 In infancy, foramen magnum stenosis poses the greatest risk of mortality and morbidity.3,37 Through childhood, this condition can negatively affect sleep quality (due to disordered breathing), hearing, and the ability to perform daily activities Pain and impaired function caused by spinal stenosis is the source of greatest morbidity in adults with achondroplasia and, collectively, these manifestations can substantially impair the quality of life of these individuals.14,26,33,35,36

Infancy (0–2 years)

In infancy, foramen magnum stenosis caused by the premature fusion of cranial base synchondroses can cause severe neurological complications, sleep-disordered breathing, life-threatening compression of the brain stem, and sudden death.3,37 Some of these infants can present with subtle or no clinical symptoms,3,4 and management guidelines recommend a sleep study, MRI of the cervicomedullary junction, comprehensive neurological examination, and assessment of growth and development with achondroplasia-specific tools.1,5,29 More than half of children with achondroplasia have sleep-disordered breathing.20,24,38 Thoracolumbar kyphosis is present in almost all infants and, although this excessive spinal curvature resolves in most children once they start walking,

Figure 1: Radiographic features of achondroplasia and related FGFR3 skeletal dysplasia

(A) A newborn patient with achondroplasia and molecularly confirmed pathogenic FGFR3 missense variant 1138G→A (Gly380Arg) The common skeletal features include large calvarium with

prominent frontal, parietal, and occipital regions, decreased size of skull base, decreased interpedicular distances from vertebrae L1 to L5, short pedicles, bullet-shaped and posterior scalloping of vertebrae on lateral view, flat and rounded ilia with absence of iliac flaring, broad and trident pelvis (horizontal superior acetabulum and narrowed sacrosciatic notches), and shortened long bones with metaphyseal flaring and cupping The hand shows trident configuration with brachydactyly, characterised by broad, short, and cone-shape phalanges (B) Newborn patient with hypochondroplasia

and molecularly confirmed pathogenic FGFR3 missense variant 1620C→G (Asn540Lys) Notable features include short long bones, short femoral necks, and mild shortening of the pedicles on the

lateral spine film The radiographic skeletal features are milder compared with patients with achondroplasia and often missed (C) A fetus with thanatophoric dysplasia type 1 and molecularly

confirmed pathogenic FGFR3 missense variant 742C→T (Arg248Cys) The radiographic phenotype is distinctive, characterised by short ribs causing narrowed, bell-shaped thorax, severe platyspondyly,

short ilia with trident acetabulum, and severely short and broad long bones The scapulae can appear dysplastic Bowed femora are present in thanatophoric dysplasia type 1, whereas craniosynostosis and straight femora are observed in thanatophoric dysplasia type 2.

Illustration: 23tlchild0215_1Editor:

Author:

Name of illustrator: Neil SmithDate started: 1.2.24a

about 10–15% will have persistent or progressive kyphosis requiring bracing or spinal fusion.6,25,39 Recurrent upper airway obstruction and acute otitis media are reported in up to 70–90% of infants and young children with achondroplasia, often requiring adenotonsillectomy and insertion of ventilation tubes.5,14,20,21,38

Early childhood (3–5 years)

In young children aged 3–5 years with achondroplasia, foramen magnum stenosis can still present or recur, although more rarely.3,19 Other common medical complications in this age group include sleep-disordered breathing with obstructive sleep apnoea and hypopnoea, recurrent middle-ear infection and fluid with secondary hearing deficit leading to speech delay, and genu varum.6,20,21,24

Older children and adolescents (6–18 years)

In older children and adolescents, sleep-disordered breathing, persistent middle-ear fluid, and genu varum are common medical issues About 10–20% of children and adolescents can present with symptoms of spinal stenosis in early childhood, which has an increasing prevalence with age.20,25,40 Many children also report chronic pain, particularly back and leg pain, and fatigue.35,41 During this critical period in the lifespan, a young person with achondroplasia becomes self-aware and might struggle with their short stature while simultaneously trying to cope with peer relationships and the demands of schooling This is also the period during which lifestyle choices and habits—such as weight management, exercise, drug or substance use, and responsibility for health-care management—have as much influence on overall physical function as the primary skeletal manifestations of achondroplasia.

Adults and family

Having a child with achondroplasia affects parents and caregivers This impact includes concerns about potential medical complications and the child’s future prospects, social life, and vocational opportunities.35,42

For many families, time spent dealing with the medical issues related to achondroplasia is considerable, which influences the entire family, their social life, and work.15,34 These aspects need to be recognised and appropriate supports need to be offered for individuals with achondroplasia and their families over their lifespan In many countries, people with achondroplasia face discrimination and stigmatisation because of their condition, and community education, advocacy, and legislation must minimise this prejudice.

Diagnosis and management

The diagnosis of achondroplasia is clinical and based on characteristic physical and radiographic findings.1 Over the past decade in the USA, the majority of patients with achondroplasia have been diagnosed antenatally (via

ultrasound with molecular confirmation) or clinically at birth.23 This diagnostic process might be delayed in countries that do not have skeletal dysplasia reference centres Clinical data and radiographs can be sent to global networks such as the International Skeletal Dysplasia Society and European Skeletal Dysplasia Network for expert opinion to expedite the accurate diagnosis of achondroplasia in these situations, especially if the presentation is atypical Molecular confirmation is traditionally done with Sanger sequencing for the causative pathogenic variants or by relevant gene panels The utility of molecular confirmation of a suspected clinical diagnosis of achondroplasia includes informing the parents of reproductive options and is a pre-requisite for initiation of targeted therapies.

Several guidelines exist relating to the optimal management and care for infants and children with achondroplasia The most recent and comprehensive guidelines include the 2022 international consensus statement on the diagnosis, multidisciplinary management, and lifelong care of individuals with achondroplasia1 and the recommendations provided by the American Academy of Pediatrics, last updated in 2020.5 Both organisations recommend referral to a reference centre experienced in achondroplasia immediately after diagnosis and that further management be provided by a multidisciplinary team experienced in achondroplasia in collaboration with local health-care providers, including paediatricians Close monitoring during the first 2–3 years of life (by means of clinical

Figure 2: The FGFR3 signalling pathway and therapeutic targets in achondroplasia

Transmembrane FGFR3 pathogenic variant (yellow star) in achondroplasia causes activation of downstream pathways, leading to the inhibition of chondrocyte proliferation and hypertrophy, and therefore impaired

endochondral ossification The therapies approved or in development for the treatment of achondroplasia target

parts of this pathway to overcome this inhibition, including the blocking of RAF1 (C-type natriuretic peptide analogues, including vosoritide and navepegritide); the inactivation of the FGFR3 tyrosine kinase (infigratinib and SAR-442501); the inactivation of the MAPK pathway (meclizine); and the blocking of FGF2 binding to FGFR3 (RMB-007) FGF2=fibroblast growth factor 2 FGFR3=fibroblast growth factor receptor 3 AP2K=mitogen-activated protein kinase kinase MAPK=mitogen-AP2K=mitogen-activated protein kinase NPR2=natriuretic peptide receptor 2 STAT=signal transducer and activator of transcription.

For the International Skeletal Dysplasia Society, see

For the European Skeletal Dysplasia Network, see

www.esdn.org

neurological examination, poly somnography, and MRI scanning) is critical due to the high risk of complications consequent to foramen magnum stenosis and sleep-disordered breathing, including sudden death.1,5

These guidelines specifically address management recom mendations for children and adolescents with achondroplasia and can act as a useful standard of care resource for paediatricians who manage these patients.

Until about 2021, the treatment of individuals with achondroplasia has been purely symptomatic or reactive to medical complications Placing ear ventilation tubes (grommets) to alleviate chronic middle-ear fluid is common, with the intention to improve hearing and avoid development of chronic middle-ear infection Patients who have symptomatic sleep-disordered breathing with apnoea

or obstruction accompanied by hypoxia and hypercapnia commonly have adenoidectomies and tonsillectomies.38

Individuals who are refractory to these measures are typically treated with continuous positive airway pressure while sleeping.

For infants and young children with symptomatic compression of the brainstem and upper cervical cord, surgical enlargement of the foramen magnum with or without decompression at the level of the C1 and C2 vertebrae is done Hydrocephalus is sometimes present concurrent with the upper cervical compression In the past, hydrocephalus was treated by a ventricular shunt that often required revisions or replacement More recently, the realisation that enlargement of the foramen magnum and decompression of the brainstem could reduce or resolve

Figure 3: Common medical complications and health issues in people with achondroplasia by age, including estimated prevalence

Prevalence ranges are approximate, based on the medical literature Blue shading indicates the presence of risk.

Risk across the lifespan Central sleep apnoea3,21

Obstructive sleep apnoea14,20,22–24

Persistent thoracolumbar kyphosis14,25

Symptomatic spinal stenosis6,20,26

Leg malalignment6,14

Otitis media infections22,27

Chronic middle-ear effusion20,21

Delayed motor milestones6,18,29

Psychosocial health issues, impairedhealth-related quality of life32,34,35

the hydrocephalus has decreased the frequency of shunt placement in children with achondroplasia.1

Painful and progressive genu varus deformity and tibial bowing, which negatively affect physical function and daily life, can be treated with hemi-epiphysiodesis or osteotomies In infants and young children with achondroplasia who have a delay in motor skill acquisition that is beyond what is expected for this condition, physical and occupational therapy might assist As the child grows, additional adaptive equipment offered through occupational therapy to manipulate buttons, toilet independently, and handwrite can also be helpful Planning for this adaptive equipment is especially important when the child starts school.

Two population-based studies have shown that 70–80% of patients required at least one achondroplasia-related surgery (ie, tubes or adenotonsillectomy, foramen magnum decompression, spine surgery, and leg surgery).21,23 Ideally, a multi disciplinary team of specialists should provide longitudinal care to all children with achondroplasia.1 This team can include a neurosurgeon, orthopaedic surgeon, otolaryng-ologist, respiratory physician, physical therapist, and an experienced coordinator of these services, such as a medical geneticist or paediatric endocrinologist Close communication between this speciality team and the primary care physician is essential throughout the lifespan to ensure optimal management.

Until 2021, the only approved drug therapy for children with achondroplasia was growth hormone in Japan However, this treatment is not a precision therapy as children with achondroplasia are not deficient in growth hormones, and improve ments in growth velocity are typically only seen in the first 24 months of treatment, with no documented increases in final adult height.43 If growth hormone (or one of the new precision medications) is prescribed for a young patient with achondroplasia, then a paediatric endocrinologist might also be part of the multi disciplinary team.

Therapies that target pathogenesis of achondroplasia have been a substantial unmet need The first clinical trials of such potential therapies have been done only in the past decade, leading to the identification and approval of the first precision therapy for achondroplasia (table 2).

Approved precision treatment: vosoritide

After a decade-long translational process from basic science and proof-of-concept studies with animal models to clinical trials in children with achondroplasia, vosoritide, a modified analogue of C-type natriuretic peptide (CNP), became the first approved therapeutic agent for children with achondroplasia The first clues that CNP might have a key role in the regulation of endochondral bone growth in humans came from observations that loss-of-function mutations in its receptor (natriuretic peptide receptor-B [NPR2]) caused

a form of severe dwarfism (acromesomelic dysplasia, Maroteaux type)61 and that mutations in NPCC (the gene

encoding CNP) caused short stature in an autosomal dominant manner.62 Conversely, over expression of CNP causes generalised skeletal overgrowth in humans with a Marfan-like phenotype.63 These bidirectional phenotypic consequences of loss-of-function and gain-of-function mutations in the CNP pathway64 were encouraging evidence that CNP modulation might have an effect in disorders of endochondral bone growth like achondroplasia.

These observations led to further scrutiny of the role of CNP administration in animal (mouse) models Continuous systemic administration of native CNP in a mouse model of achondroplasia increased the impaired bone growth observed in these mice65 and led to the modification of its native structure to resist degradation in the stomach, thereby increasing its half-life and making it amenable to administration by daily subcutaneous injection.66 This modified CNP (vosoritide) also resulted in amelioration of the dwarfism phenotype in these mice, providing proof of concept in an animal model that CNP could be an option for children with achondroplasia to improve bone growth.

These data led to the first human trial of vosoritide in children with achondroplasia aged 5–14 years,44 all of whom had participated in an observational baseline growth study for at least 6 months.67 This trial was a phase 2, open-label, sequential cohort, dose-finding study in 35 patients, which showed that daily administration of vosoritide had a mild side-effect profile at the doses tested (2·5–30 μg/kg per day), and sustained increases in annualised growth velocity compared with baseline growth were observed in children who received 15 μg/kg or 30 μg/kg per day The observed increases in annualised growth velocity

Adenotomy or adentonsillectomy14,21

Recurrent upper airway infections, obstructive sleep apnoea 45–50% Ventilation tubes14,21Chronic middle-ear effusion50–57%Spinal fusion25Thoracolumbar kyphosis 4–5%Spinal decompression20Symptomatic spinal stenosis10–20%

Arm or leg extension0–90%**Country dependent (eg, <1% in the USA, UK, and Australia and about 60–90% in Spain, Italy, and Japan).

Table 1: Estimated proportion of children with achondroplasia

undergoing surgical treatment

were similar in children who received these doses of vosoritide.

Given these promising phase 2 results, a pivotal, double-blind, randomised-controlled, phase 3 trial was done in 121 children aged 5–18 years with achondroplasia to further evaluate the efficacy and safety of vosoritide at the 15 μg/kg per day dose This 1-year study45 confirmed that the main side-effect of vosoritide was mild injection site reactions and showed a significant increase in annualised growth velocity over baseline in the children randomised to vosoritide compared with those administered placebo (adjusted mean difference 1·57 cm per year, 95% CI 1·22–1·93) After 52 weeks of this trial, 119 of the children enrolled in an extension study in which all participants received vosoritide,46 with persistent positive effects on growth at 2 years and improvements in body propor tionality observed After the positive results in older children with achondroplasia, a clinical trial of vosoritide in children aged 3 months to 5 years with achondroplasia was started to examine the effects of vosoritide in this age group This trial showed that vosoritide had a mild side-effect profile in this age group and resulted in a difference in the change from baseline in height deficit in children Notably, there were increases in facial volume, facial sinus volume, and foramen magnum area in children aged 3–6 months with achondroplasia treated with vosoritide compared with the placebo group.47

The results of the phase 3 trial, combined with pre-liminary data supplied to agencies from the treatment trial of children aged 2–5 years with achondroplasia, led to the approval of vosoritide by the European Medicines Agency (EMA) for the treatment of children older than 2 years with achondroplasia (until growth plate closure) in 2021 Based on the evaluation of the full dataset from the clinical trial of children with achondroplasia aged

3 months to 5 years,47 vosoritide was approved by the US Food and Drug Administration for all children with achondroplasia with open growth plates (ie, from birth) in October, 2023 Vosoritide is approved in 46 countries for the treatment of children with achondroplasia, and in Japan and Australia this approval has been obtained from birth until growth plate closure Given the success of this drug development programme for children with achondroplasia, preliminary trials are now underway to assess the safety, efficacy, and optimal dose of vosoritide therapy in other related FGFR3 growth conditions such as hypochondroplasia (NCT04219007) and isolated short stature.

Other therapies in clinical development Navepegritide

Buoyed by the promise of CNP analogues for the treatment of achondroplasia, Ascendis Pharma has developed a sustained-release, longer-acting form of CNP (navepegritide) that was designed to provide more consistent levels of CNP to the growth plate To achieve this, they linked CNP to an inert carrier molecule, shielding CNP from clearance and potentially prolonging its effects on the growth plate After proof-of-principle studies in animals,48 a phase 1 human study was done in healthy adult men showing that this long-acting CNP was well tolerated with a pharmacokinetic profile compatible with once-weekly dosing.49

The phase 1 data led to an observational growth and natural history study in children with achondroplasia aged 0–8 years to investigate the baseline annualised growth velocities in this cohort and natural history data on comorbidities (NCT03875534) Children from this

achondroplasia were then eligible for recruitment into a phase 2, double-blind, randomised-controlled,

Vosoritide44–47Blocks gain-of-function

FGFR3 signal at RAF1 CNP analogue Approved for use in children—varying ages from birth to 5 years until end of growth

Daily subcutaneous

injection BioMarin Navepegritide48–50Long-acting form of CNP CNP analogue bound to

inert carrier to prolong half-life

Phase 2 completedWeekly subcutaneous

injection Ascendis Pharma Infigratinib51–54FGFR1–3 inhibitorTyrosine kinase inhibitor Phase 2 completedDaily oral tabletsQEDRecifercept55Soluble form of FGFR3Ligand trapPhase 2: trial ceased

(futility) Subcutaneous injection Pfizer SAR44250156FGFR3 antibodyMonoclonal antibodyLead-in growth study

ongoing Twice-weekly subcutaneous injection Sanofi Meclizine57,58Histamine 1 receptor

blocker Antihistamine Phase 1a Oral once and twice daily tablets None RBM-00759,60FGF2 inhibitorRNA aptamerPhase 1Weekly subcutaneous

injection Ribomic FGFR=fibroblast growth factor receptor CNP=C-type natriuretic peptide FGF=fibroblast growth factor.

Table 2: Summary of therapies (approved or in development) for children with achondroplasia

dose-escalation trial of navepegritide administered weekly by subcutaneous injection to assess the harms and benefits of this therapy.50 Doses of navepegritide from 6 μg/kg per week to 100 μg/kg per week were tested in escalating dose cohorts versus placebo, randomly assigned 3:1 Navepegritide was well tolerated at all doses tested, with a low frequency of injection site reactions compared with the frequency of these reactions reported for once-daily injections of vosoritide In addition, navepegritide at the 100 μg/kg per week dose resulted in significant increases in annualised growth velocity compared with placebo.50

The annualised growth velocity in 11 children with achondroplasia grew a mean of 5·42 cm per year (95% CI 4·74–6·11) compared with 4·35 cm per year (3·75–4·94) for the placebo group (p=0·022) These data led to a pivotal phase 3 trial of weekly navepegritide in children with achondroplasia and showed that weekly CNP administration might also be a potential therapeutic option for children with achondroplasia.50

Infigratinib is an orally bioavailable selective inhibitor of FGFR1–3 and has shown promise in the treatment of previously treated or metastatic intrahepatic cholangio-carcinoma51 driven by somatic mutations in FGFR2

Based on these data and amelioration of the bone phenotype (including the size of the foramen magnum and bony spinal canal) in mouse models of achondroplasia treated with infigratinib,51 observational growth and intervention clinical trials have started in children (aged 2·5–16 years) with achondroplasia to assess the safety and efficacy of this oral therapy (PROPEL [NCT04035811] and PROPEL-2 [NCT04265651]).53 The phase 2 dose-finding study (PROPEL-2) showed that children allocated to the highest dose cohort of infigratinib (0·25mg/kg per day) had no treatment-related adverse events and grew an annualised average of 3 cm per year more than their baseline growth velocity as assessed in the preceding observational study.54 These data are encouraging, especially given that this drug is administered orally in a small tablet, which can be sprinkled on food for young children A pivotal phase 3 trial commenced in December, 2023 (NCT06164951).

Based on data that a soluble FGFR3 molecule (Recifercept), which acts as a ligand trap, improved the bone phenotype in the achondroplasia mouse model,55

this potential therapy was developed by Therachon Pharma and then Pfizer, and observational and interventional clinical trials commenced in children aged 0–10 years with achondroplasia (NCT03794609 and NCT04638153) In 2022, these trials were terminated for futility, as no increase in annualised growth velocity was observed in children randomly assigned to receive

recifercept compared with children who received placebo at the doses tested.

In 2021, a human monoclonal antibody against FGFR3 (SAR-442501) received orphan designation from the EMA56 for the potential treatment of children with achondroplasia Sanofi has commenced an observational study to collect longitudinal growth measurements and evaluate the use of digital biomarkers (eg, home-based sleep monitors and wearable devices to monitor physical activity) in children aged 0–10 years with achondroplasia as a prelude to a phase 2 intervention trial of this FGFR3 antibody compound In October, 2023, an open-label phase 2 study of SAR-442501, administered as twice-weekly subcutaneous injections, commenced in children with achondroplasia from birth to age 12 years (NCT06067425).

Meclizine (also known as meclozine), a readily available over-the-counter oral antihistamine used commonly for the treatment of motion sickness, was identified as a possible treatment for achondroplasia and promoted longitudinal bone growth in the achondroplasia mouse model.57 This finding led to a phase 1a trial of once or twice daily meclizine administration in 12 Japanese children aged 5–11 years with achondroplasia to generate pharmacokinetic data for possible future clinical trials Meclizine was well tolerated with no serious adverse events.58

RBM-007 is an RNA aptamer developed to bind specifically to fibroblast growth factor 2, consequently blocking its contact with FGFR3 RBM-007 was shown to rescue FGFR3 signalling in wild-type mouse tibia, restore chondrocyte differentiation in induced pluripotent stem cells from humans with achondroplasia, and normalise abnormal growth in a mouse model of achondroplasia,59

leading to the hypothesis that it might be effective in treating achondroplasia RBM-007 is in early clinical development in Japan.60

Future directions

The past decade has seen the approval of the first precision therapy for children with achondroplasia (vosoritide) and clinical development of other potential therapies (table 2) The next decade will probably see further delineation of the balance of harms and benefits of these new treatments, in addition to identifying which agents are most effective in ameliorating the co-morbidities associated with achondroplasia Agents that are shown to improve the abnormal development of the craniofacial skeleton in infants with achondroplasia and the growth of the foramina located at the base of the skull (especially the foramen magnum) will be of great potential clinical importance Long-term clinical studies

will find out if these improve ments reduce incidence of sudden infant death, sleep-disordered breathing, and the need for decompression and craniofacial surgery The optimal timing of initiation and dosing of these therapies and whether they might be used in combination to leverage efficacy will be evaluated by future trials.

Given that these therapies have been developed by pharmaceutical companies, innovative ways of ensuring availability of and equity in access to these treatments globally for children with achondroplasia must be prioritised Such efforts will take international co-operation and compromise between governments and pharmaceutical companies and will require advocacy and active participation from individuals with achondroplasia, their families, and support organisations to reduce costs.

There are and will continue to be people with achondroplasia and their families who choose not to use these new medications, especially if the main goal is to increase linear growth, as reflected by clinical trials’ primary endpoints To these individuals, short stature is a major contributor to their intrinsic personal identity and not a characteristic to be altered—these views must be respected Long-term observational data are required to find out if these new pharmaceuticals will also alter baseline morbidity and mortality associated with achondroplasia These new therapies will never replace the need for holistic care across the lifespan, advocacy, community education, and political support for individuals with achondroplasia and their families.

The disruptive new treatments for children with achondroplasia have transformed the natural growth history in this condition and have the potential to enable better health and reduce morbidity and mortality for these children These therapies should be made available to as many children and families who wish to use them, and long-term studies should continue to delineate safety and efficacy measures beyond linear growth, such as functionality, quality of life, and improvements in the surgical and medical burden of this condition.

Search strategy and selection criteria

We searched PubMed for original research and review articles published in English from Jan 1, 2000, to Dec 20, 2022, with the following search terms: “achondroplasia”, “C-natriuretic peptide”, “growth hormone”, “FGFR3”, “achondroplasia management”, and “treatment” We also searched ClinicalTrials.gov and the EudraCT database for registered clinical trials using “achondroplasia” as the search term We selected the articles, trials, and review papers that most closely aligned with the aims of this Review.

RS wrote the first draft All authors added to and revised the manuscript and agreed to its final submission.

Declaration of interests

RS declares educational grants from BioMarin and Sanofi; consulting fees from BioMarin, QED, Ascendis, and Pfizer; honoraria from BioMarin and QED; travel support from BioMarin, QED, and Ascendis; participation on a data safety monitoring board or advisory board for BioMarin and QED; and clinical trial equipment from BioMarin, QED, Ascendis, and Pfizer JH-F declares grants from BioMarin, Pfizer, and QED paid to her institution for clinical trials; consulting fees from BioMarin, QED, and Novo Nordisk; and travel support from BioMarin and QED SOF declares honoraria from BioMarin paid to his institution; travel support from BioMarin; and participation on a data safety monitoring board or advisory board for BioMarin and Sanofi, with honoraria paid to his institution PY declares no competing interests.

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