A phase three global clinical trial led by the Murdoch Children’s Research Institute (MCRI) has shown a new drug boosts bone growth in children born with achondroplasia, the most common type of dwarfism.
The randomized, double-blind, placebo-controlled trial results, led by MCRI clinical geneticist Professor Ravi Savarirayan, have been published today in the prestigious medical journal, The Lancet.
Achondroplasia is the most common cause of dwarfism and is caused by overactivity of the FGFR3 protein, which slows bone growth in children’s limbs, spine, and the base of their skull.
The experimental drug, vosoritide, blocks the activity of FGFR3, potentially returning growth rates to normal. Previous MCRI-led trials have confirmed vosoritide was safe to give to young people with dwarfism.
This new randomized controlled trial conclusively shows it is also effective increasing bone growth over one year of daily injections.
Professor Savarirayan said, “This drug is like releasing the handbrake on a car, it lets you get up to full speed instead of having to drive with the brakes on.”
Achondroplasia is a genetic bone disorder affecting 250,000 people worldwide, or about one in every 25,000 children.
It is caused by a mutation in the FGFR3 gene that impairs bone growth and means that children grow around 4 cm per year, instead of the usual 6 to 7 cm.
Current achondroplasia treatments, like surgery, only address the symptoms. In contrast, vosoritide is a precision therapy directly targeted at the molecular cause of the disease.
BioMarin Pharmaceutical, who manufacturers the peptide drug and funded the trial, has applied to the US Food and Drug Administration to license vosoritide for its use in treating achondroplasia.
The European Medicines Agency validated the Company’s application. Australian licensing is expected to follow sometime after a successful US application.
For the trial, 121 children aged five to under 18 were enrolled, which was conducted at 24 hospitals in seven countries. In Melbourne, the trial was conducted at the Melbourne Children’s Trial Center.
The 60 children who received daily injections of vosoritide grew an average of 1.57 cm per year more than the children who received placebo, which brought them almost in line with their typically developing peers.
Professor Savarirayan said, “We know that beyond the cold hard facts and figures around growth rates and bone biology, we have hope that a treatment can improve kids’ health outcomes, social functioning and increase access to their environments.
Anecdotally, our patients tell us they now are able to do more stuff like climbing trees, jumping rocks and being more independent generally, which is specific to their experiences.”
Dr. Johnathon Day, Medical Director of Clinical Science at BioMarin Pharmaceutical Inc. said, “Vosoritide is the first potential precision pharmacological therapy that addresses the underlying cause of achondroplasia and this randomized, double-blind, placebo-controlled Phase 3 study further adds to the scientific knowledge we’ve gained over many years from the clinical development program.
I’d like to personally thank and congratulate all of the investigators and I am especially grateful to all of the children and their families who have participated in these studies,”
Paul Cohen and Elizabeth Ryan’s daughter, Sarah, was born with achondroplasia. Sarah was one of the very first patients enrolled in the trial. Mr Cohen said, “During the trial we’ve seen Sarah grow up at the same rate as her friends. She can now join in bike rides with her friends, and loves being allowed on our local waterslide.”
Although the trial did not significantly improve the children’s proportions between their upper and lower bodies, the children will be followed until they achieve their final adult height to see how long the drug’s effects last and whether they experience a growth spurt during puberty, as this doesn’t normally happen in children with achondroplasia.
Vosoritide is also being tested in children from birth to five years which may improve final height, body proportion and other age-related complications such as spinal cord compression, which can cause sudden death.
Achondroplasia—more than extreme short stature
Achondroplasia (OMIM #100800) is the most common form of disproportionate short stature, affecting 1:20,000 live births. Like some other severe growth disorders, it is also associated with potentially serious medical complications such as foramen magnum and spinal stenosis, both of which cause increased morbidity and mortality [6, 7].
Achondroplasia is caused by a heterozygous, activating mutation in the fibroblast growth factor receptor‑3 (FGFR3) gene at position 1138. Two specific mutations (1138G > A and 1138G > C) lead to an arginine to glycine substitution at position 380 (G380R) in the transmembrane domain of the FGFR3 protein, which permanently activates the receptor .
This mutated receptor, through a multistep, postreceptor cascade, puts a continuous permanent break onto chondrocyte proliferation in all growth plates. The rhizomelic appearance of individuals affected by achondroplasia suggests that faster proliferating growth plates (femur, humerus) tend to be more affected than slower ones at other sites.
Around 80% of mutations are de novo and 20% inherited, which demonstrates the reduced reproduction of affected individuals despite the dominant inheritance . Fathers of de novo patients are statistically older than average fathers, which is the subject to ongoing research .
The achondroplasia clinical phenotype has been well-described and documented over thousands of years, consisting of a large head with characteristic facies, frontal bossing and midface hypoplasia, a long narrow trunk with exaggerated lumbar lordosis, rhizomelic shortening of the limbs, limitation of elbow extension, genu varum, and trident hands. A thoracolumbar gibbus is present in infancy, which later converts into hyperlordosis. Hyperextensibility of joints and mild–moderate muscular hypotonia lead to delayed motor milestones and worsening of hyperlordosis . An extended phenotypic description has been reviewed in detail elsewhere .
Spontaneous growth and body proportions in achondroplasia
Mean adult height in achondroplasia is 132 cm in males and 124 cm in females . New disease-specific growth curves have recently been established, which also demonstrate that the main loss of height occurs in the first 2 years of life . As expected, the early onset of disproportion is caused by reduced growth of legs and arms which worsens over time .
The achondroplasia mouse model recapitulates the human phenotype, including early severe growth retardation, disproportionate limb shortening, round head, mid-face hypoplasia at birth, and kyphosis progression during postnatal development. In addition, premature fusion of the cranial sutures and low bone mass were observed in newborn mice whose phenotypes became more pronounced during postnatal skeletal development .
The increased risk of first-year deaths in infants with achondroplasia has been known since the 1980s [14, 15]. The risk of death was increased approximately 6‑fold in one study . One of the factors contributing to infant mortality is foramen magnum stenosis, which can cause cervical cord compression leading to respiratory failure and sudden infant deaths.
Narrowing of upper respiratory airways due to mid-face hypoplasia can cause obstructive apnoea. The anatomic, obstructive component of breathing complicates the assessment of central breathing abnormalities caused by brain stem compression. Overall, sleep disorders (obstructive, mixed, central) affect 30–60% of all infants with achondroplasia, necessitating polysomnography screening .
Mid-face hypoplasia and temporal bone abnormalities also lead to chronic otitis media, which in turn can cause conductive hearing loss and speech delay, often necessitating ventilation tube insertion .
Overall mortality was increased in a large study of 793 individuals with achondroplasia; predominant causes of death were sudden death in children up to age 5 years and cardiovascular disease in young adults . Life expectancy was reduced by 10 years.
A recent study of 855 individuals also demonstrated the highest risk of death in children up to age 4 years, but with improving rates, presumably due to better assessment and intervention for brain stem compression. In subjects older than 5 years, there was an increased rate of cardiovascular, cerebrovascular and accidental deaths .
Spinal canal and foramen magnum stenosis originate from the same pathophysiological cause, which is premature closure of synchondroses (cartilaginous joints). Such premature closure is found both in achondroplasia and in thanatophoric dysplasia (OMIM 187600), and in achondroplasia mouse models . In affected mice, chondrocyte-specific activation of Fgfr3 additionally induced osteoblast differentiation and bone formation around the prematurely closing synchondroses.
The authors went on to demonstrate that high FGF signalling increased the expression of the strongly osteogenic bone morphogenetic protein (Bmp), with decreased expression of Bmp antagonists. This finding indicates a possible role of Bmp signalling in the acceleration of synchondrosis fusion, paracrine activation of osteoblast differentiation and premature unification of ossification centres.
Should this be the case, then any growth-promoting treatment of achondroplasia would need to precede the timing of the synchondrosis closure in order to prevent these complications. Given the occurrence of complications from foramen magnum stenosis very early in life, the timing of future interventions would need to be shortly after, or before, birth.
Obesity is certainly an issue in individuals with achondroplasia and tends to emerge early in life. Obesity is predominantly of abdominal origin and its causes are currently not understood . Approximately 50% of children are affected . How obesity affects mobility, cardiovascular risk, occurrence of back pain and other complications has not been systematically studied, which supports the role of natural history studies for this rare disease.
Body mass index may not be the optimal parameter to assess obesity in patients with achondroplasia , due to the fact that that weight does not scale to height squared in children, which creates a size artefact in anyone who is very short [23, 24].
From disease mechanism to drug development
Fibroblast growth factor receptors (FGFRs) belong to the tyrosine kinase family and regulate various biological processes including cell proliferation and differentiation during development, as well as tissue repair. Many genetic conditions are caused by deregulation in the FGFRs signalling network. The FGFR family consists of four family members, FGFR1–4 .
Mutations in FGFR3 on chromosome 4p16.3 were first described as the cause of achondroplasia in 1994 [26, 27]. The mutation enhances the receptor’s tyrosine kinase activity and activates mainly the downstream canonical mitogen-activated protein kinase (MAPK) pathway; however, additional signalling pathways also have been implicated, e.g., STAT, Wnt/β-catenin, PI3K/AKT, and PLCγ .
The discovery of the molecular pathogeny of achondroplasia attracted the interest of industry in this rare disease, and strategies for drugs targeting the overactive FGFR3 receptor and downstream signalling pathways started to develop.
Current strategies include catching FGFR3 ligands, blocking FGFR3, and chemical inhibitors of tyrosine kinase, the intracellular element of the FGFR3 receptor, all of which currently remain in preclinical studies. More advanced are alternative strategies involving C‑type natriuretic peptide (CNP), which, via its receptor NPR‑B, antagonizes the FGFR3-induced activation of the MAPK signalling pathway in growth plate chondrocytes  and thus counteract the effects of the FGFR3 mutation.
Here we provide an overview on drug development targeting the respective pathways. Fig. 1 provides an overview over drugs in development. Whether clinical trials are being conducted was assessed on www.clinicaltrials.gov as of November 30, 2019.
Drugs targeting the FGFR3 ligands
Fibroblast growth factor 2 aptamer (RBM-007)
An aptamer is a short, single-stranded nucleic acid molecule that is selected in vitro to a target molecule based on its high and specific affinity.
These oligonucleotides are modified to resist ribonucleases and have the ability to fold, building a three-dimensional structure that binds the target. Aptamers can be applied therapeutically due to their strong and targeted, neutralizing activities. Being an aptamer, RBM-007 (APT-F2P) is highly specific for fibroblast growth factor 2 (FGF2), one of the signalling molecules that activate the FGFR3.
This RNA aptamer blocks binding of FGF2 to its four cellular receptors, inhibits FGF2-induced downstream signalling and cell proliferation, and restores osteoblast differentiation blocked by FGF2 . This aptamer also inhibits the growth of FGF2-FGFR pathway-dependent lung cancer cells . The drug is still in preclinical studies.
Soluble FGFR3 decoy (TA-46)
TA-46 is a soluble, human, recombinant FGFR3 decoy (sFGFR3), which prevents FGF from binding to the mutant FGFR3. In an animal model, sFGFR3 was injected subcutaneously twice weekly to newborn Fgfr3(ach/+) mice, throughout the growth period. Effective maturation of growth plate chondrocytes was restored in bones of treated mice, growth recovered in a dose-dependent manner, and mortality decreased .
Treatment with TA-46 decreases abdominal obesity in this animal model . TA-46 has completed phase 1 trials and has received Orphan Drug Designation from the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA).
Drugs targeting the FGFR3 and downstream signalling
Anti-FGFR3 antibody (B-701)
Vofatamab (B-701) is a human IgG1 monoclonal antibody specific targeting the FGFR3, which does not interact with other FGFRs. Since FGFR3 mutations causes a gain-of-function of the FGFR3 receptor in a variety of cancers, B‑701 is currently in clinical trials for urothelial cell carcinoma. No preclinical studies on achondroplasia have been published. To our best knowledge, the company has discontinued development of B‑701 for achondroplasia.
Tyrosine kinase inhibition (BGJ398)
Infigratinib (BGJ398), a tyrosine kinase inhibitor (TKI) that blocks FGFR1–3, is currently in clinical trials for bile duct and bladder cancer. In the Fgfr3Y367C/+ mouse model of achondroplasia  demonstrated that low doses of subcutaneously injected infigratinib reach the growth plate and have the potential to correct the achondroplasia phenotype.
BGJ398 reduced FGFR3 phosphorylation and corrected the abnormal femoral growth plates and calvaria in organ cultures from mutated mouse embryos, modified growth plate organization and lead to rapid skeletal improvements including reduced intervertebral disc defects of lumbar vertebrae, loss of synchondroses, and foramen-magnum shape anomalies.
BGJ398 also inhibited FGFR3 downstream signalling pathways, including MAPK, SOX9, STAT1, and PLCγ, in the growth plates of Fgfr3Y367C/+ mice and in cultured chondrocyte models of achondroplasia . No clinical studies with infigratinib or other TKIs have yet been conducted in individuals with achondroplasia.
In preclinical studies, the licensed anti-histamine and motion sickness drug, meclozine suppresses FGFR3 signalling by downregulating phosphorylation of ERK but not of MEK . In low doses, this re-purposed drug demonstrates its inhibitory effect on FGFR3 signalling, thereby increasing chondrocyte proliferation and differentiation, and rescuing the short-limbed phenotype in a transgenic mouse model of achondroplasia . To date, clinical studies have not been conducted.
Drugs targeting the CNP receptor NPR-B
CNP analogue vosoritide (BMN111)
The CNP antagonizes FGFR3 downstream signalling by inhibiting the MAPK pathway . The 39-amino acid CNP (CNP-39) analogue BMN111 has an extended plasma half-life due to its resistance to neutral endopeptidase. Lorget et al.  demonstrated decreased phosphorylation of extracellular signal-regulated kinases 1 (ERK1) and 2 (ERK2) in achondroplasia human growth plate chondrocytes, confirming that BMN111 inhibits FGF-mediated MAPK activation.
BMN111 treatment in the Fgfr3(Y367C/+) mouse model led to a significant recovery of bone growth, with an increase in axial and appendicular skeleton lengths, improvements in dwarfism-related clinical features such as flattening of the skull, reduced crossbite, straightening of tibiae and femora, and correction of the growth plate defect.
The authors concluded that their results provided proof of concept that BMN 111 might benefit individuals with achondroplasia and hypochondroplasia .
In 2019, the results of a phase 2 dose-finding and extension study (NCT02055157 and NCT02724228) using BMN111 (vosoritide) in 35 children with achondroplasia (aged 5–14 years) were reported . The drug was given as a once daily subcutaneous injection and a dose of 15 mcg/kg was established.
The first 6 months of treatment demonstrated a dose-dependent increase in the annualized growth velocity, and a sustained increase in annualized growth velocity of 1.5 cm/year was observed for up to 42 months. The most common adverse events were injection-site reactions. Serious adverse events occurred in four patients, including obstructive sleep apnoea, tonsillar hypertrophy, thyroglossal cyst, and syrinx. Therapy was discontinued in 6 patients.
TransCon CNP is a pro-drug, consisting of CNP (CNP-38) conjugated via a cleavable linker to a polyethylene glycol carrier molecule. The pro-drug is injected once weekly subcutaneously and slowly releases active CNP to provide sustained systemic CNP levels.
Preclinical data in mice and cynomolgus monkeys have shown efficacy of CNP, which avoids high systemic CNP bolus concentrations which can induce cardiovascular side effects . A phase 2 clinical trial in children commences in 2020 (NCT04085523).
Human CNP (CNP-53)
Another CNP peptide in development is the human CNP with 53 amino acids (CNP-53) which has been tested in CNP-KO rats which are phenotypically similar to CNP-KO and FGFR3-KO mice. After subcutaneous administration of human CNP-53 from 5 weeks of age for 4 weeks, the impaired longitudinal skull length, craniofacial morphology and foramen magnum size improved at 9 and 33 weeks of age, indicating at least partial rescue.
Whilst synchondrosis at the cranial base in CNP-KO rats normally closes at 9 weeks, this closure was incomplete in CNP-KO rats treated with CNP-53. Since skeletal findings in CNP-KO rats resemble human achondroplasia, treatment with CNP-53 or a CNP analogue may restore craniofacial morphology, foramen magnum size and short stature .
resource link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098936/
More information: Ravi Savarirayan et al. Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomized, double-blind, phase 3, placebo-controlled, multicentre trial, The Lancet (2020). DOI: 10.1016/S0140-6736(20)31541-5