Vosoritide in achondroplasia: Hope, hurdles, and the road ahead

The 21^st century has ushered in a revolution in Mendelian disorders. Sequencing of the whole human genome and the advent of high-throughput sequencing technologies have identified genetic etiologies for more than 6,000 genetic disorders. With exome sequencing becoming the first-tier test for possible genetic phenotypes, etiological diagnosis has become easier and is being done by clinicians with and without medical genetics training. The long-awaited gene therapy successes are also among the major highlights of this century. Other than gene therapy, drug therapies based on an understanding of the pathogenesis of the disorders have shown early successes. Enzyme replacement therapies for lysosomal storage disorders, pathway-based treatments for RASopathies, and small interfering RNA-based therapies for acute intermittent porphyria, hypercholesterolemia, primary hyperoxaluria type 1 and hereditary transthyretin-mediated amyloidosis are some examples. The drug vosoritide, developed for achondroplasia, is an example of targeting molecular pathology. It has been more than a decade since animal studies showed proof of concept about the effect of vosoritide on the growth plates, and more than 5 years since the first report of its efficacy and safety in children was published.

Achondroplasia is the commonest skeletal dysplasia, and its characteristic phenotype makes clinical diagnosis easy. It occurs due to a gain-of-function mutation in the FGFR3 gene. Mutations at position 1138 of the gene are present in all patients of achondroplasia from India, with 1138G>A in 94.7% and the rare 1138 G>C substitution in 5.3%.^[1] The C-type natriuretic peptide down-regulates aberrant FGFR3 signaling in chondrocytes by inhibiting the mitogen activated protein kinase-extracellular signal regulated kinase (MAPK-ERK) pathway. Vosoritide is a recombinant analog of the C-type natriuretic peptide that has been engineered to resist degradation and increase its half-life. Based on this evidence, vosoritide has been approved for use in children with achondroplasia and open epiphyses from birth in the USA, Japan, and Australia, and from age ≥4 months in the European Union.^[2] It is interesting to know that the DNA variations in NPR2 gene, which codes for natriuretic peptide receptor B (which binds the extracellular ligand, C-type natriuretic peptide), cause another skeletal dysplasia, namely acromesomelic dysplasia.

The mechanism of action of vosoritide is targeted to the pathogenetic gain-of-function FGFR3 mutation causing achondroplasia, and scientifically appears to be a very effective way of treating the disorder. This brought a wave of positivity and great hope among patients with achondroplasia, especially children and their families. The most important problem in achondroplasia is markedly short stature, with an average adult height of around 130 cm. Before vosoritide, the available treatments for short stature in achondroplasia, such as growth hormone (GH) therapy and limb lengthening surgeries, provided limited benefit, with the latter being too invasive and prolonged. Early studies of vosoritide established the safety profile and documented an increase in growth velocity over a few weeks.^[3] In 2021, vosoritide (trade name: Voxzogo^®, BioMarin Pharmaceuticals) became the first approved, disease-modifying pharmaceutical treatment for achondroplasia. It is approved by the Federal Drug Agency of the USA, the European Medicines Agency, Japan, and became available in Australia in May 2023. Initially approved for children above 5 years of age, it has been documented in younger children as well.^[4]

For such chronic progressive disorders, documentation of efficacy is a challenge unless there is dramatic improvement with therapy, as seen with enzyme replacement therapy for Gaucher disease type I. In the 52-week trial, children receiving vosoritide grew 1.57 cm more than those receiving a placebo.^[3] The follow-up study confirmed the gain in height with vosoritide. The mean (standard deviation [SD]) change from baseline for height Z-scores, referenced to the average-stature population, was 0.91 at the end of 4.5 years.^[2] When projected for the future, the estimated additional height gain for participants treated with vosoritide versus those untreated was 20 cm for boys and 16 cm for girls over 11 years from 6 to 16 years of age. This study also showed improvements in lumbar lordosis and knee curvature. The projected gain appears to make a sufficient difference in the outcome of the lives of the patients with achondroplasia, but the efficacy may vary from patient to patient, as seen from individual spaghetti plots^[3] and other publications from different countries.^[5] In the study by Morillas-Amat et al.^[5] in the current issue of the journal, a third of the patients had an increase in height Z-score of <0.3. A French study on 62 participants showed an increase in height Z-score referenced to the average-stature population of 0.38.^[6] Some of the children on treatment reached +2 SD for the achondroplasia-specific growth curves, but none of the children who had reached 15–18 years of age on treatment approached −2 SD of the normal growth curves.

Many studies have shown positive effects of vosoritide on growth and a favorable safety profile, and experts have suggested inclusion of the drug in the management of achondroplasia.^[7] The detailed management guidelines have been developed by an Australian group.^[8] It is important to note that apart from drug therapy, the management of achondroplasia has many other components, like surveillance for complications such as sleep apnea, foramen magnum stenosis, and lumbar canal stenosis, under the supervision of a multidisciplinary team. The availability of targeted disease-modifying therapy brings a ray of hope to the patients’ lives. It is important that before starting vosoritide, the children and families have an understanding of the disease and realistic expectations about the variability of height gain in individuals and the unavailability of long-term results about clinically meaningful height outcomes. In addition to medical complications, patients with achondroplasia have the burden of emotional and psycho-social issues related to severe short stature, affecting quality of life.^[9] At present, the effect on adult height is uncertain, and so the effects on other skeletal defects and body proportions. Although one feels that starting treatment during the neonatal period or infancy may give an advantage in terms of adult height, the study on children from 3 to 59 months showed only a modest difference in change from baseline in height Z-score between the vosoritide and placebo groups (0•25 with 95% CI: 0.02–0.53).^[4] The achondroplasia community is very well aware of the drug but may not have a clear idea about the limited information about the effect on adult height outcomes, and practically no information about the effects on issues other than height. They may be anxious about long-term safety effects.^[10] On this background, the absence of a dramatic increase in height and the burden of daily injections may affect the compliance and continuation of therapy.

The height of adults with achondroplasia is 6–7 SD below the normal for the population. With the available data, the remarkable change in the adult height Z-scores is not expected. This is not in favor of convincing the cost-effectiveness of vosoritide to the policy makers. The cost of the drug is way above the limit of government funding under the National Policy for Rare Diseases in India. The patient’s families and support groups are very eagerly waiting for the only available disease-specific therapy for their loved ones at the earliest. The cost of drugs for rare diseases is a major hurdle for patients from low- and middle-income countries. As none of the clinical trials had Indian patients, it may be a good idea to do some post-marketing survey funded by the government in collaboration with the manufacturing company for a limited period of 1–2 years on a small group of Indian patients aged around 5–6 years, to assess meaningful gains in the growth velocity and height SD. These data will help the stakeholders to make a combined decision in the interest of patients.

The arduous journey to cure or normalization of life is difficult for most of the genetic disorders, though the twenty-first century has ushered in many novel therapies in the arena of monogenic disorders, with many more in the pipeline. Other than bisphosphates for osteogenesis imperfecta, vosoritide is the only specific disease-modifying therapy for skeletal dysplasia. Although many individuals with achondroplasia are leading fruitful and healthy lives with a positive attitude, the burden of short stature, body image issues, and other medical complications cannot be ignored. Making the drug available to all patients, along with the unmet need for more effective molecules, will continue to drive policymakers and researchers to seek solutions. Till then, the importance of supportive care and surveillance for complications is to be stressed on the patient families and treating physicians alike.