Efficacy of vosoritide treatment in patients with achondroplasia

INTRODUCTION

Achondroplasia is a type of skeletal dysplasia characterized by disproportionate short stature. This condition is caused by activating mutations in the fibroblast growth factor receptor 3 (FGFR3) gene, leading to impaired endochondral ossification of the epiphyseal plate and excessive inhibition of bone growth.^[1,2]

Patients with achondroplasia experience various clinical complications, including obstructive sleep apnea, recurrent otitis media, hyperlordosis, and spinal cord compression, along with the psychological and social consequences associated with short stature.^[3-5] It is estimated that the final adult height for individuals with achondroplasia in Caucasian populations is 131 ± 5.6 cm for males and 124 ± 5.9 cm for females.^[6]

Until recently, the treatment of achondroplasia has primarily focused on managing complications arising from the condition.^[7] However, there is growing interest in targeted therapies that address its underlying pathophysiology. In 2021, the European Medicines Agency^[8] approved vosoritide, a C-type natriuretic peptide analog, as a promising therapeutic strategy. Vosoritide binds to its receptor natriuretic peptide receptor type B, counteracting the effects of FGFR3 receptor activation and promoting endochondral bone growth in epiphyseal plates, as well as chondrocyte proliferation.^[9,10]

Initially, its authorization was limited to patients with a confirmed diagnosis of achondroplasia aged over 2 years. Two years later, the indication was extended to patients over 4 months of age. In March 2023, the Spanish Agency of Medicines and Medical Devices (AEMPS) approved vosoritide for the treatment of achondroplasia in Spain.^[11,12]

To date, most of the available evidence on the effects of vosoritide in patients with achondroplasia comes from the phase 3 clinical trial conducted by Savarirayan et al.^[13] The primary objective of this study was to compare the annualized growth velocity (AGV) between patients receiving vosoritide and those in the placebo group. The results showed an increase in AGV of 1.71 cm/year after 52 weeks, along with an average change in height Z-score of +0.27.

MATERIALS AND METHODS

We conducted a retrospective cohort study of pediatric patients diagnosed with achondroplasia who were treated with vosoritide for at least 1 year at a tertiary hospital. The diagnosis was genetically confirmed in all cases, with the G1138A mutation identified. Vosoritide (Voxzogo^®, BioMarin Pharmaceutical Inc.), which is commercially available as lyophilized powder in three strengths (0.4 mg, 0.56 mg, and 1.2 mg per vial), was administered according to the expert consensus protocol for the management of patients with achondroplasia receiving vosoritide. The prescribed dose was 15 µg/kg/day through a single daily subcutaneous injection, using the available presentation that most closely matched the calculated dose for each patient. None of the patients had undergone limb lengthening surgery.

Follow-up included regular outpatient visits, during which auxological evaluations and physical examinations were performed quarterly, blood tests were conducted semiannually, and hand X-rays were taken annually.^[14,15]

The following variables were analyzed: age, sex, AGV, bone age, height, height Z-score, arm span/height (A/H), ratio sitting height/standing height (SH/H), pubertal stage at treatment initiation, and adverse effects reported during treatment.

The standardization of height Z-score and AGV was carried out using Spanish population growth charts developed by Carrascosa et al.^[16] Height measurements were taken using a conventional stadiometer, and sitting height was measured with a seated stadiometer, both of which were calibrated weekly. Arm span was measured using an anthropometric breadth caliper. Bone age was determined by comparing left hand and wrist X-rays with the Greulich and Pyle atlas.

For data analysis, we used Jamovi software (version 2.3.28.0). Categorical variables are expressed as percentages. Normally distributed quantitative variables are presented as mean ± standard deviation (SD). Non-normally distributed quantitative variables are presented as median and quartiles. Normality was assessed using the Shapiro–Wilk test.

To identify differences between baseline and 1-year treatment values, we used the paired Student’s t-test, except for SH/H ratio, which was analyzed using the Wilcoxon signed-rank test.

To analyze differences based on sex and age, the independent Student’s t-test was used after confirming variance homogeneity with Levene’s test.

For comparisons based on pubertal stage, we used the Kruskal–Wallis test.

All statistical analyses were performed with a significance level of P < 0.05 and a 95% confidence interval.

RESULTS

We present data from 14 patients diagnosed with achondroplasia who were treated with vosoritide for 1 year.

The mean age of the patients was 9.29 ± 2.79 years, with an age range from 4 to 13 years. All patients had open growth plates. The mean bone age in males was 9.2 years, and in females, it was 7.5 years. Among the 14 patients analyzed, 4 were female (28.6%). At treatment initiation, 71.4% (10/14) of the patients were in the prepubertal stage (Tanner stage I), three patients were at Tanner stage II, and one patient was at Tanner stage III. Table 1 presents the patients’ data at baseline and after 1 year of treatment.

The results showed a significant increase in AGV of 0.89 ± 1.05 cm/year (P = 0.021), an increase in AGV Z-score of 1.3 ± 2.2 (P = 0.042), an absolute height gain of 6.03 ± 1.70 cm (P < 0.001), and an increase in height Z-score of 0.34 ± 0.38 (P = 0.007) 1 year after treatment initiation.

No statistically significant differences in AGV increase were found when classifying patients by pubertal stage (P = 0.95) or sex (P = 0.52).

Considering a clinically relevant increase in height Z-score after 1 year of vosoritide treatment as +0.3, we observed that 9 patients showed improvement in height Z-score, while 5 patients did not reach this threshold [Table 2].

Regarding body proportions, at baseline, the mean A/H ratio was 0.87 ± 0.05, increasing slightly to 0.88 ± 0.03 after 12 months. The SH/H ratio remained stable, with values of 0.64 ± 0.03 at baseline and 0.63 ± 0.02 at 12 months. No statistically significant differences were found in the A/H ratio (P = 0.124), whereas a significant change was observed in the SH/H ratio (P = 0.047) after 1 year of treatment.

Bone age progressed appropriately in all patients. No patient showed an increase in the bone age/chronological age ratio >0.02 after 1 year of treatment.

Regarding treatment safety, no serious adverse events were reported. The most common side effect, reported in three patients, was pain at the injection site. One patient experienced occasional loose stools. Another patient had an episode of leg weakness, which resolved spontaneously, along with occasional headaches. These symptoms were not attributable to other causes.

DISCUSSION

In this study, an average increase of +0.34 in height Z-score was observed, with an absolute mean height gain of 6.03 cm. These results are comparable to those obtained in the phase 3 trial conducted by Savarirayan et al., in which patients treated with vosoritide (15 µg/day) showed an AGV increase of 1.71 cm/year after 52 weeks and an average change in height Z-score of +0.27.^[13] The mean height change for treated patients was +5.59 ± 1.06 cm.

Data from CrescNet, a competence network dedicated to the continuous and long-term monitoring of growth and weight in children and adolescents, showed a height Z-score increase of 0.45 (SD = 0.75) in 85 patients treated with vosoritide after 1.23 years.^[17]

Cormier-Daire et al.^[18] analyzed 22 patients with a mean age of 8 years treated with vosoritide for 12 months. Their study reported AGV increases of up to 6.0 cm/year and an absolute height gain of approximately 6 cm, results similar to those observed in our cohort.

It is important to highlight that, despite the overall increase in AGV observed, not all patients in the study experienced a clinically relevant improvement in height Z-score (35.7% of patients had a height Z-score increase of <0.3).

This finding raises questions about the clinical relevance of AGV as a predictive parameter for assessing the actual impact of treatment on growth and height gain. Nonetheless, the generalizability of these results is limited by the small sample size and the short treatment duration.

Since there are both responder and non-responder patients to vosoritide therapy (in terms of height Z-score changes), further studies would be valuable to identify the factors influencing treatment response. Understanding these variables will be crucial for optimizing therapy.

Given the small sample size, the potential influence of pubertal status on changes in AGV could not be adequately assessed. This represents a limitation of the present study, and larger cohorts are needed to clarify the interaction between pubertal development and response to vosoritide.

We lack data beyond 1 year of treatment in our study and do not know whether height gains will be sustained over time. In the phase 2 extension trial,^[19] annual stability in height Z-score increase was observed, resulting in a total gain of +1.56 after 72 months. Furthermore, it would be interesting to investigate whether patients who did not achieve a clinically relevant response in the 1^st year might experience it later. Re-evaluating growth after an additional 12 months of treatment would be valuable to assess long-term response.

Regarding adverse events, the reported side effects in our study were similar to those described in the literature. In the study by Savarirayan et al.,^[13] injection site reactions were observed in 73% of patients treated with vosoritide, though all were mild and transient. Three patients experienced serious adverse events, but the investigator did not attribute them to the drug. In long-term extension studies, no serious adverse events were reported.^[19,20] In addition, the data published by Cormier-Daire et al.^[18] closely align with our findings, with 21 mild adverse events observed in 57 patients, 14 of which were injection site reactions.

In our cohort, bone maturation progressed appropriately, a result consistent with those reported by Savarirayan et al.^[13,21] Furthermore, considering that the ratio between bone age and chronological age is a useful tool to assess skeletal maturation relative to growth,^[22] our cohort showed a minimal increase of 0.02. This finding is reassuring, as it suggests that vosoritide did not cause disproportionate skeletal maturation relative to linear growth.

Regarding body proportionality, no statistically significant differences were found in the A/H ratio after 1 year of treatment. Although a statistically significant change was observed in the SH/H ratio (P = 0.047), the difference was not clinically relevant (0.64 at baseline vs. 0.63 at 1 year). In the phase 3 trial by Savarirayan et al.,^[13] no changes in body proportionality were observed after 12 months. However, in extension studies, improvements in proportionality were reported, with a mean change in the upper-to-lower segment ratio of −0.09 (0.11) after 2 years of treatment and −0.23 (0.18) after 7 years.^[19,20]

Vosoritide has demonstrated an improvement in height in patients with achondroplasia. However, this improvement varies among individuals, with some patients not responding to treatment. Nonetheless, it is important to note that there are currently no alternative therapeutic targets for achondroplasia, although numerous clinical trials are underway exploring new potential treatment options.

CONCLUSION

Our findings, including a mean increase of 0.34 in height Z-score after 1 year of vosoritide treatment, are consistent with previously published data. While some patients did not show a clear improvement in height Z-score, the treatment was overall effective and well tolerated, with no acceleration in bone maturation and no serious adverse events reported. Although AGV is a useful parameter, its utility as a sole indicator of treatment efficacy may be limited, particularly in small samples. Larger, long-term studies are needed to confirm the clinical benefits of vosoritide and to better understand the relationship between AGV, height gain, and other meaningful outcomes.