Efficacy and safety of Vosoritide in achondroplasia: A systematic review and meta-analysis

Literature search

Cochrane, PubMed, and Embase were systematically searched on May 10, 2024, for studies published between January 2000 and May 2024. This timeframe was selected to capture all relevant clinical and translational research on achondroplasia. Since vosoritide, the only approved targeted therapy for achondroplasia, received regulatory approval in late 2021, setting 2000 as the lower limit ensured inclusion of studies contributing to its development as well as other contemporary interventions. In addition to database searches, literature was also searched on Google Scholar to identify grey literature relevant to this systematic review.

Search strategy

The title was structured according to the PICOST framework. Controlled vocabulary and Boolean operators were used to define the population (achondroplasia patients) and intervention (vosoritide), following the indexing standards of each database. A detailed search strategy is provided in Supplementary Material I.

Screening the studies

Following the search, all retrieved records were extracted and added to Rayyan tool. Duplicates were removed and the retrieved records were subsequently screened according to the inclusion/exclusion criteria (Supplementary Material I). Titles and abstracts were screened first, followed by full texts, with CP and MP conducting independent screening and resolving discrepancies through NC.

Data extraction

PRISMA checklist and PROSPERO registration guidelines were followed and adhered to while doing systematic review and meta-analysis. Data extraction was carried out by CP, and independently reviewed by both CP and AU. The included studies were subjected to qualitative analysis, and when data were comparable, a quantitative analysis was also performed. Quantitative analyses were performed using RevMan (version 5.4). Missing data, where applicable, were addressed using the RevMan calculator. A fixed-effect model was employed for analyses with heterogeneity less than 50%, and a random-effects model was applied when heterogeneity exceeded 50%.

Quality assessment

Two reviewers (AU and MP) assessed the quality of included studies using Risk of bias (RoB) to evaluate their methodological validity. Eligible study designs comprised randomised clinical trials (RCTs) and quasi-experimental research published in peer-reviewed journals. The Revised Cochrane Risk of Bias Tool (RoB 2) was applied to RCTs. However, for non-randomised studies with no control group, the NIH quality assessment tool was used. These tools assessed key aspects including study design, methodology, data analysis, and interpretation. Low, moderate, or high risk of bias were thus assessed.

Data characterisation and analyses

A total of 1,314 records were retrieved from four databases (Supplementary Material I). After removing duplicates, 1,091 records were screened by title and abstract (Fig. 1), and 1,039 were excluded for being descriptive studies, reviews, preclinical work, unrelated conditions, or non-English reports. In the second screening, 52 abstracts were reviewed, of which 46 were excluded (conference abstracts =40; insufficient or irrelevant data=6). Finally, six studies (five clinical trials and one case report) were included for data extraction.

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Fig. 1.

PRISMA flow diagram illustrating the literature search strategy, screening process, and selection of studies included and excluded in the systematic review, detailing the number of records identified, screened, assessed for eligibility, and finally included in the analysis.

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Risk of bias assessment

The included studies underwent quality assessment. Both RCTs showed a low risk of bias, while the pre-post studies were rated as fair quality. The RCTs by Savarirayan et al (2020, 2024)9,10 were well conducted, providing reliable evidence for safety and efficacy. The pre-post study, assessed using the NIH quality assessment tool, showed good methodological quality with clear objectives, defined eligibility criteria, consistent interventions, and appropriate analyses. Overall, the studies demonstrated strong methodological rigor, supporting the reliability of the findings and certainty of the evidence. Details are provided in Table I, Supplementary Tables I, II and III.

Study characteristics

Three multicentre clinical trials, one pharmacokinetic study, and one case report were included for analysis. The phase II dose-escalation study enrolled 35 patients (5–14 yr) treated with daily subcutaneous vosoritide (2.5–30 µg/kg) for 42 months. The phase III double-blind, randomised trial included 121 patients (5–18 yr) receiving vosoritide (15 µg/kg) or placebo for 52 wk, followed by an open-label extension where all 119 participants received vosoritide. In total, 154 patients were treated for 1–3.5 yr. The pharmacokinetic study included data from phase II and III participants, while the case report described cardiovascular adverse events (AEs) in two infants (Table II).

The studies were conducted in seven countries at 24 sites including the Australia (n=2), Europe [Spain (n = 3), Germany (n = 2), United Kingdom (n = 3), Turkey (n=1)], United States (n = 10), and Japan (n=3).

Vosoritide injections were given once daily subcutaneously with side rotation. Initially, the drug or placebo was given at study site and afterwards at home by trained caregivers. Full clinical medical assessments were done at each visit at screening, days 1, 2, 3 and 10, then at week 6 and at months 3, 6, 9 and 12.

Patient characteristics

Patients with genetically confirmed achondroplasia, ambulatory status, and at least six months of baseline growth data were included across trials with similar criteria. Exclusions included fused growth plates, planned bone surgery, untreated sleep apnoea, or other growth-affecting conditions. The phase III RCT used 1:1 randomisation stratified by sex and Tanner stage, with separate randomisation for seven Japanese participants. Participants were aged 5–18 yr, primarily of non-Hispanic ethnicity (Table III).

Safety measurement

Safety measures were assessed, based on the occurrence of unpleasant events and serious adverse events, laboratory findings, clinical examination, ECG and EEG results, and antibody response (if any). Imaging assessments showing spine, arm bone, leg bone measurements, growth plate data, bone mineral density, and bone age data were also collected in the studies. Adverse events (AEs) occurred in all patients across the three trials, with no deaths reported. In the phase II study, safety data were available for six patients each in cohorts 1 and 2 (up to 52 months), 10 patients in cohort 3 (45 months), and eight patients in cohort 4 (34 months). Detailed AEs are shown in Figure 2.

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Fig. 2.

Adverse events reported across clinical trials evaluating Vosoritide in achondroplasia. The figure illustrates the distribution and frequency of adverse events observed among treated participants. Subfigure (A) represents patients with serious adverse events, (B) depicts patients experiencing any adverse events, and (C) shows the total number of patients with reported adverse events across all studies, highlighting the overall safety profile of Vosoritide.

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In phase III study, the most common AE was non-serious, transient injection-site reactions. Nine serious AEs unrelated to the study drug occurred in seven patients: four placebo participants experienced grade 3 adenoidal hypertrophy, grade 3 appendicitis, grade 2 dyspnoea, grade 3 increased intracranial pressure, and grade 3 spinal cord compression, while three vosoritide-treated patients had grade 3 influenza, grade 3 sleep apnoea, grade 3 radial fracture, and grade 2 adenoidal hypertrophy.

Pharmacokinetic profile of vosoritide

Drug activity using cGMP and its pharmacokinetic profile along with endochondral ossification markers including serum collagen X marker (CXM), a degradation fragment of type X collagen was studied. PK analysis was performed by plasma vosoritide concentrations in phases II using a validated enzyme-linked immunosorbent assay (ELISA) and III studies using electrochemiluminescence assay (ECLA). Positive correlation was reported for plasma vosoritide AUC0-60min with the body weight and age (P< 0.001) and vosoritide exposure was shown to be consistent throughout the study duration of 52 wk (Fig. 3). A plateau in the exposure-response curve at 15µg/kg supported the dose chosen for phase III study.

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Fig. 3.

Pharmacokineticparameters evaluated following Vosoritide administration in achondroplasia patients. Subfigures represent (A) time to reach maximum plasma concentration (Tmax), (B) area under the concentration–time curve over different intervals (AUC₀–₆₀, AUC₀–t, AUC₀–∞), and (C) maximum plasma concentration (Cmax), providing an overview of drug absorption and systemic exposure.

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Efficacy measures

Potential bias

Participants, study personnel, caregivers administering injections and those assessing the outcome data were all blinded to group assignment in phase II study¹⁰ and phase III study¹¹ to minimise the potential bias. In addition, in quasi experimental studies^11,12 which were open labelled, hope bias plays a significant role.

Meta-analysis

Both mean difference (MD) and least square mean difference (LSMD) were reported across studies. Since LSMD accounts for baseline differences but reflects the same outcome as MD, we treated LSMD values as equivalent to MD for descriptive comparison. Results are presented narratively and in tables, emphasising consistent trends across studies rather than pooled effect estimates. The LSMD with 95% CI, from the control and intervention group of clinical trials^9,12 were evaluated. Two articles included^9,12 for meta-analysis from all the included articles. Four articles which were not RCTs were exempted from the meta-analysis. With random-effects models, the meta-analysis was conducted using RevMan 5.4 software. The results were presented as the mean difference and 95% CI using an inverse-variance.

Two clinical trials including 90 participants in the intervention group and 93 in the control group reported LSMD in annualised growth velocity. Using random-effects models, the LSMD between groups was 2.40 (95% CI: 1.94–2.86), with high heterogeneity (I² = 96%, P< 0.00001), demonstrating that vosoritide significantly increased annualised growth velocity (Fig. 4). For height z-score, the LSMD between the vosoritide and control groups was 0.38 (95% CI: 0.22–0.53), with low heterogeneity (I² = 21%, P< 0.00001), indicating a significant improvement with vosoritide. For the upper-to-lower body segment ratio, the LSMD between the vosoritide and control groups was −0.05 (95% CI: −0.09 to −0.02), with no heterogeneity (I² = 0%, P< 0.005), indicating a non-significant effect on z-score.

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Fig. 4.

Forest plot illustrating the pooled effect estimates for Vosoritide intervention in achondroplasia, depicting changes in annualised growth velocity, height Z-score, and upper-to-lower body segment ratio. Each parameter is presented with its corresponding confidence interval (CI), reflecting the overall efficacy and consistency of treatment outcomes across included studies.

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