medwireNews: Basket trial findings indicate that vosoritide therapy may improve growth in children with short stature related to rare genetic disorders of the Ras–mitogen-active protein kinase (MAPK) pathway.
“[V]osoritide led to marked increases in growth velocity in children with RASopathies, ACAN [aggrecan], and NPR2 [natriuretic peptide receptor 2] deficiency, raising the possibility that vosoritide could be an effective precision medicine for all growth disorders affecting the MAPK pathway”, say Andrew Dauber (Children’s National Hospital, Washington DC, USA) and co-workers.
The phase 2 study included 30 children (73.3% boys) aged 3–11 years (mean age 7.2 years) and a known genetic cause of short stature. Eleven children had a RASopathy, including eight cases of Noonan syndrome, two cases of neurofibromatosis type 1 and a single case of Costello syndrome. Seven had alterations to the NPR2 gene, which encodes the C-type natriuretic peptide receptor, and 12 had alterations to the ACAN gene, which encodes aggrecan, a cartilage proteoglycan found on growth plates and articular surfaces.
Following a 6-month observation period, the children were given daily treatment with subcutaneous vosoritide 15 µg/kg for 12 months. Two patients discontinued therapy, but the remaining children had “excellent” adherence to treatment, the researchers say, with a median administration rate of 99.3%.
Height efficacy
The participants experienced an increase in their absolute annual growth velocity (AGV), from 4.53 cm/year in the observation period to 8.09 cm/year during treatment, giving a significant gain of 3.56 cm/year that was detectable after 6 months of treatment. This in turn lead to a significant increase in age- and sex-adjusted AGV z-score from –1.34 to 2.66 standard deviation (SD).
Of note, the significant increase in AGV occurred in all three groups of children, with mean treatment gains of 3.33 cm/year in those with RASopathy, 3.03 cm/year in those with NPR2 alterations and 4.76 cm/year in those with ACAN alterations.
The standing height SD score (SDS) improved significantly from –3.09 SD at baseline to –2.52 SD at month 12, and again, improvement was seen in all three groups.
“Notably, the increases in growth velocity seen in these cohorts are much larger than those seen in a Phase 3 trial of vosoritide for achondroplasia (1.57 cm/year) or in our previously published results in children with hypochondroplasia (1.81 cm/ year)”, the researchers write in The Journal of Clinical Endocrinology & Metabolism.
“It is possible that vosoritide is more effective in RASopathies, ACAN, and NPR2 deficiency, as its mechanism of action is much more proximate to the molecular pathophysiology than in achondroplasia and hypochondroplasia”, they continue.
And Dauber et al add that “[i]t is plausible that in RASopathies, ACAN, and NPR2 deficiency, increased signaling through MAPK is responsible for a larger proportion of the growth impairment, thus making them more amenable to a precision medicine targeting this pathway.”
They also observe that there was no significant change in the ratio of bone age to chronological age over the course of the study, “suggesting that these short-term height gains may translate into increases in adult height.”
Safety findings
Overall, 40% of children had one or more injection site reactions, all of which were grade 1 or 2 and resolved without intervention. None of the children discontinued therapy within the first year due to treatment-related adverse events (AEs) or experienced significant cardiovascular AEs.
However, five children who participated in the long-term extension phase of the study stopped vosoritide therapy following treatment-related AEs. These included two children with severe genu valgum who developed slipped capital femoral epiphyses requiring growth surgery, a third patient who developed coxa valga and slipped capital femoral epiphyses, and a further two who developed significant genu valgum.
Noting reports of predispositions to these complications in patients with these genetic conditions – particularly during periods of rapid growth induced by growth hormone treatment – the researchers say that “it is possible that these skeletal complications are a specific result of vosoritide treatment” accelerating growth.
They therefore conclude: “Caution should be taken with long-term use, and clinicians should be aware of the potential for the development of genu valgum and slipped capital femoral epiphyses.”
By Lynda Williams
medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2026 Springer Healthcare Ltd, part of Springer Nature
