medwireNews: Simvastatin treatment has not significantly improved growth in a randomised phase 3 trial of children with Noonan syndrome (NS), French researchers report in eClinicalMedicine.
“These findings do not support the routine off-label use of simvastatin for growth promotion in children with NS”, write Thomas Edouard (Toulouse University Hospital) and co-authors.
The team explains that NS “is caused by germline variants affecting components of the RAS/mitogen-activated protein kinase (MAPK) signalling pathway, resulting in multisystem involvement including short stature, skeletal abnormalities, cardiac defects, and neurocognitive impairment.”
Following preclinical research indicating that statins may attenuate hyperactivation of the RAS/MAPK pathway and provide growth and neurocognitive benefits, the team randomly assigned children aged 6–15 years with genetically confirmed NS and growth impairment to receive oral simvastatin or placebo for 12 months. Simvastatin was initiated at 10 mg/day for month 1 and increased to 20 mg/day at month 2, with children aged 6–12 years continuing at this dose, and older children increasing their dose to 40 mg/day.
The primary endpoint of the study was the change in serum insulin-like growth factor (IGF)-1 levels at 12 months. This was comparable between the 26 children given simvastatin and the 27 given placebo, with respective increases of 0.13 log ng/mL and 0.21 log ng/mL, and a –0.08 log ng/mL difference between the groups that did not reach statistical significance.
Nor was there a significant difference in IGF-1 levels among the subgroup of 42 children with a pathogenic or likely pathogenic PTPN11 variant, the researchers say.
There was a significant treatment difference in the full cohort found by pubertal status, but this effect was only noted among the 15 patients at Tanner stage 2 or higher. “Given the limited sample size and greater pubertal and genetic heterogeneity of this subgroup, these findings should be interpreted with caution,” Edouard et al remark.
Moreover, there were no significant differences between the simvastatin and control groups regarding other growth-related measures, such as height, growth velocity, IGF-binding protein 3, and growth plate markers, and this remained true when assessed among carriers of PTPN11 variants or by pubertal status.
The team also measured a raft of bone parameters, including bone mineral density, procollagen type 1 N-terminal propeptide and C-terminal telopeptide of type I collagen, but only serum levels of Dickkopf-related protein (DKK)1 showed a significantly greater decrease at 12 months with simvastatin versus placebo
This improvement in DKK1 levels was accompanied by a significantly better Ea/Aa ratio, the echocardiographic parameter of left ventricular diastolic function, at 12 months with simvastatin versus placebo but there were no other cardiac differences between the groups. Nor were there differences in metabolic outcomes, such as glycaemia, insulin levels, or behavioural and emotional function assessments.
The researchers advise that the DKK1 and Ea/Aa ratio findings were “of borderline statistical significance, and were not accompanied by measurable clinical improvements” and therefore “should be considered exploratory and require confirmation.” But they suggest further research could determine whether statins in combination with direct RAS/MAPK pathway inhibitors may be useful in NS.
Nevertheless, Edouard et al highlight that their study indicated for the first time that serum levels of C-type natriuretic peptide (CNP) positively correlated with growth velocity in children with NS, with low levels associated with normal amino-terminal propeptide of CNP levels that “may be consistent with altered CNP bioavailability rather than impaired production”.
They believe that this finding supports “further investigation of the CNP pathway in NS” and affords “additional rationale for the ongoing clinical evaluation of CNP analogues as a therapeutic strategy in NS.”
By Lynda Williams
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