medwireNews: Treatment with a C-type natriuretic peptide (CNP) prodrug significantly increases annualised growth velocity (AGV) in children with achondroplasia and offers additional health benefits, say the APPROACH trial investigators.
“By providing continuous exposure to active CNP, navepegritide offers a convenient once-weekly dosing regimen that promotes growth and improves lower limb alignment and HRQoL [health-related quality of life], report Ravi Savarirayan (Murdoch Children’s Research Institute, Melbourne, Victoria, Australia) and co-workers in JAMA Paediatrics.
For the phase 2b trial, 84 children aged 2–11 years, who had a genetically confirmed diagnosis of achondroplasia (93% with FGFR3 variant 1138G>A) and had not received prior growth-promoting therapy, were randomly assigned to receive weekly subcutaneous navepegritide 100 µg/kg (n=57) or placebo (n=27) for 52 weeks.
The two treatment groups were balanced for age (mean 5.6 vs 6.0 years) and gender (54 vs 52% boys). All patients had at least 6 months of height measurements before baseline and an average achondroplasia-specific height z score of 0, “indicating that the trial population was comparable in height to the broader population of untreated children with achondroplasia”, Savarirayan and team explain.
The primary efficacy endpoint of a significant improvement in AGV with navepegritide at week 52 was met, with a least squares (LS) mean improvement of 5.89 cm/year versus 4.41 cm/year with placebo, translating to an average greater improvement of 1.49 cm/year with the CNP prodrug. The difference in AGV between the groups was observed from 12 weeks and continued through to week 52, the researchers add.
The LS mean treatment difference in AGV at 52 weeks was smaller among the 31 children younger than 5 years than their older counterparts (1.02 vs 1.78 cm/year), with mean treatment differences of 1.41 cm/year in those aged 5–8 years and 2.48 cm/year in those aged 8 years and older.
The change in height z score from baseline to 52 weeks was significantly greater with navepegritide than placebo based on both achondroplasia-specific and average-stature reference data (LS mean differences=0.28 and 0.30), with children given the CNP prodrug showing “consistently increased” height z scores over 52 weeks whereas placebo-treated patients had stable or decreasing scores.
“At baseline, disproportionate bone growth was evident, with an elevated upper to lower body segment ratio vs children of average stature”, the authors say, but navepegritide therapy significantly decreased this ratio at week 52 to a greater extent compared with placebo (–0.04 vs –0.02).
Navepegritide therapy was also associated with stabilisation of the mean fibula-to-tibia length ratio, indicating a reduction in disproportionate fibular overgrowth compared with an increase with placebo. In addition, children treated with navepegritide experienced “[i]mprovements in lower limb alignment”, as indicated by a reduction in the tibia–femoral angle and mechanical axis deviation (ie, distance between the centre of the knee and the weight-bearing axis of the leg), whereas these measures worsened among the controls.
The researchers suggest that these improvements with navepegritide might help to “reduce the mechanical strain on joints in the lower limbs and contribute to long-term reductions in joint dysfunction, pain, and the need for corrective orthopedic surgery.”
Navepegritide was also associated with numerically greater improvements on all subscales of the Achondroplasia Child Experience Measures–Physical functioning (ACEM) scale by week 52, compared with placebo, including a significant LS mean treatment difference for improvement in ACEM-Physical Functioning in a prespecified analysis of children younger than 5 years.
Savarirayan et al emphasize that these HRQoL benefits were “more pronounced in children with greater baseline burden, as assessed with the ACEM, highlighting that those with more severe functional limitations may benefit most from navepegritide treatment.”
They add: “Importantly, the benefits of navepegritide were achieved without accelerating bone age or negatively affecting spinal curvature.”
Two children discontinued navepegritide therapy, one each at weeks 26 and 34, due to parental withdrawal and unrelated to adverse events (AEs) in both cases.
The majority of patients in the navepegritide and placebo groups experienced AEs (91.2 vs 96.3%), most of which were grade 1 or 2. There were four grade 3 AEs among the navepegritide group, namely localised infection, otitis media, vertebral foraminal stenosis, and cerebral ventricle dilatation, and one case of sleep apnoea in the placebo group. There were no grade 4 AEs or deaths, no cases of fracture or symptomatic hypotension, and all injection site reactions were “transient and mild”, the researchers remark.
They conclude: “Collectively, the results of this trial suggest navepegritide could become a transformative treatment option for children with achondroplasia, offering meaningful improvements in height and health outcomes beyond height.”
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