Vosoritide therapy may benefit children with achondroplasia aged under 60 months

medwireNews: Vosoritide may be given to children with achondroplasia aged under 60 months after phase 2 trial findings point to a tolerable adverse event (AE) profile and an increase in height Z score compared with placebo.

On the basis of the results, use of the recombinant C-type natriuretic peptide analogue has been expanded from children aged over 5 years to now include infants from birth in the USA and Japan, and from 4 age months in Europe.

“We hope these data will support paediatricians and other health-care specialists who are assessing the risks and benefits of initiating vosoritide treatment in children with achondroplasia younger than 5 years”, say Ravi Savarirayan (University of Melbourne, Victoria, Australia) and co-workers.

“They also provide a baseline against which the harms and benefits of other potential precision therapies for achondroplasia in young children can be measured”, they write in The Lancet Child & Adolescent Health.

The study included 75 children (49% girls) with genetically confirmed achondroplasia and the daily vosoritide dose was determined based on pharmacodynamic findings from a sentinel group of 11 children.

Sixty-four children were randomly assigned to receive an age-determined dose of vosoritide or placebo, including 31 children aged 24–59 months (15.00 µg/kg per day), 16 children aged 6–23 months (30.0 µg/kg per day) and 17 infants aged less than 6 months (30.0 µg/kg per day).

Children in the vosoritide and placebo arms received treatment for an average 363 and 365 days, respectively, giving corresponding total treatment exposure of 42.7 and 32.0 person–years.

All participants had at least one AE and the annual rate of AEs was 204.5 events per patient given vosoritide and 73.6 events per patient given placebo. The most common AEs in these groups were injection site reactions (79 vs 41%) or erythema (77 vs 41%), pyrexia (37 vs 59%) and upper respiratory tract infection (37 vs 34%).

Serious AEs occurred in 7% of vosoritide-treated patients, with individual cases of oxygen saturation decrease, respiratory syncytial virus bronchiolitis and sudden infant death syndrome and pneumonia. One death was reported in a 1-year-old boy with multiple pre-existing conditions, respiratory infections and complications and spinal cord compression due to foramen magnum stenosis.

In addition, 19% of placebo-treated patients experienced serious AEs including epilepsy, autism, gastroenteritis, vomiting and parainfluenza virus, respiratory distress, skull fracture and otitis media.

There were no “clinically significant cardiovascular changes” and blood pressure changes during treatment were “mild, transient, and asymptomatic”, the researchers say, except for one patient given vosoritide who had a single hypotensive event that resolved spontaneously.

At week 52 of follow-up the children given vosoritide had a 0.25 gain in the least squares mean height Z score change from baseline compared with their placebo-treated counterparts that was “consistent” across the three patient age groups, albeit this was lower than the 1.57 cm/year gain reported previously in older children, the investigators say.

Vosoritide therapy was also associated with a gain in the least-squares mean annualised growth velocity of 0.78 cm/year and a least squares mean gain in standing height or body length of 0.77 cm/year compared with placebo.

“We found no evidence of disproportionate skeletal growth, acceleration of bone age, or abnormal bone morphology”, Savarirayan and co-authors write.

However, compared with baseline findings, magnetic resonance imaging (MRI) of the skull and brain at week 52 showed that children aged less than 6 months given vosoritide had greater increases in facial volume, sinus volume and foramen magnum area than those given placebo.

The researchers acknowledge that “[t]he main limitation of this 52-week study is that the effect of vosoritide treatment on the expected final adult height and functionality, quality of life, and medical complications in these young children could not be assessed.”

All participants have therefore been enrolled in an extension study that will continue until adulthood to determine these outcomes, they say, including whether MRI changes in the youngest children will “translate into a decrease in the incidence of sudden infant death, sleep disordered breathing, and necessity for neurosurgical decompression of the foramen magnum.”

By Lynda Williams

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2023 Springer Healthcare Ltd, part of the Springer Nature Group

Lancet Child Adolesc Health 2023; doi:10.1016/S2352-4642(23)00265-1
Lancet Child Adolesc Health 2023; doi:10.1016/S2352-4642(23)00265-1
Martin Savage
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