medwireNews: Dupilumab, used as an add-on to usual treatment for moderate-to-severe childhood asthma, was “well tolerated with an acceptable safety profile” in the long term, say the LIBERTY ASTHMA EXCURSION trial investigators.
Treatment-emergent adverse events (TEAEs) occurred in 232 (64%) of 365 children aged between 6 and 11 years treated with dupilumab during the trial, which was a 52-week open-label extension of the phase 3 LIBERTY ASTHMA VOYAGE study where participants had been randomly assigned to receive the biologic agent or placebo alongside their usual medium- or high-dose corticosteroids.
Most of the observed TEAEs seen in the extension trial involved the upper airways, with nasopharyngitis, pharyngitis, and upper respiratory tract infection reported in around 9–10%, 6–10%, and 4–8% of children, respectively, and injection site reactions occurred in 3–7% of patients.
There were 52 (14%) TEAEs that the investigators considered related to treatment, seven (2%) serious adverse events (SAEs), and three (1%) TEAEs that led to treatment being discontinued. All of which occurred in children treated with dupilumab in both the extension study and the original trial. There were no TEAE-related deaths.
“The safety profile of dupilumab in EXCURSION (overall population) was similar to that observed in the VOYAGE parent study,” report Leonard Bacharier (Vanderbilt University Medical Center, Nashville, Tennessee, USA) and associates in The Lancet Respiratory Medicine.
EXCURSION involved 90% of the children who participated in VOYAGE, of whom 240 had been treated with dupilumab and 125 with placebo every 2 weeks by subcutaneous injection for 1 year. Dupilumab had been dosed according to bodyweight, at 100 mg for children of 30 kg or under and 200 mg for those above this bodyweight threshold.
For the extension study, all children were treated with dupilumab. This was again based on bodyweight and an additional dose of 300 mg every 4 weeks was added for those who had already been treated with dupilumab and whose bodyweight had increased above the 30 kg threshold, with a further protocol amendment also switching to this dose for select patients weighing less than 30 kg.
“Consistent with VOYAGE, some cases of non-serious and non-severe parasitic infections were reported,” Bacharier et al observe. Four of the six parasitic infection cases seen were enterobiasis, with one case each of ascariasis and toxocariasis.
One of the SAEs highlighted by the investigators was a single case of pulmonary tuberculosis (TB) in a child who had received dupilumab in both the VOYGAGE and EXCURSION trials; however, the child lived in an area endemic for TB, and had been treated with seven courses of oral corticosteroids.
In addition to the safety findings, “dupilumab showed persistent reductions in severe asthma exacerbations,” when compared with the start and end of the original trial, say the investigators.
At the start and end of VOYAGE, the unadjusted annualized severe exacerbation rates in children treated with dupilumab and placebo were a respective 2.56 and 2.16, and 0.33 and 0.67. At the end of EXCURSION, the severe exacerbation rate was 0.12, regardless of the original treatment allocation.
“[T]his also led to reduced exposure to systemic corticosteroids, which is of great importance to children due to the many adverse effects of continued exposure to systemic corticosteroids. Moreover, dupilumab led to sustained improvement in lung function in this patient group,” the EXCURSION investigators conclude.
In a related comment, Emmanouil Paraskakis (University Hospital of Heraklion, Greece) and Andrew Bush (Imperial College and Royal Brompton Hospital, London, UK) congratulate the investigators.
“We commend the authors for moving the field beyond extrapolation from studies in adults into children,” they note, observing that EXCURSION, when considered with VOYAGE, represents the first 2-year data on an injectable monoclonal agent in children with severe asthma.
The editorialists note, however, that “EXCURSION could have been unsuccessful at detecting a side-effect with a prevalence of 1%. Hence, post-marketing surveillance is of great importance.”
They also comment that the study is part of a “new era in which novel effective treatment based on solid evidence should become available for every child with asthma.”
Future work should look to further unravel the underlying pathogenic mechanisms of severe pediatric asthma and determine age-appropriate biomarkers, recommend Paraskakis and Bush.
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