Dr. Sanjeev Khindri
The US Food and Drug Administration (FDA) approved once-daily inhaled corticosteroid (ICS) fluticasone furoate (Arnuity Ellipta) for the maintenance treatment of children from 5 years old with asthma last week, aligning the GlaxoSmithKline therapy with only a handful of once-daily therapies marketed for pediatric asthma patients. According to GSK, the field is still in dire need of more convenient treatment options,
The therapy, from GlaxoSmithKline (GSK), now joins a small list of once-daily therapies licensed in the country for this particular pediatric asthma population — a space still in need of more convenient treatment options, according to GSK. Director and Project Physician Lead Dr. Sanjeev Khindri, in the days following the drug's announced approval during the 2018 American Thoracic Society (ATS) International Conference in San Diego, CA, reflected on the major clinical development and detailed what more is to come in the field of pediatric asthma.
MD Magazine: Can you provide some more background into the details of the trials supporting fluticasone furoate for children with asthma? What were chosen as important metrics to gauge, speaking particularly to pediatric patients?
Dr. Sanjeev Khindri: The submission included data from a pivotal study [HZA106855] assessing the efficacy and safety of once daily fluticasone furoate in children aged 5-11 years (inclusive) with uncontrolled asthma (symptomatic on either SABA alone, SABA plus non-ICS controller or SABA plus low-dose ICS). In the pivotal study [HZA106855] 593 children were randomized (1:1:1:1:1) to receive either placebo once daily, fluticasone propionate 100 mcg twice daily, or fluticasone furoate 25 mcg, 50 mcg, or 100mcg once daily. Note that this study also evaluated dose response for 3 strengths of ARNUITY and included fluticasone propionate as an active comparator. The primary endpoint of the 12-week study was the mean change from baseline in daily morning peak expiratory flow (PEF). Two further studies assessed the effects of inhaled once-daily fluticasone furoate in children aged 5-11 years (inclusive): one study [HZA107112] looked at effects on lower leg growth (assessed via knemometry) and another study [HZA107118] evaluated its effect on the hypothalamic-pituitary-adrenocortical axis (assessed using serum cortisol). The approved dose in children aged 5-11 years in the US is 50 mcg once-daily, delivered using the Ellipta inhaler.
There is reference made to the difficulties of running clinical studies with the age group Arnuity Ellipta is now indicated for. Can you elaborate on the challenges of pediatric asthma trials, and how GSK research responded to such challenges to achieve supporting clinical results?
The challenges in this age group (5-12 years old) are multi-faceted and linked. Complexity of recruiting and retaining children in clinical studies wherein scheduling has to take account of not only the child but the parent/caregiver, anxiety and significant stress around blood tests and conducting spirometry in children and compliance with treatment and assessments. Feedback from parents, children and investigative staff was instrumental in refining study design and procedures in the completing the two subsequent safety studies and in the currently ongoing Phase III study (HZA107116: NCT03248128) of FF combined (fixed dose) with vilanterol (VI) in children with persistent asthma (see below). The important changes/strategies we adopted were: use of animated, targeted consent/assent for children, provision of dedicated study rucksacks for children, establishing buddies such that participating would not be the only patients at clinic visits, discussions and agreements to remove/limit safety blood tests/ECGs given prior data for both FF specifically and the ICS class more widely and familiarization visits to site including spirometry.
Is there any plan to conduct longer-duration, or extension trials for Arnuity Ellipta?
We are currently undertaking a 12-month, placebo-controlled study (HZA114971: NCT 02889809) to evaluate and quantify the effect of FF 50 mcg on growth velocity as measured by stadiometry in pre-pubertal children in asthma. This study is part of Pediatric Study Plan agreed with the US FDA. The study is due to complete in 2022. Whilst we are not planning any further/extension studies for Arnuity Ellipta in asthmatic children aged 5-12, we have recently started a global phase 3, 6-month study (HZA107116: NCT03248128) to evaluate the safety and efficacy of FF/VI in children aged 5-18. In those aged 5-12 we will be evaluating FF/VI 50/25 versus FF 50 whilst in those aged 12-18 we will be evaluating FF/VI 100/25 versus FF 100. This latter study is part of an agreed Pediatric Study Plan for FF/VI (Breo) in the US and Paediatric Investigation Plan in the EU.
The treatment is now among only a few for this patient population. How important is it for the addition of new, more effective and more tolerable therapies for children with asthma?
It is critically important we provide prescribers and their patients/parents with a choice of effective and safe medicines that have been evaluated in appropriate and robust clinical trials. The approval of Arnuity Ellipta 50 mcg for children aged 5-12 based on the clinical study package discussed above provides a safe and effective medicine delivered in an easy to use once-daily device.