Results and learnings from amber, a decentralized phase i study assessing the pharmacokinetic and pharmacodynamic profile of inhaled velsecorat, a non-steroidal, selective glucocorticoid receptor modulator, in adolescents with asthma

ABSTRACT

Rationale Asthma is characterized by chronic inflammation;inhaled corticosteroids (ICS) are the preferred antiinflammatory treatment at all severity levels. Velsecorat, a once-daily inhaled non-steroidal selective glucocorticoid receptor (GR) modulator potentially has an improved risk-benefit profile compared to ICS. The aim of this Phase 1 study (AMBER, NCT03976869) was to establish the pharmacokinetic (PK) and pharmacodynamic (PD) profile of velsecorat in adolescents to enable inclusion of this population in phase 3 studies. Necessitating long site visits, PK studies are challenging to conduct in adolescents, disrupt patient school attendance and interfere with the daily lives of the patients' families. In AMBER, we revolutionized the conduct of this type of study by bringing the study directly to the patient's home (Figure 1). Methods This open-label, multi-center study enrolled 36 adolescents (12-17 years) with Global Initiative for Asthma (GINA) step 2 asthma. After a 2-3-week washout of asthma controller, patients received 360μg velsecorat inhaled once-daily for two weeks, with short acting β-agonists allowed as rescue medication. The primary objective was to determine steady state PK;key secondary endpoints were safety and change from baseline in;trough FEV1, plasma cortisol, and asthma control as measured by the asthma control questionnaire-5 (ACQ-5). Study site visits were combined with telemedicine and home nursing visits, as well as collection of daily dairy data via smartphone app. Results Following administration of velsecorat, individual steady state exposure parameters in patients aged 12-14 and 15-17 years were within the same range. Change from baseline in adjusted mean plasma cortisol levels, mean ACQ-5 scores and mean Day15 FEV1 were limited and not clinically significant. Velsecorat was well tolerated, and no new safety concerns were identified. During the COVID-19 pandemic, patient recruitment was accelerated, highlighting that the decentralized design of AMBER, was more suitable for social distancing practices than the traditional site-centric trial model. Participant and caregiver surveys administered at study end revealed that most participants were willing to participate in similar decentralized trials in the future. Conclusions Overall, the results support the advancement of velsecorat into phase 3 studies including adolescents. AMBER offered a convenient and patient-centric study experience for adolescents and their families during the pandemic. Decentralized studies has the potential to become a new standard by offering a flexible convenient, safe and patient-friendly study format for an adolescent population, as shown by the high recruitment and retention rate during the peak of the COVID-19 pandemic.