The phase IIIb PONENTE trial* aims to assess if adults with severe eosinophilic asthma who are treated with benralizumab can safely reduce their doses of oral corticosteroid (OCS) therapy, while still maintaining asthma control.

“PONENTE will evaluate a protocol for OCS tapering, including reduction to less than the physiological dosage of prednisone or equivalent 5 mg/day, following benralizumab initiation for OCS-dependent patients with severe eosinophilic asthma,” said the researchers.

Participants in this ongoing multinational, open-label study are adults with severe, uncontrolled eosinophilic asthma who have been on high-dose inhaled corticosteroids plus long-acting β₂-agonists (LABAs) for ≥6 months and long-term OCSs for ≥3 months (stable dose for ≥4 weeks pre-enrolment). They receive subcutaneous benralizumab 30 mg Q4W for the first three doses, then Q8W. [ATS 2019, abstract P711]

OCS dosage reduction begins at week 4 after the second dose of benralizumab, with the reduction schedule based on baseline dose and asthma control, until reaching a dose of 5 mg/day.

The primary efficacy endpoint is to identify the proportion of patients who can achieve a 100 percent reduction in daily OCS dose (or dose of ≤5 mg/day if adrenal insufficiency [AI] is the reason for no further dose reduction) maintained for ≥4 weeks without worsening of asthma. Patients who achieve this will be enrolled in the 6-month maintenance phase of the trial, with OCS dose increased if they experience worsening of asthma.

“Long-term OCS use can … suppress the hypothalamic-pituitary-adrenal (HPA) axis, potentially resulting in AI,” said the researchers. As such, participants in the PONENTE trial who reduce their OCS dose to 5 mg/day and maintain it for 4 weeks will be monitored for AI.

Patients whose cortisol levels suggest partial AI will undergo an adrenocorticotropic hormone stimulation test within 1 week of the cortisol test. Patients who do not have AI will have their OCS dose reduced by 2.5 mg Q4W. Among those with AI or partial AI, OCS dose will be reduced by 1 mg Q4W until a follow-up test after 2 months. At this point, patients who still have AI or partial AI will follow the same schedule while those with normal results who are receiving OCSs at ≤3 mg/day could cease their OCSs. If two tests done 3 months apart indicate complete AI, patients will not have further OCS dose reductions.

The study allows for continuous, but slower, OCS reduction following the first asthma exacerbation (after recovery) but not after a second exacerbation, where patients will either continue the current OCS dose or take a dose one step greater than the one pre-exacerbation.

Results of this trial will add on to that of the phase III ZONDA** trial which demonstrated that over 28 weeks, patients with severe asthma who received benralizumab reduced their OCS dosage by a median 75 percent from baseline compared with a 25 percent reduction among those who received placebo, while still maintaining disease control.

However, the 28-week duration of the ZONDA trial did not enable the researchers to assess if benralizumab would allow for the eventual elimination of OCS altogether.

“[The results of the PONENTE trial] will provide valuable guidance for clinicians on tapering OCS dosage for patients being treated with benralizumab,” said the researchers. “PONENTE will be the largest OCS-sparing trial for patients with severe asthma conducted to date and the first to directly address AI management,” they added.

The PONENTE trial also has other advantages over previous studies in this field, including a longer maintenance phase (about 24–34 weeks compared with 4 weeks) and a tapering schedule that being dependent on baseline corticosteroid dose and asthma control, is “personalized” to each patient, they said.

“These results aim to direct future clinical practice on OCS tapering following introduction of biologics, and potentially drive guideline changes,” they said.