Reducing steroid use in asthma patients receiving biologic therapies poses a significant challenge and was the focus of the recent PONENTE trial (oral corticosteroid elimination via a personalized reduction algorithm in adults with severe, eosinophilic asthma treated with benralizumub). The trial explored the use of benralizumab in patients with severe, eosinophilic asthma. Benralizumab is an anti-interleukin monoclonal antibody, indicated as add-on maintenance treatment for adults with severe eosinophilic asthma, inadequately controlled despite high-dose inhaled glucocorticoids and long-acting β2-agonists. Severe eosinophilic asthma is a form of severe asthma, associated with increased eosinophil (a type of white blood cell) involvement in airway inflammation and in peripheral blood.^[1]

Along with other biologics, benralizumab can reduce exacerbations, improve lung function and disease control, and enable clinicians to decrease oral steroid use in severe asthma. However, 20-60% of patients on benralizumab still receive oral steroids that are associated with a wide range of side-effects including suppression of the hypothalamic-pituitary-adrenal axis, which can increase eosinophil levels. The authors of the PONENTE study believe this anomaly is driven by lack of data and poor clinical consensus surrounding the speed at which steroids can be reduced, and the need to evaluate adrenal insufficiency in steroid reduction protocols. The PONENTE study was designed to address these knowledge gaps, by evaluating the effectiveness and safety of a rapid, individualized steroid-reduction algorithm after benralizumab initiation. The protocol included adrenal insufficiency monitoring, with those results influencing the protocol’s individualization.

PONENTE was a multinational, multicenter, open-label, single-arm study carried out at 138 asthma treatment centers across 17 countries. The trial enrolled 598 adults (≥18 years) with severe, eosinophilic asthma (blood eosinophil count ≥150 cells per µl at enrolment or ≥300 cells per µl in the previous year). Here, we focus on the results of the steroid reduction phase of the study; detailed exclusion and inclusion criteria have been published separately for those who would like to know more.^[2] 

During the screening period (up to 2 weeks), patients were switched to daily oral prednisone or prednisolone if they were on other glucocorticoid treatments. Eligible patients underwent a 4-week induction phase with stable steroid dosage, receiving three 30mg subcutaneous benralizumab doses every four weeks, starting at week 0, followed by eight weekly doses thereafter. Patients received benralizumab through the induction, oral corticosteroid reduction and follow-on maintenance phases. 

The oral corticosteroid reduction phase began at week four and was variable and personalized based on patients’ asthma control status, steroid dose and adrenal function status as follows:

• The steroid reduction phase ranged from 8 to 24 weeks
• Phased reduction for patients starting on ≥5mg/day
  • Fastest reduction (5mg/day per week) at ≥ 20mg/day dose
  • Lower reductions (2.5mg/day per 4 weeks) as doses approached ≥5mg/day
• Adrenal function was monitored from 5mg/day (standardized protocol) prior to further dose tapering
  • Applied to patients reduced to, or starting from 5mg/day glucocorticoid therapy
  • Daily cortisol evaluation using standardized protocol
    • Adrenocorticotropic hormone (ACTH) stimulation tests at later stages
  • Steroid reduction directed by adrenal function: slower reduction and/or reduction breaks could be applied

Patients completed the Asthma Control Questionnaire 6 (ACQ-6) once a week throughout all phases of the study, including induction, as part of the assessment of clinical status. Where patients experienced asthma exacerbations, further steroid reductions were allowed at a slower rate after recovery, with the pace dictated by their current glucocorticoid dose. Further reductions were stopped for all patients who had two exacerbations or losses in asthma control.

The primary endpoints for this phase of the study were the percentage of patients who:

• Eliminated oral corticosteroid use for at least 4 weeks and
• Eliminated use or achieved a daily steroid dosage of ≤5mg for ≥ 4 weeks if the reason for no further reduction was adrenal insufficiency

Secondary endpoints included asthma control levels and exacerbation frequency.

Nearly all patients achieved a reduced steroid dosage

The results of the steroid reduction phase of the PONENTE study are very encouraging given the historic data on the proportion of severe asthma patients who remain on oral steroids after starting biologic therapies.  

Nearly all patients (91.5%, 95% CI 88.9-93.6%) eliminated oral corticosteroids or achieved a daily dose of ≤5mg regardless of the reason for stopping the reduction. The median daily oral steroid dose reduction was 100% (-100 to 100%). In addition:

• 62.9% (95% CI 58.9-66.8) achieved the primary endpoint of eliminating oral glucocorticoids
• 81.9% (95% CI 78.6-84.9%) of adrenally insufficient patients achieved the goal of eliminating steroids or achieving a daily dose of ≤5mg
• 81.8% (95% CI 78.5-84.8%) of patients achieved ≥50% dosage reduction

Dosage reductions were achieved regardless of baseline eosinophil counts, baseline steroid dose or glucocorticoid treatment duration, although there was a trend to smaller reductions in patients with the highest baseline dosages. Time to achieve dosage reduction correlated with baseline steroid dose, with a median dosage reduction of 4.4 weeks for 5mg/day to up to 25.0 weeks for higher doses.

A template for the development of steroid-reduction protocols

While this is a relatively small study focused on a single phenotype in severe asthma patients, it clearly demonstrates that personalized oral steroid reduction protocols can enable the rapid and safe reduction of oral glucocorticoids in severe asthma patients. The results are even more impressive given the inclusion of patients with adrenal insufficiency.  

And though the PONENTE protocol itself may not be appropriate for all asthma patients, the study provides a proof-of-principle for the development of steroid reduction protocols. The approach could inform the design of future studies to support the development of protocols and guidelines to deliver robust, rapid and safe steroid reduction protocols for patients starting on biologics and other steroid sparing therapies. 

While the study focused on a severe asthma cohort, it’s clear that the methodology has the potential to inform studies in other disease areas where there is a need to reduce steroid use and exposure, especially now that clinicians are able to measure and monitor steroid-toxicity using the STOX® Suite.  

References

1. Menzies-Gow A, Gurnell M, Heaney LG et. al. Oral corticosteroid elimination via a personalized reduction algorithm in adults with severe, eosinophilic asthma treated with benralizumab (PONENTE): a multicentre, open-label, single-arm study.  Lancet Respiratory Medicine, 10:47-58. (2022). https://doi.org/10.1016/s2213-2600(21)00352-0
2. Menzies-Gow A, Corren J, Bel EH, et al. Corticosteroid tapering with benralizumab treatment for eosinophilic asthma: PONENTE trial. ERJ Open Res 2019; 5: 00009–2019. DOI: 10.1183/23120541.00009-2019

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