Oral corticosteroid elimination via a personalised reduction algorithm in adults with severe, eosinophilic asthma treated with benralizumab (PONENTE): a multicentre, open-label, single-arm study

Summary

Background

No consensus exists on how to reduce oral corticosteroids after the initiation of biologics in severe asthma. The PONENTE trial evaluated the effectiveness and safety of a rapid, individualised steroid-reduction algorithm, including adrenal insufficiency monitoring, after benralizumab initiation.

Methods

This multicentre, open-label, single-arm study was done at 138 clinical asthma treatment centres across 17 countries. We enrolled adult patients (age ≥18 years) with severe, eosinophilic asthma (blood eosinophil count ≥150 cells per μL at enrolment or ≥300 cells per μL in the previous year) requiring maintenance oral corticosteroids for at least 3 months preceding enrolment. Patients received benralizumab 30 mg (subcutaneous injection) every 4 weeks for three doses, then every 8 weeks thereafter. The oral corticosteroid reduction phase began at week 4 with daily oral corticosteroid dosages reduced by 1–5 mg every 1–4 weeks depending on the starting dosage, asthma control, and adrenal function status. Adrenal function was assessed with an early morning serum cortisol measurement, followed by adrenocorticotropic hormone stimulation when required, once patients achieved a daily oral corticosteroid dosage of 5 mg/day for 4 weeks. Repeat cortisol measurements were taken for patients with evidence of adrenal insufficiency at first testing. Asthma control was assessed with the Asthma Control Questionnaire-6 (ACQ-6) weekly throughout the induction and oral corticosteroid reduction phases. The primary endpoints were the percentage of patients eliminating daily oral corticosteroids, sustained for at least 4 weeks, and the percentage achieving elimination or a daily prednisone or prednisolone dosage of 5 mg or less, for at least 4 weeks, if the reason for no further reduction was adrenal insufficiency. Safety and efficacy analyses included all patients who received at least one dose of benralizumab and were descriptive. We present results after the oral corticosteroid reduction phase; a maintenance phase is ongoing. The trial is registered with ClinicalTrials.gov, NCT03557307.

Findings

Between April 1, 2018, and Sept 5, 2020, of 705 patients assessed for eligibility, 598 were recruited and all received at least one dose of benralizumab. Overall, 376 (62·88%, 95% CI 58·86–66·76) of 598 patients eliminated oral corticosteroids and 490 (81·94%, 78·62–84·94) of 598 eliminated use or achieved a dosage of 5 mg or less if the reason for stopping the reduction was adrenal insufficiency. Subgroup analysis showed that dosage reductions were achieved irrespective of baseline eosinophil count, baseline oral corticosteroid dosage, or oral corticosteroid treatment duration. Adrenal insufficiency was detected in 321 (60%) of 533 patients at first assessment and in 205 (38%) of 533 patients 2–3 months later. The safety profile was consistent with previous experience. Most patients (448 [75%] of 598) had no asthma exacerbations during the oral corticosteroid reduction phase with an annualised exacerbation rate of 0·63. Of 598 patients, 38 (6%) experienced a total of 46 exacerbations resulting in emergency department or urgent care visits or hospitalisations.

Interpretation

Despite a high prevalence of adrenal insufficiency, most patients with eosinophilic asthma treated with benralizumab achieved elimination of oral corticosteroids or maximal possible reduction using a personalised dosage-reduction algorithm.

Funding

AstraZeneca.

Introduction

Severe asthma affects 5–10% of patients with asthma, and substantially increases the risk of repeat exacerbations, impaired quality of life, and increased health-care and societal costs.1, 2, 3 Treatment of severe asthma includes high-dosage inhaled corticosteroids plus controller medications such as long-acting β₂-agonists.⁴ Current guidelines recommend biologics as the preferred controller medication for severe asthma, with low-dose oral corticosteroids as another less preferable option.⁴ However, 20–60% of patients with severe asthma regularly use oral corticosteroids,5, 6, 7 which are associated with adverse effects,1, 4, 8 including depression, diabetes, and cardiovascular disease.2, 8, 9 Importantly, exposure to exogenous corticosteroids can also cause suppression of the hypothalamic-pituitary-adrenal axis, which can result in adrenal insufficiency, a common but seldom-assessed sequela of oral corticosteroid use.10, 11 The associated diminished stress response can lead to inadequate defence against intercurrent illness including infection.¹² The equivalent of two to four courses (cumulative exposure 0·5–1·0 g) of oral corticosteroids can cause serious adverse events,¹³ including adrenal insufficiency, and the risks increase with longer term therapy, more frequent courses, and higher cumulative dosages.2, 14, 15 If not detected and corrected, adrenal insufficiency might be life-threatening (ie, adrenal crisis), particularly during periods of stress (eg, intercurrent illness).16, 17

Research in context

Evidence before this study

We searched PubMed for English-language clinical trial reports of oral corticosteroid reduction algorithms in severe asthma published in the last 10 years (Jan 1, 2011, to Jan 1, 2021). We used the search terms “oral corticosteroid reduction” and “severe asthma” and “clinical trial”. The search yielded 63 results, including reports of 12 phase 3 trials and four prospective observational trials evaluating the safety or efficacy (or both) of biologics in steroid-dependent patients with asthma; nine of these reports addressed the steroid-sparing ability of biologics. The search only yielded two reports that provided an algorithm for withdrawing oral corticosteroids: one multicentre, single-blind, parallel-group, randomised, controlled trial of a type-2 biomarker strategy for dosage reductions and one pragmatic, randomised, prospective, multicentre study of the use of an internet-based oral corticosteroid reduction protocol. We also searched for reports on the assessment of adrenal insufficiency in severe asthma published in the last 10 years. We used the search terms “severe asthma” and “adrenal insufficiency”. The search yielded 21 results, including three case reports of children with steroid-induced adrenal insufficiency, one report of diagnostic strategies for adrenal insufficiency, one report of age-related and sex-related risk factors for adrenal insufficiency, and only one trial of a biologic that evaluated oral corticosteroid-dosage reductions in patients with severe asthma. Biologics for severe asthma have been shown to decrease exacerbation rates, improve lung function, improve symptom control, and decrease oral corticosteroid use. Benralizumab is an interleukin-5 receptor α-directed cytolytic monoclonal antibody that activates antibody-dependent cell-mediated cytotoxicity, ultimately decreasing eosinophilic inflammation. Benralizumab's steroid-sparing effects were demonstrated in the ZONDA trial: benralizumab was associated with a 75% median oral corticosteroid-dosage reduction (compared with a 25% reduction with placebo) and an annual asthma exacerbation rate that was 70% lower than placebo. However, ZONDA, as well as other steroid-sparing trials of biologics, used a conservative approach for oral corticosteroid reductions due to the presence of a placebo arm. Additionally, the trials did not provide guidance to health-care providers on managing oral corticosteroid reductions in the context of adrenal insufficiency.

Added value of this study

The PONENTE study was an open-label, single-arm study that included nearly 600 adults with severe, eosinophilic asthma receiving benralizumab. The findings revealed that oral corticosteroid use can be eliminated or nearly eliminated using a variable dosage-reduction algorithm that includes rapid oral corticosteroid tapering until reaching physiological dosages (ie, 5 mg prednisone or prednisolone daily) followed by a personalised oral corticosteroid reduction based on the degree of adrenal insufficiency. Nearly all patients achieved elimination or maximal possible reduction of daily oral corticosteroid dosages, even when adrenal insufficiency was detected. Dosage reductions were achieved regardless of baseline blood eosinophil count, length of oral corticosteroid use, or baseline oral corticosteroid dosage. The PONENTE study confirms the effectiveness of benralizumab in reducing oral corticosteroids while improving asthma control and reducing exacerbations and provides a novel and effective oral corticosteroid reduction protocol that can be used in clinical practice to eliminate or reduce oral corticosteroids even when adrenal insufficiency is initially detected.

Implications of all the available evidence

The introduction of biologics for the treatment of severe asthma has substantially changed the treatment landscape and provided an unprecedented opportunity to eliminate or nearly eliminate oral corticosteroids for patients with severe asthma. However, this opportunity brings with it the challenge of adrenal insufficiency after long-term maintenance oral corticosteroids are removed. There is currently no consensus on how to safely approach oral corticosteroid reductions, and health-care providers use their own criteria to determine the speed and extent of oral corticosteroid reductions. For this reason, many patients treated with biologics remain on long-term oral corticosteroids for longer times or at higher dosages than necessary. For the first time, PONENTE provides an algorithm for oral corticosteroid-dosage reductions and adrenal function monitoring that might facilitate elimination of daily oral corticosteroids for patients with severe asthma, which is a necessary and valuable addition to the current knowledge of asthma treatment.

Biologics for severe asthma have been shown to decrease exacerbation rate, improve lung function and symptom control, and decrease oral corticosteroid use.18, 19, 20 Severe asthma is a heterogenous condition with multiple different phenotypes and endotypes. Severe eosinophilic asthma is associated with eosinophilic inflammation in the airways, usually in combination with elevated peripheral blood eosinophil counts. Benralizumab, a cytolytic monoclonal antibody against interleukin-5 receptor-α, activates antibody-dependent cell-mediated cytotoxicity, ultimately decreasing eosinophilic inflammation.²¹ Benralizumab is indicated as an add-on maintenance treatment in adult patients with severe eosinophilic asthma inadequately controlled despite high-dose inhaled corticosteroids plus long-acting β₂-agonists. In the ZONDA trial, which included patients with severe asthma associated with eosinophilia, benralizumab was associated with a 75% median reduction in oral corticosteroid dosage (compared with a 25% reduction with placebo) and an annual asthma exacerbation rate that was 70% lower than with placebo.²¹

A key aim of severe asthma management is to reduce and, if possible, eliminate oral corticosteroid use via methods such as increased adoption of biologics.⁴ This aim is frequently not achieved because of a combination of scarce data and poor clinical consensus with regard to the speed of oral corticosteroid dosage reduction or the need for adrenal insufficiency evaluation in corticosteroid reduction protocols after biologics are initiated.²² Previous studies of the corticosteroid-sparing benefit of biologics included slow and cautious dosage reduction schemes, especially from high oral corticosteroid dosages, owing to the inclusion of placebo groups.21, 22, 23, 24, 25 Previous studies also did not objectively assess adrenal insufficiency.21, 23, 25 In clinical practice, oral corticosteroid dosages should be reduced to physiological concentrations as quickly as possible, and monitoring for adrenal insufficiency should accompany the reductions to minimise the risk of adrenal crisis associated with discontinuation of exogenous corticosteroids. But, given the scarcity of guidance, especially for patients with some degree of adrenal insufficiency, individual health-care systems and providers use their own criteria to determine the speed and extent of oral corticosteroid reductions.16, 22

The PONENTE trial was designed to address the current knowledge gaps, by evaluating the effectiveness and safety of expediently eliminating oral corticosteroids after benralizumab initiation by use of an accelerated, personalised algorithm, with monitoring and management of adrenal insufficiency, in adults with severe, eosinophilic asthma.²⁶ The study's aims were to establish if oral corticosteroids can be safely reduced to physiological equivalent dosages (5 mg/day prednisone or prednisolone) more quickly in a single-arm trial than in placebo-controlled trials; to understand the extent of adrenal insufficiency in patients with severe asthma receiving long-term oral corticosteroids; to show that adrenal insufficiency can be objectively evaluated and managed during oral corticosteroid reduction; and to establish if further oral corticosteroid reduction in patients with partial adrenal insufficiency, or in those who recover from complete adrenal insufficiency, is possible with repeat assessment of adrenal function.²⁶

PONENTE included a 4-week induction phase and an oral corticosteroid reduction phase of variable duration that depended on starting oral corticosteroid dosage, adrenal status, and clinical symptomology. The 24–32-week maintenance phase of the trial is ongoing. This report provides results of the corticosteroid reduction phase.