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.

中文翻译：

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使用贝那利珠单抗 (PONENTE) 治疗的成人重度嗜酸性哮喘患者通过个性化减少算法消除口服皮质类固醇：一项多中心、开放标签、单臂研究

背景

对于严重哮喘患者开始使用生物制剂后如何减少口服皮质类固醇，目前尚无共识。PONENTE 试验评估了贝那利珠单抗开始后快速、个体化的类固醇减少算法的有效性和安全性，包括肾上腺功能不全监测。

方法

这项多中心、开放标签、单臂研究在 17 个国家的 138 个临床哮喘治疗中心进行。我们招募了患有严重嗜酸性粒细胞性哮喘的成年患者（年龄≥18 岁）（入组时血嗜酸性粒细胞计数≥150 个细胞/μL 或前一年≥300 个细胞/μL），在入组前需要维持口服皮质类固醇至少 3 个月。患者每 4 周接受 30 毫克贝那利珠单抗（皮下注射），共 3 剂，之后每 8 周一次。口服皮质类固醇减少阶段从第 4 周开始，根据起始剂量、哮喘控制和肾上腺功能状态，每 1-4 周将每日口服皮质类固醇剂量减少 1-5 mg。通过清晨血清皮质醇测量评估肾上腺功能，然后在需要时进行促肾上腺皮质激素刺激，一旦患者达到每天 5 毫克/天的口服皮质类固醇剂量，持续 4 周。在首次测试时对有肾上腺功能不全证据的患者进行重复皮质醇测量。在整个诱导期和口服皮质类固醇减少阶段，每周使用哮喘控制问卷 6 (ACQ-6) 评估哮喘控制情况。主要终点是消除每日口服皮质类固醇的患者百分比，持续至少 4 周，以及实现消除的百分比或每日泼尼松或泼尼松龙剂量为 5 毫克或更少，持续至少 4 周，如果没有进一步的原因减少是肾上腺功能不全。安全性和有效性分析包括所有接受过至少一剂贝那利珠单抗且具有描述性的患者。我们展示了口服皮质类固醇减少阶段后的结果；维护阶段正在进行中。该试验已在 ClinicalTrials.gov 注册，NCT03557307。

发现

在 2018 年 4 月 1 日至 2020 年 9 月 5 日期间，在评估合格的 705 名患者中，招募了 598 名患者，他们都接受了至少一剂贝那利珠单抗。总体而言，598 名患者中有 376 名（62·88%，95% CI 58·86–66·76）消除了口服皮质类固醇，598 名患者中有 490 名（81·94%，78·62–84·94）消除了使用或达到了剂量如果停止减少的原因是肾上腺功能不全，则为 5 mg 或更少。亚组分析表明，无论基线嗜酸性粒细胞计数、基线口服皮质类固醇剂量或口服皮质类固醇治疗持续时间如何，都可以减少剂量。首次评估时，533 名患者中有 321 名（60%）被检测出肾上腺功能不全，2-3 个月后，533 名患者中有 205 名（38%）被检测出肾上腺功能不全。安全概况与以前的经验一致。大多数患者（598 名中的 448 名 [75%]）在口服皮质类固醇减少期没有哮喘发作，年发作率为 0·63。在 598 名患者中，38 名 (6%) 总共经历了 46 次恶化，导致急诊或紧急护理就诊或住院。

解释

尽管肾上腺功能不全的患病率很高，但大多数接受贝那利珠单抗治疗的嗜酸性粒细胞哮喘患者通过个性化的剂量减少算法实现了口服皮质类固醇的消除或最大可能的减少。

资金

阿斯利康。