Patients who take benralizumab for severe eosinophilic asthma can reduce their inhaled corticosteroid doses while maintaining asthma control for up to 48 weeks, according to a study published in The Lancet.

These findings support Global Initiative for Asthma (GINA) recommendations for reduced inhaled corticosteroid (ICS) doses for patients with severe asthma who have favorable responses to biologic therapy, the authors wrote.

“The results offer critical evidence for the potential for patients to safely reduce medication burden,” David J. Jackson, MBBS, MRCP, MSc, PhD, clinical professor of respiratory immunology, School of Immunology & Microbial Sciences, Guy’s Hospital, King’s College London, told Healio.

Previously, there were no prospective data supporting these recommendations, Jackson said. The SHAMAL study was designed to address the evidence gaps and provide clear guidance on how to step down maintenance treatment while maintaining asthma control.

“The results offer critical evidence for the potential for patients to safely reduce medication burden,” Jackson said.

Jackson called it the first-ever prospective trial to demonstrate that a targeted biologic treatment, benralizumab, can enable a significant step-down of ICS therapy in patients with severe eosinophilic asthma (SEA) while maintaining asthma control, with most patients remaining exacerbation-free.

“Long-term, high-dose ICS usage carries the potential for significant side effects and can negatively impact patients,” Jackson said. “Reduced ICS usage decreases the chances of ICS dose-related risks of adverse events, including adrenal suppression, cataracts, osteoporosis-related fractures, and diabetes.”

Study design, results
The SHAMAL study included 168 adults (mean age, 57.7 years; 53% women; 75% white) diagnosed with SEA whose disease was classified as controlled based on a five-item Asthma Control Questionnaire (ACQ-5) score of less than 1.5 at the first visit in the study.

These patients also had been using high ICS doses after initiating treatment with benralizumab (Fasenra, AstraZeneca), with three or more doses of the biologic, before their first visit in the study, which included a 4- to 8-week screening and run-in period, a 32-week reduction period and a 16-week maintenance period.

During the reduction period, the 125 patients (mean age, 58.1 years; 55% women; 76% white) in the treatment reduction group began with 30 mg of benralizumab once every 8 weeks in addition to two inhalations of 200 µg of ICS and 6 µg of formoterol twice a day for maintenance, with 200 µg of ICS and 6 µg of formoterol as needed.

Next, these patients reduced their dose of ICS and formoterol to one inhalation twice a day for maintenance with ICS and formoterol as needed, followed by sole use of the ICS-formoterol reliever.

The 43 patients (mean age, 56.5 years; 47% women; 72% white) in the reference group also took 30 mg of benralizumab once every 8 weeks, with 400 µg of budesonide and 12 µg of formoterol per inhalation, for two inhalations twice a day and salbutamol reliever as needed, during the reduction period.

By the end of the reduction period, 110 (92%) of 119 patients had reduced their maintenance doses of ICS-formoterol, including 18 (15%) whose doses were reduced to a medium dose, 20 (17%) whose doses were reduced to a low dose, and 72 (61%) whose doses were reduced to a reliever only.

Additionally, 91% of patients in the reduction group had no exacerbations during tapering.

The reduction group included 113 (96%) of 118 patients with a non-missing dose who maintained the same daily dose of ICS-formoterol between the end of the reduction period and the end of the maintenance period.

Mean changes from baseline in total daily ICS doses, including maintenance and reliever doses, from randomization through the end of the study included –1,171 µg (standard error [SE] = 43.33) for the reduction group and –351 µg (SE = 76.06) for the reference group.

Least square (LS) mean changes from baseline to the end of the reduction period in ACQ-5 scores included 0.16 (SE = 0.04) for the reduction group and 0.06 (SE = 0.07) for the reference group.

Similarly, LS mean changes from baseline to the end of the reduction period in asthma quality of life questionnaire for 12 years and older (AQLQ[S]+12) scores included –0.03 (SE = 0.06) for the reduction group and 0.01 (SE = 0.1) for the reference group.

Also by the end of the reduction period, the reduction group included 93 (74%) with no deterioration in their ACQ-5 scores and 85 (68%) with no deterioration in their AQLQ(S)+12 scores. The reference group included 30 (70%) with no deterioration in their ACQ-5 scores and 31 (72%) with no deterioration in their AQLQ(S)+12 scores.

Both groups finished the full study periods with similar annualized asthma exacerbation rates (AERs), the researchers said, including 0.14 (95% CI, 0.09-0.23) for the reduction group and 0.14 (95% CI, 0.06-0.31) for the reference group.

Additionally, throughout the study period, 109 (87%) of the reduction group and 38 (88%) of the reference group remained exacerbation free.

LS mean changes from baseline to the end of the study for prebronchodilator FEV1 included –88.9 mL (SE = 27.2) for the reduction group and 5.9 mL (SE = 47.5) for the reference group.

At the end of the study, mean fractional exhaled nitric oxide concentrations included 48.8 ppb (SE = 41.1) with an LS mean change of 22.92 ppb (SE = 3.33) for the reduction group and 27.8 ppb (SE = 18.71) with a LS mean change of 3.41 ppb (SE = 5.72) for the reference group.

The patients who had reduced their doses to reliever only by the end of the reduction period had the largest LS mean changes from baseline in FEV1 (–146.7 mL; SE = 34.6) and in FeNO concentrations (31.99 ppb; SE = 4.09) by the end of the study compared with all the other patients.

Also, the patients who had reduced their doses to reliever only by the end of the reduction period had a mean of 6.3 (standard deviation, 7.87) reliever inhalations per week.

The reduction group additionally included 48 (56%) patients who experienced clinical remission defined as an ACQ-5 score of less than 1.5 by the end of the reduction period and 48 (54%) with clinical remission by the end of the maintenance period.

Also, 61 (73%) of the patients in the reduction group strongly agreed that their current inhaler therapy was easy to use at the end of the reduction period, 55 (66%) said it worked to manage their asthma, and 43 (51%) said it relieved their asthma symptoms, with these positive responses maintained through the end of the maintenance period.

Throughout the study, 91 (73%) of the patients in the reduction group and 35 (83%) in the reference group experienced adverse events, which the researchers called similar. Serious adverse events included 12 (10%) in the reduction group and five (12%) in the reference group. There were no deaths during the study.

Conclusions, next steps
Overall, the researchers said, 92% of the patients successfully reduced their high doses of ICS, including more than 60% who reduced doses to anti-inflammatory relievers only without any change in their asthma control and 87% who had no exacerbations through the end of the maintenance period.

“SHAMAL shows that ICS therapy reduction is possible with benralizumab, a significant step in moving patients away from long-term high dose ICS usage,” Jackson said. “Results offer the potential for patients to safely reduce medication burden.”

Also, Jackson said, SHAMAL provides clear guidance on how to step down maintenance treatment while maintaining asthma control.

However, the researchers said, similar studies involving other biologics with different mechanisms than benralizumab are needed before firm recommendations for withdrawing ICS could be made.

Reference: https://www.kcl.ac.uk/news/major-breakthrough-for-severe-asthma-treatment