AT THE ERS CONGRESS 2016
LONDON (FRONTLINE MEDICAL NEWS) – The investigational treatment benralizumab significantly reduced the number of exacerbations that patients with severe, uncontrolled asthma experienced during the course of a year in two phase III studies.
In the SIROCCO and CALIMA trials, which altogether involved more than 2,000 adult patients, the annual exacerbation rate (AER) was cut by 28%-51%, compared with placebo when benralizumab was added to standard combination therapy of an inhaled corticosteroid (ICS) and a long-acting beta-agonist (LABA).
Benralizumab treatment was also associated with significant improvements in lung function (up to 159 mL increase in FEV1), and reduced daily asthma symptoms of wheeze, cough, and dyspnea versus placebo. There were also improvements seen in patient-reported measures of asthma control and quality of life.
The results of these two multicenter, randomized, double-blind, placebo-controlled, parallel group studies were published in full online in The Lancet to coincide with their presentation at the annual congress of the European Respiratory Society.
Benralizumab is a humanized, monoclonal antibody that has been shown to rapidly and almost completely deplete the number of eosinophils in the blood, airways, and bone marrow, Eugene R Bleecker, MD, who presented the results of the SIROCCO study, explained at the meeting.
Dr. Bleecker, who is the director of the Center for Genomics and Personalized Medicine Research at Wake Forest University in Winston-Salem, N.C., observed that benralizumab “works a little bit differently” to other interleukin (IL)-5–targeting monoclonal antibodies, such as mepolizumab and reslizumab. Rather than target the IL-5 ligand itself, benralizumab binds to IL-5 receptors present on the surface of eosinophils. This action activates natural killer cells, which then destroy the eosinophils via antibody-dependent cell-mediated cytotoxicity.
Phase IIb data have already shown a benefit for benralizumab versus placebo in patients with uncontrolled asthma with high (300 cells/mcL or greater) eosinophil counts in the blood. The aim of the SIROCCO and CALIMA phase III trials was thus to examine the efficacy and safety of the novel agent further in this patient population.
In SIROCCO, 1,205 patients were randomized, and 1,306 were randomized in CALIMA. Key inclusion criteria were physician-diagnosed asthma requiring ICS/LABA therapy and at least two exacerbations in the past 12 months. Patients also needed to be symptomatic during a 4-week run-in period before being randomized to one of three study groups. The groups included one that received benralizumab at a subcutaneous dose of 30 mg every 4 weeks; another that received benralizumab at a subcutaneous dose of 30 mg every 4 weeks for the first three doses then a 30 mg dose or placebo injection alternating every 4 weeks; and a third group that received placebo injections every 4 weeks.
The mean age of patients in both studies and across treatment arms was broadly similar, ranging from 47 to 50 years. Around two thirds of the study population was female, with similar baseline characteristics.
The primary endpoint was the AER in patients with a blood eosinophil count of 300 cells/mcL or higher. In SIROCCO this was measured at 48 weeks and in CALIMA at 56 weeks. The respective AERs for placebo and for the 4- and 8-week dosing regimens of benralizumab were 1.33, 0.73, and 0.65 in SIROCCO and 0.93, 0.6, and 0.66 in CALIMA. This represented a 45% reduction in the AER for the 4-week and a 51% reduction for the 8-week regimens of benralizumab versus placebo in SIROCCO, and a 36% and 28% reduction, respectively, in CALIMA.
There was a large placebo effect and the overall population recruited into CALIMA may have had less severe asthma than the patients who participated in SIROCCO, the principal investigator for CALIMA, Mark FitzGerald, MD , pointed out during a press briefing organized by AstraZeneca. “But when you look at the composite of both studies together, you can see that the results are quite robust,” said Dr. FitzGerald, the director of the Centre for Lung and Heart Health at Vancouver Coastal Health Research Institute.
There was also some evidence that patients who had three or more prior exacerbations fared better, he said, highlighting the importance of defining the patient population who may benefit the most from this treatment.
Something that needs to be investigated further is why patients given the 8-week benralizumab regimen seemed to do better, at least numerically, than those given the 4-week regimen. Dr. FitzGerald suggested that “because eosinophil cells are such a powerful driver of disease, perhaps you may not actually need to be treated as frequently as historically we might have done.”
Other similar biologic agents need dosing every 2 to 4 weeks, but perhaps every 8 weeks is a possibility in the future for benralizumab. A lot can be learned from how biologics are used in rheumatology, he suggested, where treatments have started being given less frequently, because the biology of the various rheumatic diseases is now better understood.
Any adverse event was reported by a similar percentage of actively-treated (71%-75%) and placebo-treated (73%-78%) patients. The frequency and nature of other adverse events were similar to placebo.
The SIROCCO and CALIMA trial data will form part of AstraZeneca’s U.S. and EU regulatory submissions later this year for benralizumab as a treatment for severe, uncontrolled, eosinophilic asthma.
“Potentially, when it becomes available, benralizumab will provide a new therapeutic option for this class of patient.” Dr. FitzGerald said.
Benralizumab is also being investigated as a possible treatment for patients with less severe eosinophilic asthma in the BISE phase III study and as an option for those with severe chronic obstructive pulmonary disease who have high levels of eosinophils in the phase III VOYAGER program.
AstraZeneca and Kyowa Hakko Kirin funded the studies. Dr. Bleecker is the principal investigator for the SIROCCO trial and disclosed receiving research funding or consulting for AstraZeneca-MedImmune, Boehringer Ingelheim, Genentech/Roche, GlaxoSmithKline, Johnson & Johnson (Janssen), Merck, Novartis, Sanofi, Cephalon/Teva, and Regeneron-Sanofi. Dr. FitzGerald disclosed acting as an advisory board participant, receiving funding or fees, or both from AstraZeneca, ALK Abello, Boehringer Ingelheim, Hoffman-La Roche, Genentech, GlaxoSmithKline, MedImmune, Merck, Novartis, and Teva.
