ERS 2016: AstraZeneca prepares to file benralizumab for severe eosinophilic asthma following positive pivotal Phase III data.
By Christina Vasiliou, Senior Analyst
11 September 2016
I joined Datamonitor Healthcare in early 2014, having completed an MPhil in Bioscience Enterprise at the University of C...
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Three late-breaking abstracts on registration studies of AstraZeneca’s benralizumab were presented at the European Respiratory Society (ERS) Congress, which was held in London, UK, on 3–7 September 2016. Data from the pivotal SIROCCO and CALIMA Phase III studies showed that benralizumab, a monoclonal antibody against interleukin (IL)-5 receptor alpha, significantly reduced exacerbations and improved lung function and asthma symptoms when administered as an add-on therapy to patients with severe asthma and elevated eosinophils, who are uncontrolled by high-dosage inhaled corticosteroid (ICS)/long-acting beta 2 agonist (LABA) therapy. The Phase III BISE study, which was conducted following a request by the US Food and Drug Administration (FDA) to evaluate the efficacy and safety of the IL-5Rα inhibitor in patients with mild-to-moderate asthma, showed a significant increase in lung function and improved asthma symptoms in the benralizumab group compared to placebo. AstraZeneca indicated that it plans to file benralizumab for regulatory approval in severe asthma with eosinophilic inflammation simultaneously in the US and EU in 2016. Based on this, Datamonitor Healthcare forecasts benralizumab to launch in Q4 2017 at the earliest.
Benralizumab is the first biologic to target the IL-5 receptor, unlike GlaxoSmithKline’s 2015-approved Nucala (mepolizumab) and Teva’s 2016-approved Cinqair (reslizumab), that target the IL-5 ligand. The lack of comparative head-to-head trials with these biologics makes comparison of efficacy and safety challenging, particularly for a drug class which, to date, has only limited real-world use. Key opinion leaders interviewed by Datamonitor Healthcare suggest that benralizumab’s mechanism of action results in a faster onset of action, giving the drug a competitive advantage.
“Well, benralizumab is slightly different because it targets the IL-5 receptor, and theoretically that has an advantage because it means you would get more rapid reduction of eosinophils in the airways, whereas the other two drugs reduce airway eosinophils by stopping them coming into the airway. So, the prediction is that benralizumab would have a faster onset of action…”
EU key opinion leader
Furthermore, benralizumab will likely have a more convenient dosing schedule than the approved IL-5 inhibitors. AstraZeneca noted that it intends to file for approval with a regimen of 30mg every eight weeks (Q8W), while the approved dosing frequency for Nucala and Cinqair is every four weeks (Q4W).
Phase III SIROCCO and CALIMA studies in severe uncontrolled asthma
Benralizumab demonstrated a reduction in annual exacerbation rates, improved lung function, and led to higher QoL outcomes versus placebo
SIROCCO and CALIMA were both randomized, double-blind, parallel-group, placebo-controlled trials. In the SIROCCO study, 2,681 adult and adolescent patients were enrolled, 1,205 of whom were randomly assigned: 407 to placebo, 400 to benralizumab 30mg Q4W, and 398 to benralizumab 30mg Q8W. In the CALIMA study, 2,505 adult and adolescent patients were enrolled, of whom 1,306 were randomized: 440 patients were randomly assigned to placebo, 425 to benralizumab 30mg Q4W, and 441 to benralizumab 30mg Q8W. All patients had a physician-based diagnosis of asthma for at least one year and at least two exacerbations while on high-dosage ICS/LABA therapy in the preceding year. The primary endpoint of both trials was annual exacerbation rate ratio versus placebo.
Both benralizumab regimens in the SIROCCO trial reduced the annual asthma exacerbation rate compared to placebo over 48 weeks of treatment. Patients with baseline blood eosinophil counts of at least 300 cells per μL receiving benralizumab Q4W and Q8W had, on average, estimated annual exacerbation rates of 0.73 and 0.65, respectively, compared to 1.33 for patients in the placebo group. At week 48, both benralizumab dosing regimens significantly improved pre-bronchodilator forced expiratory volume in one second (FEV1) compared with placebo. Asthma control and health-related quality of life (QoL) improvements were significantly greater for patients receiving benralizumab Q8W compared to placebo, but were not significantly greater for the Q4W regimen.
In the CALIMA trial, patients with baseline blood eosinophil counts of 300 cells per μL or greater receiving benralizumab Q4W and Q8W had, on average, estimated annual exacerbation rates of 0.60 and 0.66, respectively, compared to 0.93 for patients in the placebo group. Notably, the differences in the annual exacerbation rates observed between benralizumab and placebo were smaller in the CALIMA trial than in the SIROCCO trial. In the CALIMA study, 36% and 28% reductions in the estimated annual exacerbation rates versus placebo were observed in the benralizumab Q4W and Q8W groups, respectively, compared to 45% and 51% reductions in the SIROCCO trial. However, Dr J Mark FitzGerald highlighted that both studies met their primary endpoints. Additional results from the CALIMA study showed that patients receiving benralizumab Q4W and Q8W had significantly improved pre-bronchodilator FEV1, while only patients receiving benralizumab Q8W had significantly improved total asthma symptom scores.
In both trials, baseline eosinophil counts were predictive of improved response to benralizumab treatment, with patients with greater than 300 cells per μL at baseline having significantly improved pre-bronchodilator FEV1 versus placebo. Conversely, patients with eosinophil counts of less than 300 cells per μL had a non-significant difference in bronchodilator FEV1 compared to placebo. Similarly, post-hoc analysis highlighted that exacerbation history was also predictive of a greater treatment benefit, with Professor Eugene Bleecker noting that these findings were unsurprising.
Benralizumab was well tolerated overall, with no unexpected safety signals
Benralizumab was generally well tolerated in the two pivotal Phase III trials, with worsening asthma and nasopharyngitis being the most common adverse events observed. The table below summarizes the adverse events for both benralizumab regimens and placebo in the SIROCCO and CALIMA studies.
Phase III BISE study in mild-to-moderate asthma
The relatively short-term BISE study included 211 mild-to-moderate asthma patients, randomized 1:1 to benralizumab 30mg Q4W or placebo. The primary endpoint, change from baseline in pre-bronchodilator FEV1 at week 12, was achieved. The trend of greater improvements with benralizumab being associated with patients with greater baseline eosinophil counts was also observed in the BISE study, although was not statistically significant. While a reduction in asthma symptoms with benralizumab versus placebo was observed at week 12, Professor Bleecker noted that the difference did not reach statistical significance. Similarly, while greater control and QoL improvements were observed in the benralizumab group, the difference from placebo was not significant. Benralizumab was well tolerated overall in the BISE study, with similar adverse event and serious adverse event frequencies observed between the benralizumab and placebo groups during on-treatment period.
The relevance of the BISE trial data in a real-world clinical setting was questioned
The audience at ERS 2016 noted that while the data from the BISE trial are welcome and promising, it is unlikely that a high-cost and relatively higher-risk agent such as benralizumab will be used in the mild-to-moderate patient population, where conventional therapy offers adequate and cost-effective control of asthma. Professor Bleecker highlighted that the trial was required by the FDA, suggesting that, at least initially, AstraZeneca is highly unlikely to seek approval for benralizumab in mild-to-moderate asthma. This is in line with the latest comments from AstraZeneca’s Tom Keith-Roach, vice president for respiratory, inflammation, and autoimmune, who confirmed that the company will file for approval of benralizumab for the treatment of severe eosinophilic asthma.
Datamonitor Healthcare expects benralizumab to see the greatest uptake of all the marketed and late-phase biologics being developed for the treatment of asthma. As with other biologics in asthma, benralizumab’s overall uptake will be limited to a small subset of patients who are inadequately controlled on available therapies, but its expected high price point will mean high returns.
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