New analysis of Fasenra Phase III GALATHEA and TERRANOVA COPD trials identifies factors associated with exacerbation rate reductions

Data presented at the ERS International Congress 2019 and published in The Lancet Respiratory Medicine

Additionally, first patients enroled in Fasenra Phase III RESOLUTE trial in COPD

AstraZeneca today announced results from a pre-specified secondary analysis of the Phase III GALATHEA and TERRANOVA trials for Fasenra (benralizumab) in moderate to very severe chronic obstructive pulmonary disease (COPD).

As previously reported in 2018, the Phase III GALATHEA and TERRANOVA trials did not meet their primary efficacy endpoints.

The new data, presented today at the European Respiratory Society (ERS) International Congress 2019 in Madrid, Spain and published in The Lancet Respiratory Medicine, identified baseline clinical characteristics associated with reduced annual rates of moderate and severe COPD exacerbations with Fasenra, supporting further clinical study.

For patients with baseline blood eosinophil counts of 220 cells per microlitre or greater, the baseline clinical characteristics that were the strongest predictors of annual exacerbation rate reduction with Fasenra 100mg every eight weeks compared with placebo were:

•       a history of frequent (three of more) exacerbations in the previous 12 months¹

•       low baseline lung function (Forced Expiratory Volume in 1 second (FEV1) less than 40% predicted)¹

•       improvement in lung function (15% or more) following short-acting bronchodilators.¹

The greatest treatment effect with Fasenra 100mg compared with placebo was seen in the subpopulation of patients who had baseline blood eosinophil counts of 220 cells per microlitre or greater, were receiving triple inhaled therapy (ICS/LAMA/LABA) and had experienced three or more exacerbations during the previous 12 months. These patients, who represented approximately 20% of the original trial primary analysis population, achieved a 30% reduction in the rate of moderate and severe exacerbations compared with placebo (rate ratio versus placebo [95% CI]: 0.70 [0.56, 0.88]), based on a pooled data analysis.¹

AstraZeneca today also announced that the first patients have been enroled in the Phase III RESOLUTE trial that will investigate the efficacy and safety of Fasenra 100mg in patients with moderate to very severe COPD who are treated with triple inhaled therapy, have a history of frequent exacerbations and elevated peripheral blood eosinophils. The trial will enrol an estimated 900 patients and is expected to complete in the second half of 2023.²       

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, said: “COPD is a complex, debilitating disease that affects more than 380 million people worldwide. New analyses from the Phase III GALATHEA and TERRANOVA trials suggest that elevated blood eosinophil counts combined with certain clinical characteristics could help identify a subpopulation of patients with COPD who could benefit from Fasenra. Building on these results, we have initiated RESOLUTE, a new Phase III trial to further investigate Fasenra’s potential in COPD.”

Dr. Gerard J. Criner, Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine, Temple University and principal investigator, said: “COPD exacerbations are devastating events for patients and can lead to permanent loss of lung function, hospitalisation and death. Treatment options for patients who continue to experience exacerbations despite receiving maximal maintenance therapy are very limited. These important findings support further investigation of Fasenra 100 mg for patients with elevated blood eosinophil counts who continue to have frequent exacerbations despite being on triple inhaled therapy.”

The safety and tolerability findings in these trials were consistent with the known profile of Fasenra.

About COPD

COPD is a progressive disease which can cause obstruction of airflow in the lungs resulting in debilitating bouts of breathlessness.³ It affects an estimated 384 million people worldwide and is predicted to be the third leading cause of death by 2020.³ Improving lung function, reducing exacerbations and managing daily symptoms such as breathlessness are important treatment goals in the management of COPD.³

An estimated 40% of moderate to severe COPD patients on triple inhaled therapy - inhaled corticosteroid (ICS)/long-acting muscarinic antagonist (LAMA)/long-acting beta2-agonist (LABA) remain uncontrolled and continue to experience exacerbations.⁴ COPD exacerbations significantly impair quality of life and are linked to disease progression, accelerated decline in lung function, and increased hospitalisations and mortality.^5,6,7

Elevated blood eosinophil counts for patients with COPD are associated with increased exacerbation risk and increased responsiveness to inhaled corticosteroid treatment.¹

About GALATHEA and TERRANOVA

GALATHEA and TERRANOVA were randomised, double-blinded, placebo-controlled, parallel-group trials that assessed the safety and efficacy of Fasenra 30mg and 100mg for preventing COPD exacerbations in patients with blood eosinophil counts 220 cells per microlitre or greater and a history of moderate to very severe COPD exacerbations, who were receiving treatment with dual or triple inhaled maintenance therapies. The overall trial populations in GALATHEA and TERRANOVA comprised 1,656 and 2,254 patients, respectively. The trials did not meet their primary endpoints of annual exacerbation rate in moderate to very severe COPD.⁸

Pre-specified analyses (both individual and pooled GALATHEA and TERRANOVA trial data) were conducted to identify baseline factors associated with reduced annual COPD exacerbation rates during Fasenra treatment compared with placebo.

In both trials, Fasenra 100mg every eight weeks (Q8W; first three doses every four weeks) reduced the annual rate of severe exacerbations (leading to hospitalisation) by more than 30% compared with placebo, a clinically relevant outcome in this severe COPD patient population. In the original analysis, patients with baseline blood eosinophil counts of at least 220 cells per microlitre, and with at least three prior exacerbations in the 12 months prior to enrolment, demonstrated a 39% and 23% reduction in moderate to severe exacerbations in GALATHEA and TERRANOVA, respectively, with the 100mg dose of Fasenra compared to placebo.  Patients with baseline blood eosinophil counts of at least 220 cells per microlitre and on triple inhaled therapy showed an 18% and 17% reduction in moderate to severe exacerbations in GALATHEA and TERRANOVA, respectively, with Fasenra 100mg compared to placebo.^8,9,10

About RESOLUTE

RESOLUTE is a multicentre, randomised, double-blind, chronic-dosing, parallel-group, placebo-controlled Phase III trial to evaluate the efficacy and safety of Fasenra 100mg administrated subcutaneously (SC) every four weeks for the first three doses, then every eight weeks in patients with moderate to severe COPD with a history of frequent exacerbations and elevated blood eosinophils.²

Eligible patients must have a history of ≥2 moderate and/or severe COPD exacerbations in the previous year despite receiving triple inhaled therapy as well as a baseline blood eosinophil count of at least 300 cells per microlitre.

About Fasenra

Fasenra (benralizumab) is a monoclonal antibody that binds directly to the IL-5 receptor alpha on eosinophils and attracts natural killer cells to induce rapid and near-complete depletion of eosinophils via apoptosis (programmed cell death).^11,12

Fasenra is AstraZeneca’s first respiratory biologic, now approved as an add-on maintenance treatment in severe eosinophilic asthma in the US, EU, Japan and other countries, with further regulatory reviews ongoing. Fasenra is also in development for severe nasal polyposis, other eosinophilic diseases, and chronic obstructive pulmonary disease. The FDA granted Orphan Drug Designation for Fasenra for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA) in November 2018, hypereosinophilic syndrome (HES) in February 2019 and eosinophilic oesophagitis (EoE) in August 2019.

Fasenra was developed by AstraZeneca and is in-licensed from BioWa, Inc., a wholly owned subsidiary of Kyowa Kirin Co., Ltd., Japan.

About AstraZeneca in respiratory diseases

Respiratory is one of AstraZeneca’s three therapy areas, and our medicines reached more than 18 million patients as maintenance therapy in 2018. AstraZeneca’s aim is to transform asthma and COPD treatment through inhaled combinations at the core of care, biologics for the unmet needs of specific patient populations, and scientific advancements in disease modification.

The Company is building on a 40-year heritage in respiratory disease and AstraZeneca’s capability in inhalation technology spans pressurised metered-dose inhalers and dry powder inhalers, as well as the Aerosphere delivery technology. The company also has a growing portfolio of respiratory biologics including Fasenra (anti-eosinophil, anti‒IL-5 receptor alpha), and tezepelumab (anti-TSLP) which has been granted Breakthrough Therapy Designation by the US Food and Drug Administration in patients with severe asthma and is in Phase III trials. AstraZeneca’s research aims at addressing underlying disease drivers by focusing on the lung epithelium, lung immunity, lung regeneration and neuronal functions.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of diseases in three therapy areas - Oncology, Cardiovascular, Renal & Metabolism (CVRM), and Respiratory. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Visit astrazeneca.com and follow us on Twitter @AstraZeneca.

CONTACTS

References

^{1.     Criner GJ, Celli BR, Singh D, Agusti A, Papi A, Jison M, Makulova N, Shih VH, Brooks L, Barker P, Martin UJ, Newbold P. Predicting response to benralizumab in chronic obstructive pulmonary disease: analyses of GALATHEA and TERRANOVA studies. Lancet Respir Med. 2019;DOI:10.1016/ S2213-2600(19)30338-8.}

^{2.     U.S. National Institutes of Health. ”Efficacy and Safety of Benralizumab in Moderate to Very Severe Chronic Obstructive Pulmonary Disease (COPD) With a History of Frequent Exacerbations (RESOLUTE)” NCT04053634. 2019. Last Accessed September 2019.}

^{3.     GOLD. Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2018. [Online]. Available at: http://goldcopd.org. Last accessed May 2018.}

^{4.     Mullerova H, Maskell J, Meeraus WH, Galkin D, Albers FC, Gait C. Characterization of COPD patients treated with inhaled triple therapy containing inhaled corticosteroids [ICS], long-acting beta2- agonists [LABA], and long-acting muscarinic antagonists [LAMA] in the UK. Am J Respir Crit Care Med 2017; 195: A4986. abstract.}

^{5.     Hurst JR, Vestbo J, Anzueto A, et al. Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010 Sep 16;363(12):1128-38.}

^{6.     Lange P, Halpin DM, O'Donnell DE, MacNee W. Diagnosis, assessment, and phenotyping of COPD: beyond FEV₁. Int J Chron Obstruct Pulmon Dis. 2016 Feb 19;11 Spec Iss:3-12.}

^{7.     Soler-Cataluna JJ et al. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax. 2005 Nov; 60: 925-31.}

^{8.     Criner GJ, Celli BR, Brightling A, Papi A, Singh D, Sin DD, Vogelmeier CF, Sciurba FC, Bafadhel M, Backer V, Kato M, Ramierz-Venegas A, Wei YF, Bjermer L, Shih VH, Jison M, O’Quinn S, Makulova N, Newbold P, Goldman M. Benralizumab for the Prevention of COPD Exacerbations. N Engl J Med. 2019 May 20; 381(11): 1023-1034}

^{9.     Criner GJ, Celli BR, Brightling CE, et al. Bernalizumab for Chronic Obstructive Pulmonary Disease: Results of the Phase III GALATHEA Trial. Presented at the American Thoracic Society (ATS) International Conference, 17-22 May 2019, Dallas, Texas.}

^{10.  Celli BR, Criner GJ, Singh D, et al. A Dose-Ranging Study (TERRANOVA) of Benralizumab for Moderate to Severe Chronic Obstructive Pulmonary Disease. Presented at the American Thoracic Society (ATS) International Conference, 17-22 May 2019, Dallas, Texas.}

^{11.  Kolbeck R, Kozhich A, Koike M, et al. MEDI-563, a humanized anti–IL-5 receptor a mAb with enhanced antibody-dependent cell-mediated cytotoxicity function. J Allergy Clin Immunol. 2010 Jun;125(6):1344-1353.e2.}

^{12.  Pham TH, Damera G, Newbold P, Ranade K. Reductions in eosinophil biomarkers by benralizumab in patients with asthma. Respir Med. 2016; 111:21-29.}