The failure of AstraZeneca’s biologic drug Fasenra (benralizumab) in chronic obstructive pulmonary disease (COPD) could be due to the antibody’s activity being limited to only those patients with an asthma-COPD overlap.

In May, AstraZeneca announced two Phase III study failures – TERRANOVA and GALATHEA – for Fasenra in COPD.

As the drug is already approved in severe asthmatics, the overlapping patients – having what is known as the asthma-COPD overlap syndrome (ACOS) phenotype – could be further explored, experts said. The drug was approved in November 2017 to treat severe asthmatics with an elevated eosinophil (white blood cell) count greater than or equal to 300cells/microlitre.

Following the results, experts suggested that Fasenra’s efficacy could be limited to those who also had underlying asthma, which could have contributed to the trial failures. However, since multiple factors influence an ACOS phenotype, like smoking history and timing of onset of asthma, the identification of Fasenra responders using this phenotype still remains less than straightforward.

AstraZeneca did not respond to a request for comment but stated in a press release that it will analyse the complete datasets to further understand the results.

Prior to these results, analysts had assigned a 40% chance of success for the studies, and a $1.3bn sales estimate for asthma and COPD. Since then, they have limited their optimism concerning Fasenra’s role in asthma.

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ACOS phenotype likely responsive

While the Phase II trial was not positive, experts and analysts noted positive trends in patients with an elevated eosinophil count of greater than or equal to 200 cells/microlitre coupled with Fasenra’s proven efficacy in severe asthma, which could potentially be amplified in a larger Phase III study.

It could be possible that the trending responses seen in previous Phase II studies were due to the selection of patients who did not have pure COPD, said Imperial College London professor of respiratory cell and molecular biology Ian Adcock. A subgroup analysis of the Phase III studies could reveal responders to be the patients who also have asthma, he added. Other experts agreed, while noting the theory was still speculation with no available data. A systematic review of 19 asthma and COPD studies suggested a pooled ACOS prevalence of 27% in COPD patients in population-based studies.

Experts also pointed to disappointment with GlaxoSmithKline’s similar drug Nucala (mepolizumab), which failed one of its two pivotal COPD studies in September 2017, raising questions on this overall approach of biologics in a general COPD population. The pivotal Nucala studies do not provide any data on patients with ACOS, and the study paper discusses this as a potential limitation in identifying responders.

COPD biomarkers: more data needed

However, it is not enough to classify patients as ACOS while trying to look for a subpopulation of patients that could respond to Fasenra, said University of Manchester professor of clinical pharmacology and respiratory medicine Dr Dave Singh. ACOS can be a broad umbrella term, said Singh and Dr Michael Wechsler, co-director of the Cohen Family Asthma Institute in Denver, Colorado. Both academics noted that any of the factors like the timing of onset of disease (childhood or adult), smoking or eosinophilic disease could be a driver for ACOS and influence responses to biologic therapies.

Furthermore, if the ACOS subset was to be identified as potential responders, it is still difficult for general physicians to identify whether the underlying condition is asthma, emphysema or bronchitis in the clinic, said Wechsler. If a patient has a history of asthma and then gets COPD due to smoking, the exact underlying biology an antibody needs to target for efficacy is still not clear, said Dr Peter Kardos, pulmonologist, Group practice and center, Pulmonology, Allergology and Sleep Medicine, Frankfurt, Germany.

Even the one positive study with Nucala, METREX, had a significant reduction in exacerbations – an episode of disease worsening – only in patients with elevated eosinophils and not in all trial patients, said Dr Antonio Anzueto, professor at UT Health San Antonio’s Department of Pulmonary Diseases and Critical Care Medicine. The full data is required to understand which subgroup benefited from Fasenra and how they can be identified for future treatment, he added.

A selective biomarker to classify COPD patients and better understand who will respond to Fasenra is still missing, said Anzueto and Adcock.  The subgroup of responders may also be defined by those patients in whom the IL-5 pathway is most active in causing symptoms, noted University Health Network Asthma & Airway Centre director Dr Kenneth Chapman in Toronto, Canada.

Impact of eosinophil levels

Unlike its use in severe asthma, Fasenra’s COPD trials did not select patients based on eosinophil counts, but the trial protocol mandated eosinophil count monitoring. Despite having that as an available data source, experts were not overly optimistic about using an elevated eosinophil measure to identify COPD patients. Eosinophils can be the main or only driver for exacerbations in asthma but that is not the case with COPD, said Singh.

The correlation of blood eosinophils to a biologic response remains poor in COPD, agreed Adcock. It is not clear if in COPD, patients with elevated eosinophils tend to also be asthmatic or that an increase in eosinophils leads to asthma, but it appears that a biologic therapy would have no effect on a pure COPD patient, he added. Exacerbations in COPD can be heterogeneous and caused by a number of factors including higher eosinophils, infections or bronchiectasis links, said Anzueto.

Also, the exacerbation rate in COPD patients is already reduced by 30-40% in most patients with bronchodilator use, and the margin to improve on this for biologics is very narrow, said Anzueto.

AstraZeneca’s market cap is £69.2bn ($93bn).

Manasi Vaidya is a reporter for Pharmaceutical Technology parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.