Key biological pathways in respiratory disease: eosinophilic disease

WRITTEN BY

Gary Anderson, Chief Scientist, Respiratory, Inflammation and Autoimmune Innovative Medicines, AstraZeneca

AstraZeneca has developed a new strategic framework for respiratory research and development, organised around four central ‘biological pathways’. Learn more about how the company’s respiratory business is pursuing the next generation of therapies by exploring common features of asthma, chronic obstructive pulmonary disease and other respiratory and autoimmune diseases.

Our goal of forging new paradigms for the treatment, and eventual cure, of respiratory disease requires a unique blend of innovation and pragmatism.

The unmet needs in the field are many and complex. The next generation of therapies must leverage the full array of genomic, molecular and biological insights emerging from leading-edge respiratory science.

Long-term ambitions such as regenerating lung tissue must be tempered by R&D capable of translating radical concepts into more immediate therapeutic advances to enhance disease management and quality of life.

AstraZeneca has reconciled these goals, and established a unifying principle to accommodate the acute heterogeneity of respiratory diseases, with an elegant new scientific framework that maps out four central ‘biological pathways’ to chronic obstructive and autoimmune conditions.

In a recent position paper, Alvar Agusti et al outlined the concept of ‘biological pathways’, identifying distinct clinical and biochemical features that span chronic airway diseases and form a platform for targeted therapy1. They called for a fresh approach to managing asthma and chronic obstructive pulmonary disease (COPD), one that moved away from categorising patients in broad disease terms, such as ‘severity’ or response to background therapy.

Instead, the authors proposed identifying biological pathways in each patient which would recognise asthma and COPD as a continuum of different diseases. These may share the same underlying biological driver of disease, or ‘endotype’, as well as similar observable features, or ‘phenotypes’, amenable to individualised treatment.

The fact that the pathways are treatable reconciles truly disruptive science with practical and translatable applications of that science. It looks for common features in respiratory disease whose inhibition or modification may be linked relatively easily to clinical benefit.

Four biological pathways

AstraZeneca has selected four key biological pathways that align with its overarching strategy of applying targeted therapy, initially to enhanced management of symptoms and exacerbations in respiratory disease, and in the longer term widening the focus to prevention of disease onset and progression, as well as disease reversal.

Corresponding mainly to late-stage assets in AstraZeneca’s respiratory and autoimmunity pipeline, these predominant pathways are:

  • Eosinophilic disease
  • T2-driven disease
  • Epithelial-driven pathology
  • Autoimmunity

These are areas in which AstraZeneca is carving out scientific leadership in targeted medicine. Much has already been achieved in the respiratory disease area through highly effective molecules incorporated in sophisticated delivery vehicles.

Nonetheless, an urgent need remains to raise the bar with earlier intervention and targeted therapies that address the molecular underpinnings of disease.

That may involve a monoclonal antibody, an antisense oligonucleotide or a combination of large and small molecules. It may be delivered via injection or through advanced inhaler technology, for short-term relief or for long-term disease modification.

The organising principle, though, is to understand the fundamental drivers of asthma and COPD in subsets of patients and elucidate the associated disease pathways. This would enable application of an optimal set of mechanism-driven therapeutic strategies for each biological pathway and the various manifestations of disease arising from it.

Disruptive science

AstraZeneca has not abandoned the strategy it historically pursued in respiratory R&D, using its inhalation technologies and clinical-development efficiencies to competitive advantage in areas that were mature or substantially de-risked.

At the same time, though, it wants to pursue disruptive science that results in genuinely transformative medicines with significantly improved patient benefits.

Articulating biological pathways will also enable the company to define more effectively the terms and measurable endpoints for respiratory diseases in clinical trials, easing the traditionally rocky transition from Phase I to Phase II studies, where too many molecules fail to deliver on target.

Eosinophilic traits

An example of driving disruptive change in an already well-defined research area is the first of AstraZeneca’s biological pathways, eosinophilic disease.

Some 20-30% of patients with COPD2 and around 40-60% of severe asthmatics have eosinophilic airway inflammation3, as defined by elevated levels of eosinophils in the blood.

Eosinophils were first identified as a potential driver of respiratory disease in the 1880s and eosinophilic inflammation is now among the most widely recognised and consistent asthma phenotypes.

Clinical benefits

Evidence from the scientific literature on registered and investigational medicines targeting this pathway suggests that inhibiting or directly depleting eosinophils yields important clinical benefits, such as better asthma control, substantial reduction of exacerbations and improved lung function, particularly in patients with moderate-to-severe disease who are not controlled on available therapies4.

Following mixed results in early clinical trials of monoclonal antibodies targeting the eosinophilic pathway during the mid- to late-1990s, attention shifted to patient stratification using eosinophils as a biomarker to predict clinical response to therapy5.

By characterising and exploring biological pathways to illuminate specific triggers of disease activity, researchers can address these with highly targeted medicines that will define a whole new era of patient management in the respiratory field.

This is the first in a series of blogs exploring the scientific rationale behind AstraZeneca’s biological pathway framework for respiratory disease.

References

  1. Agusti A, Bel E, Thomas M et al. Treatable traits: toward precision medicine of chronic airway diseases. European Respiratory Journal. 201.47(2):410-9
  2. Varricchi G, Bagnasco D, Borriello F et al. Interleukin-5 pathway inhibition in the treatment of eosinophilic respiratory disorders: evidence and unmet needs. Current Opinion in Allergy & Clinical Immunology. 2016: 16(): 186-200
  3. Zhang JY, Wenzel SE. Tissue and BAL based biomarkers in asthma. Immunol Allergy Clin North Am. 2007; 27: 623–632.
  4. Mukherjee M, Sehmi, R, Nair P. Anti-IL5 therapy for asthma and beyond. World Allergy Organization Journal. 2014; 7:32. DOI: 10.1186/1939-4551-7-32.
  5. Bartminski G, Crossley M, Turcanu V. Novel biomarkers for asthma stratification and personalized therapy. Expert Rev Mol Diagn. 2015 Mar;15(3):415-30. doi: 10.1586/14737159.2015.988613. Epub 2014 Dec 5.

Atlas ID: 976448.011 
Date of next review: May 2017