Peter Howarth (pictured above), Global Clinical Scientific Lead for Biologics at GSK looks at the emerging science behind eosinophils and how it is helping to guide the company’s research and development programme.
All of us have eosinophils in our blood – a type of white blood cell that forms part of the immune system. Historically, research has focused on how the overproduction of eosinophils may be involved in the development of disease.
Having too many eosinophils in certain tissues is an important contributor to a range of conditions including severe eosinophilic asthma (SEA), nasal polyps, eosinophilic oesophagitis and rarer, systemic diseases such as eosinophilic granulomatosis with polyangiitis (EGPA) and hypereosinophilic syndrome (HES).
However, recent evidence suggests that not all functions of eosinophils are detrimental and that, as Howarth put it, “like many things in life, there is a balance”. He explains: “Eosinophils are also present in healthy individuals, indicating that they are probably also important in maintaining health. Emerging science suggests that eosinophils have multifunctional roles that can be both helpful and harmful, and this is what we want to understand better.
“Much of this evidence has so far come from animal studies, which have identified that eosinophils help protect the body against bacterial, viral and parasitic infection, help maintain body weight, potentially help prevent ageing, play a role in tissue repair and have responsibilities in immune regulation. Some of these findings are now also being proven in humans and it may be that there are distinct eosinophil sub-types: those involved with disease and those important to health. Understanding this heterogeneity and how such information can be used for patient benefit is essential.”
While our full understanding of eosinophils is still evolving, Howarth is well-placed to speak on this topic having been involved in researching eosinophils for almost 40 years, since the 1980s when starting his research career in Southampton, UK before going on to be Professor of Allergy and Respiratory Medicine at Southampton University.
Working as a clinician at this time meant he was caring for patients with allergies and asthma, in particular severe asthma. It was in this role that he became involved in the first large clinical trial to specifically investigate whether reducing eosinophilic inflammation by targeting anti-Interleukin 5 (IL-5) with anti-IL5 biologic treatments would help patients with severe asthma. IL-5 is a protein that drives eosinophil production. Participation in two further similar clinical trials soon led to him starting to work more closely with GSK, eventually taking on his current position at the company.
Investing to improve patient outcomes
“In some ways eosinophils are simple, and in some ways they are very difficult.” Howarth explained that while it is now very easy and inexpensive for hospitals to measure eosinophil count as part of standard blood tests, what is proving more challenging is translating the existing animal studies to help characterise the different eosinophil populations in humans and, as a result, better understand their biology.
This is why GSK is building on its heritage in this area and taking a lead in advancing eosinophil science, collaborating with the scientific community to invest in new research initiatives and enhance understanding. “There are now technologies that are helping move this research forward and GSK is supporting a number of independent researchers who are trying to address these questions as part of a research grant scheme called the Supported Studies programme.”
Howarth said they are supporting more than 60 studies across 24 countries to progress eosinophil science. “We are hoping this will give us a lot more insight into eosinophil biology. Understanding eosinophil biology will help us better direct treatments for patients and target the detrimental inflammatory eosinophils while maintaining the beneficial, or resident, eosinophil populations.”
Investigating different patient populations
The company’s commitment to the research of eosinophils led them to question whether they could also help patients with other conditions that are impacted by eosinophils. “After seeing positive results for patients with SEA, the natural thought process was, could this approach help people with other diseases associated with an abnormal level of eosinophils?”
Results from a comprehensive phase 3 clinical trial programme so far indicate that it could. Howarth explained that, although systemic eosinophil diseases are rare, GSK believes these patient populations need more options. In EGPA for example, he noted that “with current standard treatment, over a five-year period 10-15% of patients still die from EGPA and treatment can carry long-term adverse effects, so there is a big unmet need in this area”.
Another rare systemic condition that GSK is investigating is HES, a disease of unknown aetiology where patients have very high levels of eosinophils infiltrating organs such as the heart, gut, lungs, nerves and the skin. This can lead to organ damage and can be life-threatening.
GSK has also recently completed a large clinical study of patients with chronic rhinosinusitis with nasal polyps who have had surgery but whose nasal polyps have returned and are severe enough to warrant further surgery. This study was the first to investigate an anti-IL-5 therapy in patients with nasal polyps and the data was presented for the first time at the European Respiratory Society (ERS) International Congress earlier this month.
Interestingly, Howarth explained that a proportion of patients with COPD also have eosinophilic inflammation. GSK is now conducting a further phase 3 study in this area and while Howarth notes they have no results as yet, and it will be a while before they do, this is a good example of their ‘follow the science’ approach to R&D, looking at where a particular mechanism of action could have potential across multiple diseases, to help the greatest number of patients.
Impacting clinical practice
In line with its R&D focus on the immune system, GSK believes that investment in this area is key, with the end goal of improving treatment options, supporting decision-making in clinical practice and ultimately achieving better outcomes for patients. Progress has already been made, with GSK’s research helping to advance diagnostic tests used to select targeted treatments. In the past, doctors would hunt for eosinophils in patients’ sputum under a microscope.
One of the early GSK studies showed that blood eosinophil count was a better biomarker of who would respond to treatment targeting eosinophils. “Sputum provides a sample of the central airways which only makes up 10% of the airways, but asthma affects the whole of the airways. We discovered that blood eosinophil level is a more effective biomarker in determining treatment.”
This discovery changed the way patients were tested for eosinophils, providing a low-cost, simple and accurate way to assess eosinophil levels in patients, in turn leading to better informed treatment decisions. The eosinophils test is now well-established as the most predictive biomarker for response to anti-IL5 biologic therapy, making it a key part of managing patients with the eosinophilic type of severe asthma.
Questions remaining
Howarth said further research is needed in order to fully understand the heterogeneity of eosinophils in humans and confirm whether there is a beneficial population as well as detrimental population. “We would then like to take that forward to understand how eosinophils maintain health, what the biomarkers are for those, and whether we can measure them in clinical practice and assess how different treatments affect them.”
Howarth believes that GSK is in a prime position to lead in this area,. “GSK has an extraordinary heritage in respiratory research to try to benefit patients with respiratory conditions, helping millions of patients worldwide. GSK has the patients’ interests at its focus, looking for the unmet need. Really the focus on eosinophil research is related to that and it’s a very exciting and pivotal time in eosinophil research at the moment.”