Once seen as a single condition, asthma is now known to be a heterogeneous disease with many distinct phenotypes. Unfortunately, not all these subgroups respond to existing treatments, meaning the search for targeted therapies is gathering pace. Dr Yassine Amrani of the University of Leicester tells Abi Millar how his work into the pathogenesis of asthma could ultimately help change these patients’ lives.
Asthma is on the rise. At present, the condition affects around 300 million people globally, a figure projected to swell to 400 million by 2025. Within the UK alone, around 5.4 million people have been diagnosed, costing the NHS around £1bn a year.
In most cases, the disease is eminently treatable. While it cannot be cured, it can be managed through various well-established drugs – most commonly an inhaled beta2-agonist alongside oral corticosteroids. This enables the majority of patients to lead a relatively normal lifestyle.
Unfortunately, around 5-10% of patients suffer from a more severe variant of the disease, in which their breathing is perpetually compromised. For these patients, the condition is classed as ‘difficult to control’. Among these more seriously afflicted patients, asthma remains a significant cause of morbidity and mortality, as well as impinging heavily on their everyday existence. Around 1,400 people in the UK lose their lives to asthma each year.
The situation is especially troubling for the small group of sufferers who remain resistant to treatment. Because corticosteroids do not benefit these patients, their symptoms are much harder to manage and they require a complex and specialised (not to mention expensive) form of care.
It’s a conundrum that, for many years, foxed the research community – why are these particular patients so unresponsive to anti-inflammatory drugs? Only over the last decade or so have answers begun to emerge, with the heterogeneity of the disease becoming increasingly apparent.
Rather than seeing asthma as a single disorder, albeit with different degrees of severity, we now understand it as a series of distinct but overlapping inflammatory disorders, each with its own blend of genetic and environmental causes. This means severe asthma is not simply a point on a spectrum – it’s an entirely different phenotype.
“The problem is, we’re still using a non-specific definition and a non-specific treatment,” says Dr Yassine Amrani, principal investigator at Leicester Respiratory Biomedical Research Unit. “We have extensive evidence to say that asthma is a syndrome with multiple clinical and inflammatory phenotypes, but the clinical definition of asthma does not take these into account.’
“The other problem is that while the common treatments are cheap and effective, they target inflammation in general rather than one specific pathway, so we don’t know precisely how they work. We treat the symptoms, not the cause.”
An outdated definition
At present, asthma is classed as ‘a chronic inflammatory disease of the airways in which many cells and cellular elements play a role’. This definition, from the Global Initiative for Asthma, goes on to specify that ‘the chronic inflammation is associated with airway hyper-responsiveness that leads to recurrent episodes of wheezing’ and that the associated airflow obstruction is often reversible with treatment.
While generally fit for purpose, this definition is somewhat vague. Various cluster studies, which try to discriminate between the asthma population based on different markers, have isolated a number of subgroups that could benefit from specific forms of treatment rather than being shoehorned into a single model. Naturally, this is particularly critical for patients who are resistant to the usual drugs.
“We think that by discovering the phenotype and being able to discriminate between these patients we’d be able to provide a better treatment because we understand the basic underlying mechanism,” Amrani explains.
Amrani has been studying the pathobiology of asthma for the last 20 years. At his lab in the University of Leicester, he is aiming to better unravel what drives the disease, as well as exploring why it presents so differently in different patients. More recently, his interest has shifted to finding novel therapeutic alternatives that might help the non-responders.
His work has already cast new light on how asthma occurs. While inflammation in the lungs was once seen purely as an immune response, more recent evidence suggests that the lung resident cells may play a supporting role, producing a variety of pro-asthmatic cytokines that drive inflammation. Building on these findings, Amrani was the first in the field to suggest that this inflammation might directly alter the function of smooth muscle in the airways, diminishing the lung function.
“During an asthma attack, the muscle contracts, narrows the airways and prevents the patient from breathing,” he explains. “It’s therefore the main target for a bronchodilator, such as a beta2-agonist. What I’ve been trying to understand is how the muscle plays a role in the disease besides triggering these acute asthma attacks. We found that certain inflammation-causing molecules, by acting on the muscle directly, could change its involvement in the disease and participate in bronchial hyper-responsiveness.”
Bronchial hyper-responsiveness – essentially an increased sensitivity of the airways to any stimulus – is a signature, albeit, underexplored feature of asthma. And while these inflammatory mediators are probably not the only mechanism responsible, it appears they do play a contributory role. As Amrani sees it, this has important implications for treatment-resistant patients.
“Corticosteroids, which are the best anti-inflammatory drugs on the market, may work in part by suppressing inflammation in the muscle, and we have evidence to suggest that that’s not the case in the most severe patients,” he says. “So it’s important to understand why, for these patients, the inflammatory potential of the cells in this lung resident tissue is not inhibited by the drug. This is the main recent interest of my lab.”
His lab has created various systems to model what is happening to these patients. Through taking cell samples, and exposing them to a wide variety of stimuli, the team has been able to identify certain molecules that seem to affect responsiveness to corticosteroids. While further in vivo studies will be necessary to see whether the findings can be validated, Amrani hopes that the molecules may one day provide suitable targets for therapy.
Among asthma researchers in general, the last few years have been typified by a search for better tailored drugs. As a result, the market is becoming far more diversified, with as many as 250 asthma-related products in the pipeline.
“Asthma has changed,” says Amrani. “There was little advance in terms of therapies until we found out that asthma is composed of different phenotypes, and that targeted therapy is the way forward.”
Targeted drug therapy
Monoclonal antibodies are perhaps the most vibrant area of interest. Novartis and Roche / Genentech produce a drug called Xolair, which targets IgE, the antibody involved in allergic responses. In late 2015 this was joined by GSK’s Mepolizumab, which targets the IL-5 receptors and is intended for severly asthmatic patients with an eosinophilic phenotype.
Then there is fevipiprant, the first new asthma pill in 20 years, which is being funded by Novartis and researched by some of Amrani’s colleagues at Leicester. Following a promising phase III trial reported in the Lancet, in which participants saw their sputum eosinophil count reduce to near normal levels, the drug is being heralded as a ‘game changer’.
Dr Samantha Walker, Asthma UK’s director of research and policy, said: “This research shows massive promise and should be treated with cautious optimism.”
While these are clearly exciting times, the field is still littered with failed drugs candidates, largely because so many of the underlying mechanisms remain poorly understood.
“The best asthma treatment would be the right one given to the right patient,” muses Amrani. “While the success of some monoclonal antibodies is undeniable, we can’t generalise because they don’t work for everyone. So the pattern going forward is how we can define ways to find the best responder. We are moving away from this concept of one size fits all.”
In 2007, a landmark study suggested that asthma can be split into two distinct patient groups: TH2-high and TH2-low. Otherwise known as T-helper cells, TH2 cells play a role in the immune system by releasing a cascade of proteins that regulate immune response. Some people with asthma show more TH2 activity than healthy controls, while others show less, and the two groups display divergent responses to treatment. To date, most of the research interest has been directed at the TH2-high group of patients.
“There are at least eight different monoclonal antibodies that have been tested in TH2-high patients, so I think we are getting there in terms of being able to treat that subset,” says Amrani. “The issue is, these drugs work for some patients with that phenotype but not for all, so we need to understand more about the pathogenesis of the disease. The other issue is TH2-low patients, some of whom do not respond to corticosteroids. There is still work to be done for them.”
In essence, while the field is certainly moving forward, we still have a long way to go. Amrani believes researchers need to focus on identifying the right phenotypic biomarkers, which will in turn help distinguish between the various subgroups of asthma and predict response to different therapies.
“The issue will always come back – how do we define the best responding population?” he says. “There are many new and elegant therapies in development, and for some patients, the use of monoclonal antibodies will change their quality of life. But whether you come up with monoclonal antibodies or not, it won’t change the fact that other patients are poor responders. I still believe there’s work to be done in better understanding why that is.”
Given how disabling severe asthma can be – marked by a poor quality of life, lower life expectancy and a surge in intensive care admissions – breakthroughs in this line of work can’t come soon enough.
This article appears in the 2016 vol 2 edition of Practical Patient Care