Discovery of Asthma Subtypes Suggests New Therapies

by Miltiades Markatos / Pneumonologist – A new understanding of different subsets of patients with severe allergic asthma may pave the way to developing biologic therapies that effectively target the specific inflammatory responses a particular patient exhibits, a new study suggests.

David F. Choy, from Genentech Inc, South San Francisco, California, and colleagues recently published the results of the translational and preclinical work in Science Translational Medicine.

Although the vast majority of patients with asthma can manage their condition with inhaled therapies, including inhaled steroids, the approximately 10% of patients who are resistant to inhaled steroid treatment consume the greatest healthcare resources, said study coauthor Joseph R. Arron, MD, PhD, director of Immunology Discovery in Research and Early Development at Genentech.

“These are the patients that turn up in [the] emergency room with really bad asthma attacks and have the most morbidity from their disease”, Dr. Arron told. “This is the target population for these new biologic therapies.” The new therapies will cost more, but treat the patients already requiring the most care.

The only current biologic therapy approved for asthma is omalizumab (Xolair, Genentech/Novartis), a humanized antibody to immunoglobulin E, but Genentech and other companies have been working to develop a second generation of biologics for asthma that target specific inflammatory pathways.

“Nobody has gotten any of these approved yet, but we’ve all reported clinical trials where a subset of patients benefits from a drug and a subset of patients doesn’t benefit from the drug”, Dr Arron said. “It’s in these patients that we’re really trying to understand what’s going on.”

The new data provide clues to what is going on and may point the way toward more effective biologic therapies. Two adaptive immune responses that target extracellular pathogens include T helper 2 cells (Th2) and T helper 17 cells (Th17). Th2 cells target parasites and involve cytokines interleukin 5 (IL-5) and IL-13, whereas Th17 cells target simple pathogens, such as bacteria and fungi, and involve IL-17.

“An aberrant Th2 response has for many years thought to underlie asthma and allergic disease,” Dr Arron said. Patients with asthma show an inappropriate Th2 immune response to environmental stimuli such as cat dander or dust mites. But research published about 6 years ago, Dr Arron said, revealed that only about half of patients with severe asthma show Th2 inflammation, which explains the limited success of several unapproved Th2-targeting biologics still in clinical trials. The drug furthest along, with positive phase 3 results, is mepolizumab, which targets IL-5. Another drug, reslizumab, also targets IL-5, and three others (lebrikizumab, tralokinumab, and dupilumab) all block IL-13.

By analyzing biopsied lung samples from 51 patients with asthma, researchers in the current study discovered three distinct groups of patients: those with a Th2 inflammatory response in their airways, those with a Th17 inflammatory response, and those with neither. No patients had both Th2 and Th17 inflammatory responses simultaneously.

“All of the patients with an IL-17 signature had previously been exposed to steroids, suggesting that steroids might have a contributory role in promoting a TH17 signature in these subjects, either directly or through inhibition of the Th2 pathway,” writes Anthony K. Shum, MD, an assistant professor of medicine at the University of California San Francisco, in an accompanying commentary.

“We thought maybe it’s kind of like whack-a-mole,” Dr Arron said. “If you knock down the Th2 response, the Th17 pops up, and if you knock down Th17 with something else, then the Th2 will pop back up. It may be oscillating between those two states.”

And that is exactly what a subsequent experiment in a mouse model showed: inhibiting the Th2 response increased the Th17 response, and vice versa.

“When we inhibited both, that really suppressed the inflammation in the mice to a greater extent than either at one time,” Dr Arron said. The next step is to find out whether inhibiting both pathways might treat the subset of patients who do not respond to the Th2 inhibiting drugs in development. Previous research has already established the use of blood eosinophils or levels of the protein periostin as biomarkers to identify increased Th2 inflammation in the airways, so biopsies would not be necessary to identify the patients who could benefit from these therapies.

“These Th2 cytokine inhibitors, such as anti-IL-5 and anti-IL-13 drugs, seem to provide significant clinical benefit for a lot of patients with severe asthma,” Dr Arron said. But in those patients who do not benefit, it may be that IL-17-caused inflammation is driving their severe asthma, on its own or due to suppression of the Th2 cytokines. “It will be interesting in the future to determine whether perhaps if we block both of these cytokines at the same time, we might have even greater efficacy in patients with severe asthma.”

The research was funded by the National Institutes of Health, Asthma UK, the UK’s National Institute for Health Research, and Genentech Inc, which is developing several biologic therapies for asthma.

Nine authors are currently or previously were Genentech Inc employees, and two other authors received funding from Genentech for this research. The other authors and Dr Shum have disclosed no relevant financial relationships.

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