Asthma Phenotypes: Evolution from Clinical to Molecular Approaches

In the era of precision medicine, it is becoming more common to differentiate patients with severe asthma based on their pathophysiology to identify which new biologic treatment is most appropriate. Asthma type is classified based on the inflammatory molecular mechanism and most are familiar with the Type 2 inflammatory pathway versus the non-Type 2 pathway—also, commonly referred to as eosinophilic versus non-eosinophilic. There is an unmet need for treatments for non-Type 2 asthma. But there are several different biological treatments that target the Type 2 pathway and physicians can struggle in deciding which treatment would be best for which patient. Currently, the four biological therapies with specific targets in the Type 2 pathway, which are approved by the FDA for use in severe asthma are:

• Omalizumab (targets IgE);
• Mepolizumab and reslizumab (targets IL-5); and
• Dupilumab (targets IL-4/IL-13; recently approved in October 2018, so most guidelines are not yet updated to reflect this approval).

One informative treatment approach is to understand the phenotype through measuring and grouping the biomarkers that contribute. Biomarkers indicate the extent of disease present in an individual. For Type 2 asthma there are six proposed biomarkers: blood eosinophils, FeNO, Total IgE, Specific IgE, Periostin, and DPPT4. Evidence from several studies supports overlapping biomarkers that help inform the particular phenotype of asthma that the patient has, but there are still not enough data to completely understand the ratios/profile of each biomarker to distinguish the molecular pathway to be targeted.

In order to begin to tease apart which level of which biomarker represents a certain population of patients with severe asthma, Stephen Peters, MD, PhD, the Thomas H. Davis Chair in Pulmonary Medicine at Wake Forest School of Medicine, and colleagues conducted a the Precision Medicine in Severe Asthma (PrecISE) trial, a multi-center phase 2 trial with an adaptive design. The primary objectives of the trial are:

• identify novel therapies that work in biomarker-defined subgroups or severe asthmatic patients, and
• optimize the subgroups targeted for treatment by refining the biomarkers and subgroup definitions.

The premise of the trial is that each of the biological treatments has a role in severe asthma therapy. In order to determine the patients in whom each treatment is most efficacious, an understanding of the asthma phenotype/biomarker subgroup is required. Although a head-to-head trial comparing the efficacy of the biological treatments has been requested among asthma researchers, Dr. Peters urged his colleagues to reconsider , as “that type of trial would be dependent on the patient population that is enrolled in the study,” he said, suggesting instead to “focus on identifying patient characteristics that give an individual patient the best chance to respond to the best biologic for him/her.”

As severe asthma treatment in practice is based on the type of asthma the patient has, treatments tend to be personalized.  Physicians are already checking on how inflammation is mediated in patients, but this approach may not be enough. “N of 1” clinical trials could be a strategy to further individualize asthma treatment through genome sequencing and collecting individual data points in a database. The goal is to ultimately create a network of information about different groups of patients that follow similar responses to the same treatment. This builds upon defining the subgroups of asthma patients defined by specific molecular biomarkers by using phenotypes and N of 1 trials to further personalize asthma treatment.

“We are moving towards more personalized and precise medicine,” Peters concluded.