It has become clear in recent years that rather than being a homogeneous disease, asthma comprises a heterogeneous mix of conditions that manifest themselves with similar clinical features - chronic airway inflammation, reversible airflow obstruction, and a variety of respiratory symptoms (e.g., wheezing, shortness of breath, chest tightness). As such, it is now generally acknowledged that several underlying pathophysiological processes can lead to asthma, and several phenotypes and endotypes of asthma have been characterized and continue to be studied and further refined.1

Despite the progress made in understanding the pathophysiology, the majority of asthma patients are still treated with a one-size-fits-all approach, which typically includes some combination of an inhaled corticosteroid (ICS), a long-acting β2 agonist (LABA), and a leukotriene inhibitor prescribed as a maintenance treatment, as well as a short-acting bronchodilator - typically a short-acting β2 agonist - used as a rescue agent during acute episodes. Only when the disease becomes more severe and difficult to control with a high-dose LABA/ICS combination, is a more-personalized approach to treatment employed. Fortunately, the standard LABA/ICS combination treatments work well for most persistent asthma patients and only a small percentage of asthmatics require additional maintenance therapies (e.g., biologics) to manage their disease. However, given the high diagnosed prevalence of asthma in the United States and Europe, this small percentage of treatment-refractory asthmatics translates into a relatively large number of patients suffering from frequent, severe asthma exacerbations, which are challenging for physicians to control.

Driven by this unmet need, four new treatments targeting patients with difficult-to-control asthma have been approved since 2015; these include the biologic IL-5 inhibitors, mepolizumab (GSK’s Nucala), reslizumab (Teva’s Cinqair/Cinqaero), and benralizumab (AstraZeneca’s Fasenra), as well as the long-acting muscarinic receptor antagonist (LAMA) tiotropium (Boehringer Ingelheim’s Spiriva). These agents, together with oral corticosteroids (OCSs) and the veteran anti-IgE biologic omalizumab (Roche/Novartis’ Xolair), now constitute the basis of severe, refractory asthma treatment. All approved asthma biologics target Th2-mediated (Th2-high) asthma, a subtype of the disease that is characterized by an underlying Th2 cell-mediated (Type 2) inflammatory response in the lung’s airways. This subtype of asthma is typically associated with elevated levels of blood and/or sputum eosinophils, activation of Th2 cytokines (e.g., IL-5, IL-4, IL-13), and increase in IgE production. Thus, the availability of biological therapies targeting Th2-mediated inflammation provides treatment options to Th2-high patients who are refractory to OCSs and also offers corticosteroid-sparing alternatives for patients who would otherwise require frequent or prolonged administration of OCSs to achieve disease control. In addition to the biologics mentioned above, a further therapy, Sanofi/Regeneron’s IL-4/IL-13 antagonist dupilumab (marketed as Dupixent for Atopic Dermatitis), is expected to receive approval and launch for asthma in the near future. In common with other asthma biologics, dupilumab offers mechanisms of action targeting Th2-mediated inflammation. According to a  Regeneron/Sanofi press release2, dupilumab demonstrated efficacy in the overall patient population recruited into its Phase III trial (those with low and high Th2 status), however, based on available data, patient response appears to clearly correlate to Th2 status (i.e., the higher the eosinophil count, the more likely a patient is to respond). Therefore, despite the string of recent and upcoming approvals for severe, refractory asthma, all current and late-stage emerging asthma biologics target partially overlapping subpopulations of severe, refractory patients with Th2-mediated asthma, and none of these agents seem to be able to clearly address the needs of patients whose asthma is not primarily mediated by the Th2 pathway (i.e., Th2-low or non-Th2 asthma patients), keeping the level of unmet need in severe, refractory asthma high.3

 

“Right now, there is a lot of redundancy with the biologics, but we still need something for what I call a ‘fat neutrophilic patient,’ those who have a different type of inflammation. They don’t have eosinophils, so mepolizumab is going to be useless for them. They typically do not respond to steroids, but they definitely have an inflammation component and they are not doing well currently because they are treated with the same drugs as eosinophilic asthma, and they don’t respond very well to them."

—Pulmonologist, United States

 

Th2-low asthma is also a heterogeneous group, with several phenotypes identified; including late-onset asthma, asthma driven by obesity, pollutants, smoking, and viral or bacterial infections. The underlying causes of Th2-low asthma could be attributed to several cellular signaling pathways, including oxidative stress, neutrophilic inflammation caused by dysregulation of the Th17 pathway, Th1-related processes, and may include a Th2 component as well. The progress in understanding and targeting the Th2-low phenotypes of asthma lags behind that for Th2-high disease, and the lack of effective maintenance agents for Th2-low asthma constitutes a distinct clinical problem. Attempts have been made in the past to develop therapies targeting signaling pathways involved in the pathogenesis of Th2-low asthma, but to-date, all have proven unsuccessful. For example, the TNF-alpha pathway was previously implicated in several aspects of the airway pathology in asthma and thus, TNF-alpha inhibitors, etanercept (Amgen/Pfizer’s Enbrel) and golimumab (Janssen/Merck’s Simponi), were both tested in patients with severe, refractory asthma. However, no significant efficacy was established in these trials, and in the case of golimumab, Janssen abandoned their plans for the agent in asthma due to an unfavorable risk/benefit profile. Interestingly, in a post-hoc analysis of the golimumab trial, efficacy was established in patients with late-onset asthma; therefore, it is possible that a subset of Th2-low asthmatics (i.e., those whose asthma has an underlying TNF-alpha component) could have potentially benefited from the TNF-alpha blockade, but no further trials of TNF-alpha inhibitors in asthma are currently planned. Another attempt at targeting Th2-low disease focused on inhibiting neutrophilic inflammation, as this type of inflammation can be detected in many corticosteroid-refractory patients with asthma (in fact, one hypothesis proposes that the use of high doses of corticosteroids could actually worsen the neutrophilic asthma phenotype). Driven by this theory, two IL-17 inhibitors, brodalumab (Valeant’s Siliq/Leo Pharma’s Kyntheum) and secukinumab (Novartis’ Cosentyx) were investigated in trials with refractory asthma patients. Although both agents were unable to produce a desirable treatment effect in these studies, an efficacy signal was seen in a subgroup of patients in the brodalumab trial (those defined with high reversibility of FEV1 in response to albuterol). Given the signals towards efficacy in sub-groups of investigated Th2-low patients, it is plausible that the failures of anti-TNF-alpha and anti-IL-17 agents were not due to the lack of relevancy to asthma pathogenesis, but rather because the Th2-low population is highly heterogeneous and proper biomarkers need to be identified and used to recruit patients into these trials, in order to enrich the study population with the most-likely responders.

The  most encouraging progress in targeting Th2-low asthma was made recently by Amgen/AstraZeneca, when their thymic stromal lymphopoietin (TSLP) inhibitor tezepelumab showed robust efficacy in reducing asthma exacerbation rates in patients with both high and low Th2 status.4 In severe, refractory asthma patients with elevated blood eosinophils (>250 cells per microliter), tezepelumab achieved a reduction of 61-71% in annualized asthma exacerbation rates, relative to placebo; while in patients with lower blood eosinophil levels (<250 cells per microliter), the agent achieved comparable reductions of 56-79%. When the results of the trial were stratified based on patients’ Th2 status (Th2-high status was defined as IgE level > 100 IU/ml and blood eosinophil count ≥ 140 cells/microliter, Th2-low status defined as IgE level ≤100 IU/ml or blood eosinophil count <140 cells/microliter), tezepelumab demonstrated a 63-82% reduction in the annual exacerbation rate in patients with Th2-low status, compared with a 51-71% reduction in the group of patients with Th2-high status, suggesting that tezepelumab could be equally efficacious in both subpopulations of asthmatics. It is unclear from the data available if different subpopulations of Th2-low asthma patients showed varying response to the treatment with tezepelumab and whether drug’s robust efficacy extends to patients whose asthma does not have a Th2 component. Tezepelumab is now in Phase III trials, and - before the drug is approved for asthma - it would be interesting to see if Amgen and AstraZeneca perform a post-hoc analysis exploring how patients with different endotypes/phenotypes of Th2-low asthma responded to tezepelumab, and whether biomarkers could be identified and developed to aid with determining which patients within the Th2-low population have the best chance of responding to this biologic.

On the heels of tezepelumab’s trial, additional agents with promise in patients with non-Th2 asthma are being tested in Phase II trials. Among these is AbbVie/Boehringer Ingelheim’s risankizumab, an IL-23 inhibitor designed to disrupt IL-23/IL-17 signaling and thus, has the potential to demonstrate efficacy in patients with underlying IL-17-mediated neutrophilic inflammation. Interestingly, the trial is only recruiting severe, refractory asthmatics with high reversibility of FEV1 in response to albuterol, exactly the subgroup of patients in which efficacy was previously shown in the brodalumab trial. The trial is expected to be completed in February 2018 and results are eagerly awaited. Other potentially promising mechanisms of action include targeting toll-like receptors and the histamine H4 receptor, which could be involved in the pathogenesis of both Th2-high and -low asthma, with several agents focusing on toll-like receptor signaling currently in Phase II development.

Although it is too early to predict if any of these earlier-stage agents can demonstrate robust efficacy in patients with non-Th2 asthma, it is becoming increasingly clear that due to the heterogeneity of asthma, a more personalized approach is the future of severe asthma treatment. As more agents - and more mechanisms of action - become approved for this population, the availability of biomarkers predicting patient’s response to the available treatments will aid physicians with choosing the most-appropriate - and most-effective - therapy for each patient.

References

  1. Wenzel SE, et al. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med. 2012; 18(5):716-25.
  2. Regeneron, press release, September 11, 2017.
  3. Please see DRG’s Asthma | Unmet Need | US/EU content: https://decisionresourcesgroup.com/report/315214-biopharma-detailed-expanded-analysis-severe-asthma/
  4. Corren J, et al. Tezepelumab in Adults with Uncontrolled Asthma. N Engl J Med. 2017;377(10):936-946.

Relevant Reports:

Asthma [ Unmet Need | Severe Asthma | US-EU | 2017 ]

Asthma [ Current Treatment | Detailed Expanded Analyses Asthma (EU5) ]

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Elena Kozhemyakina, Ph.D., is a principal business insights analyst at Decision Resources Group, specializing in pharmaceutical market analysis of immune system disorders with expertise in asthma, chronic obstructive pulmonary disease, systemic lupus erythematosus, and other related conditions.
Prior to joining Decision Resources Group in 2014, Dr. Kozhemyakina completed a postdoctoral fellowship at Harvard Medical School, where she investigated molecular mechanisms involved in limb patterning, cartilage formation and pathogenesis of osteoarthritis. She has authored multiple peer-reviewed publications focused on molecular signaling of developmental disorders.

 

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