We’re on the eve of yet another wave of new treatments for severe asthma. Having recently adjusted clinical practice to accommodate multiple monoclonal antibody treatments, if results from Phase 2 studies of several small molecule drugs (SMDs) continue to show promise, treatment paradigms are likely to shift again.^1,2 To understand more about SMDs currently in Phase 3 studies for severe asthma, the limbic spoke with John Upham, Professor of Respiratory Medicine at Princess Alexandra Hospital and the University of Queensland.

“Most of us are becoming more comfortable with screening patients for suitability for the monoclonal antibody treatments. Given how unwell severe asthma patients are, we’ve not necessarily faced challenges with convincing patients to trial these therapies. So when we look at how new treatments could fill current gaps, we’re really talking about more accessible options that could drive better adherence than existing therapies,” Prof. Upham began.^1,3

Oral therapies offer hope to improve compliance and offer alternative drug targets

Prof. Upham noted that,“despite treatment guidelines, many patients with asthma remain poorly controlled. One challenge is the heterogeneity of symptoms, underpinned by different patterns of airway inflammation and remodelling. Until the introduction of the monoclonal antibody therapies, there were limited options to offer patients with severe asthma above and beyond inhaled therapies and oral corticosteroids.” ^2,4 He continued, “while monoclonal antibody therapies may deplete cytokine production or immunoglobulins themselves, which underpin inflammation, for reasons we’re not quite sure of, not everyone responds to this type of therapy. Because they are larger molecules, they’re restricted to the injection route of administration. This adds to the complexity and cost of treatment as well. Targets that act higher up the inflammation cascade have therefore been of interest in clinical trials. Several of these are oral therapies which are an attractive option and may be easier to administer.”^2,3

Inflammation in asthma is complex and interconnected

Asthma is often associated with a Type-2 immune response, referred to as Type-2 high asthma. However, at least half of patients with asthma have a T2-low phenotype.¹

Type 2 inflammation is typically mediated by a plethora of cell types, including antigen presenting cells, mast cells, and T_H2 cells.¹ Until recently, only the allergen-dependant pathway was considered an important target, but now it is clear that non-allergen pathways are also involved.³ The current monoclonal antibody drug targets for severe asthma hinge on the eosinophilic cytokine interleukin (IL)-5 –the target for mepolizumab and benralizumab, and IgE receptors on mast cells, basophils and dendritic cells for omalizumab.⁵ “Given these targets are found on distinct cell populations, there’s been a gap in terms of a drug target that hits multiple cell types in the cascade,” added Prof. Upham.³

PGD₂ – a target that’s present in multiple immune cell types

The prostaglandin D₂ (DP₂) receptor signalling pathway has garnered interest in recent years, due to the prospect that SMDs could play a crucial role in asthma treatment. Prostaglandin D₂ (PGD₂) is a pro-inflammatory lipid mediator released primarily from mast cells, antigen-presenting cells and T_H2 cells often as a result of allergen-dependent activation, but not always.³

PGD₂ exerts its effects through interacting with two receptors (prostaglandin D₂ receptor 1 [DP₁] and the prostaglandin D₂ receptor 2 [DP₂]). The DP₂ receptor is present on the membrane surface of different cells including: T_H2 cells, type 2 innate lymphoid cells (ILC2),and eosinophils. The DP₂ receptor is also referred to as the chemoattractant receptor homologous molecule (CRT_H2), when expressed on T_H2 cells. ³

PGD₂ can be released in either a non-allergen or allergen-dependant manner.² Via the non-allergen dependant pathway, PGD₂ is released following indirect activation of mast cells or direct activation via complement, sphingolipids and others. Via the allergen-dependant pathway, allergens trigger a cascade of events that cuase the release of PGD₂.³ This initiates a signalling cascase through the DP2 receptors in target (T_H2 cells, type 2 innate lymphoic cells [ILC2] and eosinophils).³ Indeed, analysis of sputum secretions shows PGD₂ levels are increased in asthma, increasing further in severe disease and in response to antigen challenge.³

“So you can see the theoretical advantages of this as a drug target compared with the monoclonal antibody treatments we have access to today. This target clearly plays a key role in the pathophysiology of asthma across multiple cell types,” notes Prof. Upham.¹ He continues, “the theory is that antagonism of PGD₂ may accelerate clearance of T_H2 cells from inflamed tissue, promoting resolution of underlying inflammation.”³

Clinical trials of SMDs that target the PGD₂ receptor are underway

Currently there are molecules in Phase 2 and 3 clinical trials that target this pathway. These molecules are being explored in a range of patient types ranging from mild-to-moderate uncontrolled allergic asthmatics, moderate-to-severe asthmatics with elevated eosinophil counts, patients uncontrolled on low-dose ICS and as an add-on therapy for patients with poorly-controlled severe asthma (GINA 4/5).² “We’re watching the Phase 3 trials with great anticipation after seeing the results from Phase 2,” remarked Prof. Upham.

“It’s an exciting time to be in respiratory medicine,” noted Prof. Upham. “SMDs that target multiple cell types in the inflammatory cascade offer hope for more patients. It’s not that we are entering an era where we need to be relaxed about phenotyping the severe patient. On the contrary, as more treatment options become available, it’s going to be even more important to get the details right so that we can choose the right treatment for the right patient,” Prof. Upham concluded.^1,5

This article was sponsored by Novartis, which has no control over editorial content. The content is entirely independent and based on published studies and experts’ opinions, the views expressed are not necessarily those of Novartis.

References

1. Roth-Walter F, et al. Allergy 2019 Mar;74(3):432-448.
2. White C, et al. Expert Opin Investig Drugs 2018;27(2):199-207.
3. Domingo C, et al. Respir Res 2018;19(1):189.
4. Katsaounou P, et al. ERJ Open Res 2018;4(4):00076-2018.
5. Nixon J, et al. Pharmacol Ther 2017;169:57-77.