New treatments for severe asthma

Patients with severe asthma account for 5% to 10% of cases and need improved therapies.

New therapies that have good potential to reach the clinic in the next five years include:

- biological agents targeting pro-inflammatory cytokines such as interleukin-5 and interleukin-13
-inhaled ultra long-acting β2-agonists
- once daily inhaled corticosteroids

Severe asthma - differential diagnosis and management (click to enlarge the image):



Potential targets for novel therapies include:

- CRTH2, chemoattractant receptor-homologous molecule expressed on Th2 cells
- FLAP, lipoxygenase-activating protein
- interleukins
- PPAR, proliferator-activated receptor
- PDE, phosphodiesterase
- PGD2, prostaglandin D2

Omalizumab

In patients with allergic asthma, omalizumab (anti-IgE) improves symptoms and reduces exacerbations. However, preliminary data from a 5-year safety study raised concerns about increased cardiovascular events and further confirmation is awaited by the FDA.

Mepolizumab

Anti-IL5 monoclonal antibody (mepolizumab) treatment may be helpful in patients with refractory eosinophilic asthma (2 NEJM studies).

Anti-IL4 and IL-3

Several monoclonal antibodies targeting IL-4 and/or IL-13 in asthma are in development. Both IL-4 and IL-13 exert their actions through the IL-4Rα/IL-13Rα1 receptor complex.

Pitrakinra is a recombinant protein that binds to IL-4Rα. It is being developed as an inhaled medication.

Anti-IL-2R (CD25)

Daclizumab is a humanized monoclonal antibody that binds to CD25 subunit of the high-affinity IL-2R. It inhibits IL-2 binding and T-cell activation.

Ultra-LABAs

Inhaled ultra long-acting β2-agonists (ultra-LABAs) have a longer half-life than current LABAs and can be used for once daily administration. Indacaterol is currently licensed for COPD.

Combinations of once-daily ultra-LABAs with inhaled corticosteroids (ciclesonide) are in development.

LAMAs

New inhaled long-acting antimuscarinic agents (LAMAs) agents, such as aclidinium, are also in development.

Bronchial thermoplasty (BT)

Bronchial thermoplasty was approved by the FDA in 2010. Long-term 5-year safety data reported absence of significant clinical complications and maintenance of stable lung function. However, bronchial thermoplasty was associated with a short-term increase in asthma-related morbidity.

Phosphodiesterase (PDE)-4 inhibitors

High doses of phosphodiesterase (PDE)4 inhibitors may be required to treat severe asthma, and at that doses GI effects limit their use. Inhaled PDE4 inhibitors may help.

Peroxisome proliferator-activated receptor-γ (PPARγ) agonists

Peroxisome proliferator-activated receptor-γ (PPARγ) agonists have anti-inflammatory effects. Clinical trials of oral PPARγ agonists are underway.  The first human study of PPAR-gamma agonist showed some benefit (Disclaimer: I was one of the lead investigators and co-wrote the article).

From the NHS Choices channel: Professor Peter Barnes from the National Heart and Lung Institute at Imperial College, London, explains what he would want to know if he was diagnosed with asthma:



References:

BMC Medicine | Full text | Emerging therapies for severe asthma. Neil C Thomson*, Rekha Chaudhuri and Mark Spears. BMC Medicine 2011, 9:102 doi:10.1186/1741-7015-9-102.

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