Biologicals: How can they treat severe chronic upper airways diseases (SCUAD)?
What could a possible biomarker for severe chronic upper airways diseases look like?
A possible biomarker could be, for example, an increase of IgE, IL-5, or IL-13. This is why we want to use the studies on biologicals to find out which specific indicators can be used as biomarkers. Once the biomarkers are defined, we can pick the exact monoclonal antibody for the treatment of a patient representing the respective endotype.
This means you will use the existing biologicals-studies on patients with severe chronic upper airways diseases for finding a link between the response rates and a possible biomarker?
Exactly. For example, Omalizumab is targeting IgE, the typical indicator of an allergic disease. One would expect, that patients with a high IgE-level would respond better to Omalizumab than patients with a rather low IgE-level. Unfortunately the correlation is not so clear in this case because many urticaria patients respond very well to Omalizumab, even though urticaria is not an allergic disease associated with increased IgE. Obviously IgE is not the only factor which is relevant for the effectiveness of Omalizumab. It seems like targeting IgE may provoke a cascade of events which can affect many other biomarkers.
Another biological, Dupilumab is targeting the receptor which controls the pathways of IL-4 and IL-13 but we are not using Dupilumab for treating patients who have an increase of these receptors. Our studies with Dupilumab have shown that one the markers mainly affected is IgE, which is released as a consequence of the stimulation of the IL-13 pathway. We are still at the beginning of understanding how these mechanisms are working.
To sum it up: We still do not understand the link between biomarkers and the patients’ response to treatment with biologicals. We definitely need to do more studies, which means, we need to classify the patients we include in the studies, not only according to phenotypic information, but also according to their endotypes.
What else is important in respect to treating SCUAD with biologicals?
Biologicals are very effective – 80 to 90 percent of the patients treated are responding to the therapy.
A general advantage of biologicals is that the prevalence of side effects is much lower than for traditional systemic therapies, while the positive effects are quite similar. Compared to systemic corticosteroids, which are the traditional medication for severe chronic upper airways diseases like severe chronic rhinosinusitis, severe allergic rhinitis, nasal polyposis and Samter’s triad, this is a substantial advantage.
So far, biologicals have one great disadvantage, their price! Corticosteroids are moderately inexpensive and biologicals are extremely expensive. But I am sure that, in the future, this will gradually change and biologicals might be produced much easier and at lower costs. Biologicals could then be used even for a broader group of patients and not only for those with severe uncontrolled symptoms. Maybe, in the future, biologicals could even be used to avoid the development of diseases in patients at risk.
So which biologicals are currently being researched?
In respect to upper airway diseases, we are talking about Omalizumab which is targeting IgE, Mepolizumab and Benralizumab which are targeting IL-5 and Dupilumab which blocks IL-4 and IL-13 pathways. There are three or four more biologicals like, for example, Lebrikizumab and Tralokinumab for IL-13 which are being developed at the moment, but those studies have not started yet.
How can patients to benefit from biologicals, do they have to participate in studies?
Some biologicals, like e.g. Omalizumab are already available in some countries for the treatment of severe asthma. Mepolizumab is available in Germany and soon will be in Spain but only for the treatment of severe asthma, which is mainly associated with upper airway inflammatory diseases – 70 to 80 percent of the patients are affected of chronic rhinosinusitis.
Interestingly we can see positive effects in the nose, when we treat asthma patients with biologicals but we have no biologicals available - so far - for the indication of severe chronic upper airways diseases like, for example, severe chronic rhinosinusitis.
What will be the next step in SCUAD-research?
Finding biomarkers will definitively be our next, very important goal for research. Our objectives in precision medicine in respect to severe chronic upper airways diseases are to study the endotypes and the mechanisms of action and to find the target molecule we have to treat to get a positive response. The final goal is a more precise treatment of patients!
Prof. Mullol, thank you very much for this interview!
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