Biologics: new in the treatment of asthma

New biological preparations based on monoclonal antibodies promise to translate asthma treatment into the field of personalized medicine.

According to the WHO, around 235 million people suffer from bronchial asthma all over the world. Experts believe that 20% have a severe form of the disease, among them 20% have uncontrolled asthma (symptoms, including cough, wheezing, choking attacks, are usually observed day and night, making it difficult for normal work and forcing to constantly use the inhaler).

Most asthmatics are treated with inhaled glucocorticosteroids , but for patients with severe asthma, standard therapy usually does not work, because asthma has many causes and forms. Thus, interleukins , information molecules secreted by cells of the immune system, play a crucial role in some forms of asthma . Interleukin-5 (IL-5), for example, stimulates the maturation of eosinophils and their migration from the bone marrow. Eosinophils protect against infections, but can cause inflammation in the lungs in response to allergens. Interleukin-13 (IL-13) and interleukin-4 (IL-4) help eosinophils penetrate the lung tissue, provoke epithelium cells to produce excess mucus and increase the rigidity of the respiratory tract.

Under the influence of IL-13, lung epithelium cells produce another substance that is involved in the development of chronic inflammation in bronchial asthma, the periostin protein , and with an uncontrolled course of the disease, its level rises, correlating with an increase in IL-13.

When pharmacists and doctors understood this, they set about creating a biological targeted therapy aimed at blocking these interleukins . Thus, a series of new drugs based on monoclonal antibodies (produced by immune cells belonging to one cell clone) was developed .

What do pharmaceutical companies offer?

Some biologics had a difficult fate. Thus, the first tests of mepolizumab in the late 1990s failed miserably, and GlaxoSmithKline put the medicine on the shelf. As a result of a similar situation Schering Plow (now part of Merck ) stopped developing reslizumab and sold the rights to it to another company.

Both drugs block interleukin-5 (IL-5). Scientists have suggested that this can reduce the number of eosinophils and, accordingly, reduce the symptoms of asthma. They thought they would help all asthmatics, but it turned out that not all patients with asthma are provoked by interleukin-5.

Today it is already clear: the first tests were unsuccessful because they tested the drug on the wrong patients. In 2009, when mepolizumab testing was resumed, a monthly course of subcutaneous injections was shown to reduce the incidence of asthma attacks by 53% compared with the placebo group and reduce the daily dose of oral corticosteroids without losing control over asthma in people with high eosinophils who did not reduced by corticosteroids. At the end of 2015 , mepolizumab was approved in Europe and the United States for the maintenance treatment of patients over 12 years of age with severe asthma and eosinophilia .

Clinical trials reslizumaba Israeli company Teva Pharmaceutical Industries ended September 2014, proving that a 30-day course of injecting the drug to patients with uncontrolled asthma and elevated eosinophil levels reduces the number of seizures by 50–60% compared with the placebo group. In 2016, the drug was registered in Europe and the USA for the treatment of adult patients with severe eosinophilic asthma.

Benralizumab of the British company AstraZeneca has a slightly different principle of action: it blocks not its own interleukin-5, but its receptor, reducing the level of eosinophils in sputum and blood. Phase III clinical trials, which ended in May 2017, showed that 28 weeks after starting therapy, benralizumab reduced glucocorticoid consumption by 75% (by 25% in the placebo group), and the frequency of asthma attacks on an annualized basis decreases by 55–70 % The tool is intended for subcutaneous administration every four or eight weeks. An application for registration of a medicine was filed with the US Food and Drug Administration in November 2016.

Pharma companies are engaged in other interleukins – IL-13 and IL-4. In 2016, Roche presented the results of phase III trials of the drug lebrikizumab for patients with elevated serum periostin or blood eosinophils. Alas, the effect was less pronounced than in phase II studies, where a 60% decrease in the number of asthmatic attacks was observed in patients with elevated periostin levels .

Good prospects for dupilumab , created jointly by Regeneron and Sanofi . The action of the drug is based on the inhibition of the common receptor IL-4 and IL-13. Dupilumab is already registered in the United States as a treatment for atopic dermatitis and is now undergoing Phase III clinical trials for use in uncontrolled persistent asthma in adults and adolescents 11-16 years old. The companies plan to submit an application to the US Food and Drug Administration for licensing the drug by the end of 2017. Dupilumab is undergoing tests for the treatment of nasal polyps and eosinophilic esophagitis.

Pros and cons

The main drawback of biological products is their high cost. In the US, the annual course of omalizumab costs $ 10,000, mepolizumab – $ 32,500.

There are other disadvantages. Indeed, even among asthmatics with the “correct” biological profile, it is difficult to determine which interleukin blocker to give to a particular patient, since biomarkers linked to a specific drug can be combined. “What to give to patients: an inhibitor of IL-5 or an IL-13 blocker? – asks Liam Heaney, an asthma researcher at Queens University in Belfast (UK) and the head of the Refractory Asthma Stratification Program (RASP). “We cannot say for sure.”

Some doctors are generally skeptical of biologics. So, pulmonologist Parameswaran Nair from McMaster University in Hamilton, Ontario, Canada, I am convinced that uncontrolled asthma is most often the result of improper or irregular use of available funds. Even in the placebo group in the third phase of metolizumab, the number of attacks decreased by 50%, he stresses. The doctor believes that a more accurate prescription of existing drugs and the work of teaching patients to regular and proper use of them will allow to achieve the same results as expensive monoclonal antibodies.

In addition, biological products – it is not a panacea. “Of course, we see a significant difference in the number of complications, but this is not a complete cure. Ideally, we would like to create a drug that would completely cancel any other therapy, ”says Anthony Montanaro , head of the department of allergy and clinical immunology at the University of Oregon Health and Science in Portland (USA).

But despite all the shortcomings, biopreparations are a real breakthrough, says Anna Murphy , pharmacist and consultant on respiratory diseases at university clinics at Leicester Trust of the National Health Service of the United Kingdom: “This is a new step towards personalized medicine. I am pleased to think that someday it will be possible to say: “Let’s find out what provokes asthma in this patient, and find the right treatment for him.”

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