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Boehringer Ingelheim researchers to focus on inflammation

Boehringer Ingelheim is hoping to find ways to use anti-inflammatory mechanisms of action to improve the treatment of respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma. Clinical studies will show what kind of improvements patients can expect from the substances, which are currently at different stages of development. Drugs to widen the bronchia, marketed by Boehringer Ingelheim, will in the medium term become indispensable in the treatment of chronic obstructive pulmonary diseases and asthma.

Dr. Florian Gantner. © Boehringer Ingelheim

Florian Gantner believes that anti-inflammatory substances have a complementary character in that they have the potential to indirectly improve the lung function. The 42-year-old biologist and pharmacologist is in charge of the Pulmonary Disease Research division of Boehringer Ingelheim's research centre in Biberach.

Many respiratory diseases start with inflammation, which is more or less the pathogenicity model on which the company's lung research is based. Gantner explains that the lung's own remodelling processes which result in emphysema, are considered to be a late disease stage, and the remodelling processes themselves are to a great extent controlled and accelerated by chronic inflammatory reactions.

COPD is triggered by inflammation

It is believed that COPD is the result of excessive inflammatory reactions in the respiratory tracts, which arise due to regular exposure to cigarette smoke and other harmful substances. The inflammatory reactions triggered by these harmful substances eventually lead to pathophysiological reactions in the lung tissue. During an excessive inflammatory reaction, the lung epithelium reorganises, and the number of mucus-producing cells in the lung increases to clear the harmful particles from the respiratory tracts. Florian Gantner describes this as a physiological defence reaction that becomes hyperreactive and results in a permanent urge to cough. This means that fibroses can also be seen as excessive healing processes.

Pathophysiology model of COPD, where pharmacological developments are targeted at excessive inflammation. © Boehringer Ingelheim

Gantner explains that there is substantial evidence that confirms the assumption that cigarette smoke leads to inflammatory reactions. However, he adds that the cocktail of around 4,000 more or less toxic substances in cigarette smoke must not be taken as the only cause of COPD, and similar diseases. Whilst this might be the case in highly developed countries, the example of India shows that Indian women who have spent many years cooking food on open fires have also been diagnosed with COPD. Gantner explains that people exposed to diesel exhaust gas in areas of high population density can also be prone to COPD and he highlights that the genetic disposition of COPD sufferers might also play an important role in the development of COPD.

Key problem: huge compensation ability of the lungs

Medical treatment of COPD is hindered by the fact that the lungs have a huge capacity for compensation. Only when large parts of the lungs cease to function completely, do COPD sufferers experience problems when they are under heavy strain. COPD therapy can only focus on treating the symptoms. Gantner is convinced that the only causal therapy for COPD is to give up smoking, or better still, to never start smoking.

Antimuscarinic drugs as the starting point

Boehringer Ingelheim has been developing drugs for the treatment of respiratory diseases for many decades. The pharmaceuticals producer was the first to produce modern antimuscarinic drugs. Natural antimuscarins such as atropine have long been used for the treatment of respiratory diseases. However, these plant substances have severe side effects on the central nervous system. Boehringer has developed quarternary antimuscarinic drugs, a new substance class that is unable to enter the brain due to its structure. Once inhaled, the drugs are therefore able to exert their effect principally in the lungs.

This substance class inhibits the contraction of the smooth muscles. The natural agonist of smooth muscles, acetylcholine, triggers the contraction of the muscles, including the contraction of the respiratory tract muscles. Elevated quantities of acetylcholine are released in COPD patients. The name of this substance class is derived from the muscarinic receptors, of which five subtypes are known. Subtype M3 is important for the respiratory tracts. Antimuscarinic drugs block this receptor, widen the airways and help COPD patients to breathe with less effort. Therefore, these substances are also referred to bronchial dilators (bronchodilators). Boehringer’s tiotropium is the first long-acting anticholynergic drug with a 24-h effect. Boehringer also sells non-prescription mucolytic drugs.

Bronchodilators and beta-agonists dominate the market

There are no anti-inflammatory drugs currently available for the treatment of COPD. Bronchodilators, including antimuscarinic drugs and a second substance class (so-called beta-agonists) that exerts the same effect as antimuscarinic drugs on the basis of different mechanisms, dominate the market. Due to their effect, beta-agonists are regarded as an important complementary therapy to the basic therapy involving antimuscarinic drugs. In contrast to COPD, asthma is mainly treated with inhaled corticosteroids that have an anti-inflammatory effect. However, Gantner explains that steroids and their efficiency in treating COPD have not yet been “sufficiently validated”. An antibody-based therapy targeting anti-IgE is currently also being used to treat severe asthmatics who have high anti-IgE (class E anti-immunoglobulin) levels that are the major cause of allergic reactions.

Goal: tablets to complement inhaled substances

Boehringer Ingelheim’s respiratory disease specialists are particularly focusing on the inflammatory processes in the lung that are characteristic of diseases such as COPD and asthma. The chronic course of these two diseases involves different cells, which requires different strategies to be put in place. Gantner explains that, with the exception of steroids, there are no anti-inflammatory therapies available to treat respiratory diseases. Boehringer Ingelheim’ s objective is to develop “orally available drugs” that can be taken in tablet form and that can ideally be used in addition to inhaled drugs. Gantner does not believe that inhaled drugs will be replaced: “Bronchodilators will continue to have a place in the treatment of respiratory diseases.”

Other strategies to treat exacerbations arising during the course of COPD and asthma

Chronic respiratory diseases are often associated with additional inflammatory reactions caused by viruses or bacteria, which often lead to acute exacerbations of COPD and asthma. This then requires clinical treatment, which is extremely costly for the health system. In a large-scale study, tiotropium has been shown to reduce exacerbations and hence expensive hospital stays. The researchers at Boehringer Ingelheim are working to find additional and targeted therapies to either prevent or treat such exacerbations.

The respiratory disease researchers at Boehringer Ingelheim believe that epithelial cells have a key function in lung inflammation. © Boehringer Ingelheim

Research at the Boehringer Ingelheim site in Biberach is mainly focused on finding targets for treating these recurrent inflammatory processes that worsen as a result of smoking or due to contact with antigens in the case of asthmatics. Gantner explains that the company's research focuses on the key immune cells: in the case of COPD these are mainly neutrophil granulocytes and macrophages, as well as epithelial cells ("which are believed to orchestrate the inflammatory reaction); in the case of asthma the key cells are eosinophil granulocytes, type 2 T-helper cells and mast cells. This is the basis of the search for different targets - different molecular targets for future drugs - either for use as inhibitors, activators or modulating agents.

Halting the remodelling process in the epithelium

Boehringer Ingelheim has two mechanisms in early clinical development: the first mechanism is designed to halt the remodelling process of the epithelium and hence the increased production of mucus-producing goblet cells. This therapeutic approach is aimed at preventing the release of secondary messenger substances that attract neutrophil granulocytes from the blood into the airways; at the same time, the same mechanism normalises the pathologically increased production of mucus.

The company also hopes to start clinically testing a second approach in 2010. This approach is aimed at blocking an enzyme that controls inflammation, i.e. an enzyme that suppresses the migration of blood leukocytes into the tissue, thereby preventing the release of secondary messenger substances. This leads to the suppression of the migration of further inflammatory cells into the tissue. The researchers hope that the two anti-inflammatory approaches will help to indirectly improve lung function when used alongside standard therapies. A particular objective of the two approaches is to reduce the number of hospitalisations, which is particularly high in the case of exacerbations.

The Biberach-based company is currently pursuing more than a dozen projects of which the majority are in the preclinical stage of testing. Gantner told us that innovative approaches for the treatment of asthma and COPD are currently in clinical development.

Focus on severe asthma

Pathophysiology model of COPD, where pharmacological developments are targeted at excessive inflammation. © Boehringer Ingelheim
The strategic orientation in the respiratory disease indication is anchored in the firm conviction that considerable improvements are still possible in terms of COPD therapy. In terms of bronchial asthma, the company is concentrating on treatment for patients suffering from severe asthma. The company also works with external specialists, for example from the Californian biotech company Actimis. The two companies currently have an anti-inflammatory non-steroidal asthma therapy in Phase II of clinical development. In addition, the companies are also developing a substance for the treatment of idiopathic pulmonal fibrosis, which is also undergoing Phase II clinical testing. Gantner is convinced that there is huge need for drugs for the treatment of this disease.

Niche indications to enter Boehringer Ingelheim’s product portfolio?

Boehringer Ingelheim is currently assessing the possibility of including niche indications such as cystic fibrosis into its portfolio, either in cooperation with partners or with own resources. Gantner believes that although the indication portfolio will expand in the future, the number of research and development projects per indication will fall.

As an internationally known respiratory disease specialist, Boehringer Ingelheim receives many offers from biotechnology companies and universities. The company’s specialists carefully assess whether these offers fit into the company’s strategy and whether the necessary financial resources are available. The company is extremely ambitious to develop products for the biopharmaceutical market and it is also assessing the possibility of including new biological entities (NBEs) in its development pipeline, in addition to COPD and asthma. Gantner believes that the NBEs will complement the NCEs because they are likely to expand the spectrum of therapeutically interesting targets.

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