At its 3rd International Research & Development (R&D) press conference, Boehringer Ingelheim gave journalists insights into its R&D pipeline. Around 200 scientists at the company’s site in Biberach are investigating new treatment options for patients with COPD (chronic obstructive pulmonary disease), asthma, idiopathic lung fibrosis, lung cancer and other respiratory diseases. In addition, the researchers are also focusing on the R&D of compounds for the treatment of cardiometabolic and neurological disorders.
Boehringer Ingelheim has vast experience and a long tradition in respiratory compounds; the company’s involvement with respiratory compounds started in 1921 with the respiratory analeptic Lobelin; the asthma compound Aludrin was introduced in 1941 and the Berotec inhalation aerosol for the treatment of asthma and Atrovent for the treatment of COPD were introduced in the 1960s and 70s. With Spiriva (which contains the compound tiotropium), the family-run business owns a blockbuster drug that achieved a sales volume of over three billion euros in 2011. In 2001, tiotropium was the first once-daily anticholinergic (LAMA) inhaler to provide 24-hour bronchodilation in COPD. According to Boehringer, tiotropium has been used by 25 million patients and is the most prescribed COPD therapy worldwide.
According to the World Health Organisation, more than 210 million people suffer from COPD worldwide. In the majority of cases, the disease is caused by smoking and air pollution. COPD is a polygenic disease in which gene-environment interactions play a yet to be determined role in disease onset. Moreover, COPD patients also suffer from cardiac diseases, diabetes, osteoporosis and depression.
There is still no cure for COPD. The disease limits the airflow, causing shortness of breath and the sudden worsening of COPD symptoms (exacerbation) that can last for an extended period of time. COPD guidelines make it clear that pharmacotherapies are only able to alleviate the symptoms, improve bodily performance and quality of life and/or reduce the frequency of exacerbations. More than three million people died of COPD in 2005, which accounts for around five percent of all deaths worldwide. In addition, the COPD guidelines of German associations expect the situation to become even worse; in 2020, COPD is projected to become the third most common cause of death and rank fifth (at present 12th out of a total of 15) worldwide in burden of disease.
Respiratory compounds (in particular those used to treat COPD and asthma) achieved a worldwide sales volume of around 44 billion US dollars in 2010. Around 300 drug candidates are in pharmaceutical companies’ asthma pipelines; around 140 drug candidates are in the R&D pipeline for the treatment of COPD and allergic rhinitis. According to a list published by the Association of Research-based Pharmaceutical Companies, five COPD drug candidates are currently in the R&D pipeline and are expected to receive marketing authorisation in 2015. The association also lists seven asthma drug candidates, including three biopharmaceutical ones.
Research in the field of respiratory diseases at Boehringer Ingelheim is focused on exacerbation prevention and resolution in asthma and COPD as well as disease modification and airway remodelling (e.g. mucus production). Moreover, the research team of Florian Gantner, Vice President Respiratory Diseases Research at Boehringer Ingelheim, is focused on inflammatory pathways in asthma and severe COPD, lung tissue damage and idiopathic lung fibrosis as well as non-small cell lung cancer.
The recent press conference in Biberach made it clear that Boehringer Ingelheim’s research strategy is aimed at maintaining the company’s leading position in bronchodilation research. In addition, the company is focused on working towards an understanding of chronic respiratory disease progression and the subsequent long-term consequences of the disease. In the respiratory area, Boehringer Ingelheim’s pipeline includes seven early clinical stage compounds (phase I and II) and a range of late-stage compounds (phase III and registration).
Boehringer Ingelheim’s late-stage respiratory compounds include: Olodaterol, a once-daily, long-acting beta2 agonist (LABA) for the treatment of COPD that was developed as an ideal combination partner for tiotropium (Spiriva) and intended for the maintenance treatment of COPD as a fixed dose combination of Olodaterol with the long-acting muscarinic antagonist tiotropium.
The planned combination therapy targets the respiratory muscles in two ways: the established and approved compound tiotropium prevents the muscle cells from contracting (i.e. closing), while the new Olodaterol dilates the airways by relaxing the muscle cells. Indirectly, these efforts suggest that the company intends to combine its blockbuster drug Spiriva with other compounds with the goal of preventing huge financial losses once the patent protection of Spiriva expires.
Boehringer’s blockbuster drug tiotropium will potentially enable the company to achieve further income as the compound has been shown to be an effective asthma drug. A phase III study published in the New England Journal of Medicine (DOI: 10.1056/NEJMoa1209606) published in September 2012 substantiates these hopes. The controlled study involved 912 asthma patients (the patients remained symptomatic despite receiving optimal maintenance treatment with inhaled corticosteroids (ICS) and bronchodilators (long-acting beta agonists (LABA)) randomised to additional tiotropium. The study came up with unexpected results.
While the researchers anticipated improvements in lung functions when adding tiotropium to usual care regimes, the significant reduction in the risk of exacerbations came as a surprise, as patients were already receiving optimal maintenance treatment as defined by the GINA guidelines. Additional studies are currently being carried out to substantiate the results for all age groups and all disease grades. Bernd Disse, researcher at Boehringer Ingelheim, sees it as problematic that around 50% of asthma patients do not receive optimal control and that many patients underestimate the lack of control. He also highlighted that the company’s asthma research is therefore focusing in particular on the prevention of asthma exacerbations.
The latest novel asthma research in phase II studies at Boehringer Ingelheim focuses on a new mode of action, i.e. the blockade of the CRTH2 receptor, involved in asthma pathogenesis. According to information from the COPD and Asthma competence network, around five percent of adults and 10 percent of children suffer from asthma in Germany (worldwide: 300 million people). This chronic disease, which is characterised by airway inflammation and obstruction, can be better treated than COPD, but is not understood in enough detail to permit permanent medicinal cure.
In developed countries, where asthma is most common, the disease accounts for up to two percent of a nation’s health budget. Major asthma risks include a combination of genetic disposition and the inhalation of compounds and particles, including house dust mites, pollen, mould, tobacco smoke, polluted air, which can cause allergic reactions and irritate the airways.
In autumn 2012, Boehringer Ingelheim submitted a marketing authorisation application to the European Medicines Agency (EMA) for approval of afatinib for the treatment of patients with EGFR-mutation positive non-small cell lung cancer (NSCLC). Afatinib blocks four cell surface receptors that belong to the ErbB receptor family. One of these receptors, epidermal growth factor receptor (EGFR), is overexpressed in lung tumours due to altered tumour DNA. Around ten to 15 percent of Caucasian NSCLC patients and 40 percent of all Asian patients have lung tumours with EGFR mutations. NSCLC is the most common type of lung cancer; 85 percent of lung cancer patients diagnosed annually in Europe have NSCLC. Non-small cell lung cancer can be divided into different subgroups which have to be specifically diagnosed and treated. More than 50% of all NSCLC subtypes are not yet known. Around 25% of all NSCLC patients have EGFR mutations. Boehringer Ingelheim representatives reported that the submission is based on a clinical trial programme (phase III study) in which afatinib demonstrated superiority to best-in-class chemotherapy of non-squamous NSCLC. In addition, afatinib-treatment led to a better control of disease-related symptoms as well as a better quality of life (see press release of 20th September 2012: Boehringer Ingelheim submits first oncology compound, afatinib* for European approval).
Nintedanib is Boehringer Ingelheim’s second late stage (phase III) compound for the treatment of lung cancer (NSCLC). The compound simultaneously inhibits factors that are relevant for angiogenesis and tumour growth, most importantly the vascular endothelial growth factor receptors (VEGFR) 1-3, fibroblast growth factor receptors (FGFR) 1-3 and platelet-derived growth factor receptors (PDGFR). By blocking these signalling pathways, it is believed that nintedanib has the potential to reduce tumour growth and spread. The compound is also in clinical development as a treatment option for other solid tumours, including NSCLC and ovarian cancer. Lung cancer is the most common and most deadly form of cancer in the world. In Europe, it accounts for 391,000 cancer cases annually, and 342,000 deaths each year. Only seven percent of patients are still alive five years after diagnosis.
With the small molecule tyrosine kinase inhibitor nintedanib, Boehringer Ingelheim hopes to be able to treat idiopathic pulmonary fibrosis (IPF), which is the most deadly interstitial lung disease known. Results of two phase III studies are expected to become available in 2014. IPF is a rare (orphan) disease, with a prevalence varying between 14 and 43 people per 100,000 worldwide. However, experts expect the number to be as high as three million. The disease affects more men (> 50 years of age) than women; the cause of the disease is largely unknown. IFB leads to serious breathing problems as a result of fibrotic lung tissue, which in turn causes the lungs to shrink. Around 50% of all IPF patients die within two to three years of diagnosis. After pancreatic and lung cancer, IPF has the worst prognosis, reported Prof. Dr. Luca Richeldi from the Centre for Rare Lung Diseases at the Modena University Hospital and principal investigator of the phase-II trial (N Engl J Med 2011; 365: p. 1079-1087). At present, a drug marketed by the US biotech company InterMune is the only drug approved for the treatment of light to moderate IPF in adults in the EU and Japan.
References:Respiratory Research & Development Press Conference 2012, Biberach, 31st Oct. 2012
Vogelmeier. C. et al.: Leitlinie der Deutschen Atemwegsliga und der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin zur Diagnostik und Therapie von Patienten mit chronisch obstruktiver Bronchitis und Lungenemphysem (COPD), DOI: 10.1055/s-2007-959200
Nationale Versorgungsleitlinie Asthma (July 2011): https://www.gesundheitsindustrie-bw.dewww.versorgungsleitlinien.de/themen/asthma/index_html
The Asthma, COPD & Allergic Rhinitits Market Outlook to 2016 (https://www.gesundheitsindustrie-bw.dewww.bionity.com/de/marktstudien/7730/the-asthma-copd-amp-allergic-rhinitis-market-outlook-to-2016.html)