Boehringer Ingelheim presents robust pipeline highlighting its Respiratory R&D

Boehringer Ingelheim announced today that patients and physicians may have several innovative respiratory treatments available in the coming years. At its 3rd International Research & Development press conference, Boehringer Ingelheim unveiled a pipeline of unique asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and lung cancer compounds that builds on the company’s vast respiratory experience over many decades.

One of the best explored and profiled areas in Respiratory R&D at Boehringer Ingelheim is bronchodilation, the key treatment target in COPD. The biggest research success in this area to date is tiotropium, which has been marketed for ten years under the brand name Spiriva®. Tiotropium was the first inhaled once-daily anticholinergic (LAMA) to provide 24-hour bronchodilation in COPD and with 25 million patient years’ experience, it is the most prescribed COPD therapy worldwide.The company’s research strategy steps forward to maintain its leading position in bronchodilation research with an additional focus towards the understanding of chronic respiratory disease progression and the subsequent long-term consequences of the disease.

At the press conference, Prof Andreas Barner, Chairman of the Board of Managing Directors at Boehringer Ingelheim, and scientist within Boehringer Ingelheim’s own R&D division in Biberach, Germany revealed details of the company’s extensive overall pipeline.

In the respiratory area, Boehringer Ingelheim’s promising pipeline includes seven early clinical stage compounds (phase I and II) and a range of late-stage compounds (phase III and registration). The late stage respiratory compounds include:

• Olodaterol*, a once-daily, long-acting beta2 agonist (LABA), for the treatment of chronic obstructive pulmonary disease (COPD) that was developed as an ideal combination partner for tiotropium and intended for the maintenance treatment of COPD
• A fixed dose combination of this new LABA with the long-acting, once-daily muscarinic antagonist (LAMA) tiotropium
• An additional advanced compound, nintedanib* for the treatment of idiopathic pulmonary fibrosis
• and the ErbB-Family blocker afatinib* for the treatment of non-small cell lung cancer (NSCLC) patients harbouring EGFR mutations.

Respiratory disease research and development at Boehringer Ingelheim will further focus on:

• Exacerbation prevention and resolution in asthma and COPD
• Disease modification and airway re-modeling e.g. mucus production
• Inflammatory pathways in asthma and severe COPD
• Lung tissue damage and lung fibrosis
• Lung cancer.

Professor Andreas Barner highlighted the company’s commitment to innovative research and development programmes despite additional complexity, increased cost, and regulatory or market access hurdles. He emphasized that the delivery of innovative new medicines demands the highest quality in clinical trials and in addition proof of affordability for society.

“In the past decade Boehringer Ingelheim has conducted 1,348 studies in 111 countries across all our therapeutic areas within our own global Research and Development organisation with 7,000 colleagues in R&D and Medicine. Challenging times lie ahead in the development of breakthrough innovations for clinical and medical research. We have therefore pioneered in many therapeutic areas to partner with academic institutions, universities and research consortia for continued success,” Professor Barner said.

Professor Klaus Dugi, Corporate Senior Vice President Medicine at Boehringer Ingelheim emphasised,

“We are ‘walking an extra mile’ at Boehringer Ingelheim with regard to many aspects of clinical trials. We introduce thorough testing methods often many years prior to such methodology being requested by guidelines. We also heavily invest in landmark studies to assess ‘real world conditions’ in which patients receive additional investigational compounds on top of their standard medication. Clearly this may make outstanding clinical trial results more difficult to achieve, in contrast to comparing new compounds with placebo only. We are proud that we can nonetheless demonstrate our results translate into patient benefit.”

COPD (chronic obstructive pulmonary disease)

Boehringer Ingelheim ensures that ‘real-world conditions’ are mimicked as much as possible by allowing all severities of symptomatic COPD and all background therapies during our large phase III and IV outcome studies such as the landmark 4-year UPLIFT™ study, the POET-COPD™ (Prevention Of Exacerbations with Tiotropium) study, the 17,000-patient-TIOSPIR™ study, the olodaterol phase III program and the TOviTO™ phase III clinical trial programme for the fixed-dose combination of Spiriva® (tiotropium) and olodaterol.

Among external institutions conducting health technology assessments, the German IQWiG (Institut für Qualitaet und Wirtschaftlichkeit im Gesundheitswesen) has recently confirmed that Spiriva® provided additional benefit compared to the entire group of long–acting β-agonists (including salmeterol, formoterol and indacaterol).1 The IQWiG assessment was largely based upon the head-to-head POET-COPD study, comparing the effects on acute worsening of the disease (exacerbations) of two long-acting bronchodilators Spiriva® and salmeterol. The study showed significantly better outcomes with Spiriva® in reducing COPD exacerbations compared to salmeterol.2

Asthma

Recently, results from the phase III PrimoTinA-asthma™ studies were received with great enthusiasm by pulmonologists, as the study included asthma patients who are still symptomatic despite the available treatment options.3

The results of the PrimoTinA-asthma™ study revealed that tiotropium significantly reduced severe asthma attacks (exacerbations).3 While scientists were anticipating improvements in lung function when adding tiotropium to usual care (Inhaled Corticosteroids/LABA), the significant reduction in the risk of exacerbations came as a surprise – especially given that the patients were already receiving optimal maintenance treatment as defined by the Global Inititative for Asthma (GINA) guidelines.4

The latest novel asthma research in phase II studies at Boehringer Ingelheim focuses on a new mode of action, the blockade of the CRTH2 receptor, involved in asthma pathogenesis.

IPF (idiopathic pulmonary fibrosis)

Idiopathic pulmonary fibrosis (IPF) is an orphan disease, with a prevalence varying between 14 and 43 people per 100,000 worldwide.5 However the impact of the disease is high with 50% of patients dying within 2-3 years after diagnosis.6 There is a high unmet medical need for effective new treatments.

Nintedanib is an investigational small molecule tyrosine kinase inhibitor (TKI) which targets growth factor receptors that have been shown to be potentially involved in pulmonary fibrosis.7 Data from the Phase II study have been summarised by the lead investigator Prof. Dr. Luca Richeldi who states that “the positive trends in slowing the decline in lung function over time, reducing the incidence of acute exacerbations and improving the quality of life with nintedanib are a promising proof of concept.”8 Just recently, recruitment into the pivotal Phase III sister trials INPULSIS™-1 and INPULSIS™-2, investigating the efficacy and safety of nintedanib in IPF, has been completed. Results are expected to become available in 2014.

Lung Cancer

Boehringer Ingelheim has recently submitted a Marketing Authorisation Application to the European Medicines Agency (EMA) for approval of afatinib, the first irreversible ErbB Family Blocker, as a treatment for patients with EGFR (ErbB1) mutation-positive non-small cell lung cancer (NSCLC).

The LUX-Lung 3 registration trial revealed unprecedented first line efficacy in patients with EGFR-mutation positive NSCLC treated with afatinib.9 In addition afatinib led to a better control of disease related symptoms versus chemotherapy as well as a better quality of life.9

Boehringer Ingelheim’s second lung cancer compound in phase III clinical development is nintedanib, an oral agent that simultaneously inhibits VEGFR, PDGFR and FGFR, three receptors which are relevant for angiogenesis and tumour growth.

Lung cancer is the most common and most deadly form of cancer in the world.10 In Europe, it accounts for 391,000 new cancer cases annually, and 342,000 deaths each year.11

References

1. Institute for Quality and Effiiciency in Healthcare. Press release August 2012. Tiotropium has advantages for patients with COPD Available at: https://www.iqwig.de/sid49f219o1cavo6fi4d5f8fulausqujccm/tiotropium-has-advantages-for-patients-with-copd.1489.en.htmll Accessed October 2012.
2. Vogelmeier C, Hederer B, Glaab T, et al. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med 2011;364(12).
3. Kerstjens HAM, Engel M, Dahl R, et al. Tiotropium in Asthma Poorly Controlled with Standard Combination Therapy. N Eng J Med Published online 3 Sept 2012 (www.nejm.org).
4. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease. Updated 2009. Available at http://www.ginasthma.org. Accessed October 2012.
5. Raghu G, Weycker D, Edelsberg J, et al. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2006;174:810-6.
6. Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011;183:788-824.
7. Selman M, King TE, Pardo A, et al. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med. 2001;134(2):136-51.
8. Richeldi L, Costabel U, Selman M, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med. 2011;365(12):1079-87.
9. Yang JCH, Schuler MH, Yamamoto N, et al. LUX-Lung 3: A randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFR-activating mutations. Oral presentation at American Society of Clinical Oncology, Chicago, June 4, 2012. Oral abstract #LBA7500.
10. Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010; 127 2893-2917.
11. Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer 2010; 46 765-781.

* Olodaterol, afatinib and nintedanib are investigational compounds. Their safety and efficacy have not yet been fully established.