New Phase III data presented for first time demonstrate tiotropium Respimat® significantly improves lung function and provides sustained bronchodilation in asthma patients who remain symptomatic despite ICS treatment

Data from the MezzoTinA-asthma® Phase III twin studies presented for the first time today at the 2013 European Respiratory Society (ERS) congress also show that once-daily tiotropium provides a statistically significant and clinically relevant improvement in asthma control in patients who remain symptomatic despite treatment with ICS.²

Assessment of the severity of asthma in patients is now commonly based on the intensity of treatment needed to achieve good management of symptoms.⁵ These new data add to evidence from the PrimoTinA-asthma® Phase III trials involving patients who remained symptomatic despite at least ICS/LABA therapy. The PrimoTinA-asthma® trials had shown that the addition of tiotropium Respimat® significantly increased time to first severe asthma exacerbation, as well as time to first episode of asthma worsening compared with standard care.³

Professor Huib A M Kerstjens

Professor Huib A M Kerstjens of the University Medical Centre, Groningen, The Netherlands said: “These results are important because they give us insight for the first time into the efficacy of tiotropium in the subset of asthma patients who remain symptomatic despite using moderate-dose ICS. A significant proportion of asthma patients treated with ICS, as recommended in the guidelines, continue to experience symptoms that impact their ability to lead a full life.”

“Importantly, both for physicians and their patients, these data show that the addition of tiotropium may provide improvements in asthma control and lung function that are clinically meaningful. I was personally amazed at how well these results compare to the treatment with the LABA in the active control arm. These data increase our understanding of tiotropium’s potential efficacy across asthma severities as an add-on treatment for patients who continue to experience symptoms despite current standard treatments,” concluded Professor Kerstjens.

Despite current treatment options, at least 40% of patients with asthma remain symptomatic and may experience frightening and potentially life-threatening asthma exacerbations (attacks).⁴ All patients in the MezzoTinA-asthma® studies were symptomatic despite moderate dose ICS therapy.

Addition of tiotropium in asthma significantly improves lung function

The MezzoTinA-asthma® Phase III studies have shown that, in patients with symptomatic asthma, tiotropium Respimat® added on to moderate-dose ICS significantly improved lung function endpoints, including peak FEV1 (0-3h) and trough FEV1 vs. placebo and provided sustained bronchodilation over 24 hours.

In MezzoTinA-asthma® 1, at week 24, all three active treatments significantly improved peak FEV1 (0-3h) response§ vs. placebo: differences of 236 mL for tiotropium 2.5μg once-daily; 198 mL for tiotropium 5μg once-daily and 213 mL for salmeterol 50μg twice daily (all p<0.0001). In MezzoTinA-asthma® 2, at 24 weeks, the peak FEV1 response vs. placebo was again significantly higher for all three active treatments: differences of 211 mL for tiotropium 2.5μg once-daily, 169 mL for tiotropium 5μg once-daily and 176 mL for salmeterol 50μg twice-daily (all p<0.0001).¹

In MezzoTinA-asthma® 1, at week 24, all three active treatments significantly improved trough FEV1 response** vs. placebo: differences of 185 mL for tiotropium 2.5μg once-daily; 152 mL for tiotropium 5μg once-daily and 123 mL for salmeterol 50μg twice-daily (all p<0.0001). In MezzoTinA-asthma® 2, at 24 weeks, trough FEV1 response vs. placebo was again significantly improved for all three active treatments: differences of 176 mL for tiotropium 2.5μg once-daily, 133 mL for tiotropium 5μg once-daily and 106 mL for salmeterol 50μg twice-daily (p≤0.0002).¹

Addition of tiotropium in asthma achieves significant and clinically relevant improvements in asthma control

The MezzoTinA-asthma® Phase III studies have shown that tiotropium added on to moderate-dose ICS significantly improved asthma control in patients with asthma who are symptomatic on ICS.

The mean baseline Asthma Control Questionnaire (ACQ) total score was 2.18 (SD 0.49). Using a definition of responders as those patients with an improvement ≥0.5 for the ACQ, both doses of tiotropium significantly improved the ACQ responder rate at 24 weeks compared with placebo. A similar ACQ responder rate was observed with tiotropium and the active comparator the LABA salmeterol.²

The ACQ responder rate for placebo was 57.7% (299/518); 64.5% (332/515; p=0.03) for tiotropium 2.5μg once-daily; 64.3% (330/513; p=0.03) for tiotropium 5μg once-daily; and 66.5% (356/535; p=0.004) for salmeterol 50μg twice-daily.²

Tiotropium well tolerated

In the MezzoTinA-asthma® Phase III studies, tiotropium Respimat® was well tolerated in patients with asthma who were symptomatic on ICS.¹

Discontinuations due to adverse events (AEs) were 2.5% in the placebo group; 1.2% for tiotropium 2.5μg once-daily; 1.7% for tiotropium 5μg once-daily; and 1.8% for salmeterol 50μg twice-daily.

The overall frequency of AEs and serious adverse events (SAEs) was balanced between the groups. The most common adverse events were asthma (exacerbations) and decreased peak expiratory flow, which were comparable between the treatment groups. Dry mouth, cough and dysphonia (hoarseness) occurred in less than 2% of patients taking tiotropium.

“The results from the MezzoTinA-asthma® twin trials demonstrate tiotropium’s efficacy in an even broader range of asthma patients. They add to the significant evidence we have from the PrimoTinA-asthma® Phase III clinical trials, which had previously shown the efficacy and safety of tiotropium in asthma patients who remained symptomatic despite treatment with at least ICS/LABA therapy,” said Professor Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim.

“The UniTinA-asthma® programme reflects our commitment to profile tiotropium Respimat® for the full range of asthma patients from mild to very severe across all age groups,” Professor Dugi continued. “These new data give us confidence that tiotropium could become an important new add-on treatment option for those patients with asthma who remain symptomatic despite current standard treatments, which include ICS therapy,” he concluded.

About the MezzoTinA-asthma® studies

The MezzoTinA-asthma® twin trials are two identical international, double-blind, randomised, placebo-and active-controlled, parallel-group Phase III trials that included asthma patients aged 18-75 years who remained symptomatic while on moderate-dose ICS.^1,2

These studies were designed to test the efficacy of tiotropium 5 μg and 2.5 μg once-daily as add-on therapy in patients using moderate-dose ICS vs. placebo, with a blinded salmeterol arm serving as an active comparator. A total of 2,103 patients using moderate-dose ICS were randomised to receive additional tiotropium Respimat® 5 μg or 2.5 μg once daily, salmeterol 50 μg twice-daily (as the active comparator), or placebo, for 24 weeks.^1,2

In addition to ICS, patients in the MezzoTinA-asthma® Phase III studies were permitted to receive concomitant anti-allergic background therapy, including antihistamines, nasal steroids and leukotriene modifiers. Other long-acting beta-2 agonists were not permitted.^1,2

The pre-specified co-primary endpoints were peak FEV1 (0-3h) response and trough FEV1 response after 24 weeks. Asthma control responder rate was the third co-primary endpoint.^1,2

Study inclusion criteria included a pre-bronchodilator FEV1 60-90% predicted and asthma control questionnaire score ≥1.5 while on moderate-dose ICS (400-800 μg budesonide equivalent). All patients must have been on maintenance treatment with a moderate, stable dose of inhaled corticosteroid for at least 4 weeks prior to their first visit. Patients had a ≥3 month history of asthma, diagnosed before the age of 40 years; and were life-long non-smokers, or ex-smokers who smoked less than 10 pack-years†† and who quit smoking at least one year before study enrolment.^1,2

Baseline characteristics in patients were similar across both trials and all treatment groups; of the 2103 randomised patients, 2100 were treated; the mean post-bronchodilator FEV1 was 88.8% predicted.^1,2

About UniTinA-Asthma®

The MezzoTinA-asthma® studies are part of a large international Phase III clinical trial programme named UniTinA-asthma. The UniTinA-asthma® Phase III clinical trials are evaluating the efficacy and safety of tiotropium Respimat® in patients with symptomatic asthma despite ICS therapy (with long-acting beta2-agonist (LABA) or alone).

UniTinA-asthma® consists of a total of 11 studies investigating tiotropium Respimat® added to usual care in adults, adolescents and and children (age 1+) with persistent asthma across the spectrum of asthma severity. UniTinA-asthma®, which involves more than 4,000 patients in over 150 sites globally, is addressing the unmet need of patients who remain symptomatic despite today’s therapies.

The first data to come from UniTinA-asthma® were the PrimoTinA-asthma® studies, which demonstrated the efficacy and safety of tiotropium in asthma patients who remained symptomatic despite treatment with at least ICS/LABA therapy. Data from the PrimoTinA-asthma® studies have since been published in the New England Journal of Medicine.³

About asthma

Asthma is a chronic disorder of the airways characterised by airway inflammation and bronchoconstriction, leading to limited airflow into and out of the lungs and an increased production of mucus.⁶

When a person with asthma comes into contact with an asthma trigger (e.g. viral infection, pollen, smoke), their airways can become more inflamed, swollen and constricted and produce excess mucus. These reactions cause the airways to become narrower and irritated, making it difficult to breathe.⁶

People suffering from asthma experience recurrent episodes of wheezing, breathlessness, chest tightness and coughing.⁶ These episodes may be punctuated by periods of more severe and sustained deterioration in the management of symptoms, termed an asthma exacerbation or asthma attack.⁶

Estimates of the numbers of people affected by asthma worldwide vary from 100 to 300 million.^7-10 The prevalence of asthma is highest in industrialised countries. Worldwide, approximately 180,000 deaths are attributable to asthma each year,7 although there is considerable regional variation in mortality rates.¹¹

The economic costs associated with asthma are estimated to rank as one of the highest among chronic diseases. Globally, the economic costs associated with asthma exceed those of tuberculosis and HIV/AIDS combined.⁷ Developed economies can expect to spend up to 2% of their healthcare budget on asthma.¹⁰

By avoiding asthma triggers, one can help to reduce the severity of asthma. Although asthma cannot be cured, appropriate management can control the disease and enable people to enjoy a good quality of life. However, epidemiological data have shown that, despite treatment, at least 40% of adults with asthma remain symptomatic, which could result in lifestyle restrictions, and might even require emergency care.⁴ These patients could benefit from new treatment options.

About tiotropium

Tiotropium is a long-acting inhaled anticholinergic bronchodilator and was the first inhaled maintenance treatment to provide significant and sustained improvements in lung function in COPD patients with once-daily dosing. Tiotropium works by opening narrowed airways and helping to keep them open for 24 hours.

The tiotropium Respimat® in asthma clinical development programme is being jointly developed by Boehringer Ingelheim and Pfizer with Boehringer Ingelheim managing the operations for all clinical development activities. The existing alliance contract between Boehringer Ingelheim and Pfizer allows for commercialisation by both companies.

About Respimat® Soft MistTM Inhaler

Developed by Boehringer Ingelheim, Respimat® Soft MistTM Inhaler (SMI) is a new generation inhaler delivering a unique Soft Mist^TM12,13 that is easy to inhale,¹⁴ and is preferred by patients compared to other currently available inhalers.^15-16

References

1. Kerstjens HAM, Bleecker E, Meltzer E et al. Tiotropium as add-on therapy to inhaled corticosteroids for patients with symptomatic asthma: lung function and safety ERS 2013 abstract 4629.
2. Kerstjens HAM, Bleecker E, Meltzer E et al. Tiotropium as add-on to inhaled corticosteroids significantly improves asthma control as reflected by the ACQ responder rate ERS 2013 poster P4130.
3. Kerstjens HAM, Engel M, Dahl R et al. Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med 2012; 367 (13): 1198-1207.
4. Bateman ED, Boushey HA, Bousquet J, et al; GOAL Investigators Group. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med. 2004;170 (8): 836-44.
5. Taylor DR, Bateman ED, Boulet LP, et al. A new perspective on concepts of asthma severity and control. Eur Respir J. 2008; 32(3):545-54.
6. Global Initiative for Asthma (GINA). Pocket Guide for Asthma Management and Prevention. Available at: http://www.ginasthma.org/documents/1/Pocket-Guide-for-Asthma-Management-and-Prevention [last accessed 05/06/13].
7. World Health Organization. WHO factsheet 206: bronchial asthma. Available at: www.who.int/mediacentre/factsheets/fs206/en. [last accessed 05/06/13].
8. European Federation of Allergy and Airway Diseases Patients Association. http://www.efanet.org/asthma/ [last accessed 05/06/13].
9. World Health Organization. WHO factsheet 307: Asthma. Available at: http://www.who.int/mediacentre/factsheets/fs307/en/index.html [Accessed 05/06/13].
10. Masoli M, Fabian D, Holt S, et al. The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy 2004; 59: 469-478.
11. Masoli M, Fabian D, Holt S, et al. Global Burden of Asthma. Developed for Global Initiative for Asthma (GINA). 2003. Available at http://www.ginasthma.org/pdf/GINABurdenReport.pdf [Accessed 05/06/13].
12. Dhand R. Aerosol Plumes: Slow and steady wins the race. J Aerosol Med 2005; 18(3): 261-63.
13. Hochrainer D, Hölz H. Comparison of aerosol velocity and spray duration of Respimat® Soft MistTM Inhaler and pressurized Metered Dose Inhalers. J Aerosol Med 2005; 18(3): 273-282.
14. Kardos P, Golisch W, Wolf K. New SoftMistTM Inhaler is effective and easy to use in patients with asthma and COPD. Eur Respir J 2005; 26 (Suppl 49): 338s.
15. Hodder R, Reese PR, Slaton T. Asthma patients prefer Respimat® Soft MistTM Inhaler to Turbohaler. Int J Chronic Obstruct Pulm Dis 2009; 4: 225-232.
16. Schuermann W, Schmidtmann S, Moroni P, et al. Respimat® Soft MistTM Inhaler versus hydrofluroalkane metered dose inhaler: patient preference and satisfaction. Treatm Respir Med 2005;4 : 53-61.

*Please note: Tiotropium Respimat® is currently NOT APPROVED for use in asthma. Tiotropium’s safety and efficacy have not yet been fully established in asthma

†Inhaled corticosteroids

‡Long-acting beta2-agonists

§Difference between the maximum FEV1 measured within the first 3 hours post dosing and the FEV1 measurement at baseline (10 minutes before the first dose of trial medication)

**Difference between the trough FEV1 measured at the end of the dosing interval (24 hours post drug administration) and the FEV1 measurement at baseline (10 minutes before the first dose of trial medication)

††1 pack of cigarettes daily for 10 years