COPD: Evaluating the Pipeline

MARCH 23, 2015
Michael R. Page, PharmD, RPh
Several new treatments for COPD are in development.
Chronic obstructive pulmonary disease (COPD) is a progressive pulmonary disease associated with wheezing, shortness of breath, and copious sputum production.1 Patients with COPD may develop the condition as a result of exposure to lung irritants including tobacco smoke, air pollution, chemical fumes, and dust. COPD is projected to be the third leading cause of death worldwide by 2030, up from the fifth leading cause in 2002.2 A variety of new medications and combination treatments are in development to help patients with COPD achieve improved symptom control and a better quality of life (Online Table).

Table: Pipeline Agents in Development for COPD
Treatment Pharmaceutical Company Phase
SAMA
Glycopyrrolate Sunovion 3 (recruiting)
LAMA
Glycopyrronium bromide Novartis 3 (some complete, others recruiting)
LAMA/LABA
Olodaterol/tiotropium bromide Boehringer-Ingelheim 3 (complete)
Indacaterol/glycopyrronium bromide Novartis 3 (some complete, others recruiting)
Anti-IL-5 monoclonal antibodies
Benralizumab AstraZeneca 3 (recruiting)
Mepolizumab GlaxoSmithKline 3 (recruiting)
IL-5 = interleukin-5; LABA = long-acting β2-agonist; LAMA = long-acting muscarinic antagonist; SAMA = short-acting muscarinic antagonist.
Adapted from references 4-9, 11-13, and 19-23.

SAMAs and LAMAs
Short-acting muscarinic antagonists (SAMAs) are a mainstay of treatment for COPD, but these medications must be inhaled multiple times daily. Newer longacting agents may help improve adherence through once-daily administration. These long-acting muscarinic antagonists (LAMAs) include tiotropium and aclidinium. One LAMA (glycopyrronium bromide) and 1 SAMA (glycopyrrolate) are in late-stage development as treatments for COPD.3

Glycopyrrolate
Phase 2 efficacy data with twice-daily glycopyrrolate inhalation solution have been reported in patients with moderate to severe COPD. The medication, which is administered through the eFlow nebulizer system, was tested at 4 dosage strengths (12.5 mcg, 25 mcg, 50 mcg, and 100 mcg daily). After 28 days of treatment, patients receiving glycopyrrolate inhalation solution experienced improvements in forced expiratory volume in 1 second (FEV1) ranging from an average of 117 mL at the lowest dose to 177 mL at the highest dose.4 A long-term phase 3 trial of the medication is currently recruiting participants.5

Glycopyrronium Bromide
Glycopyrronium bromide is an inhaled LAMA for patients with moderate to severe COPD. This inhaled maintenance treatment has long-term efficacy similar to tiotropium.6 In a phase 3 noninferiority trial of glycopyrronium versus tiotropium, investigators evaluated improvements in FEV1 over 12 weeks. Although glycopyrronium led to a more rapid FEV1 improvement on day 1, the 2 treatments improved FEV1 to an equal degree by week 12.7

In long-term phase 3 trials, when compared with placebo, patients receiving glycopyrronium bromide 50 mcg, inhaled daily, for moderate to severe COPD experienced improvements in lung function were maintained over 52 weeks of therapy. Treatment also reduced dyspnea symptoms, improved health status and exercise endurance, and reduced rates of COPD exacerbations.8 Medications for COPD that include glycopyrronium bromide have been approved abroad, but are not yet approved in the United States.9

LABA/LAMA
Unlike older long-acting beta2-agonists (LABAs), such as salmeterol and formoterol, that require twice-daily dosing, indacaterol and olodaterol are members of a new generation of LABAs that are used once daily. By combining these medications in a single product that can be used once daily, scientists hope to improve adherence in patients with COPD who may have difficulty maintaining a twicedaily inhaler regimen.10

Olodaterol/Tiotropium Bromide
Near-term approval is expected for a combination of 2 medications that are already available in single-ingredient formulations: the LAMA tiotropium (Spiriva HandiHaler [tiotropium bromide] inhalation powder) and the once-daily LABA olodaterol (Striverdi Respimat [olodaterol] inhalation spray). In phase 3 trials, this combination has been studied in more than 7000 patients with COPD.11

In a short-term phase 3 trial, patients with COPD received placebo, olodaterol, tiotropium, or combination treatment with tiotropium and olodaterol over the course of 6 weeks. Investigators evaluated a primary end point of a change in the area under the FEV1 curve over 24 hours. The average improvement in the primary end point over the same measure in patients receiving placebo was 280 mL with the high-dose regimen (tiotropium 5 mcg/olodaterol 5 mcg; P <.0001) and 277 mL with the low-dose regimen (tiotropium 2.5 mcg/olodaterol 5 mcg; P <.0001).12

Similarly, in a long-term phase 3 trial, after 6 months of treatment, combination therapy with tiotropium 5 mcg/olodaterol 5 mcg improved trough FEV1 by 140 mL on average—greater than the improvements observed with tiotropium 2.5 mcg/ olodaterol 5 mcg (118 mL), tiotropium 2.5 mcg (73 mL), tiotropium 5 mcg (80 mL), or olodaterol 5 mcg (55 mL). These trials were submitted to the FDA in August 2014, and the medication is currently under FDA review.13

Indacaterol/Glycopyrronium Bromide
In a 12-week, placebo-controlled study, investigators randomized 449 patients with moderate to severe COPD in a 1:1 ratio to receive inhaled indacaterol/glycopyrronium or inhaled indacaterol alone. The combination treatment offered significantly better improvements in trough FEV1 both on day 1 (by a mean of 74 mL; P <.001) and at week 12 (by a mean of 64 mL; P <.001).14

In other trials, combination treatment with indacaterol/glycopyrronium also outperformed tiotropium in terms of increases in trough FEV1, reductions in rescue medication use, and changes in patient-reported dyspnea and lung function scores.15,16 Additionally, a recent network meta-analysis of COPD treatments concluded that indacaterol may be the most effective agent in terms of improving trough FEV1, second in efficacy only to glycopyrronium and tiotropium.17 Phase 3 trials are complete, and approval has already been secured in Japan and Europe.9

Anti-IL-5 Monoclonal Antibodies
The interleukin-5 (IL-5) receptor is known to regulate the differentiation, development, survival, and migration of cells involved in regulating immunity, including eosinophils, basophils, and mast cells. Monoclonal antibodies that block the IL-5 receptor may help reduce levels of eosinophils to exert anti-inflammatory effects.18 Two treatments of this type in late-stage trials for COPD are benralizumab and mepolizumab.

Benralizumab
In a phase 2a study, investigators examined the efficacy of benralizumab in reducing COPD exacerbations. Patients involved in the study were between the ages of 40 and 85 years, had moderate to severe COPD, and had documented elevations in sputum eosinophil levels. Patients received placebo or benralizumab 100 mg subcutaneously, with the first 3 doses administered every 4 weeks and the remaining 5 doses administered every 8 weeks, for a total of 48 weeks of treatment. Although benralizumab did not reduce the annualized COPD exacerbation rate, after 56 weeks, benralizumab improved FEV1 by a mean of 130 mL in patients receiving active treatment, while patients receiving placebo experienced a mean FEV1 reduction of 60 mL (P = .014).19 A phase 3 trial of benralizumab is currently recruiting patients with COPD.20

Mepolizumab
Mepolizumab, another IL-5 receptor antagonist, is in phase 3 trials as an adjunct to standard background therapies in patients with COPD who are at a high risk for exacerbations. Two 52-week clinical studies in the phase 3 program are expected to enroll a total of approximately 1500 patients.21 Patients will receive mepolizumab subcutaneously at a dose of 100 mg every 4 weeks. Study recruitment is ongoing.22,23

In Summary
Treatments in late-stage development for COPD include long-acting bronchodilators, antimuscarinic agents, and IL-5 receptor antagonists. With more treatment options and more convenient dosing regimens, pipeline agents for COPD management are likely to improve the ease-of-use and efficacy of treatment in patients with this debilitating disease.


Michael R. Page, PharmD, RPh, earned his PharmD from the Ernest Mario School of Pharmacy at Rutgers University. He has worked as a community pharmacist at CVS Pharmacy and is currently clinical editor in clinical and scientific affairs at Pharmacy Times.

References
  1. National Heart Lung and Blood Institute. What Is COPD? National Institutes of Health website. www.nhlbi.nih.gov/health/health-topics/topics/copd. Accessed February 2015.
  2. World Health Organization. Chronic obstructive pulmonary disease (COPD). World Health Organization website. www.who.int/mediacentre/factsheets/fs315/en/. Accessed February 2015.
  3. Pulido-Rios MT, McNamara A, Obedencio GP, et al. In vivo pharmacological characterization of TD-4208, a novel lung-selective inhaled muscarinic antagonist with sustained bronchoprotective effect in experimental animal models. J Pharmacol Exp Ther. 2013;346(2):241-250.
  4. Sunovion Pharmaceuticals Inc announces dose ranging data from phase 2 study of SUN-101 (glycopyrrolate) inhalation solution for treatment of patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) [news release]. Marlborough, MA: Sunovion Pharmaceuticals Inc, October 27, 2014. www.sunovion.com/news/pressReleases/20141027.pdf. Accessed February 2015.
  5. ClinicalTrials.gov. A long-term safety trial of treatment with nebulized SUN-101 in patients with COPD (GOLDEN-5). https://clinicaltrials.gov/ct2/show/NCT02276222. Accessed February 2015.
  6. Prakash A, Babu KS, Morjaria JB. Profile of inhaled glycopyrronium bromide as monotherapy and in fixed-dose combination with indacaterol maleate for the treatment of COPD. Int J Chron Obstruct Pulmon Dis. 2015;10:111-123.
  7. Prakash A, Babu KS, Morjaria JB. Profile of inhaled glycopyrronium bromide as monotherapy and in fixed-dose combination with indacaterol maleate for the treatment of COPD. Int J Chron Obstruct Pulmon Dis. 2015;10:111-123.
  8. Riario-Sforza GG, Ridolo E, Riario-Sforza E, Incorvaia C. Glycopyrronium bromide for the treatment of chronic obstructive pulmonary disease. Expert Rev Respir Med. 2015;9(1):23-33.
  9. Novartis first-in-class once-daily dual bronchodilator Ultibro Breezhaler (QVA149) achieves near simultaneous approval for COPD patients in Europe and Japan [news release]. Basel, Switzerland: Novartis, September 23, 2013. www.novartis.com/newsroom/media-releases/en/2013/1730580.shtml. Accessed February 2015.
  10. Montuschi P, Ciabattoni G. Bronchodilating drugs for chronic obstructive pulmonary disease: current status and future trends. J Med Chem. Published online January 14, 2015.
  11. Boehringer Ingelheim announces US filing for the fixed-dose combination tiotropium plus olodaterol for patients with COPD. Ridgefield, CT: Boehringer-Ingelheim, August 19, 2014. http://us.boehringer-ingelheim.com/news_events/press_releases/press_release_archive/2014/08-19-14-boehringer-ingelheim-us-filing-fixed-dose-combination-tiotropium-plus-olodaterol-patients-copd.html. Accessed February 2015.
  12. Boehringer Ingelheim presents first phase 3 data on fixed-dose combination of tiotropium plus olodaterol in COPD. Ridgefield, CT: Boehringer-Ingelheim, May 21, 2014. http://us.boehringer-ingelheim.com/news_events/press_releases/press_release_archive/2014/05-21-14-boehringer-ingelheim-presents-first-phase-3-data-fixed-dose-combination-tiotropium-plus-olodaterol-copd.html. Accessed February 2015.
  13. Boehringer Ingelheim presents pivotal phase III data for the investigational fixed-dose combination of tiotropium + Olodaterol in COPD. Ridgefield, CT: Boehringer-Ingelheim, September 8, 2014. http://us.boehringer-ingelheim.com/news_events/press_releases/press_release_archive/2014/09-08-14-boehringer-ingelheim-presents-pivotal-phase-iii-data-investigational-fixed-dose-combination-tiotropium-olodaterol-copd.html. Accessed February 2015.
  14. Vincken W, Aumann J, Chen H, Henley M, McBryan D, Goyal P. Efficacy and safety of coadministration of once-daily indacaterol and glycopyrronium versus indacaterol alone in COPD patients: the GLOW6 study. Int J Chron Obstruct Pulmon Dis. 2014;9:215-228.
  15. Rodrigo GJ, Plaza V. Efficacy and safety of a fixed-dose combination of indacaterol and glycopyrronium for the treatment of COPD: a systematic review. Chest. 2014;146(2):309-317.
  16. Mahler DA, Decramer M, D'Urzo A, et al. Dual bronchodilation with QVA149 reduces patient-reported dyspnoea in COPD: the BLAZE study. Eur Respir J. 2014;43(6):1599-1609.
  17. Cope S, Donohue JF, Jansen JP, et al. Comparative efficacy of long-acting bronchodilators for COPD: a network meta-analysis. Respir Res. 2013;14:100.
  18. Molfino NA, Gossage D, Kolbeck R, Parker JM, Geba GP. Molecular and clinical rationale for therapeutic targeting of interleukin-5 and its receptor. Clin Exp Allergy. 2012;42(5):712-737.
  19. Brightling CE, Bleecker ER, Panettieri RA Jr, et al. Benralizumab for chronic obstructive pulmonary disease and sputum eosinophilia: a randomised, double-blind, placebo-controlled, phase 2a study. Lancet Respir Med. 2014;2(11):891-901.
  20. ClinicalTrials.gov. Benralizumab efficacy in moderate to very severe chronic obstructive pulmonary disease (COPD) with exacerbation history (GALATHEA). https://clinicaltrials.gov/ct2/show/NCT02138916. Accessed February 2015.
  21. GSK announces start of phase III programme for mepolizumab in patients with COPD [news release]. London, UK: GlaxoSmithKline, April 29, 2014. http://us.gsk.com/en-us/media/press-releases/2014/gsk-announces-start-of-phase-iii-programme-for-mepolizumab-in-patients-with-copd/. Accessed February 2015.
  22. ClinicalTrials.gov. Mepolizumab in chronic obstructive pulmonary diseases (COPD) with eosinophilic bronchitis. https://clinicaltrials.gov/ct2/show/NCT01463644. Accessed February 2015.
  23. ClinicalTrials.gov. Efficacy and safety of mepolizumab as an add-on treatment in chronic obstructive pulmonary disease (COPD). https://clinicaltrials.gov/ct2/show/NCT02105961. Accessed February 2015.


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