New Options in COPD Therapy

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asthmaOnce-daily dosing with a very long-acting beta2-agonist (VLABA) would be a significant convenience and compliance-enhancing advantage leading to improved clinical outcomes in patients with asthma and chronic obstructive pulmonary disease (COPD). A once-daily VLABA will pave the way for a fixed-combination inhaler: with an inhaled corticosteroid in asthma and COPD and an inhaled long-acting anticholinergic for use in COPD.

Carmoterol 

Carmoterol is one such new VLABA in clinical development for asthma and COPD, and clinical data on a new metered-dose inhaler (pMDI) formulation were presented at the European Respiratory Society 16th Annual Congress. Professor Peter Barnes led off the discussion addressing the need for such a very long-acting agent. The inhaled route is preferred over the oral route when using VLABA because both routes allow excellent smooth muscle relaxation and bronchodilation, and the mast cells that are involved in bronchoconstriction are positioned close to the airway lumen and accessible to the inhaled route. Therefore, drug delivery via the inhaled route provides a much better bronchoprotective effect than the oral route. An airway that is bronchodilated continuously for 24 hours expends theoretically much less energy than airways subjected to repetitive closure when short-acting agents are used. Prof. Jean Bousquet, from France, presented information on a new, once-daily long-acting beta2-agonist (LABA), carmoterol.

This agent has a rapid onset, is a selective (RR) pure isomer, and is a full beta2-agonist -- which is in phase 2 clinical development as a hydrofluoroalkane pMDI with Chiesi's proprietary modulite technology.[1] This agent is also being developed as a fixed combination with an inhaled corticosteroid, and it is stable for at least 18 months at room temperature. The pharmacologic profile of carmoterol includes the fact that its potency in isolated guinea pig trachea is greater than formoterol and salmeterol. It is over 100 times more selective for bronchial muscle than myocardial tissue. This agent has been studied in healthy volunteers and in asthmatic patients with multiple escalating doses; there were no dose-response effects on glucose level and serum potassium, and very little tremor occurred except at the highest doses of 12-16 micrograms (mcg). Clinically, 2 mcg seems like the appropriate dose. No significant differences occurred in the QTc interval or in heart rate. Prof. Bousquet concluded that once-daily carmoterol demonstrated 24-hour bronchodilating effects. All doses had a rapid onset of action. Doses from 1.5 to 3 mcg produced clinically meaningful increases in forced expiratory volume in 1 second (FEV1), which persisted for 24 hours. In all doses tested, carmoterol was well tolerated with a good safety profile and no clinically relevant systemic effects.[2]

Ashley Woodcock, from the United Kingdom, performed a chronopharmacology study and compared carmoterol with formoterol. Whether the dose is given in the morning or at night, carmoterol was effective. The evening dosing, however, differentiated carmoterol from formoterol. Evening dosing with an ultra-long-acting beta-agonist also fits well with the once-daily inhaled steroid in combination for asthma. Further studies are clearly necessary.[3] In a second study, carmoterol 2 mcg once daily was as effective as formoterol 12 mcg twice daily after 7 days of treatment in patients with persistent asthma. There was a difference in lung function vs the placebo in trough FEV1 of 160 mL. Carmoterol once daily had a similar safety and tolerability profile when compared with formoterol twice daily. Previous data showed that tolerance to the bronchodilating effects of LABAs has been controversial.[4]

P. Maison-Blanche, from Paris, France, reported on the cardiovascular safety of carmoterol. He noted that as the heart rate increases, the QTc interval on an electrocardiogram can be influenced by changes in heart rate. Regardless of slight increases in heart rate, no higher incidence of cardiovascular events was associated with the LABA when compared with placebo. Cardiovascular assessment performed in multiple clinical trials supports phase 3 development of carmoterol because it appeared to be quite safe.[5]

On the basis of these data, my conclusion was that carmoterol once daily in all studies consistently showed clinically important bronchodilation over the 24-hour dosing interval. Together with the fast onset of action, once-daily dosing of carmoterol is as effective as formoterol 12 mcg twice daily. There is a favorable safety record as to its tolerability. Further clinical development will aim to establish the favorable risk-benefit profile in this new VLABA, especially when combined with once-daily corticosteroid in the same inhaler for the treatment of asthma and COPD.

Salmeterol

There has been a lot of controversy about the use of the LABA salmeterol for both asthma and COPD. New data offered a more positive note in that the combination of salmeterol/fluticasone (SFC) improves the inspiratory to total lung capacity (IC/TLC) ratio and exercise endurance time in patients with COPD.[6] B. Celli and colleagues[7] reported on an interesting 8-week, randomized, double-blind, parallel-group trial comparing SFC 50/250 mcg with salmeterol 50 mcg and placebo. A total of 185 COPD patients were enrolled. The IC/TLC ratio and exercise time were greater with the combination therapy. The IC/TLC increased by 16%. Predose SFC increased the IC/TLC ratio by 11%, whereas salmeterol increased it by 4%. In patients with an IC/TLC ratio ≤ 0.25 at baseline, the IC/TLC ratio increased to > 0.25 in more patients on SFC compared with salmeterol or placebo. This improvement in air trapping/hyperinflation has been shown to correlate with improved survival in other studies in COPD.[8] The study authors concluded that treatment with a LABA and inhaled corticosteroid together in SFC improves the IC/TLC ratio more than the long-acting bronchodilator or placebo alone.

Inhaled maintenance therapy and the risk for first or subsequent emergency department hospitalization in patients with COPD were studied by T.E. Delea and colleagues.[9] Data from a large US health insurance claim database from 1998 to 2004 were used, and 36,076 subjects were identified. SFC exposure was associated with a 57% lower risk for a first or subsequent COPD-related emergency department visit or hospitalization compared with ipratropium. This combination was also better than the combination of short-acting albuterol and ipratropium and with monotherapy in reducing visits to the emergency department and hospitalizations.[9]

Arformoterol

Another ultra-long-acting beta2-agonergic agent, nebulized arformoterol, was studied in a large population of patients with COPD, and the data were presented in poster format by John Hanrahan and his colleagues,[10] in Boston, Massachusetts. Data were reported on 1456 patients with COPD, with mean FEV1 of 1.3 L/second, who received nebulized arformoterol 15 mcg twice daily, 25 mcg twice daily, or 50 mcg once daily, or salmeterol 42 mcg twice daily or placebo. The primary outcome was the percentage of change from baseline FEV1. The results showed that the improvement in trough FEV1 was greater for arformoterol and salmeterol than for placebo, both after the first dose and at week 12. The 25-mcg twice-daily use for arformoterol increased the FEV1 by 19%. All of the doses of LABAs were safe. This agent will provide a new, efficacious, and safe LABA for use by nebulization.[11]

Indacaterol

Indacaterol, a novel, once-daily beta2-agonist, also provided effective 24-hour bronchodilation in moderate-to-severe COPD. S. Rennard and colleagues[11] conducted a 7-day randomized, double-blind, placebo-controlled study with an 8-day, open-label extension with tiotropium and studied the efficacy and safety of indacaterol. Some 635 patients received indacaterol 50, 100, 200, 400 mcg once daily by a multidose dry powder inhaler. Dose-dependent FEV1 increases vs placebo were seen for indacaterol at all time points on days 1 and 7. On day 1, the peak FEV1 increase was 290 ± 30 mL. The trough FEV1 was measured at 22 and 24 hours, and differences with placebo were 120 mL with the 200- and 400-mcg doses. The indacaterol trough FEV1 compared favorably to the improvement with tiotropium. In conclusion, this drug was well tolerated and provided effective, dose-related, 24-hour bronchodilation with an onset of action of 5 minutes. These encouraging results with indacaterol warrant further study, possibly combined with once-daily long-acting muscarinic antagonists (LAMAs) and inhaled corticosteroids.[11]

Long-acting Inhaled Beta2-Agonist and Anticholinergic Drugs

Cazzola and colleagues,[12] from Italy, studied the effects of a long-acting inhaled beta2-agonist and anticholinergic drugs on respiratory function and arterial blood gases. Patients received tiotropium 18 mcg, salmeterol 50 mcg, or formoterol 12 mcg. All treatments improved lung function. The effect of salmeterol and tiotropium on gas exchange was slower in onset and more prolonged than with formoterol. A transient decrease in PaO2 was noted with formoterol (0-180 minutes), more so than with the salmeterol treatment group, whereas the tiotropium patients had the least decline in PaO2. This transient decline in PaO2 is well known with short-acting beta-agonists and now can be extended to LABAs. Perhaps it is due to changes in ventilation/perfusion with more vasodilation transiently than bronchodilation. Therefore, oxygen saturation should be monitored if LABAs are used in patients with compromised respiratory status.[12]

Towards a Revolution in COPD Health

There has been a lot of controversy as to whether LABAs increase deaths in asthma and COPD. The landmark study Towards a Revolution in COPD Health (TORCH) was a 3-year study of 6184 patients powered on the primary outcomes of all-cause mortality and the difference between the combination of SFC vs placebo. In addition, COPD mortality was evaluated along with lung function, exacerbations, and health status. Physicians and patients in 42 countries participated, and 23% of the patients were from North America. The average patient's age was 65; 76% were males; and 82% were whites. The body mass index on average was 25 kg/m2; the cumulative pack-years of smoking was 43; 10% of the patients had very severe disease; 50% had severe disease; and over 30% had moderate COPD with the Global Obstructive Lung Disease (GOLD) Guideline severity staging system. The combination SFC improved lung function more than the 2 monocomponents as well as placebo. Furthermore, there was an initial substantial improvement in lung function with active therapy, and it took over 2.5 years for those receiving the combination to return to the baseline level at the beginning of the study. With monotherapy with either agent, deterioration occurred faster than the combination. In contrast, those who were on placebo lost lung function at the usual rate. A second very interesting observation is that the combination reduced the yearly rate of decline in FEV1, a surrogate for disease modification. Also of interest is the fact that the combination reduced the total number of exacerbations and reduced the number of exacerbations requiring oral steroids and hospitalization. The primary outcome, however, was all-cause mortality. Here again, the combination had a significant effect in that it produced a 17% risk reduction in death and a 2.6% absolute reduction. The P value was extremely close to significance at P = .052. Also, the monotherapy arm with salmeterol had better survival statistics than placebo, although it did not reach statistical significance. There was uniformity in that all of the outcomes favored the combination. The improvement in survival, the reduction in exacerbations, the yearly decline in FEV1, and hospitalization was very encouraging.[13] The fact that there was a mortality benefit to LABA as opposed to increased deaths seen with LABAs in the Salmeterol Multi-center Asthma Research Trial (SMART),[14,15] reported by Salpeter and colleagues,[16] is also remarkably reassuring to physicians. Certainly, a prospective study, such as TORCH, is a more accurate way of answering the question of safety of LABAs in COPD vs a meta-analysis.

Conclusion

In general, the future for LABAs looks bright with attractive long-acting agents, such as carmoterol, indacaterol, and arformoterol, on the horizon and the combination of LABAs/inhaled corticosteroids as in TORCH, proving to be not only safe, but offering the potential for disease modification and enhanced survival.

References

  1. Cazzola M, Matera MG, Lotvall J. Ultra long-acting beta 2-agonists in development for asthma and chronic obstructive pulmonary disease. Expert Opin Investig Drugs. 2005;14:775-783. Abstract
  2. Kottakis I, Nandeuil A, Raptis H, Linberg SE, Bousquet J. Comparison of the efficacy and safety of 5 different doses of the novel very long acting beta2-agonist carmoterol. Program and abstracts of the European Respiratory Society 16th Annual Congress; Munich, Germany; September 2-6, 2006. Poster 3865.
  3. Nandeuil A, Kottakis I, Raptis H, Roslan H, Ivanov Y, Woodcock A. Safety and tolerability of the novel very long acting beta2-agonist carmoterol given as a 2mcg qd dose: 8 days comparison with formoterol and placebo in patients with persistent asthma. Program and abstracts of the European Respiratory Society 16th Annual Congress; Munich, Germany; September 2-6, 2006. Poster 3859.
  4. Kottakis I, Nandeuil A, Raptis H, Savu A, Linberg SE, Woodcock A. Efficacy of the novel very long-acting beta2 agonist carmoterol following 7 days once daily dosing: comparison with twice daily formoterol in patient with persistent asthma. Program and abstracts of the European Respiratory Society 16th Annual Congress; Munich, Germany; September 2-6, 2006. Poster 3858.
  5. Linberg SE, Heyman E, Nandeuil MA, Kottakis I, Maison-Blanche P. Cardiac safety of the novel very long-acting beta2-agonist carmoterol following single rising doses in healthy volunteers. Program and abstracts of the European Respiratory Society 16th Annual Congress; Munich, Germany; September 2-6, 2006. Poster 3861.
  6. Perng DW, Wu CC, Su KC, Lee YC, Perng RP, Tao CW. Inhaled fluticasone and salmeterol suppress eosinophilic airway inflammation in chronic obstructive pulmonary disease: relations with lung function and bronchodilator reversibility. Lung. 2006;184:217-222. Abstract
  7. Celli B, Emmett A, Crater G, Kalberg C. Salmeterol/fluticasone propionate (SFC) improves the inspiratory to total lung capacity ratio (IC/TLC) and exercise endurance time in patients with COPD. Program and abstracts of the European Respiratory Society 16th Annual Congress; Munich, Germany; September 2-6, 2006. Poster 4395.
  8. O'Donnell DE, Sciurba F, Celli B, et al. Effect of fluticasone propionate/salmeterol on lung hyperinflation and exercise endurance in COPD. Chest. 2006;130:647-656. Abstract
  9. Delea TE, Hagiwara M, Akazawa M, Stanford R. Inhaled maintenance therapy and risk of first or subsequent emergency department visit/hospitalization in patients with COPD. Program and abstracts of the European Respiratory Society 16th Annual Congress; Munich, Germany; September 2-6, 2006. Poster 4401.
  10. Hanrahan JP, Kerwin E, Cheng H, Grogan DR, Baumgartner RA. Arformoterol in COPD: safety results from two pooled phase 3 trials. Program and abstracts of the European Respiratory Society 16th Annual Congress; Munich, Germany; September 2-6, 2006. Poster 2500.
  11. Rennard S, Bantje T, Higgins M, Jack D, Owen R. Indacaterol, a novel once-daily 2-agonist, provides effective 24-hour bronchodilation in moderate-to-severe COPD. Program and abstracts of the European Respiratory Society 16th Annual Congress; Munich, Germany; September 2-6, 2006. Poster 3053.
  12. Cazzola M, Morelli N, Pizzolato S, Buratto P, Belloli E, Centanni S. Effects of long-acting inhaled-adrenergic and anticholinergic drugs on respiratory function and arterial blood gases in patients with COPD. Program and abstracts of the European Respiratory Society 16th Annual Congress; Munich, Germany; September 2-6, 2006. Poster 3049.
  13. Celli B, Calverley PMA, Anderson JA, et al. The TORCH (TOwards a Revolution in COPD Health) study: salmeterol/fluticasone propionate (SFC) improves health status, reduces exacerbations and improves lung function over three years. Program and abstracts of the European Respiratory Society 16th Annual Congress; Munich, Germany; September 2-6, 2006. Poster E312. Available at: http://www.ersnet.org/learning_resources_player/abstract_print_06/main_frameset.htm Accessed October 4, 2006.
  14. Wooltorton E. Salmeterol (Serevent) asthma trial halted early. CMAJ. 2003;168:738.
  15. Perera BJ. Salmeterol multicentre asthma research trial (SMART): interim analysis shows increased risk of asthma related deaths. Ceylon Med J. 2003;48:99.
  16. Salpeter SR, Buckley NS, Ormiston TM, Salpeter EE. Meta-analysis: effect of long-acting beta-agonists on severe asthma exacerbations and asthma-related deaths. Ann Intern Med. 2006;144:904-912. Abstract
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