An unexpected survival benefit in a head-to-head comparison of GlaxoSmithKline’s (GSK) asthma blockbuster Seretide/Advair (salmeterol/fluticasone propionate) and Boehringer Ingelheim’s Spiriva (tiotropium bromide) in patients with chronic obstructive pulmonary disease (COPD) has taken some of the sting out of the non-approvable letter received by GSK from the US FDA last August for the higher-dose version of the Advair Diskus inhaler in COPD.

Results of the European INSPIRE (Investigating New Standards for Prophylaxis in Reduction of Exacerbations) study, published in the American Journal of Respiratory and Critical Care Medicine (2008: Vol 177, pp 19-26), showed that Seretide 50/500µg Diskus (50 micrograms of salmeterol powder plus 500 micrograms of fluticasone propionate powder) reduced the risk of COPD patients dying from any cause by 52% compared with those taking Spiriva. INSPIRE was the first prospective study to report a statistically significant difference in the relative risk of all-cause mortality between two established treatments for COPD, GSK noted.

The researchers also found a small but statistically significant benefit in the health status of COPD patients using Seretide versus those on Spiriva. However, there was no significant difference in the exacerbation rate between the two therapies, which was the two-year study’s primary endpoint. Exacerbations (a sudden worsening of symptoms) are the key drivers of morbidity and mortality in COPD. Moreover, Boehringer Ingelheim criticised the emphasis laid by GSK on the mortality data, saying INSPIRE “was powered for the efficacy endpoint, but was not designed as a mortality trial”.

The INSPIRE study compared the relative efficacy of Seretide 50/500µg twice daily and Spiriva 18µg once daily in preventing exacerbations and related outcomes in 1,323 patients with severe or very severe COPD. The modelled annual exacerbation rate was 1.28 in the Seretide group and 1.32 in the Spiriva group (rate ratio: 0.967; 95% confidence interval (CI): 0.836 – 1.119; P = 0.656).

Health status as measured by the St George’s Respiratory Questionnaire (SGRQ) – a validated instrument used to assess the impact of airway disease on overall health, daily life and perceived well-being – showed marked improvements in the Seretide group versus Spiriva from early in the study, with the SGRQ total score for Seretide coming out 2.07 units lower at two years than the Spiriva group score (95% CI: 0.1 – 4.0; P = 0.038).

In terms of mortality, a reduced risk of dying on Seretide was seen by week 13 of treatment; after two years, 21 patients (3%) had died in the Seretide group compared with 38 (6%) in the Spiriva group (P = 0.032). Patients on Spiriva were 29% more likely to withdraw from the study – usually a consequence of rapid deterioration – than those on Seretide, with the probability of dropping out before week 104 measured at 34.5% in the Seretide and 41.7% in the Spiriva group (P = 0.005). However, pneumonia was reported more frequently in the Seretide than the Spiriva group (8% versus 4%), as was candidiasis (6% versus 3%).

No definitive conclusions
According to COPD authority Wisia Wedzicha, Professor of Respiratory Medicine at University College London and the Royal Free and University College Medical School in London, the “results seen in INSPIRE showing improvements in quality of life and survival are important for patients with COPD. There is no cure for COPD, so we must manage the disease as effectively as possible to provide patients with the best outcomes.”

But Boehringer Ingelheim downplayed the mortality findings, pointing out that patients who did not complete the study were not followed up and there was no independent adjudication of individual fatal cases. “No definitive conclusions, therefore, can be drawn from the apparent differences between the two treatment arms,” the company stated. The overall safety findings, including overall fatal events, were consistent with a population of patients with severe and very severe COPD, it said.

Treatment guidelines recommended tiotropium as first-line maintenance therapy for patients with all severities of COPD, while inhaled corticosteroids were recommended for patients with severe or very severe COPD and a history of repeated exacerbations, Boehringer Ingelheim noted.

Seretide/Advair is GSK’s best-selling drug, and the line was extended in 2003 when the European Union approved the higher-dose 500 Accuhaler for the symptomatic treatment of severe COPD, i.e., patients with a FEV1 (forced expiratory volume) below 50% of the predicted normal lung function, a history of repeated exacerbations and significant symptoms despite regular bronchodilator therapy. In 2007 the European labelling was exapanded to include patients with a FEV1 below 60% of the predicted normal before administering a bronchodilator.

In the USA, though, the Food and Drug Administration took GSK and analysts by surprise in August 2007 when it asked for more data on Advair 50/500 Diskus, specifically addressing how the higher-dose version compared with the currently approved 50/250µg strength. A FDA advisory committee had voted 11 to 0 that Advair 50/500 could significantly reduce the risk of exacerbations in COPD patients. However, the committee was not convinced – voting 9 to 2 against – that the data presented by GSK provided substantial evidence in support of a survival benefit for the 50/500 version.