GlaxoSmithKline has been left stunned by a decision by US regulators to issue a ‘not approvable’ letter the highest dose of its asthma inhaler Advair Diskus for the treatment of chronic obstructive pulmonary disease.

In issuing the letter, the US Food and Drug Administration questioned how a 500/50 microgram dose of Advair/Seretide (fluticasone and salmeterol) compared to the currently approved 250/50 strength in order to allow for appropriate dosing recommendations. GSK said it will be meeting with the agency to discuss this request in more detail and determine next steps, including discussion of data the firm has recently generated on the reduction of exacerbations with the Advair 250/50 strength.

Katharine Knobil, vice president of respiratory clinical development for COPD at GSK said that “we are very surprised and disappointed by this FDA decision” particularly given the outcome of the agency’s advisory committee meeting in May. The latter voted unanimously (11 to 0) that Advair 500/50 demonstrated a significant reduction in the risk of exacerbations in patients with COPD, the fourth leading cause of death in the USA.

Ms Knobil added that “we believe in the strength of the data; this application is based on the results of the largest COPD study conducted in more than 6,000 patients over three years. We are committed to working with the FDA to address any questions they have and to pursue a way forward.” Given the comments made by the advisory committee in May, that way forward may require a head-to-head comparison of the highest dose and the 250/50 dose of Advair, which GSK has not put before the agency. Instead, the firm submitted data from three clinical trials to the FDA in support of the new indication for Advair, including the landmark 6,100-patient TORCH study which showed a 2.6% improvement in survival over three years among patients receiving Advair compared to placebo.

Some observers believe that the not ‘approvable letter’ is a sign that the FDA is taking an ever-more cautious line when it comes to giving the green light to drugs but whatever the reason, a new approval would have helped GSK add to its already impressive sales of Advair which reached £871 million in the second quarter. More cash in the coffers would have been particularly welcome at a time when the firm is suffering from sliding sales of the diabetes drug Avandia (rosiglitazone), as prescribers pull back following a meta-analysis that alleged increased risk of cardiovascular disease.