Serevent warning focuses attention on the need for combination therapy
(Published 10 December 2004)

The recent announcement by the FDA's associate director for science and medicine that sales of GlaxoSmithKline's asthma drug Serevent should be restricted, or halted, led to an estimated 3.8% fall in the company's share price. However, Datamonitor's Laura Harris comments that, with Seretide accounting for the majority of GSK's asthma sales, the panic may be premature.
During a senate hearing, convened following the withdrawal of Merck & Co.'s COX-2 Vioxx (rofecoxib) in September, the FDA's David Graham commented that the safety profile of five other currently marketed drugs should be closely examined. Pfizer's COX-2 Bextra (valdecoxib), similar to Vioxx, was mentioned, as were Astra-Zeneca's cholesterol-lowering statin Crestor (rosuvastatin calcium), Roche's acne treatment Accutane (isotretinoin) and Abbott's weight loss drug Meridia (sibutramine hydrochloride monohydrate). It was at the same hearing that Dr Graham raised concerns about GSK's asthma inhaler Serevent (salmeterol).

Beta2-agonists called into question

Although widely used for over a decade, Serevent has come under fire in recent years due to the results of a GSK sponsored safety study, known as SMART (Salmeterol Multi-center Asthma Research Trial). Initiated in July 1996, SMART was designed to assess the adverse effects of Serevent, following concerns regarding the safety of regular use of short-acting and long-acting beta2-agonists in the management of asthma.

Interim analysis in late 2002 found that there was an increased incidence of life-threatening asthma related events, particularly in the African-American population. In the salmeterol group, there were a total of 13 deaths out of 13,174 patients treated for 28 weeks, or 0.1%, versus 0.03% (4 of 13,179) for those on a placebo.

Consequently, a black box warning was added to the Serevent US product labeling in August 2003. This stated that data from a large, placebo-controlled, US study comparing the safety of salmeterol or placebo, added to usual asthma therapy, showed a small but significant increase in asthma-related deaths. Indeed, this may have had a negative impact on US sales - while 10% growth was recorded between 2000 and 2001, sales fell in subsequent years, by 26% between 2001 and 2002, and 36% in 2002-2003.

Superior safety of Seretide

However, the majority of sales erosion can be attributed to the 2001 launch of GSK's combination asthma product, Seretide (salmeterol/fluticasone) in the US. The drug, which is known as Advair in the US, combines Serevent with GSK's inhaled corticosteroid Flixotide (fluticasone) in a Diskus inhaler. Seretide is currently the best selling asthma product, generating $3.2 billion of sales in the seven major markets in 2003. Although a key part of Seretide's appeal is its simple administration and convenience in enabling patients to take two asthma therapies simultaneously, the improved safety profile of salmeterol when administered concomitantly with a corticosteroid adds to Seretide's appeal.

Current asthma guidelines (National Asthma Education and Prevention Program) recommend that patients requiring more than as-needed short-acting beta2-agonists should be prescribed regular and adequate doses of an inhaled anti-inflammatory asthma medication, such as inhaled corticosteroids, for optimal benefit in the management of their asthma.

Although there was a low level of inhaled corticosteroid use in SMART, at 47% of the study population, data demonstrated that, in these patients, there were no significant differences in primary and asthma related adverse events, including death. In contrast, in patients who did not receive inhaled corticosteroids, there were a statistically significant greater number of asthma-related deaths in all patients taking salmeterol compared to those taking the placebo.

Serevent sales to suffer

In light of this data, and the current recommendations for combination therapy if using a long-acting beta2-agonist (LABA) such as salmeterol, Seretide is likely to experience continued market success. This will be at the expense of Serevent, which, following the FDA's comments last week, is likely to be infrequently used alone and will, therefore, suffer greater sales erosion.

However, if GSK can ensure continued patient switching to Seretide, the company's overall respiratory sales are unlikely to suffer and may actually increase as patients and physicians recognize the added convenience of Seretide. Furthermore, the Diskus is less expensive than the two monotherapies, conferring an additional benefit. As long as GSK can separate the public's perception of Seretide/Advair from that of Serevent, a sizeable task given the similarity of the products, it is likely that the initial panic caused by the FDA's comments will be relatively short-lived.

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