AstraZeneca is developing a new indication for its current leading asthma medication Symbicort (budesonide/formoterol), known as Symbicort Maintenance and Reliever therapy (SMART). The SMART approach allows patients to increase the dose of Symbicort (a combination of an inhaled corticosteroid and long-acting bronchodilator) during worsening of symptoms, which may offer a paradigm changing approach to asthma therapy; reducing the severity of asthma exacerbations by empowering patients to control their symptoms and to break free from the fear of asthma attacks which limit their life activities. The successful approval of Symbicorts SMART indication, expected in the EU in 2006, may provide a major incentive for physicians to switch patients from GlaxoSmithKlines (GSK) Seretide and be a significant barrier to entry of new competitors, which may have to offer variable dosing in order to compete with Symbicort. However, recent labeling changes proposed by the FDA to three asthma drugs (Advair/Seretide, Foradil, and Serevent) have significant implications for the possibility of future FDA approval of variable dosing regimes for the US market, according to a new report from independent market analyst Datamonitor* (DTM.L).

Asthma is a variable disease

Asthma is a highly variable disease, in that patients can have long periods of freedom from illness when they suffer no ill effects. However attacks (or exacerbations) are unpredictable, giving rise to fear and limiting life activities  and the attacks can be fatal and recurrent. Exacerbations involve a temporary increase in symptoms and reduction of lung function, which are most often triggered by infections due to viruses and bacteria. Current asthma maintenance therapies, such as inhaled corticosteroid/long-acting bronchodilator combination products, are generally prescribed on a fixed-dose basis. Hence, there remains an unmet need for adjustable dosing regimes that permit a temporary increase in drug dose during an asthma attack.

AstraZeneca is focusing on Symbicorts (budesonide/formoterol) adaptability for adjustable dosing though a concept known as Symbicort Maintenance and Reliever therapy (SMART), which was formerly known as Single inhaler Therapy (SiT). With the SMART approach, Symbicort is used to provide a stable dosing regime, as with GSKs Seretide (fluticasone/salmeterol), but the dose can be increased during worsening of symptoms. AstraZeneca submitted a regulatory application in Europe for Symbicort SMART in November 2003. However, the application was withdrawn in November 2004 as a result of discussions during the Mutual Recognition Process, says Datamonitor respiratory senior analyst Shaun Falkingbridge. At the time, the company expected the file to be submitted in the forth quarter of 2005, which will include data from two additional studies, known as COSMOS and SMILE. These studies compare the use of Symbicort as maintenance and reliever medication compared to traditional Symbicort or Seretide stable dosing regimes.

The new indication may be approved in Europe in the late 2006, he says.

Key to success is patient and physician education

If patients can identify the signs of a forthcoming exacerbation, SMART should allow patients to readily adjust their usual therapy as they are encouraged to use the drug as they start to get an increase in symptoms. The key to success for AstraZeneca is to convince patients and doctors that SMART offers an advance in treatment strategy by allowing patients to increase their preventative treatment earlier. From a patients perspective, one appeal of SMART is that currently some sufferers may be reluctant to contact doctors as their symptoms worsen, preferring to wait it out, only for the situation to get progressively worse. Additionally, as Symbicort is used as both maintenance therapy and symptom relief, this overcomes the need for a separate reliever inhaler, Falkingbridge says. As compliance amongst patients is negatively affected by complex treatment regimens, the Symbicort SMART approach, which requires fewer inhalers, may improve compliance because it is simpler for patients to use.

Ability to vary dose is a powerful marketing position

If Symbicorts SMART indication allows for a reduction in emergency room visits, hospitalizations and systemic steroid use, this will be a very powerful marketing position for AstraZeneca. The successful approval of Symbicorts SMART indication in the EU should provide a major incentive for physicians to switch patients from GSKs Seretide, which was the top-selling respiratory drug in 2004, to Symbicort. In 2004, the value of the ICS/LABA combination market in the five major European markets** was $1.8 billion***, with Symbicort holding a 27% market share. Datamonitor forecasts that Symbicort should increase its market share to 38% by 2008, with sales of over $1.2 billion. The competitive intensity of the class will increase dramatically from 2009 onwards as new ICS/LABA combinations are launched which may offer improvements in safety and compliance benefits such as once-daily dosing. However, the introduction of SMART may be a significant barrier to entry of new competitors, which may have to offer variable dosing in order to compete with Symbicort.

Success in US may depend on removal of blackbox warning for Foradil

AstraZeneca submitted Symbicort for approval in the US in September 2005, with a launch expected in early 2007. However, recent labeling changes proposed by the FDA to three asthma drugs (Advair/Seretide, Foradil, and Serevent) have significant implications for the possibility of future FDA approval of variable dosing regimes for the US market. While the FDAs Pulmonary-Allergy Drugs Advisory Committee advice was driven by a small but significant increase in asthma-related deaths in treated patients in a large post marketing trial with GSKs Serevent (salmeterol), the panel agreed that there may be a class effect with long-acting beta-2 agonists, and recommended that similar warnings be added to Novartiss Foradil (formoterol) label. Although Novartis has conducted a post-marketing asthma safety study with formoterol, the results were considered inconclusive, Falkingbridge says. As Symbicort contains formoterol, it will likely also be subject to the class warning.

With the ongoing uncertainty regarding whether formoterol may also cause asthma-related deaths, as with salmeterol, the FDA may be reluctant to consider approval of Symbicorts SMART regime, which results in short-term increases in the formoterol dose. However, if it can be shown that the risks are specific for salmeterol, the class warning on Foradil and Symbicort could be changed which would give a vital marketing advantage for Symbicort over Advair/Seretide, and open up the possibility for US submission of a SMART indication, he says.

However, it is unclear whether Novartis will invest significant resources towards conducting a large scale clinical trial of formoterol in order to demonstrate whether the safety issue is molecule or class specific, given that it is developing a next generation, once-daily long-acting bronchodilator, QAB-149. While this molecule will also be likely subject to the class warning, it is possible that both AstraZeneca and Novartis will position their products as safer alternatives to Seretide/Advair and Serevent, given that the risk of adverse events have only been definitely associated with salmeterol.

A paradigm changing approach?

AstraZeneca has not invested in development of a next-generation product for Symbicort, hence the future success of the drug hangs on the successful approval of the SMART indication expected in 2006. The flexible dosing may offer a paradigm changing approach to asthma therapy, reducing the severity of asthma exacerbations by empowering patients to control their symptoms and to break free from the fear of asthma attacks which limit their quality of life. However, the development of SMART also reflects the fact that the discovery of truly innovative asthma therapies which cure the disease, or prevent disease onset or progression, still remains elusive and companies need to focus on gaining the maximal clinical benefit from existing classes of drugs, Falkingbridge says.