AstraZeneca's Symbicort gives asthma patients the power to get SMART
SummaryAstraZeneca's SMART is an experimental new regimen for its leading asthma drug Symbicort. A successful approval of this regimen may provide a major incentive to switch patients from GlaxoSmithKline's Seretide and keep new rivals at bay. However, recent labeling changes proposed by the FDA have significant implications for the possibility of future US approvals of variable dosing regimes.
The SMART (Symbicort Maintenance and Reliever Therapy) 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.
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 Symbicort's (budesonide/formoterol) adaptability for adjustable dosing though 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 GlaxoSmithKline's Seretide (fluticasone/salmeterol), but the dose can be increased during worsening of symptoms.
AstraZeneca submitted a regulatory application in for Symbicort SMART in November 2003. However, the application was withdrawn in November 2004 as a result of discussions during the mutual recognition process.
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 regimen may be approved in in late 2006.
Patient and physician education are key
If patients can identify the signs of a forthcoming exacerbation, SMART should allow them 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 patient's 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. As compliance among 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.
The power of variable dosing
If Symbicort's SMART indication allows for a reduction in emergency room visits, hospitalizations and systemic steroid use, this will be a powerful marketing position for AstraZeneca. The successful approval of Symbicort's SMART indication in the EU should provide a major incentive for physicians to switch patients from GSK's Seretide, which was the top-selling respiratory drug in 2004, to Symbicort.
In 2004, the value of the inhaled corticosteroid/long-acting bronchodilator (ICS/LABA) combination market in the five major European markets was $1.8 billion, with Symbicort holding a 27% market share. 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 linked to Foradil labeling
AstraZeneca submitted Symbicort for approval in the 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 market.
While the FDA's 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 GSK's 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 Novartis' Foradil (formoterol) label. Although Novartis has conducted a post-marketing asthma safety study with formoterol, the results were considered inconclusive. 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 Symbicort's 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 submission of a SMART indication.
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 LAB, 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 developing a next-generation product for Symbicort, meaning the future success of the drug hangs on the successful approval of the SMART indication. The treatment's flexible dosing may offer a paradigm-changing approach to asthma therapy, reducing the severity of asthma exacerbations by empowering patients with the ability to control their symptoms and break free from the fear of asthma attacks that limits their quality of life.
However, the development of SMART also reflects the fact that the discovery of truly innovative asthma therapies that 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.