Global Insight Perspective | |
Significance | From a relative position of strength, GSK concentrated on data showing Advair's impact on mortality rates in chronic obstructive pulmonary disease (COPD). Meanwhile, AstraZeneca presented results from two studies indicating that Symbicort was more effective than Advair in reducing asthma exacerbations and providing rapid relief from symptoms of breathlessness in COPD patients. |
Implications | Analysts have been looking to GSK to supply a more positive assessment of Advair's benefits in prolonging the lives of COPD patients following the ambivalent preliminary data from the TORCH study released in March. AstraZeneca's findings on asthma exacerbations bolster its claims for SMART (Symbicort Maintenance and Reliever Therapy), the single inhaler therapy re-filed for European Union (EU) approval in September 2005. The Symbicort COPD data pave the way for future submissions in a market segment where Advair already has a presence. |
Outlook | In the updated TORCH presentation, the Advair data still did not quite achieve statistical significance. But the 17.5% reduction in mortality was viewed as clinically significant and a platform for broader indications at a time when Advair is under pressure over its safety record. For its part, AstraZeneca has strengthened the case for Symbicort both as a flexible-dose regimen and in the still underserved territory of COPD. |
As the later arrival of the two-in-one anti-asthmatics, with a U.S. launch not due until 2007, a narrower palette of indications and sales little more than one-third those of its rival, Symbicort has more reason to knock the competition.
In the second quarter of 2006, sales of Advair rose by 13% to £822 million (US$1.56 billion), despite the addition of a black-box warning to the product’s U.S. label and further negative publicity from a recent U.S. meta-analysis linking the drug and other long-acting beta agonists (LABAs) to a significantly increased risk of asthma-related deaths (see United Kingdom: 21 June 2006: GSK Slams U.S. Meta-Analysis Linking Serevent/Advair to Asthma Deaths).
In the same quarter, sales of Symbicort were up by a vigorous 25%, but at £308 million they were still a long way behind Advair's current monopoly of the market for combination asthma therapy. In its annual business review in June, nonetheless, AstraZeneca said Symbicort had grown by 27% over the past year, well ahead of the 17% increase in the fixed combination market, and was winning market share from Advair in those countries (outside the United States) where the two products competed.
At the annual ERS congress in Munich, AstraZeneca presented two sets of clinical data claiming superior efficacy to Advair. The first, PharmaTimesreports, was results from the COMPASS study comparing the Symbicort SMART formulation with higher fixed doses of both Symbicort and Advair using Bricanyl (terbutaline) as an asthma reliever.
While asthma patients on maintenance therapy normally have to increase their use of a short-acting beta agonist (SABA) to relieve symptoms when their condition worsens, the rationale for SMART is that the formoterol component is a long-acting beta agonist with a fast onset of action. Hence Symbicort SMART can be used both as maintenance therapy and a reliever, with patients adjusting their medication in response to varying symptoms.
As AstraZeneca reported at its annual business review, the double-blind COMPASS trial confirmed the results of the earlier COSMOS study, an open comparison of Symbicort SMART and Advair in a 'real-life' setting. In the COMPASS trial, Symbicort SMART was 39% more effective than Advair in reducing severe asthma exacerbations, as well as 28% more effective than a double dose of conventional Symbicort.
These findings contrasted sharply with those of the CONCEPT study last year, when GSK said the first head-to-head comparison of Advair and Symbicort had produced a 47% reduction in the rate of moderate/severe asthma exacerbations in patients taking Advair compared with those on Symbicort. On that occasion, AstraZeneca claimed the comparison was unfair as the Advair group was on a fixed dose, while the Symbicort patients could vary the dose themselves, taking less if needed (see United Kingdom: 25 March 2005: GSK Wins in Head-to-Head Trial with AstraZeneca's Asthma Drug).
The second trial presented by AstraZeneca at the ERS meeting was a study using a Symbicort formulation based on a pressurised metered dose inhaler that is not yet approved in the European Union (EU), PharmaTimes noted. These results showed that Symbicort had an onset of action comparable to salbutamol and was more effective than Advair in improving airway dilation five minutes after inhalation.
Clinical, Not Statistical Significance
GSK's update on the TORCH (Towards a Revolution in COPD Health) study with Advair in COPD had been eagerly awaited. In the event, only the main data were released, since the full study has been submitted for publication in the New England Journal of Medicine.
The 6,100 patients in the TORCH study were randomised into four groups: the inhaled corticosteroid fluticasone alone, the long-acting beta-agonist salmeterol alone, the fixed Advair combination or placebo. The main message was that the risk of death at three years was 17.5% lower for patients on Advair compared with those given placebo.
While this result narrowly missed statistical significance, researchers suggested it could be highly significant clinically—with the qualification that the data still presented a "very mixed picture" and more research was needed to establish with greater certainty whether Advair reduced deaths from COPD, Bloomberg reported. As APM Health Europe pointed out, an electronic poster session showed no difference in risk of death between patients receiving Advair and those on salmeterol alone, although Advair improved survival significantly compared with fluticasone. Nonetheless, researchers believe treatment recommendations and the labelling for Advair could change once the full data on relative risks of death from COPD are published.
Outlook and Implications
AstraZeneca's findings from the COMPASS study with Symbicort SMART are part of a data package submitted to the European regulatory authorities as a variation application last September. This submission contained new clinical data from the COSMOS and COMPASS trials as well as from the SMILE study, which looked at the contribution of budesonide to the 'as needed' effect of Symbicort SMART.
With Symbicort not expected on the U.S. market until mid-2007, despite a faster-than-expected approval for maintenance treatment of asthma sufferers aged 12 years and over (see United Kingdom: 24 July 2006: AstraZeneca’s Symbicort Clinches Earlier-Than-Expected U.S. FDA Nod for Asthma), AstraZeneca will be counting on the SMART formulation to fill some of that gap and give the company further leverage in softening GSK's dominance of the combination anti-asthma category. An earlier European submission for the Symbicort single inhaler therapy was withdrawn in November 2004, due to inadequate data (see United Kingdom: 4 November 2004: AstraZeneca Concedes Defeat on Rapid Symbicort Approval in EU).
In the longer term, AstraZeneca is looking at line extensions for Symbicort in paediatric asthma and COPD, with a U.S. filing for COPD envisaged in the first half of 2008. This allows GSK some breathing space to pursue its own consolidation of Advair as a key therapy for COPD, a widely misunderstood and under-diagnosed condition that is the fourth-leading cause of death in the developed world.