Symbicort catching up with Seretide in COPD.

An article published in the blue journal last month, accompanied by an editorial, draws to light two related phenomena. Firstly, the combination of an inhaled corticosteroid, long-acting beta-agonist and tiotropium is beneficial in chronic obstructive pulmonary disease. (This, at long last, gives respiratory physicians the opportunity to use 'triple therapy', a phrase which has an inexplicable allure for medicos). Secondly, for Astra-Zeneca and Symbicort (budesonide/eformoterol) it's all about catching up with Glaxo and Seretide (fluticasone/salmeterol). And they just might do it yet.

The study was a randomised, placebo controlled trial of Spiriva (Tiotropium) alone vs Spiriva and Symbicort (to use the local trade names) in combination. The Symbicort dose was 320/9mcg, which is not a dose marketted in Australia (where we have 100 or 200/6 or 400/12). Around 600 subjects were recruited, 300 or so in each arm. Subjects had to have pretty severe COPD, with an FEV1 of less than 50% predicted on their initial pre-bronchodilator spirometry, although 25% ended up categorised as moderate if the GOLD - compliant definition of post-bronchodilator FEV1 was used.

The goal of the study was to demonstrate improvement in lung function - which they did. There was a 6% improvement in pre-bronchodilator FEV1 at follow up in the 'triple therapy' (TT) group compared with the Spiriva-alone group. There were also more subjects in the TT group with a significantly improved quality of life. Most strikingly, there was a very significant (62%) reduction in exacerbations in the TT group (7.6% of patients vs 18.5% of patients) over the short 12 weeks of the trial. (It's worth noting that the definition of exacerbations here required a hospital attendance, not just an escalation of therapy with glucocorticoids directed by a doctor).

The benefits of this combination of inhaled medications in COPD now seems beyond dispute. There seems to be a class effect (ie Symbicort and Seretide are each beneficial) and we can expect Symbicort to get PBS listing in Australia at some point for patients with moderate COPD, although it does not yet currently have this.

The accompanying editorial in the blue journal does point out the following important points:

1. Although Seretide has not been demonstrated to reduce the frequency of exacerbations, the trials of Seretide in COPD had a more inclusive definition of exacerbation and the drugs can't be compared on this point on the data already to hand;
2. 40% of patients in this trial were already on 'triple therapy' before the trial, and the inhaled steroid and LABA had to be stopped. This may just be an example of trials catching up with clinical practice;
3. Not enough patients of moderate disease severity have been enrolled in the trials. Aparently a recent post-hoc analysis of the TORCH data (one of the Seretide trials) showed that patients categorised as moderate by GOLD criteria (post-bronchodilator FEV1 50-80%) had quite poor prognosis generally in terms of rate of loss of lung function, deterioration of quality of life and rate of exacerbations. If COPD is now being modelled as an inflammatory disorder and patients with relatively early disease do progress why are we not investigating the impact of antiinflammatory inhalers on earlier-stage disease?

So why do I think that Symbicort is working hard to catch up to Seretide, and that the unwritten primary-endpoint here was to win market share in patients with COPD? It strikes me that Astra-Zeneca learnt from the failure of Glaxo to demonstrate a survival-benefit for the Seretide/Spiriva combination in a big trial published in the New England Journal in 2007. Although a lot of useful secondary endpoints were hit in that trial, it is remembered as the trial that missed the jackpot. The current trial has notably not tried to aim so high. It is a short trial, with relatively few patients, and looks to me very much as if is has been put together to demonstrate that Symbicort is also 'good enough' to use in patients with COPD.

The trial authors list the following as goals of treatment in COPD:

• reducing symptoms
• improving health status and exercise tolerance
• reducing the risk of exacerbations.

These management goals are actually limited by the efficacy of the treatments we have available. They were designed for clinicians, not researchers. So having stuck to the established management goals, Astra-Zeneca have now proved that Symbicort helps to do all of what we are already doing better. It strikes me as circular thinking, and a little disappointing. Give me something new to offer my patients! Please.

Notably absent from the list of treatment goals is to 'reduce disease associated mortality'. It's not there as a goal because, apart from smoking cessation and oxygen in select patients, we don't know how to do it yet. Mortality reduction is the most meaningful of all possible treatment goals in established medical research traditions, but I suspect it is beyond the potential of our current medications in COPD.

Andrew