There was certainly a sense of palpable excitement around the novel PDE4 inhibitor Daxas (roflumilast) at this year’s European Respiratory Society’s annual meeting, which dedicated one its high profile sessions to present and discuss the data from four phase III trials of the drug, which has been filed for approval in the US and Europe. As the first oral anti-inflammatory to bestow a significant improvement in symptoms of COPD, potentially providing doctors with a much needed new weapon to treat the debilitating lung disease, the excitement is understandable.
Daxas is not a game changer for the disease, something that even the physicians involved in the trials concur with, however they believe that does not detract from the clinically meaningful impact the drug could have on certain patients’ lives. Ambiguity over who should receive the drug is likely to place obstacles on the regulatory pathway, as are certain safety aspects. However, Daxas certainly looks good enough to make it to the market; how long the journey will take is another matter.
The doctors presenting the full data from the pivotal Daxas programme, which was trailed in The Lancet two weeks ago (Nycomed's Daxas shows promise in severe COPD, August 28, 2009), were unequivocal in their desire for new treatments for COPD. The lung disease cannot be reversed by any medicine currently available; systemic symptoms which include gradual erosion of lung function and muscle wastage will eventually lead to death. Exacerbations that will occur with increasing frequency carry an incredibly high mortality risk themselves, similar to heart attack.
In terms of mortality rates the illness has gradually been climbing up the league tables; in the US it has just overtaken stroke as the second largest cause of death. In the past a largely male disease, females now represent a larger patient group in western countries because smoking rates among women have risen and they are far more susceptible to the deleterious side effects of cigarettes.
This disease burden is only expected to grow, particularly in the developing world; the World Health Organisation estimates it is already the most costly disease worldwide. Despite all this, research on the area and significant treatment breakthroughs has lagged asthma in recent years.
Increasingly effective bronchodilators like the long acting muscarinic Spiriva have been important in controlling people’s symptoms, but progress in treating the underlying inflammation has been limited.
“COPD has been a forgotten disease,” says Dr Andrew McIvor, Professor of Medicine at Canada’s McMaster University. “It doesn’t respond well to inhaled corticosteroids, which have been disease modifying drugs for asthma.”
This lack of an effective anti-inflammatory agent in COPD has left a huge gap in doctor’s armoury and this is where Nycomed and Forest Laboratories hope Daxas will slot in.
The physcians presenting these studies believe that the two 12-month trials that produced a significant improvement in lung function and 17% reduction in exacerbations in severe and very severe patients, in the absence of long acting bronchodilators, establish that Daxas has an important impact on this disease. The two six-month studies conducted in moderate to severe patients on top of long acting bronchodilators confirm that benefit is incremental to what are now widely used as first-line treatments.
The fact that this is a convenient, oral, once-a-day pill, with a new mechanism of action, has also got doctors excited.
“In a specific sub population, in those who have chronic symptoms, we have a new product, without the side effects of steroids, that can provide additional benefits,” says Professor Leonardo Fabbri of the University of Modena and Reggio, a lead author of the Daxas trials.
Another author of the trial, Professor Peter Calverley of University Hospital Aintree, agrees. “Where Daxas should be used is still a work in progress, but from where I am sitting it looks like something extra we can do.”
Because the data from these four trials was so consistent, with very similar responses seen across the board, Nycomed and Forest appear to have a strong filing, in terms of establishing efficacy. The sticking points are likely to be safety and a discussion over the label, specifically which patients should receive the medicine.
On safety, as was anticipated gastro-intestinal side effects were most common, particularly diarrhoea and nausea. This is not expected to particularly concern regulators; however weight loss detected could raise eyebrows because this was not correlated to the other GI side effects, suggesting a different underlying mechanism.
Interestingly, of those that did lose weight those with the highest body mass indexes lost the most, with slighter people proportionately less affected. Why this happened is not clear, and it is an area that regulators will examine closely.
At the end of the day, with around 10 to 15% of patients unable to tolerate Daxas, the FDA is highly likely to require a strategy to detect and manage these patients, should it grant approval.
Which patients should be prescribed Daxas was a matter of great debate at the conference; whilst underlying efficacy might have been established this question is far from answered. It seems likely that initially a narrow label for severe patients already on bronchodilators who have a history of exacerbations will be approved, but if anything is going to hold up approval, this labelling issue looks like a prime candidate.
“There is an argument to be made for use as a monotherapy, but there is a clear incremental benefit when used with a long acting bronchodilator, so it is most likely to be used in combination,” says Professor Fernando Martinez of the University of Michigan, who presented the results of the trials to the congress. He admits, however, that it will be a challenge for regulators and doctors to decide where Daxas should be used.
This of course has huge implications for the commercial value of the drug. Nycomed’s chief executive, Håkan Björklund, is sticking to his blockbuster aspirations, but admits that at least initially its use will be narrowly defined (EP Vantage Interview - Nycomed sold on Daxas opportunity, September 14, 2009).
Further trials are certainly needed to answer many of the questions raised by these data. For example conclusive research on whether the drug can extend the benefit of inhaled corticosteroids (ICS), or combination products like Advair, would be of great interest.
“I would predict it would have an added benefit (to ICS),” Professor Neil Barnes of the London Chest Hospital says. In terms of further trials, he and others would like to see studies carried out to test whether Daxas might achieve the holy grail of disease modification, and lower mortality rates.
“We badly need to know whether PDE4 inhibitors reduce the rate of decline in FEV1 (lung function). I believe there’s some hope for that, from the studies we have available,” Dr Barnes says.
Broader studies will not happen now until Nycomed and Forest are more comfortable that revenues are on the way. However, the Swiss company, after years of research, has provided strong evidence that Daxas could have a role to play in COPD, and more broadly confirmed that PDE4 inhibitors appear have a future as a respiratory agent.
What has yet to be established is how significant that role should be, and that conundrum will take more time and research to resolve.