Daxas deal leaves Altana short of breath

Pfizer has terminated the agreement to develop Daxas (roflumilast), a phosphodiesterase-IV inhibitor therapy for chronic obstructive pulmonary disease (COPD), following unimpressive results from a phase III study that do not appear to provide strong enough long-term efficacy data to warrant approval.

The term COPD covers a complex group of disorders characterized by a progressive development of airflow limitation, caused primarily by smoking. The most common symptoms of COPD include chronic cough, excessive sputum production, wheeze, shortness of breath and chest tightness, which slowly progress and eventually lead to a largely irreversible loss of lung function. Phosphodiesterase-IV is the predominant phosphodiesterase expressed in neutrophils and macrophages, so inhibitors of this enzyme should be effective in controlling inflammation in COPD.

Roflumilast falls short on early promise

Daxas (roflumilast), a phosphodiesterase-IV inhibitor, demonstrated early promise based on results from a six-month "RECORD" phase III trial, suggesting it could effective oral therapy for treatment of COPD. Roflumilast 500 micrograms had clear, if modest, activity in terms of improving lung function (FEV1) relative to placebo (+97mL) and significantly reduced exacerbations (acute worsening of symptoms) compared to placebo.

The exacerbation rate reduction of 34% at 500 micrograms dose was a strong result, however, this needed to be confirmed with one-year data in order to demonstrate convincing efficacy. Accordingly, two additional phase III trials (the "OPUS" study and the European "RATIO" study) were initiated which used exacerbations as one of the primary measures of efficacy, to reinforce results provided by the RECORD study.

However, results from the European COPD RATIO study have failed to support the six month efficacy data, as there was no statistically significant reduction in the rate of total exacerbations the key endpoint. Given that one of the highest unmet needs in COPD is a therapy that can reduce exacerbations, this is a particularly disappointing result.

While roflumilast did demonstrate a sustained improvement in lung function compared to placebo over the one-year period, the effect is less than half that shown at the end of the RECORD study, and considerably less than that produced with currently approved products for treating COPD, such as GlaxoSmithKline's Seretide/Advair (fluticasone/salmeterol) and Boehringer Ingelheim's Spiriva (tiotropium bromide). These results suggest that roflumilast does not provide strong enough long-term efficacy data to warrant approval.

What next for Daxas?

Daxas was filed with the European Agency for the Evaluation of Medicinal Products (EMEA) in February 2004. The submission only included six month data from the pivotal RECORD study.

Altana has stated is will continue development of Daxas, although it is unlikely the company will be able to achieve a significant market share, assuming it gains approval, without a multinational marketing partner and post-marketing studies that demonstrate an additive effect on improving lung function and/or reduction in exacerbations when co-prescribed with a long-acting bronchodilator. The next key milestone is the decision from EMEA, expected in September 2005.

The termination of the Daxas agreement is a short-term setback to Pfizer's desire to develop a strong COPD portfolio, which includes Spiriva (a long-acting bronchodilator) under a co-marketing agreement, and an inhaled PDE-IV inhibitor currently in phase II clinical trials. The occurrence of adverse events, particular nausea and vomiting, limits the dosage and hence the efficacy of orally administered PDE-IV inhibitors, such as Daxas. Pfizer’s PDE-IV inhibitor, by virtue of its inhaled route of administration which results in lowered systemic exposure, may have an improved therapeutic index (the ratio of the drug dose which produces an undesired effect to the dose which causes the desired effects) relative to Daxas.

The successful approval of a PDE-IV inhibitor is a key step for Pfizer as potentially it will enable the development of an inhaled dual-action PDE-IV/Spiriva combination product which will strengthen the company’s position as a heavyweight player in the COPD market.

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