Forest Laboratories announces phase 3 trial results for roflumilast

Forest Laboratories, Inc. (NYSE: FRX), an international pharmaceutical manufacturer and marketer and Nycomed, a privately owned pharmaceutical company, today announced that results of four phase III trials have been published in the prestigious peer-reviewed medical journal The Lancet showing that roflumilast, a phosphodiesterase 4 (PDE4) inhibitor, improved lung function and reduced exacerbations in patients with moderate to severe COPD.

COPD is an under-diagnosed progressive lung disease that may lead to death. Worldwide, COPD kills four people every minute and the World Health Organization (WHO) predicts that it will be the third leading cause of death by 2030. WHO estimates that 80 million people have moderate to severe COPD.

Roflumilast, a once-a-day oral tablet, would be the first in an entirely new class of treatment for COPD if it receives regulatory approval from the authorities in Europe (EMEA) and the US (FDA). The phase III placebo-controlled trials of roflumilast evaluated the treatment in two 12-month (Lancet 2009; 374: 685–694) and two six-month studies (Lancet 2009; 374: 695–703), involving 4,500 patients in ten countries. Details of the results of the four studies will be published in The Lancet on August 29 (data and information under embargo until Friday, August 28 at 00:01am GMT).

The two 12-month studies published in The Lancet demonstrated that roflumilast produced a statistically significant and clinically relevant reduction in exacerbations (lung attacks that need treatment with systemic steroids or lead to hospitalisation), even for patients who were also taking long-acting bronchodilators. The studies showed a reduction in moderate to severe exacerbations by 17 percent per patient per year (rate of 1.14 events per year with roflumilast vs. 1.37 per year with placebo, p<0.001). The reduction in exacerbations was irrespective of concomitant treatment with long-acting beta-2 agonists, a standard bronchodilator therapy.

When added to standard bronchodilator therapies in the two six-month studies, a clear trend for the reduction of exacerbations was observed with roflumilast, over and above what was achieved with these therapies alone. There was also a statistically significant difference with roflumilast in other prespecified endpoints, including median time to first exacerbation (moderate to severe in the salmeterol study, and mild, moderate and severe in the tiotropium study) and in the proportion of patients in both studies experiencing a mild, moderate, or severe exacerbation.

Lung function, as measured by FEV₁ (how much volume can be exhaled in one second), was the primary or co-primary endpoint in all four studies. Across the studies, roflumilast demonstrated a statistically significant improvement in pre-bronchodilator FEV₁, in the range of 48 to 80 mL (p<0.001).

Nausea, diarrhea and weight loss were the most common adverse events recorded in patients in the four trials, but they were generally mild to moderate in intensity and generally occurred in the first weeks of treatment.

Professor Peter Calverley, Professor of Respiratory Medicine, University of Liverpool, UK, and the lead author of the 12-month studies, said: “COPD can devastate people’s lives and exacerbations can be extremely frightening, so a novel tablet like roflumilast is really exciting for those of us treating patients. Roflumilast acts differently to bronchodilators as it acts on the underlying condition, not primarily impacting on everyday symptoms. It acts slowly and the effects, as we saw in our studies, are gradual and sustained.”

“Roflumilast could be an important new treatment for COPD,” added Professor Fernando Martinez, University of Michigan, also a lead author of the 12-month studies. “We clearly need new options for patients with COPD and the results of these studies, published in The Lancet, confirm that roflumilast is beneficial. It reduced exacerbations, or lung attacks, and significantly improved lung function, in a patient population whose lung function is very poor.”

Professor Leonardo Fabbri, Professor of Respiratory Medicine, University of Modena and Reggio Emilia, Italy, and lead author of the six-month studies, said: “Roflumilast has a novel mode of action and has the potential to become the first of a new class of drugs and potentially the only completely new treatment option for COPD in the next several years. These eagerly awaited results, published this week in The Lancet, show that in addition to confirming the sustained statistically significant improvements in lung function, roflumilast also showed a trend to reducing exacerbations when given in addition to long acting inhaled bronchodilators. The results of the two six-months trials examining the additive effect of roflumilast on top of salmeterol or tiotropium support and extend the findings of the 12-month trials, by showing a clinically relevant lung function improvement in patients with impaired lung function on top of maximum bronchodilation.”

“The lung function improvements on top of current bronchodilation clearly indicates that roflumilast improves lung function over and above what can be achieved with other COPD treatments alone. It also demonstrates that roflumilast works in a different way to current treatments and supports roflumilast’s potential to change how COPD is managed,” added Professor Klaus Rabe, Professor of Medicine at Leiden University Medical Center, also a lead author of the six-month studies.

Nycomed’s Executive Vice President R&D, Anders Ullman, said: “We are very pleased with the results published in The Lancet this week. In four studies, two 12-month studies and two six-month studies, roflumilast showed clear therapeutic potential, decreasing exacerbations and improving lung function. The uniformity of the results is really encouraging and gives us great hope that our faith in roflumilast has been confirmed. We are now undergoing the regulatory review process with the European and US authorities.”

“Based on the results from the pivotal studies published this week, it appears that roflumilast provides added activity on top of other commonly used treatments for COPD,” said Lawrence S. Olanoff, President and Chief Operating Officer of Forest Laboratories. “Roflumilast represents the first in a new class of agents to treat COPD and, if approved, would be the first oral anti-inflammatory maintenance treatment for the disease.”

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