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Apr 12, 2010
 |  BioCentury  |  Regulation

Forest Runs into Tree

FDA realities leave Forest and Nycomed with tough choices on Daxas for COPD

The presentation Forest Laboratories Inc. made at last week's Pulmonary-Allergy Drugs Advisory Committee about Daxas roflumilast to treat COPD would have been perfect - if it had been made a decade ago. For better or worse, FDA has moved on, so instead of the endorsement Forest hoped for, a regulatory strategy and procedural tactics out of synch with the realities of 2010 produced a 10-5 recommendation against approval.

Forest's experience hammers home some of the changes a decade's focus on drug safety have wrought.

Simply showing an incremental, statistically significant improvement over placebo for a broad, undifferentiated population with multiple treatment options is no longer a safe regulatory strategy.

Submitting an NDA for chronic use of a compound with known adverse effects without a proposed risk evaluation and mitigation strategy (REMS) invites skepticism from advisory committee members.

And the need to cram additional time-consuming safety reviews into drug evalutions has squeezed flexibility out of the process, making the agency reluctant to consider changes to an indication submitted six months after filing of an NDA.

As a result, the Daxas NDA, which has an undisclosed mid-May PDUFA date, is virtually certain to receive a complete response letter.

The questions going forward are what needs to be done to salvage the NDA - whether FDA will be satisfied with essentially repackaging the application with a revised indication and a REMS, or if it will require lengthy clinical trials - and whether Forest will be willing to invest sufficient additional resources to meet the agency's demands.

The specialty pharma company, which faces patent cliffs for its Namenda memantine for Alzheimer's disease and Lexapro escitalopram for depression and anxiety, paid Nycomed $100 million last summer for U.S. rights to Daxas (see BioCentury, Nov. 23, 2009).

The asset was attractive because Daxas is intended to address a serious and large-scale unmet medical need. If approved, it would be the first new type of therapy in 30 years, and perhaps the only disease-modifying drug, for the estimated 7.6 million Americans who suffer from COPD associated with chronic bronchitis.

That potential emerged unscathed from the advisory committee meeting, as patients have few good treatment options.

But a number of problems, including some that could be expensive and time-consuming to overcome, also came to light.

De factorealities

The Daxas clinical development program, which started with an IND filing in 1999, left Forest ill-equipped to deal with FDA's current de facto comparative effectiveness and safety requirements.

Although more than 15,000 COPD patients have received Daxas in four 52-week and two 24-week Phase III trials, it has never been compared to or combined with standard of care, which is use of a long-acting muscarinic agonist (LAMA) and an inhaled corticosteroid in combination with a long-acting adrenergic receptor beta 2 (ADRB2) agonist (LABA).

Forest is seeking a maintenance indication, with the expectation that patients might take Daxas for the rest of their lives. But in over a decade of clinical development, no one has taken it for longer than 12 months.

Life expectancy for COPD patients varies based on disease severity and smoking status. Smokers with severe COPD have a life expectancy of 8.5 years, according to a study by Robert Shavelle and colleagues at the Life Expectancy Project published in the International Journal of Chronic Obstructive Pulmonary Disease in April 2009.

Moreover, Forest is pursuing a compound that has demonstrated only modest efficacy and that has no discernable benefit for at least half the patients who take it. This is bound to raise questions in an era in which FDA is becoming increasingly concerned about exposing massive numbers of patients to adverse effects if benefits are minimal, or if efficacy is restricted to a small portion of the total population (see "Modest Efficacy").

Daxas was developed based on the theory that a selective phosphodiesterase-4 (PDE-4) inhibitor would target systemic and pulmonary inflammation, and that it would be free of the off-target adverse effects associated with theophylline, a generic non-selective PDE-3 and PDE-4 inhibitor approved for COPD. A range of serious cardiac and other adverse effects prevent widespread use of theophylline.

However, Nycomed and Forest have not determined Daxas's precise mechanism of action, so they can't explain why it causes its own adverse effects, particularly weight loss and neuropsychiatric symptoms.

At last week's meeting, panel member Thomas Alexander Platts-Mills challenged Forest for repeatedly calling it an anti-inflammatory drug. "I had the sense [Forest thought] if it was said often enough it would be true," he said. Platt-Mills is director of the Asthma and Allergy Disease Center at the University of Virginia Medical Center.

Since taking over the Daxas NDA in August 2009, Forest has taken steps to cope with some of these problems, and if things had gone according to plan, those steps clearly would have yielded much more favorable advisory committee recommendations.

But Forest's strategy, which hinged on modifying the indication Nycomed had sought in its...

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