The narrowed indication granted for Forest Laboratories Inc.'s newly approved chronic obstructive pulmonary disease drug Daliresp (roflumilast) means that a quarter of all diagnosed COPD patients, or three million people, will be eligible for treatment, the firm said.

Roflumilast, formerly known as Daxas, received FDA approval March 1, nearly a year after it weathered a "complete response" letter. The drug can now be marketed for use to reduce the risk of exacerbations in patients with severe COPD associated with bronchitis and a history of exacerbations.

The indication is narrower than the one Forest and, more specifically, its partner, the Swiss specialty pharma Nycomed, initially sought. It is also narrower than the indication for which the European Medicines Agency approved the drug in July 2010 (Also see "Daxas Approved In EU With Narrow Indication" - Pink Sheet, 6 July, 2010.).

Daliresp is a first-in-class phosphodiesterase 4 (PDE-4) enzyme inhibitor and the first oral medication for COPD, which is currently treated with bronchiodilators and inhaled corticosteroids, such as Boehringer Ingelheim's Spiriva (tiotropium bromide inhalation powder) and GlaxoSmithKline PLC's Advair Diskus (salmeterol/fluticasone).

Roflumilast's progress through the regulatory process on both sides of the Atlantic has been watched closely over the years by many constituents. It is one of only a few drugs to be introduced in the past few years that is likely to be prescribed by general practitioners as well as specialists.

It is also important to three companies striving to offset patent cliffs and other business challenges by introducing drugs with novel mechanisms of action that address unmet medical needs.

Nycomed developed the drug and filed an NDA for it in July 2009 seeking U.S. approval for a broad indication: maintenance treatment of COPD in patients with chronic bronchitis at risk of exacerbations. But a month later, it licensed the drug to Forest for $100 million upfront and undisclosed milestone and royalty payments (Also see "Forest Acquires U.S. Rights To Nycomed's Oral COPD Drug Daxas" - Pink Sheet, 10 August, 2009.). The partners have not disclosed further terms of the deal, but Nycomed has ceded all commercial responsibilities in the U.S. to its partner.

Forest, however, then tried to seek a narrower indication for approval, believing that would be more likely to garner FDA support. But in April 2010, the Pulmonary Allergy Drugs Advisory Committee recommended against approving Daxas due to the drug's modest efficacy and serious side effects, with some committee members hinting that they might have had a more positive view of the drug if it had been aimed at a narrower population.

The next month, however, FDA issued a "complete response" letter to Forest, noting that the request to change course came too late and asking for more analysis of data. Although Forest has not disclosed the details of FDA's demands, it did say that the agency did not request new clinical trials.

Eight randomized, double-blinded, controlled clinical trials have been done involving roflumilast, but the U.S. approval is based on two of these, involving roughly 3,000 patients. Both showed a significant reduction in the rate of moderate or severe exacerbations compared to placebo. Daliresp reduced the rate of moderate or severe exacerbations by 15% in one trial and by 18% in the other trial, Forest reported. The drug is not indicated for relief of acute bronchospasm.

No REMS Or Black Box Warning Required for Daliresp

The approval came without as many restrictions as some analysts expected, in terms of safety language and risk management. Forest said the agency is asking for a Medication Guide.

Within the medical community, Daliresp is viewed as a drug with modest efficacy and serious side effects, appropriate for a limited population (Also see "For Forest, Two Launches And Two Filings Planned In 2011 As Patent Cliff Looms" - Pink Sheet, 18 January, 2011.). As a result, analysts were not surprised by the narrow indication, although some had expected it to include moderately ill, as well as severely ill, patients.

For Forest, the approval is welcome news, as it rebuilds its product portfolio in anticipation of a huge drop in revenues when key drugs, the anti-depressant Lexapro (escitalopram) and the Alzheimer's medication Namenda (memantine) go off patent in 2012 and 2015, respectively. The positive regulatory news, along with Forest's acquisition on Feb. 22 of Clinical Laboratory Data Inc., for up to $1.2 billion upfront plus milestones, will help ease the blow of generic competition (Also see "Forest Buys Clinical Data And Extends Its Antidepressant Portfolio" - Pink Sheet, 22 February, 2011.).

Moreover, Daliresp's key patent expires on Jan. 27, 2015, although Nycomed says the drug is eligible for a patent term extension that should provide an additional five years of protection.

Forest hasn't released pricing details, and analysts' projections for its peak sales vary widely. At the optimistic end, Credit Suisse analysts project sales could reach $55 million in the U.S. in 2011 and peak at $800 million in 2020. More cautiously, UBS analyst Marc Goodman suggested that the drug would reach sales of $270 million by 2016 and $375 million by 2020. "We see Daliresp as an incremental driver for Forest, with the added benefit of offsetting some of the fixed sales infrastructure," he wrote in a same-day note.

In Europe, Nycomed licensed commercial rights to Merck & Co., retaining co-promotion rights in some countries and Canada (Also see "Merck Puffs Up Respiratory Portfolio With EU Rights To Nycomed's Daxas" - Pink Sheet, 26 April, 2010.). For Merck, Daxas is an opportunity to maintain its respiratory franchise as an important drug, Singulair (montelukast) nears loss of exclusivity.

The drug – which remains branded as Daxas in Europe – is currently being rolled out gradually across the continent and is available in Germany, the U.K., Spain, Canada and several smaller European markets.

By Wendy Diller

Forest/Nycomed's Daliresp Reaches The Market, But For Fewer Patients Than Expected

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