Amid last month's hoopla surrounding AstraZeneca plc's $1.26 billion acquisition of Ardea Biosciences Inc. and CEO David Brennan's decision to step down, the FDA's official withdrawal of lung cancer drug Iressa (gefitinib) was barely a blip on the radar.

Granted, the move had been expected since early last year, when U.S. regulators said the London-based big pharma planned to pull the new drug application after data from confirmatory studies failed to support the drug's accelerated approval as a monotherapy after failure of platinum-based and docetaxel chemotherapies in locally advanced or metastatic non-small-cell lung cancer (NSCLC). AstraZeneca even voluntarily agreed to the withdrawal, waiving its right to a hearing.

That would have made sense had the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor not shown impressive data in 2009 from a Phase III study in a clinically selected population – 1,271 Asian patients anticipated to be responsive to EGFR inhibitors.

In the earlier confirmatory trials in a broad population, Iressa missed statistical significance compared to placebo. But, when a front-line NSCLC population was screened for EGFR mutation status, Iressa as a monotherapy actually bested chemotherapy in the IPASS (Iressa Pan-ASia Study) trial, and the drug also demonstrated a more favorable safety profile vs. doublet chemo treatment.

Data from IPASS prompted a European marketing application submission and the 2009 approval of Iressa for NSCLC patients with activating EGFR mutations across all treatment lines. But in the U.S., the firm has opted not to submit the IPASS data for approval, though it has asked that the roughly 250 patients currently on treatment be allowed to continue receiving Iressa through an expanded access program.

Iressa, which gained approval in 2003, became the first in a spate of accelerated approvals that failed to deliver the goods in confirmatory studies. It was yanked from the market in 2005, remaining available only for patients with locally advanced or metastatic disease who had benefited from Iressa treatment. In 2010, the FDA asked that AstraZeneca voluntarily withdraw the drug, and in early 2011 AstraZeneca called it a business decision when it asked the agency to pull the drug.

In a statement last year, AstraZeneca simply said its does "not plan to pursue approval of Iressa in the U.S."

The pharma has declined to say why, though the fact that the drug starts losing patent protection as early as 2013 probably factored into its decision. And while Iressa's sales – $554 million in 2011 – are healthy by biotech standards, they are small when compared to AstraZeneca's blockbusters such as Crestor (rosuvastatin calcium), Seroquel (quetiapine), Nexium (esomeprazole) and Symbicort (budesonide/formoterol), and likely will do little to offset losses as those top-sellers begin to fall off the patent cliff.

And, after delivering a ghastly first quarter, in which revenues fell by 11 percent and CEO Brennan announced his June retirement, AstraZeneca clearly has more pressing concerns than a cancer drug that appears to work in only a small percentage of NSCLC patients. Despite a handful of recent deals, including the Ardea purchase and a potentially lucrative-in-the-long-term deal with Amgen Inc., the big pharma has done little to assuage fears of the dreaded patent cliff – $4 billion-per-year Seroquel lost patent protection earlier this year, gastroesophageal reflux drug Nexium starts losing protection in 2014 and cholesterol blockbuster Crestor is heading toward patent expiration in 2016. (See BioWorld Today, April 24, 2012, and April 27, 2012.)

The firm began restructuring in 2010 and, in December, disclosed another wave of cuts, reducing its U.S. sales force by 1 , 150 positions. In February, Brennan outlined a restructuring program that would affect about 7,300 positions, impacting all areas of business, that is expected to save the firm about $1 .6 billion in annual benefits by 2014.

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