Medical Device Daily Executive Editor

Here's a wild guess.

Pfizer (New York) and Nektar Therapeutics (San Carlos, California) are likely talking to their respective liability attorneys today, attempting to determine the potential impact of patient lawsuits potentially filed against them.

Pfizer yesterday issued warnings concerning cases of lung cancer among those who had been using the inhaled insulin product Exubera. It was previously marketed by Pfizer, with the drug formulation/inhaler delivery system developed by Nektar.

Pfizer last year distanced itself from the product – the first inhaled insulin to be approved by the FDA — dropping all efforts to sell or develop Exubera (Medical Device Daily, Oct. 22, 2007). And it then turned over all rights for Exubera back to Nektar, with a payment of $135 million to assuage the impact on that company (MDD, Nov. 14, 2007). At the time, Nektar said it remained committed to moving the product forward with another partner, or partners.

That too has changed.

With Pfizer's announcement yesterday, Nektar began scrambling to create added distance from Exubera, saying that it has "ceased all negotiations" with others who might have partnered on the product, specifically citing Pfizer's report of the lung cancer cases.

Nektar said it is halting any further spending to develop the product "and will not incur any additional charges related to this event."

In its announcement Pfizer said it is "updating" the product labeling for Exubera (insulin human [rDNA original]) Inhalation Powder to include a warning with safety information about lung cancer cases observed in patients who used Exubera.

It said that throughout the course of the clinical trial program for the inhaled product, six of 4,740 Exubera-treated patients developed lung cancer as compared to just one of 4,292 patients not treated with Exubera. "In addition there was a post-marketing report of lung cancer in one Exubera-treated patient," Pfizer said in its statement.

The company in its statement said that there is no evidence of a direct cause/effect relationship between Exubera, given the determination that "all patients who developed lung cancer had a prior history of cigarette smoking, and that there were too few cases to determine whether the development of lung cancer is related to the use of Exubera."

But this might be unlikely to forestall lawsuits by these patients (or even by those fearing the risk of lung cancer), given their habit of filing against large (deep-pocketed) companies – and the parallel propensity of companies, large and small, to make these kinds of cases go away via monetary settlements.

Pfizer is the first of three companies – along with three partners developing the delivery devices – that throughout the past months have exited the inhaled insulin effort.

And the news of lung cancer cases obviously serves to erect an even higher barrier for those companies still attempting to develop an inhaled insulin product as an alternative to the injected form of the drug.

This past January Novo-Nordisk (Bagsvaerd, Denmark) terminated development of its inhaled insulin product AERx iDMS, and cut hundreds of jobs at its Hayward, California site (MDD, Jan. 17, 2008). Like Pfizer, it cited the significant barriers to inhaled insulin commercialization: large development costs and little prospect for significant sales.

Novo had licensed the rights for AERx iDMS from Aradigm (Hayward, California), which had teamed up with the Danish drug firm on the product since 1998.

Then in early March, Eli Lilly (Indianapolis) reported that it was dropping further efforts to develop and commercialize its AIR Inhaled Insulin product (MDD, March 17, 2008).

The company said it was immediately shutting down activities in its clinical trials for AIR, which had moved as far as Phase III development. But the company said it saw little hope of winning FDA approval of a new drug application.

This decision impacted its device partner in the effort, Alkermes (Cambridge, Massachusetts), which has since reported restructuring efforts, specifically linking the cutbacks to Lilly's action (MDD, March 20, 2008).

Joe Feczko, MD, chief medical officer for Pfizer, emphasized, in a statement, that the company has been "vigilant" in monitoring any adverse effects related to the use of Exubera, saying that it "has shown in clinical trials to be a safe and effective medicine in the treatment of adults with Type 1 or Type 2 diabetes."

Feczko said that some patients are continuing to use Exubera, "including those enrolled in extended transition programs or clinical trials," and that the company is working with patients, and their physicians, to move them to other therapies for glycemic control.

Pfizer said it will be "discussing with regulatory agencies" the withdrawal of product marketing and the timing of the withdrawal.

It added: "Pfizer remains committed to helping diabetes patients and their doctors manage the many conditions that are associated with diabetes, including heart disease and DPN (diabetic peripheral neuropathy)."

It said it is developing new treatments for diabetes, "from genetic susceptibility at birth to the onset of devastating complications."

Howard Robin, president/CEO of Nektar, said, "Fortunately, over the past year Nektar has significantly transformed its business, moving away from inhaled insulin. We have made great progress expanding our research efforts and have built a deep pipeline of novel partnered and proprietary drugs in various stages of development."

Yet to be known is the impact of the lung cancer cases on other efforts to develop inhalable insulin.

These include:

• Work by Baxter Healthcare (Deerfield, Illinois) to develop microsphere technology administered via what it has called a "small, standard dry powder inhaler." CalIed Promaxx microspheres, the effort is to develop an insulin powder that could be delivered simply by means of an "off-the-shelf" inhaler. That effort has been in a Phase I study.

• MannKind (Valencia, California) is developing Technosphere Insulin (TI) and is in two Phase III studies designed "to confirm the sustained efficacy" of the product. Both randomized trials are scheduled to last a year. The company says that Technosphere technology creates particles with a "unique pharmacokinetic profile," leading to quicker insulin absorption rate than that seen with other insulin products, injectable and inhaled.

• Kos Pharmaceuticals (Cranbury, New Jersey) — now owned by Abbott Laboratories (Abbott Park, Illinois) — is researching ways to deliver insulin by means of an aerosolized liquid with a device similar to a standard asthma rescue inhaler.