BB&T Executive Editor

Devices and drugs are often complementary therapeutic approaches. But in the drug delivery sector, devices and drugs aren't just complementary — they are tied together. This was highlighted last month with warnings issued by Pfizer (New York) concerning a small number of cases of lung cancer among users of Exubera, the inhaled insulin product that it unexpectedly abandoned last year.

After halting all efforts to market the product last October, Pfizer had turned back all rights for Exubera to Nektar (San Carlo, California), its partner developing the drug formulation and the delivery device.

Nektar at the time said it remained committed to moving the product forward with another partner, or partners. But with announcement of the lung cancer cases, Nektar also separated itself further from Exubera, saying that it had "ceased all negotiations with others who might have partnered on the product.

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

In announcing the lung cancer cases (six, all contracted by smokers), Pfizer said it saw no causal connection to Exubera but nevertheless was was "updating product labeling, for those still using it, to include information about the lung cancers observed.

It said that over 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.

Joe Feczko, MD, chief medical officer for Pfizer, in a statment 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.

Two others make their exit

Pfizer is the first of three companies — all partnering with drug delivery companies in their development efforts — that over the past months have exited the inhaled insulin effort.

Countering the lung cancer reports, Aradigm (Hayward, California) in late April issued a statement concerning data indicating no cases of "primary lung cancer in two groups of a trial for the AERx insulin Diabetes Management System (iDMS), that it had been developing with Novo-Nordisk (Bagsvaerd, Denmark).

Novo had licensed the rights for AERx iDMS from Aradigm — the companies working together on the product for nearly 10 years — but the Danish drug firm terminated product development this past January and cut hundreds of jobs at its Hayward, California, site, citing Pfizer's withdrawal from the effort.

In reporting its findings, Aradgm, which had developed a hand-held electronic haler to deliver an agueous formation of the insulin product, cited both its human trial and preclinical work with monkeys.

A third company dropping out of the sector is Eli Lilly (Indianapolis), which in March reported dropping further efforts to develop its AIR Inhaled Insulin product. That decision impacted its device partner in the effort, Alkermes (Cambridge, Massachusetts), which then reported various restructuring moves.

Chilling the sector

Pfizer's report of lung cancers obviously serves to raise the barrier for commercializing inhaled insulin in a variety of ways, for instance by chilling the enthusiasm of potential partners for these efforts.

MannKind (Valencia, California), like Nektar, suspended its search for a partner, in early April. Mannkind is developing Technosphere Insulin 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.

Yet to be known is the much longer-term impact of the lung cancer reports and abandonment of the market by Pfizer, Novo-Nordisk and Eli Lilly.

Besides Mannkind, two other companies remain in the game:

• Baxter Healthcare (Deerfield, Illinois) is developing a microsphere technology administered via what it descrigbes as 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.

• 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.