This blog has continued researching and reporting on potential Exubera inhaled insulin risks for more than two years.

Pfizer’s and Nektar’s announcements this morning that 6 of the 4,740 patients using Exubera in clinical studies developed lung cancer confirms what this blogger has been saying all along:

That it was foolish of the FDA to rush into conditionally approving the inhaled insulin without first completing long-term safety studies of the diabetes drug.

During that time, we’ve examined studies, concerns by endocrinologists and pulmonologists about the drug, and caution by diabetics.
Nektar announced today that it “ceased all negotiations with potential partners for its inhaled insulin programs as a result of new data analysis” citing lung cancer developed by patients in Exubera safety studies.

Pfizer appeared to suggest that any diabetics who developed lung cancer while on Exubera might be at fault, since “all patients who developed lung cancer had a prior history of cigarette smoking.”
Not surprisingly, the drugmaker pooh-poohed the cancer findings, claiming there “were too few cases to determine whether the development of lung cancer is related to the use of Exubera.” Citing financial reasons, Pfizer already opted to yank Exubera from its product line last fall.

Less than a week after Pfizer decided to stop selling Exubera inhaled insulin, the Chairman of rival drug developer Alkermes cautioned that it’s AIR inhaled insulin could also affect diabetics’ lung function.

Richard Pops, Chairman of Cambridge, Mass.-based Alkeremes, told Reuters that the inhaled insulin that the company is jointly developing with Eli Lilly & Co., may also have the potential for pulmonary risks for diabetics using the drug.

Pops explained that his company is “assuming that pulmonary insulins in that regard are all pretty much the same,” but added a caveat that the 2-year long AIR insulin drug safety trials have not been completed yet.

This blog has long-reported on concerns by doctors and diabetics about Exubera’s known and unknown pulmonary risks. The fact that a competing drug developer openly acknowledged similar concerns is significant.

According to Michael Krensavage, a pharmaceutical equity analyst at Raymond James Financial, Inc. (NYSE:RJF), the launch of Exubera inhaled insulin for diabetics “has been one of the most spectular flops in the pharmaceutical industry.”

Krensavage made this analysis when interviewed about Pfizer, Inc.’s (NYSE:PFE) difficulty in launching and maintaining profitable new drugs in a highly competitive market.  “No matter how you look at it,” Krensavage concluded, Pfizer’s drug research and development efforts have yielded “a disappointing pipeline.”
Pfizer’s 8K report to shareholders disclosed Exubera’s continued market failure. “Sales of Exubera continue to be disappointing, with $4 million of worldwide revenues in the second quarter of 2007.”
Generating only $4 million in revenue on a diabetes drug for which Pfizer paid Sanofi-Aventis $1.3 billion in January 2006 is an abysmal failure, there may still be a silver-lining for diabetics.

By sticking to proven diabetes medications that do not have unknown pulmonary and related risks for diabetics that are the subject of long-term FDA-mandated drug safety studies (as a condition of the drug’s approval), endocrinologists appear likely to give their patients trusted choices for managing their care.

Even given reported the Avandia heart attack risks for Type 2 diabetics, Pfizer doesn’t seem to have convinced endocrinologists that Exubera is a better diabetes drug.

A Worcester, Mass. newspaper, interviewed a senior endocrinologist at the Joslin Diabetes Center in Boston about the potential problems and pitfalls of oral insulin delivery.

Dr. Richard A. Jackson (inset, left) explained that “a chief concern in developing oral insulin products is ensuring dosage accuracy. Insulin levels are especially sensitive,” and experience has proven that injecting insulin subcutaneously using needles delivers accurate dosing.

“Small variances in the dosing and the speed of absorption is more important for insulin than other things. If absorption through the mouth varies by 15 percent, that’s a lot,” he said.

Guess what? This concern should apply to Pfizer’s Exubera inhaled insulin, as well as other potential oral insulin delivery products currently in the pipeline undergoing clinical trials.
These include Canadian-based Generex Biotechnology Corp.’s Oral-lyn, Mannkind’s Technosphere inhaled insulin, and the Alkermes / Eli Lilly & Co. AIR inhaled insulin — all of which are undergoing clinical trials.
Dr. Jackson emphasized that a critical issues is “whether [orally delivered insulin products] can achieve the accuracy and be consistent about how much is absorbed in the mouth.”

Pfizer, along with endocrinologists and researchers, presented the results of an Exubera safety study examining the effects of Exubera inhaled insulin on Type 1 diabetics for a little over 2 years. An abstract of the study can be seen below.

Here are a few important highlights and caveats regarding the study:

• It involved nearly 300 diabetics using Exubera inhaled insulin, and another group of almost 300 diabetics using injectable insulin.
• The study focused on Type 1 diabetics.
• Dr. Jay Skyler, one of the study’s authors, is a paid Pfizer consultant and occasional spokesman for Exubera. The ex-American Diabetes Association President appears in the drugmaker’s Exubera DTC advertising spots. Skyler is a consultant for Pfizer on Exubera and chaired the company’s Global Advisory Committee. He also gets paid by competing diabetes drugmakers to hawk their drugs.
• Skyler is a paid Scientific Advisor to a competing inhaled insulin developer, Mannkind Corp.

Pulmonary Safety Following Discontinuation and Readministration of Inhaled Human Insulin (Exubera[reg]) in Adults with Type 1 Diabetes

Authors:
PRISCILLA HOLLANDER, JAY SKYLER, LOIS JOVANOVIC, SOL KLIOZE, ALAN KRASNER, RICHARD RIESE, JOANN REIS, PAMELA SCHWARTZ, Dallas, TX, Miami, FL, Santa Barbara, CA, New London, CT

Results:

This interim analysis assessed pulmonary safety following discontinuation and readministration of Exubera[reg] (EXU; (insulin human [rDNA origin]) Inhalation Powder) therapy in adults with type 1 diabetes mellitus (T1DM).
T1DM patients (18-65 years) received EXU (n = 290) or subcutaneous insulin (SC) (n = 290) for up to 2 years in an ongoing, open-label study (comparative phase), followed by 6 months of SC insulin (follow-up phase) and a 6-month extension phase during which all patients received their original randomized therapy.

Small, nonprogressive treatment group differences in change from baseline forced expiratory volume in 1 second (FEV1) and carbon monoxide diffusing capacity (DLCO) occurred early during the comparative phase, and were not driven by outliers. These differences completely resolved upon discontinuation of EXU, and recurred to the same magnitude during the extension phase. Both treatment groups maintained glycemic control and hypoglycemic event rates were similar. Median insulin antibody levels increased in the EXU arm during the comparative phase (Month 24: 63.0 [micro]U/mL), decreased during the follow-up phase to near baseline levels (Month 6: 22.0 [micro]U/mL), and increased during the extension phase (Month 6: 42.0 [micro]U/mL); they remained stable on SC (Month 24: 4.4 [micro]U/mL; Follow-up Month 6: 4.4 [micro]U/mL; Extension Month 6: 3.6 [micro]U/mL).

In conclusion, FEV1 and DLCO changes observed during discontinuation and readministration of EXU therapy are consistent with a reversible, non-progressive and non-pathologic effect on lung function in adults with T1DM. EXU readministration is not associated with an augmented IAB response.[figure1][figure2]