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.

Pfizer appears to be using a questionable new Exubera sales tactic: placing an advertorial in Medscape, a clinical practice publication owned by WebMD that targets doctors, clinicians, and other medical professionals.

The questionable piece, “Evolution of a Pulmonary Insulin Delivery System for Patients with Diabetes,” was funded by Pfizer. Just take a look at a snapshot of Pfizer’s funding acknowledgement at the very bottom of the Exubera article (Note: it’s been highlighted with red dots by this blog):

The fact that Pfizer “funded” this advertorial is disturbing.  What makes it particularly shocking is that the author, Dr. Priscilla Hollander, fails to state that the FDA did not approve Exubera for smokers.  Pfizer — the source of the article’s funding — knows that smokers were not approved by the FDA for using Exubera.

So what does the Pfizer-funded article say? Hollander (who is the Director and Lead Research at the Endocrine Center in Baylor University’s Medical Center) says only that:

…patients should be encouraged to quit smoking prior to initiation of therapy with [Exubera inhaled insulin], as patients who were current smokers or who had smoked in the previous 6 months were excluded from participation in the clinical study program.

Yet, the very first page of the FDA’s Exubera Medication Guide makes very clear that smokers cannot use Pfizer’s inhaled insulin.  That is because their risk of hypoclemia would be huge:

·  Do not use EXUBERA if you smoke, start smoking, or if you quit smoking less than 6 months ago. Smoking can increase the amount of EXUBERA you get and may cause your blood sugar to get dangerously low. If you smoke, or you quit smoking less than 6 months ago, you will need a different treatment for your diabetes. (emphasis in original)

So how could Pfizer pay for placement of a Medscape advertorial on Exubera that contains information completely contrary to the FDA’s approved Exubera Medication Guide?

Could this Pfizer-funded advertorial have been a way to circumvent compliance with the FDA’s Division of Drug Marketing, Advertising, and Communications?

How could Pfizer have funded an article which only suggests that diabetics “should be encouraged to quit smoking prior to initiation of therapy with [Exubera inhaled insulin]”?

The Pfizer-funded article is clearly misleading.  It fails to unequivocally state that the FDA did not approve Exubera inhaled insulin for use by smokers. Simply encouraging smokers to quit before using Exubera runs contrary to the FDA-approved Exubera Medication Guide.

Doctors who read this Pfizer-funded Exubera piece could mistakenly think that patients with diabetes who smoke could use Exubera.  Many general practitioners know how difficult it is for the patients to give up smoking. But simply encouraging diabetics to quit isn’t what the FDA had in mind.

Will this controversial WebMD article increase Pfizer Exubera sales to GP’s? Only time will tell.

A new ad campaign will be launched by Pfizer, Inc. (NYSE:PFE) aiming to convince diabetics that they should try the drugmaker’s Exubera inhaled insulin.

According to a Bloomberg News report by Shannon Pettypiece, Pfizer hopes to launch its direct-to-consumer (’DTC’) Exubera television ad campaign “in the second half of 2007.”
But Pettypiece warns that:

Pfizer is risking criticism by members of Congress and physician groups who say consumer advertising encourages excessive use of costly therapies.

A related concern is whether the TV ads will gloss-over, or not even mention, the concerns that a number of physicians have about the inhaled insulin’s long-term safety for diabetics using the drug. The FDA is apparently so concerned about Exubera’s long-term safety and potential pulmonary risks that the drug agency effectively conditioned approval of the drug in January of 2006, requiring Pfizer to conduct a wide variety of safety studies over the next decade on diabetics in general, in addition to diabetic children and smokers.

Drug formulary coverage for Exubera is another issue.  The insulin costs diabetics a premium over regular injectable insulin. That’s because many insurer’s don’t see a benefit to subsidizing coverage of a more expensive insulin that has yet proven itself to more effective over the long-term for diabetics.

According to Pettypoint:

Wellpoint Inc., the nation’s second- largest health insurer, charges customers more for Exubera than other insulin products because “no meaningful clinical studies are available to demonstrate that its use will result in earlier treatment, improved compliance, improved quality of life, or better long-term outcomes,” says spokesman Jim Gavin.

According to data from Wolters Kluwer Health, only about 900 prescriptions were written for Exubera by physicians each week in January of 2007.
That’s not a lot of positive cash flow for drug that took a while to develop, and cost Pfizer $1.3 billion in a deal last year with sanofi-aventis.  That deal enabled Pfizer to buy intellectual property and licensing rights from the French drugmaker that gives it exlusive worldwide rights to market the insulin.

A new diabetes research study conducted in Australia concluded that the majority of Type 1 and Type 2 diabetics will be ineligible patients for Exubera inhaled insulin usage.

The study’s results were published in the Feb. 2007 issue of Diabetes Care, the American Diabetes Association’s (ADA) scientific journal for diabetes professionals.

This study examined spirometry (i.e., lung function) and Hemoglobin A₁C (HA₁C) long-term blood sugar data from a community-based assessment of diabetics in Western Australia, the Fremantle Diabetes Study. Given the number of patients examined in the study (121 Type 1 and 1,294 Type 2 diabetics from a population of 120,097 people), and the fact that spirometry was permformed on half the subjects, the study carries some weight.

Taking smoking history and spirometry data from FEV₁ readings into account (FEV₁ is the ‘Forced Expiratory Volume’ of air exhaled by a patient during the first second of the spirometry test measuring lung function), the study found that more than 2/3 of all diabetics in the community would likely be ineligible to use Pfizer, Inc.’s (NYSE:PFE) Exubera inhaled insulin.

Those numbers were arrived at by:

• Excluding one-third of all Type 1 and Type 2 diabetics in the patient population studied, due to smoking history and spirometry results;
• That 33% exclusion was then increased to roughly 40% after taking into account diabetics in the group with chronic lung disease;
• The population of Type 2 diabetics being ineligible for Exubera inhaled insulin then “would increase to two-thirds after another seven years” under an assumption that the lung function of these patients would decline during that time (see below);
• Finallly, the authors concluded that: “[b]ased on eligibility and treatment modality data, as well as the proportion with A₁C>=7%, only about one-third of our type 2 diabetic patients had a reasonable indication for Exubera at baseline.”

Signficantly, Prof. Timothy E. Davis, on of the study’s authors, was a member of another research team that in 2004 first reported finding a link between Type 2 diabetes and reduced pulmonary function. Those findings were also taken from the research and data of the Fremantle Diabetes Study. Similarly, the study was also published in the ADA’s journal. “Glycemic Exposure Is Associated With Reduced Pulmonary Function in Type 2 Diabetes”, Diabetes Care 27:752-757, 2004.

Davis reminds doctors that the results of his study:

reinforces the need for regular review of Exubera-treated patients (including recocmmended spirometry).

While some may criticize the conclusions from this study as a being too exclusionary, Davis suggests that, to the contrary, “the present ineligibility estimates appear conservative.”

His rationale is two-fold. First, he says that the percentage of Type 2 diabetics who smoked in his Australian patient data is less when compared to U.S. data (17 vs. 23%). Second, he estimates that there will be a further decrease in the FEV₁ readings of the population due to “a minor acute therapy-related FEV₁ fall.” In other words, he predicts that the lung-function of these diabetics would continue to drop.
This study suggests extreme caution and vigilance by doctors thinking about prescribing Exubera for Type 1 and Type 2 diabetics. Since it is based on real-world problems that patients have (i.e., smoking, existing pulmonary disease, progressive and deteriorating lung function over time), it seems to serve as a cautioanry red flag.

A Cleveland Clinic pulmonologist and member of the FDA’s Endocrinology and Metabolism Advisory Committee expressed serious concern about the likelihood that
“patients with undiagnosed COPD, asthma, interstitial lung disease, or lung cancer” will use Pfizer, Inc.’s (NYSE:PFE) and Nektar Therapeutics’ (NASDAQ:NKTR) Exubera inhaled insulin.

That the conclusion of James K. Stoller, M.D., M.S. in the June 2006 issue of the Cleveland Clinic Journal of Medicine. His important article, “Inhaled Insulin: Coup or Caution,” highlights the serious risks associated with Exubera inhaled insulin usage by diabetics with Chornic Obstructive Pulmonary Disease (’COPD’), asthma, interstitial lung disease, and lung cancer.

In studies considered by the FDA, Stoller expressed concern that, ikn “a finding that was based on studies of relatively few patients with COPD followed for up to 1 year,” Exubera was shown to cause:

…a slightly increased rate of decline in forced expiratory volume in 1 second (FEV1) in patients with chronic obstructive pulmonary disease (COPD)…Notably, no longer term studies were available at the time of submission regarding the effect in patients with COPD, and no studies addressed the impact in patients with interstitial lung disease.

Stoller is worried that since “only a minority of the estimated 16 million Americans with COPD are aware of their diagnosis,” those who aren’t aware of their pulmonary problems and want to use Pfizer and Nektar’s inhaled insulin will likely be exposing themselves to serious potential drug safety risks.

He wants postmarketing surveillance of Exubera to address important safety issues like:

• What is the prevalence of Exubera use in
patients with undiagnosed COPD, asthma,
interstitial lung disease, and lung cancer?

• In these patients, what are the short-term
and long-term effects on pulmonary function,
symptoms, functional status, and survival?

• What is the incidence of lung cancer
among Exubera users and does it exceed
expected rates?

As a pulmonary specialist, Stoller is also concerned about spirometry, the lung function testing required of all Type 1 and Type 2 diabetics who are prescribed the drug by their physicians.  Will general practictioners be able to do spirometry, or will diabetics and their health insurance companies be able to pay for lung function testing prior to going on Exubera?

These are important questions. Given that the FDA gave Pfizer approval for Exubera conditioned upon the pharmaceutical company’s conducting long-term inhaled insulin safety studies, the results of long-term safety studies of Exubera on diabetics with pulmonary problems cannot come too soon.