Exubera Approved Despite Initial Lung Function Concerns

Laurie Barclay, MD

February 09, 2006

Feb. 9, 2006 -- Despite initial concerns regarding lung function, the US Food and Drug Administration (FDA) approved Pfizer's inhaled insulin Exubera for adult patients with type 1 and type 2 diabetes. The approval came on January 27, one day after approval of this drug in the European Union. This inhaled powder form of recombinant human insulin is the first new insulin delivery option introduced since the discovery of insulin in the 1920s. Trial data suggest that use of Exubera is associated with initial but nonprogressive declines in pulmonary function, with efficacy comparable to that of regular insulin and with the advantage of patient preference.

"The pulmonary safety of Exubera was a major focus of the FDA in the development and subsequent review of Exubera," FDA public affairs specialist Christine S. Parker told Medscape. "In patients without overt lung diseases, such as asthma or chronic obstructive pulmonary disease (COPD), and without concurrent smoking, a small decline in 2 common lung function parameters -- FEV 1 and DLCO -- was seen very soon after starting the drug. However, this decline did not worsen over time from the extensive database available to FDA and seems to revert to baseline levels if the drug is stopped."

In nonsmokers without pulmonary disease at baseline, there were no severe decreases in lung function attributed to Exubera, and high-resolution chest computed tomography revealed no evidence of notable lung changes. Completed phase 2 and 3 studies that followed patients for up to 4 years indicate that the differences over time in pulmonary function changes between patients treated with Exubera and control patients are small, nonprogressive, clinically insignificant, and reverse after discontinuation of Exubera therapy.

"There was some evidence that in people who stopped Exubera,...the decline in lung function was at least partially reversible, but it was not a large enough group to be able to draw a firm conclusion about that," Jay S. Skyler, MD, MACP, a professor of endocrinology, diabetes, and metabolism, and associate director of the Diabetes Research Institute at the University of Miami Miller School of Medicine in Florida, told Medscape. "The pulmonologists describe it as an acute response to exposure, a form of acute injury response that you get on initial exposure but that does not show any further evidence of decline over 2 to 4 years. What we don't yet have any idea about is what happens over 5 to 10 years."

However, few patients with progressive diabetes may actually be taking Exubera for 5 years or more, explained Dr. Skyler, who is also chairman of the National Institute of Diabetes and Digestive and Kidney Diseases' Type 1 Diabetes TrialNet. He was also a lead investigator on a study of Exubera in patients with type 1 diabetes. Most of these patients would require insulin injections after 5 years, either alone or with inhaled insulin, and most would be accustomed to self-injection and find less of an advantage to the inhaled formulation than would initial insulin users.

"The FDA, preceded by its advisory committee, found that Exubera is safe in patients with normal lung function," Ms. Parker said. "More data are needed to make a final determination on the safety in individuals with asthma or COPD and therefore the drug is not recommended, although not contraindicated, for use in those populations at this time."

Although Pfizer did not extensively study smokers, these patients have a 2 – to 5-fold higher exposure to inhaled insulin than do non-smokers, and exposure can fluctuate with changes in smoking habits. "Smoking is a contraindication to Exubera, even if the patient quit within 6 months, as is use in patients with unstable or poorly controlled lung disease," Ms. Parker says.

Recommended precautions are that patients be screened with pulmonary function tests, such as FEV 1, before starting Exubera, after 6 months of treatment, and yearly thereafter. If there is a persistent, significant decrease in FEV 1, Exubera should be discontinued. In clinical trials, other drug-related adverse effects included cough, shortness of breath, sore throat, and dry mouth. To help ensure that Exubera is used correctly, pharmacists dispensing the drug are required to distribute a medication guide containing FDA-approved information written especially for patients.

To further evaluate pulmonary safety with extended use, Pfizer has agreed to conduct a large safety study of 5000 patients over 5 years; to complete and report ongoing studies of inhaled insulin use in patients with asthma and COPD; and to provide 5- and 7-year safety information from ongoing studies in patients with type 1 and type 2 diabetes. Pfizer will also annually evaluate and report the extent to which Exubera is being prescribed for and used by smokers, to assess whether patient and physician labeling are effectively preventing such use.

Other precautions in the drug labeling are similar to those provided for other insulin products, including hypoglycemia necessitating blood glucose monitoring. Because of insufficient data on safety and efficacy, Exubera is not recommended for use in children at this time.

Dr. Skyler noted that Exubera is associated with formation of more insulin antibodies than are injectable formulations, but that "the levels are trivial compared to what we used to see with the impure insulins. In the clinical trials, there have been no demonstrated effects with Exubera of antibodies either impairing the action of insulin, or unexpected insulin release causing hypoglycemia, or any allergic reaction."

Exubera safety and efficacy have been evaluated in clinical trials enrolling a total of approximately 2500 adult patients with type 1 and type 2 diabetes. However, Dr. Skyler said that most of these trials have compared preprandial Exubera with regular insulin, whereas most experts would prefer to use a rapid-acting insulin analogue in this situation.

"In none of the studies to date in which Exubera was compared to insulin have they been able to achieve the target blood glucoses that we desire to and can achieve when meticulously using insulin analogues and insulin pumps," Dr. Skyler pointed out. "It remains an open question whether or not you can achieve optimal control with Exubera — it just hasn't been demonstrated in the trials to date."

In the October 18, 2005, issue of the Annals of Internal Medicine, Julio Rosenstock, MD, from the Dallas Diabetes and Endocrine Center in Texas, and colleagues reported on a 12-week trial of 309 patients with type 2 diabetes, no clinically significant respiratory disease, and hemoglobin A 1c level of 8% to 11% who were receiving dual oral therapy with an insulin secretagogue and sensitizer. Inhaled insulin improved overall glycemic control and hemoglobin A 1c level when added to or substituted for dual oral agent therapy. Hypoglycemia, mild weight gain, mild cough, and insulin antibodies were more common in patients receiving inhaled insulin, but pulmonary function was similar among all groups.

Dr. Skyler and colleagues performed a trial in 328 patients with type 1 diabetes who were receiving twice-daily subcutaneous basal injections of neutral protamine Hagedorn (NPH) insulin and were randomized to receive also either premeal Exubera or subcutaneous regular insulin. After 6 months of treatment, glycemic control was comparable in both groups, with decreases in mean hemoglobin A 1c of 0.3% with Exubera and and 0.1% with subcutaneous insulin. Although 2-hour postprandial declines in glucose were similar in between the groups, fasting plasma glucose levels declined more in the patients using Exubera. The study was published in the July 2005 issue of Diabetes Care.

"Exubera is an effective insulin and in head-to-head trials with short-acting insulins, appears as effective," Ms. Parker said. "Inhaled insulin from Exubera has an onset comparable to the fast-acting insulin analogues, such as Apidra, and a duration of action similar to regular insulin. It is therefore an option to use as a mealtime insulin, similar to the way the short-acting insulins are used."

Pharmacodynamic studies reveal that Exubera reaches peak insulin concentration more quickly than injected regular insulin, with peak insulin levels achieved at 49 minutes (range, 30 - 90 minutes) for Exubera compared with 105 minutes (range, 60 - 240 minutes) for regular insulin. In patients with type 1 diabetes, inhaled insulin may be added to longer-acting insulins as a replacement for short-acting insulin taken with meals. In patients with type 2 diabetes, inhaled insulin may be used alone, along with oral hypoglycemic agents or with longer-acting insulins.

"How broadly Exubera will be used is a matter of conjecture," Ms. Parker said. "It is worth noting that this product will not replace all insulin injections for patients with type 1 diabetes and in some patients with type 2 diabetes. This is because most all type 1 patients and a proportion of type 2 patients will still need long-acting insulins for basal control of blood sugars."

Compliance and patient satisfaction studies done during the clinical trials showed that patients were quite satisfied with the inhaled formulation and that quality-of-life indices improved. However, Dr. Skyler noted that patients who are motivated to participate in a clinical trial may be subject to bias favoring satisfaction with their assigned regimen.

"There's certainly a lot of pent-up enthusiasm and desire for an inhaled insulin," Dr. Skyler said, noting overwhelming local response to recent media coverage. "We've never had such a response to anything we've done — even the first islet transplants."

Although no cost-effectiveness studies have been done, and the cost per prescription has not yet been made known to the investigators, Dr. Skyler said he believes that reduction of diabetic complications in greater numbers of people could translate into healthcare savings.

"Exubera could be very helpful on a population basis to reduce the glucose burden in the country, and the complications of glycosemia, by improving overall diabetes management in people with type 2 diabetes who are otherwise reluctant to go onto insulin when they need it, and who are not having adequate glucose control, " Dr. Skyler said. "Since there is no unique advantage other than inducing some patients to use insulin earlier, the potential for widespread use of Exubera is going to be contingent on the value that payors place on it, at what price it is marketed, and what people are actually willing to pay."

Dr. Skyler is a consultant for Pfizer on Exubera and chaired the company's Global Advisory Committee. He is also a consultant regarding inhaled insulins for Mankind, Novo Nordisk, and KOS, and he is a consultant for Eli Lilly on matters unrelated to inhaled insulins.

Reviewed by Gary D. Vogin, MD

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