Clinical Safety of Inhaled Insulin

Inhaled insulin has been studied extensively in over 10,000 patients across more than 100 clinical trials demonstrating safety and efficacy. Numerous nonclinical and clinical publications have demonstrated the safety of inhaled insulin. Concern regarding first-generation inhaled insulin focused on the incidence of hypoglycemia and pulmonary safety.

Pulmonary Safety

During more than 20 years of inhaled insulin development, investigators primarily focused on three pulmonary safety issues.

Changes in lung function. 1- to 2-year trials observed small, reversible, nonprogressive changes of 1%-2% in one or two measurements of lung function [22]. These effects were not deemed clinically significant, were not detectable by the patients, and were not associated with any pathology. In the 8-year study, patients on Exubera had lung function similar to or better than patients treated with injections [25]. No signs of pulmonary inflammation were observed in two subsequent 7-month studies of Exubera [26]. Insulin is an anabolic hormone and has been shown to be beneficial to the lungs in animal models of pulmonary injury and disease [27-30].

Antibody levels. The delivery of insulin, whether by injection or inhalation, leads to the formation of circulating insulin antibodies in some patients [31]. In prior clinical development programs, the delivery of insulin by inhalation induced higher antibody levels in some patients than comparators; however, these antibodies were not associated with any adverse events and did not decrease the effectiveness, safety, or tolerability of inhaled insulin over time and were similar in type to those generated by injection [32-34]. In both injections and inhalation of insulin, the immune response does not produce an allergic reaction or inflammation except in very rare cases with injections.

Incidence of lung cancer. In the phase 3 trials conducted by Pfizer, a numerically larger but not statistically significant number of incidents of lung cancer were seen in Exubera patients who were former heavy smokers compared to former heavy smokers who used injected insulin. In a 2-year observational follow-up on the prevalence of lung cancer in Exubera patients completed in 2012, the Follow Up Study of Exubera (FUSE) study, an apparent imbalance was seen in lung cancer diagnosis between patients who were former smokers and took Exubera and those who were treated with multiple comparators [35]. After reviewing the results of the FUSE study, an independent scientific steering committee recommended that no special screening for lung cancer be conducted for patients exposed to Exubera beyond what is currently recommended. In a 2-year phase 3 clinical trial involving 385 patients conducted with another inhaled insulin product, five cases of lung neoplasia (abnormal mass of lung tissue) were seen in the injected group as compared to the three cases in the inhaled group [36]. To date, MannKind Corporation has not reported any increased risk of lung cancer during clinical trials conducted with its inhaled insulin. We are not aware of any other published studies of lung cancer incidences with inhaled insulin. High circulating insulin concentrations in diabetes, known as hyperinsulinemia, are not associated with an increase in lung cancer incidence [37]. The literature on cancer, diabetes, and insulin is long and extensive and suggests that although there is an increased incidence of some cancers in diabetes (but not lung cancer), insulin use may be associated with a decrease in cancer incidence in diabetes patients, presumably through the lowering of blood glucose [38,39].

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