Comprehensive Pulmonary Safety Review of Inhaled Technosphere^® Insulin in Patients with Diabetes Mellitus

Background and Objective: Technosphere^® Insulin (TI), a human insulin powder for inhalation (Afrezza^®; MannKind Corporation, Westlake Village, CA, USA), is an ultra-rapid-acting inhaled insulin indicated to improve postprandial glycemic control in patients with type 1 or type 2 diabetes mellitus (T1DM or T2DM). Because TI is absorbed across the alveolar membrane, the objective of this analysis was to characterize its pulmonary safety. Methods: Pooled data from 13 phase 2/3 clinical studies in 5505 patients with T1DM or T2DM treated with TI, Technosphere inhalation powder without insulin (TP; placebo), or active-comparator treatment were analyzed for incidences of respiratory treatment-emergent adverse events (TEAEs), changes in pulmonary function, and lung malignancies. Radiographic changes in the lungs were monitored in a subset of 229 patients. Results: Among 3017 patients receiving TI, the median duration of TI exposure was 168 days; median active-comparator and TP exposure durations were 363 and 149 days for 2198 and 290 patients, respectively. Respiratory TEAEs were comparable across treatments, except for a higher incidence of mild cough with TI in active-comparator studies (28.0% vs. 5.2%). Slight reversible declines in pulmonary function from baseline were observed for TI versus TP and active-comparator treatments, including in a subpopulation of patients with retrospectively identified lung dysfunction. Lung malignancies were reported in two patients on active TI therapy with a smoking history. No clinically significant changes from baseline were observed in radiographic images. Conclusions: Pulmonary safety assessment of the TI inhalation system did not identify any safety issues in individuals with either T1DM or T2DM.