FDA staff raise questions over MannKind's inhaled insulin therapy Afrezza

In FDA briefing documents released Friday ahead of an advisory panel meeting scheduled for April 1, agency staff highlighted concerns about pulmonary safety with MannKind's inhaled diabetes therapy Afrezza. Reviewers also raised questions about dosing and missing data, and added that while Afrezza, which delivers a dry powder formulation of recombinant insulin via the Gen2 inhaler, worked in type 2 diabetes, its effect on type 1 diabetes was less clear.

MannKind initially filed for approval of Afrezza in the US in 2009 as a prandial insulin to improve glycaemic control in adults with type 1 or 2 diabetes, but received a complete response letter in 2010 seeking more clinical data, and then again in 2011 after switching inhalers during the review process. In the latter case, the FDA had asked MannKind to conduct two additional trials using the new Gen2 inhaler, also known as the Dreamboat inhaler, as well as collect pulmonary safety data with the next-generation device, in order to compare the findings with the MedTone inhaler that had been used in previous late-stage studies.

In the latest review, FDA staff cautioned that "the inhaled route of administration for Afrezza and potential for chronic administration raise pulmonary safety concerns," citing respiratory-related adverse events observed from the previously approved inhaled insulin Exubera, which Pfizer stopped marketing in 2007. The reviewers pointed out that the clinical development programme for Exubera showed a small decline in forced expiratory volume in one second (FEV1) over time, and risk of bronchospasm in patients with asthma or chronic obstructive lung disease, while "lung cancer was also a concern based upon long-term safety data."

Agency reviewers said the pulmonary safety data submitted with MannKind's original application had identified several issues, including a decline in FEV1, bronchospasm in patients with underlying lung disease and cough. They noted that results from the 171 and 175 studies, which MannKind submitted to address issues raised in the 2011 complete response letter, suggest lung safety was similar between the Gen2 and MedTone inhalers, and similar to the original submission when compared to an active control or placebo. The FDA staff suggested that if approved, two post-marketing studies should be conducted to evaluate the risk of lung cancer, while labelling would be needed to limit Afrezza's use in smokers, asthma patients or those with kidney or liver impairment.

Commenting on the review, Summer Street analyst Bart Classen said "the FDA appears to concede that Afrezza is less effective than injectable insulin in both type 1 and type 2 diabetes," adding that the "documents indicate that Afrezza is associated with more ketoacidosis." The analyst noted that the agency "also appears to concede that the data used to instruct a patient to convert an injectable insulin dose to inhaled insulin dose is deficient. The pulmonary branch has strong reservations on whether large pre-approval safety studies should be performed for the Dreamboat inhaler because it is more effective than the Medtone-C inhaler." Classen remarked that the advisory panel is likely to "share our view that Afrezza should not be approved."

MannKind chief financial officer Matthew Pfeffer noted that the drugmaker is in discussions with "multiple companies" regarding co-marketing of Afrezza. He suggested that an announcement on such a deal would likely wait until after the FDA’s decision on the therapy, which is expected by April 15. Commenting on potential pricing for Afrezza, if approved, Pfeffer said "our expectation is that we'd be priced at parity with injected insulin in pen form. Getting parity pricing would be a big advantage in the marketplace." Analysts estimate that Afrezza could generate sales of $583 million in 2018.

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