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FDA Advisors Question Safety and Effectiveness of Diabetes Device, Afrezza

Deficiencies include potential effects on lung function

An initial review by the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee of the experimental inhaled insulin device Afrezza (MannKind) has raised questions about the product’s safety and effectiveness. Specifically, the committee expressed concerns about dosing, missing trial data, bronchospasm, and the treatment’s effect on lung function.

The report was issued before an April 1 meeting of outside advisers to the FDA who will discuss clinical trial data and advise the agency on whether Afrezza should be approved.

Afrezza — insulin monomer human (rDNA origin) inhalation powder, also referred to as Technosphere insulin (TI) — is a rapid-acting prandial insulin for the treatment of type 1 and type 2 diabetes mellitus (DM) in adults 18 years of age and older. TI inhalation powder is a dry-powder formulation of recombinant human insulin and contains a proprietary excipient, fumaryl diketopiperazine (FDKP).

Afrezza is a drug–device combination product consisting of TI inhalation powder delivered via the Gen2 inhaler. Patients self-administer the insulin powder by oral inhalation. The insulin powder is prefilled into cartridges packaged in blisters. The cartridges contain either 0.35 mg (10 units) or 0.7 mg (20 units) of insulin per cartridge. The patient uses the product by removing a cartridge from the blister package, inserting it into the inhaler, placing the inhaler in his or her mouth, and inhaling the powder.

The FDA’s advisors noted that the inhaled route of administration for Afrezza and the potential for chronic administration raise pulmonary safety concerns. One previously approved inhaled insulin, Exubera inhalation powder (Pfizer), has been marketed for the treatment of type 1 and type 2 DM. A review of the clinical development program for Exubera demonstrated respiratory-related adverse events, a small decline in the forced expiratory volume in 1 second (FEV1) over time, and a risk of bronchospasm in patients with asthma or chronic obstructive pulmonary disease (COPD). Lung cancer was also a concern, based on long-term safety data with Exubera.

The NDA for Afrezza was originally submitted in March 2009. In the original submission, Afrezza consisted of TI inhalation powder pre-metered into unit-dose cartridges to be delivered via the MedTone inhaler, which was claimed to be re-usable for 12 months. In March 2010, the FDA issued a complete response letter (CRL), in which several deficiencies were cited, including: 1) unproven clinical utility resulting from a failure to demonstrate adequate glycemic control versus comparators; 2) unreliability of pivotal bioequivalence study results; 3) unproven usability of the MedTone device; and 4) lack of data to support the proposed 1-year in-use life of the Medtone device.

In June 2010, in response to the deficiencies outlined in the FDA’s CRL, the applicant proposed to change the device to the Gen2 inhalation system. The newly proposed product, consisting of different pre-metered unit-dose cartridges of TI delivered by the Gen2 inhaler, was completely different from the MedTone inhaler described in the initial submission.

The FDA issued a second CRL in January 2011. Among the deficiencies listed in the letter, the issue most relevant to pulmonary safety was the lack of clinical data with the new Gen2 inhaler. The agency advised the applicant to conduct two phase III trials with the Gen2 device, with at least one of these trials including a treatment group using the MedTone inhaler.

In its new statement, the FDA’s advisors concluded that treatment with TI using the Gen2 inhaler was effective in lowering hemoglobin A1c (HbA1c) compared with placebo in patients with type 2 DM. Treatment with TI using the Gen2 inhaler was also non-inferior to insulin aspart in lowering HbA1c in patients with type 1 DM. However, because of missing study data, the reviewers questioned the robustness of this analysis.

According to the advisory panel, final conclusions for approval of the Afrezza drug–device combination product should take into consideration the comparability of TI and insulin aspart, as well as safety factors, such as hypoglycemia and effects on lung function.

Sources: Reuters; March 28, 2014; and FDA Briefing Document; March 7, 2014.

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