An FDA advisory panel yesterday recommended approval of Mannkind’s inhaled insulin candidate Afrezza for adults with type 1 or type 2 diabetes, brushing aside concerns raised in a staff report—and advancing the drug toward another formal decision by the agency that rejected it three years ago.
FDA’s Endocrinologic and Metabolic Drugs Advisory Committee recommended the agency approve Afrezza for type 1 diabetes by a 13–1 vote, and for type 2 diabetes in a separate 14–0 vote. Agency administrators typically follow panel recommendations, but not always. The Prescription Drug User Fee Act (PDUFA) date for the completion of FDA’s review of Afrezza is April 15.
The single vote against the drug’s use in type 1 diabetes cited issues raised in a critical staff report released shortly before the advisory panel held its hearing. Among them: Some patients taking Afrezza stopped treatment after developing bronchial spasms, coughing, and a decline in the functioning of their lungs.
Another concern raised: MannKind’s new drug application for Afrezza cited cartridges containing up to three units of injected insulin, and double-strength cartridges with up to six units, when its clinical trial used cartridges with up to four units and double-strength cartridges of up to eight. The company cited an equivalency study that compared its inhaled insulin with injected insulin from other companies; Afrezza would compete with two injectable insulins, Humalog sold by Eli Lilly, and Novolog sold by Novo Nordisk.
A switch of inhalers during FDA review in 2011 prompted the agency to reject Afrezza and require two additional clinical studies comparing its current inhaler to its first-generation MedTone inhaler. Yesterday, however, the drug saw smoother sailing with the advisory panel, raising hopes that Afrezza’s third time in front of the agency will be the proverbial charm.
“We are pleased with the Advisory Committee's approval recommendation in support of Afrezza, and we appreciate the thoroughness of their review," Alfred Mann, MannKind’s chairman and CEO, said in a statement. "We look forward to working with the FDA as they complete their evaluation of Afrezza. Diabetes is a major health problem in the United States, and we are committed to bring Afrezza to the many patients who might benefit from this novel product."
Afrezza combines an inhalation powder with a whistle-sized inhaler called Dreamboat™ designed for use by diabetics at the start of meals. The powder dissolves immediately when inhaled to the deep lung and delivers insulin quickly to the bloodstream. According to MannKind, peak insulin levels occur within 12 to 15 minutes of administration, compared with 45 to 90 minutes for injected rapid acting insulin analogs, and 90–150 minutes for injected regular human insulin.
In August 2013, MannKind released promising results from two Phase III trials. One study in type 1 patients compared Afrezza to insulin aspart; the other measured inhalable insulin in type 2 patients with inadequate diabetes control following metformin treatment, with or without a second or third oral medication. The type 2 study showed a drop in mean A1c levels of 0.82% in patients using Afrezza, compared to a 0.42% decrease in the comparator group. The type 1 study met its primary endpoint of noninferiority to insulin aspart.
Joseph Kocinsky, MannKind’s svp, pharmaceutical technology development, told GEN back in October that Afrezza’s Technosphere® pulmonary drug delivery platform offered competitive advantages that included ultra-fast delivery, as well as avoidance of the hepatic first-pass metabolism that reduces drug bioavailability, since the insulin in Afrezza is administered via the inhaled Technosphere formulation.
“The Technosphere technology is applicable to a wide variety of drugs (small molecules, peptides, proteins, monoclonal antibodies) and a wide variety of clinical indications like diabetes, pain, osteoporosis, and respiratory disease,” Kocinsky said at the time.
The last time an inhalable insulin reached the market was Pfizer’s Exubera®, which the company withdrew in 2007 after 13 months following disappointing sales, taking $2.8 billion in pre-tax charges, and returning product rights to partner Nektar Therapeutics. But Exubera had a clumsy foot-long inhaler, and was linked to a higher lung cancer risk since the insulin is inhaled—a concern FDA staffers also raised with Afrezza.