Mannkind's inhaled insulin

In advance of Tuesday’s hearing on MannKind's inhaled insulin, the US Food and Drug Adminstration (FDA) has outlined several safety and efficacy issues of potential concern that it will ask its Endocrinologic and Metabolic Drugs Advisory Committee to address, leading up to a vote on approval.

The product, Technosphere inhaled insulin system (Afrezza), consists of a premeal insulin powder loaded into a cartridge for oral inhalation. The company is seeking an indication as an ultrarapid-acting insulin for adults with type 1 or 2 diabetes. In type 1 patients, the indication would be for use with injected basal insulin.

Briefing documents from both MannKind Corporation and the FDA were posted Friday on the FDA website.

According to MannKind, the inhaled insulin, which is composed of recombinant human insulin and an inert excipient, has a more rapid onset and shorter duration of action than current injectable insulins and therefore "more closely mimics mealtime endogenous insulin secretion."

However, the FDA has declined to approve 2 previous versions of the product that used different inhalers (in 2010 and 2011).

The current review will primarily focus on 2 new pivotal phase 3 trials with a new inhaler (Gen2) intended for marketing, but the FDA will ask the committee to consider some of the previous data with the 2 older inhalers (MedTone C and D).

Another inhaled insulin, Exubera, was approved by the FDA in 2006 but voluntarily withdrawn from market in 2007 by its manufacturer, Pfizer, because of poor sales.

"Level of Concern" to Be Elicited

Efficacy issues that the FDA is expected to ask the panel to address include the lower bioavailability of Afrezza compared with injected insulin and the finding of some studies that increasing doses of Afrezza did not increase its glucose-lowering effect.

In the pivotal randomized trial 175, involving 353 patients with type 2 diabetes inadequately controlled on one or more oral agents, Afrezza was superior to placebo in lowering HbA1c at 24 weeks.

However, in pivotal study 171, of 344 patients with type 1 diabetes, Afrezza had significantly inferior HbA1c reduction compared with premeal injections of insulin aspart, although the difference remained within the prespecified noninferiority margin.

The FDA will also ask panel members to express their "level of concern" about effects on the lung in patients with various lung conditions and smokers, as well as about "noted imbalances not favoring Afrezza" in lung cancer and diabetic ketoacidosis in patients with type 1 diabetes, although the numbers were small.

The panel will be asked to vote separately on approval for patients with type 1 and 2 diabetes. The FDA is expected to complete its review of the new drug application by April 15, according to MannKind.