Afrezza Dosing With Other Insulins Requires More Clarity, Expert Says

Treatment algorithms are needed to guide practitioners on how much basal and prandial insulin to use in conjunction with MannKind’s inhaled insulin.

Practitioners and patients will need better evidence-based information about proper dosing and integration of MannKind Corp.’s inhaled insulin Afrezza with other insulins if the drug is to avoid the same commercial fate suffered by Pfizer Inc.’s Exubera, an endocrinology expert suggested.

During the FDA Endocrinologic and Metabolic Drugs Advisory Committee’s April 1 meeting, Henry Ford Hospital’s Abraham Thomas said it is difficult to know how to dose Afrezza and that real-world treatment algorithms need to be developed based upon more robust clinical trial experience than is currently available.

FDA’s review found that in the most recent Phase III trial in type 1 diabetes (study 171), average daily basal and prandial insulin doses were consistently higher in Afrezza-treated patients than in the insulin aspart comparator group. Nevertheless, Afrezza demonstrated less improvement in hemoglobin A1c levels.

Thomas recalled the problems with dosing Exubera, the first approved inhaled insulin, which was withdrawn from the market for commercial reasons.

Not long after FDA’s approval of the drug and before product launch, a drug safety group took issue with the product’s labeling and dosing instructions, predicting that practitioners would be challenged in converting back and forth between injectable insulin, which is dosed in units, and the inhaled insulin, which was dosed in milligrams. Such confusion would lead to medication errors, the group predicted (Also see "Exubera Labeling Could Trigger Dosing Errors, ISMP Says" - Pink Sheet, 14 Jul, 2006.).

“Exubera, from what I remember, one of the problems with it, it was really confusing,” Thomas said. “The average practitioner looked at the conversion of what you had to do with insulin to injectable insulin, and I think that was one of the problems, and also patients were confused.”

Thomas cited the need for more clinical trial data that better inform optimal dosing of Afrezza in conjunction with other meal-time prandial insulins and with long-acting basal insulin.

“Based on the data that was shown, my impression would be that you have to have a lot more basal insulin to use with this agent to meet A1c targets,” he said. “That type of real information – it’s practical, it tells us how to treat the patients.” Lacking such information, many patients may not be treated properly, he predicted.

MannKind has proposed a dosing regimen that converts between units of injected mealtime insulin and units of Afrezza. However, FDA said in its briefing material for the meeting that the proposed dosing regimen and dosing conversion factors are different than those tested in the Phase III trials evaluating the to-be-marketed inhaler device.

Clinical pharmacology data submitted by MannKind do not adequately support the new proposed dosing regimen and conversion factors, and the sponsor makes several assumptions in relying on study 171 to support the proposed dosing regimen, FDA said.