MannKind reports that its inhaled mealtime insulin product, Afrezza Inhalation Powder, provided more rapid suppression of endogenous glucose production (EGP) after a meal than the subcutaneously injected insulin lispro in patients with Type 2 diabetes. Data was presented at the American Diabetes Association’s 70th Scientific Sessions.
MannKind received a complete response letter to its NDA for Afrezza in March. Afrezza is an ultrarapid-acting therapy being developed by MannKind for the treatment of adult patients with type 1 and type 2 diabetes for the control of hyperglycemia. It is a drug-device combination product, consisting of Afrezza Inhalation Powder premetered into single-use dose cartridges and the Afrezza Inhaler.
The complete response letter related to the Afrezza application requested several items including information and currently available clinical data that support its clinical utility and information about the comparability of the commercial version of the MedTone inhaler to the earlier version of this device that was used in pivotal clinical trials. The letter cited no safety concerns but requested updated safety data. The letter also asked for changes to the proposed labeling of the cartridges, foil pouches, and cartons.
Upon receipt of the complete response letter, Alfred Mann, chairman and CEO, stated, “We had always planned to follow the original NDA for Afrezza with a regulatory submission for our next-generation inhaler rather than launch with the commercial version of the MedTone device.
“We will discuss with the FDA whether it is appropriate to use what would otherwise have been a supplemental NDA submission, which we had planned to make during the second quarter of this year, to address the agency's requests. If this approach is acceptable, we believe that this regulatory action will not have a significant impact on the timing of the commercial launch of Afrezza.”
Mealtime insulin regimens have had a number of limitations including the risk of severe hypoglycemia, the likelihood of weight gain, inadequate postmeal glucose control, the need for complex titration of insulin doses in connection with meals, and the need for injections, according to Mannkind. Additionally, these therapies have not mimicked the natural time-action profile of insulin normally seen in healthy individuals and have presented challenges in maintaining compliance.
Administered at the start of a meal, Afrezza dissolves immediately upon inhalation and delivers insulin quickly to the bloodstream, MannKind explains. Peak insulin levels are achieved within 12 to 14 minutes of administration, mimicking the release of meal-time insulin observed in healthy individuals, the firm reports.
“The finding that the effect of Afrezza on free fatty acids and glucagon was dose-dependent may be very important in understanding the consistent effect that we see with Afrezza on fasting glucose levels,” points out Peter Richardson, corporate vp and CSO. “Free fatty acids play a major role in the pathophysiology of insulin resistance, and we anticipate conducting further research in this area.”
In the study being presented today, single doses of 60 U and 90 U Afrezza were compared with 10 IU subcutaneous lispro insulin in an open-label, two-way crossover study incorporating a meal challenge (BoostPlus® 12 fl. oz. enriched with [U-13C] glucose) in insulin-treated subjects with type 2 diabetes and normal pulmonary function. The dose of 60 U of Afrezza, using MannKind’s first-generation inhalation device, provided approximately the same insulin exposure as the 10 IU dose of injected lispro.
Maximal EGP suppression occurred earlier with Afrezza based on mean profiles: 45 and 60 minutes for 60 U and 90 U, respectively, compared to 105 minutes for lispro. The greatest decrease from baseline EGP was observed after 90 U Afrezza (10.3 µmol/kg/minutes) versus 60 U Afrezza and lispro (6.9 and 7.1 µmol/kg/minutes, respectively).
Total EGP areas over curve (AOC) were comparable across groups. A significantly greater proportion of EGP AOC was observed with Afrezza up to 140 minutes postdose versus with lispro. The effect of Afrezza on free fatty acids (FFA) and glucagon was dose dependent, with an earlier (for Afrezza 90 and 60 U) and greater (for Afrezza 90 U) decrease from baseline. The highest FFA AOC was observed after Afrezza 90 U, while lispro and 60 U Afrezza were comparable. Peak glucagon concentrations and area under curve were substantially lower after 90 U Afrezza dose than after either lispro or 60 U Afrezza.