The recombinant inhaled insulin product Afrezza has received a complete response letter from the Food and Drug Administration, drug developer MannKind Corp. announced Jan. 19.

The company says it hopes that with a major protocol change, studies that are already off the ground will satisfy the letter’s requirements.

The phase III trials supporting the Afrezza application had been done with the company’s "MedTone" delivery device, but the company plans to commercialize the next-generation whistle-shaped "Dreamboat" device instead.

The main concern of the FDA’s Center for Drug Evaluation and Research is MannKind’s use of in vitro performance and clinical pharmacology data to bridge the next-generation inhaler to the phase III trials conducted using the older MedTone inhaler, MannKind explained in a statement. Two clinical studies of Afrezza will be needed with the new inhaler: one in type 2 diabetes, and one in type 1 disease. Moreover, at least one of these trials must also have an arm of patients using the MedTone inhaler to allow for head-to-head comparisons.

The complete response letter is unlikely to surprise industry observers, as the inhaled delivery had raised concerns about pulmonary safety and the product had previously received a complete response letter. Regulatory and commercial hurdles for the product have been known to be high.

A request for new trials is typically seen as one of the more damaging outcomes of a complete response letter, with potential to cause major delay to the product-launch timetable and commercial viability.

During a call with investors, MannKind executives declined to say exactly how long it will take to satisfy new requirements and resubmit its application. "We believe we can readily address these additional requests," said CEO Alfred Mann. But analysts don’t necessarily agree. In a Jan. 19 note entitled "Afrezza’s Gasping For Air," J.P. Morgan biotechnology analyst Cory Kasimov described the complete response terms as "onerous" and predicted a delay of at least a year in the "best-case scenario."

Mr. Mann described the letter as a surprise, noting that the company thought it had enough bridging data for the next-generation device. In October, company executives had indicated that they expected no new requests from the FDA.

The ball is already rolling on two phase IIIB trials of the next-generation device, compared with insulin analogs (Affinity-1 in type 1 diabetes, and Affinity-2 in type 2 diabetes, the latter of which has started enrolling patients and is listed on the clinicaltrials.gov Web site).

The protocols for these studies had already been submitted to the FDA and are very similar to what was requested in the complete response letter, executives maintained. However, the design of one study will need to be modified to include an arm using the MedTone inhaler to satisfy the complete response letter.

On top of the trials, the FDA also wants more information about performance characteristics, usage, handling, shipment, and storage of Dreamboat. Furthermore, the agency has requested an update of safety information related to Afrezza and information on proposed user training and changes to the proposed labeling of the device, blister pack, foil wrap, and cartons.

In terms of the two phase III trials now needed for approval, the FDA has indicated that after an adequate titration of study medication, there should be at least 12 weeks of relatively stable insulin dosing at the end of the treatment period. The length of the titration period in the Affinity trials is 4 weeks, and the treatment period is 12 weeks. According to current protocols, each Affinity trial has 143 patients per arm. MannKind believes that the Affinity studies would meet the requirements of the FDA, based on the wording of the complete response letter. But this is subject to discussion with the agency.

In response to analyst questions, Mr. Mann insisted that the Affinity trials do not have to be halted pending talks with the FDA, and defended the likely strategy of using ongoing trials rather than starting from scratch to satisfy the demands of the complete response letter.

One possibility is to randomize patients in one of the Affinity studies to the MedTone arm, and then start dosing later to catch up with the other study arms, executives said.

The company also clarified that the agency has not requested that the new device prove to be superior to the old one, although it could show lesser negative effects on pulmonary function, which would be a positive signal.

Asked about the possibility that MedTone would outperform the next-generation device, Mr. Mann said simply, "It won’t be superior. Dreamboat is clearly superior in many ways."

Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.

Afrezza Receives FDA Complete Response Letter