FDA is asking for two clinical trials to demonstrate the benefits of new inhalation device.

Not to anyone’s surprise, FDA decided that MannKind’s inhaled insulin product, Afrezza, cannot be approved yet. The agency’s complete response letter raised concern with the usage of in vitro performance data and clinical pharmacology data to justify commercialization of MannKind’s new inhaler, called Dreamboat, when the NDA was based on Phase III trials conducted using an earlier version of the device called MedTone.

FDA has requested that MannKind conduct two clinical trials with Dreamboat—one in patients with type 1 diabetes and one in patients with type 2 diabetes. At least one has to include a treatment group using the MedTone inhaler to obtain a head-to-head comparison of the two devices. FDA specified 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 FDA has also requested additional information concerning the performance characteristics, usage, handling, shipment, and storage of the new device, an update of safety information related to Afrezza, as well as information on proposed user training and changes to the proposed labeling of the device, blister pack, foil wrap, and cartons.

“FDA’s request for two new, longer than we expected clinical trials pushes timelines out by an additional 18 months, making MannKind’s shares dead money during that time,” points out Simos Simeonidis, Ph.D., managing director and senior biotechnology analyst at Rodman & Renshaw.

MannKind initiated studies with Dreamboat last fall. Affinity 1 is being conducted in type 1 patients and Affinity 2 in type 2 diabetics. “We plan to meet with the agency as quickly as possible in order to be confident that these trials, with appropriate modifications to incorporate a comparison to the MedTone device, will suffice in addressing the agency’s questions about patient use and robustness of the next-generation device,” says Alfred Mann, chairman and CEO of MannKind.

Dr. Simeonidis doesn’t believe that MannKind has enough cash to carry it through to the next PDUFA date but says that the firm will make it to the finish line. “The company had stated that they have cash until the third quarter of 2011. They will now need to find capital for at least another year past that point, since we don’t expect a decision by the FDA before sometime in the second half of 2012.

“So, we expect them to utilize one and probably more of the financing options available to CFO Matt Pfeffer and find ways to get to the finish line. Furthermore, given that CEO Al Mann has invested close to $1 billion of his own money into this venture, we don’t expect him to throw in the towel anytime soon.”

Joshua Schimmer, M.D., and Steve Y. Yoo, biotechnology analysts at Leerink Swann, say, “By our model MannKind still needs to raise $300 million in cash to reach profitability.” Dr. Schimmer and Yoo maintain their underperform rating and low-single digit valuation range.

Administered at the start of a meal, Afrezza dissolves immediately upon inhalation and delivers insulin quickly to the bloodstream, according to MannKind. Peak insulin levels are achieved within 12 to 14 minutes of administration, mimicking the release of mealtime insulin observed in healthy individuals, the firm adds.

“While we believe Afrezza does have an attractive PK profile, we are concerned that it should be given at doses about five to six times higher than current insulin analogues (and higher than doses used to date) in order to show comparable HbA1c reduction as analogues,” Dr. Schimmer and Yoo remark.

“Higher insulin dosing requirements could make margins unappealing for a commercial partner.

“Using the new Dreamboat inhaler which has 20 U of insulin/cartridge, we estimate the optimal dose would entail an average of three inhalations per meal. Furthermore, a higher dose introduces the question of whether MannKind’s safety data across its clinical trials at lower doses are sufficient to address the pulmonary risk (specifically lung cancer).

“We are concerned that the new Phase III studies will fall into the same trap as the previous studies: Instead of titrating Afrezza doses all the way up to cover post-prandial glucose levels at 2–3 hours, suboptimal dosing levels may be administered by an erroneous focus on the 0.5–1.5 hour post-prandial glucose levels,” Dr. Schimmer and Yoo state. “If Afrezza is appropriately dosed, we would expect the Phase III study results to be positive catalysts.”

Commenting on the design of Affinity 1 and 2, Mann asserts, “Consistent with the direction we received in the complete response letter, these trials are designed to focus on careful titration of insulin dose and include at least 12 weeks of stable dosing.”

In October the agency issued a second complete response letter that raised issues that had not been discussed in the first letter from the agency, points out Dr. Simeonidis. “We note that according to MannKind’s 3/15/2010 press release following receipt of the first CRL, the FDA had not requested new clinical trials.

“With the obvious caveat that we have not seen either CRL, and assuming that the company’s interpretation of the first CRL is accurate, we view the agency’s decision to bring up a new issue in this second CRL that had not been brought up in the first CRL (despite the fact that the agency had actually extended the NDA review time from the usual 10 to 12 months), as further evidence of the FDA’s (more specifically, the FDA’s Division of Metabolism and Endocrinology Products) current conservative and, in many cases, unpredictable stance.”

A recent NDA from Amylin Pharmaceuticals and Eli Lilly for their diabetes drug Bydureon followed a similar fate with the FDA. Dr. Simeonidis believes that “it is plausible, especially given the agency’s current conservative stance around diabetes drugs, that the FDA moved the goalposts on MannKind, as they did with Amylin and Lilly in their Bydureon application.”

Bydureon is an extended-release version of exenatide for injectable suspension; Byetta, which is already on the market, is a twice-daily form of exenatide. On October 20, Amylin and Lilly reported that the FDA asked them to conduct a thorough QT (tQT) study with exposures of exenatide higher than typical therapeutic levels of Bydureon. The agency also has asked for results of the Duration-5 study to evaluate the efficacy and thus safety and effectiveness labeling details for the commercial formulation of Bydureon.

The previous complete response letter was received in March 2010. It raised issues related to the finalization of the product labeling with accompanying Risk Evaluation and Mitigation Strategy (REMS) and clarification of existing manufacturing processes.

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