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If Approved -- FDA Drug Labeling Could Decide Ultimate Success of MannKind's Afrezza

The U.S. Food and Drug Administration's (FDA) delay in completing its review of MannKind Corp.'s ultra rapid-acting insulin therapy, called Afrezza, by the expected action date of January 16 has added to uncertainty over the commercial prospects of this experimental inhaled insulin. If approved, success of the drug-device (combination) will likely be determined not by the timing of the agency's decision, but by the wording of the FDA's drug label.

MannKind (Nasdaq: MNKD) explained that the FDA had not yet completed its inspection of the insulin manufacturing facilities of N.V. Organon, a third-party supplier to the company. "The agency must complete this inspection before it can finalize its review of our NDA," said Alfred Mann, chairman and chief executive officer. "To our knowledge, all other FDA inspections of third-party suppliers and clinical trial sites are complete, as is the pre-approval inspection of MannKind's manufacturing facility in Danbury, Connecticut."

As part of the ongoing discussions between MannKind and the FDA, the agency did request that the trade name of the product (formerly known as Afresa) be changed in order to avoid confusion with another medication. Medicines being incorrectly dispensed have been linked to denominators as simple as packaging or drug names that sound or look alike. Although the company wouldn't identify the medicine in question, any drug with seven letters, beginning with 'A,' from Abreva (cold sores) to Aprida (fast-acting insulin) or Advair (inhalable asthma drug) -- if written in the illegible script that physicians are notoriously known for -- could lead to mistaken prescription fills at the pharmacy level.

Despite a robust late-stage clinical trial program (with more than 4,500 adult patients) for Afrezza, demonstrating non-inferiority to current meal-time insulin, MannKind has been unable to outrun the long shadow of doubt cast by Exubera, the inhaled insulin device voluntarily withdrawn in October 2007 by Pfizer (due to disappointing sales). The commercial failure of Exubera should not signal defeat for MannKind's efforts to deliver insulin via the lungs, as there are significant differences between the two products, including (i) size of Afrezza delivery device is significantly smaller; (ii) dosing -- Pfizer erred in marking Exubera insulin doses in milligrams instead of units; and, (iii) dearth of formulary and managed care acceptance.

If approved, it is what is put on the drug label, often referred to as the package insert, that will likely decide the success or failure for Afrezza. The labeling regulates what MannKind can and can't say in advertising and promotional materials about the drug. Industry watchers are divided as to the FDA's level of comfort with the chronic administration of insulin through the lungs, especially with a reported six cases of primary lung cancers diagnosed among Exubera-treated patients. Mandated pulmonary function tests (PFT) and/or any potential mention of the risk of cancer (proven or not) in the label could be deal breakers for the drug.

CEO Mann opined during a presentation at the JPMorgan healthcare conference last week that the action letter would likely not require lung function testing. Nonetheless, given long-term safety issues with the use of inhaled insulin in smokers or those diabetics with chronic obstructive pulmonary diseases -- including cancer risk or the diffusing capacity of carbon monoxide -- the Afrezza labeling will likely mandate [at worst] a black box labeling or [at best] caution against use in certain subsets of diabetics.

Chief financial officer Matt Pfeffer stressed in a phone interview with me on Monday that Mann's comments on PFTs represented his opinion as a private investor -- and were not representative of the company's position (as MannKind had not yet resolved discussions with the FDA over the specifics for labeling).

Mann also said during the presentation "[we] have nothing from our side that's due." Pfeffer concurred, but did mention to me that the company has initiated a new [ongoing] study, the aim of which is to compare the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of inhaled doses of Technosphere formulated insulin with those of subcutaneous insulin. This new bioequivalency data, said Pfeffer, would be required for a planned supplemental NDA for an easier-to-use, next-generation inhaler device (dubbed within the company as "Project Dreamboat").
Pfeffer reiterated that trial data demonstrates that (in addition to glycemic control) Afrezza-treated patients with type 1 and type 2 diabetes had less weight gain and lower risk of hypoglycemia than patients treated with subcutaneous insulin injections. However, the company's ability to communicate these treatment advantages to primary care doctors and endocrinologists alike rests in the hands of the FDA.

Curiously, not one critic of inhaled delivery platform technologies has mentioned reports of higher levels of insulin antibodies being found in diabetic patients receiving inhaled insulin. This point could prove moot, as little evidence exists that the development of such antibodies to exogenous insulin affects glucose control or contributes to ß-cell failure. Nonetheless, it will be interesting to follow whether the FDA requires MannKind to note a potential humoral response in Afrezza's labeling. [Ed note. To date, however, there has been no evidence of treatment-induced insulin antibodies occurring in patients treated with Technosphere insulin.]

Venture capitalists often guage the potential success of new technologies by their ability to fulfill unmet medical needs and by the level of commercial interest. Naysayers reference Pfizer's shelving of Exubera and MannKind's inability to partner a deal prior to receipt of the FDA's action letter as signs that the company's inhaled Technosphere delivery system -- even if approved -- will prove to be a commercial disappointment. If the FDA doesn't disarm MannKind with a restrictive drug label, Alfred Mann & Company might just prove critics wrong.

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