May 15, 2008 (Vol. 28, No. 10)

Firm Could Have to Combat Challenges to FDA Approval as well as General User Perceptions

Not too long ago a number of firms were vying for a slice of the anticipated $1 billion inhaled insulin market. Now, Mannkind ( is the only company still standing in the clinical development space. Poor uptake of the first such approved product, Exubera, and negative study results related to the same therapy have plagued the sector.

Yet, Mannkind is holding strong with Phase III data expected in the summer. The company believes that its Technosphere Insulin therapy is superior to injected insulin products on the market as well as Pfizer’s Exubera. Perceptions of its safety, however, both at the regulatory level as well as with physicians if sanctioned will stand in the way of Technosphere realizing its full market potential, according to Aileen Salares, biotechnology analyst at Leerink Swann.

Salares downgraded Mannkind to a Market Perform when Pfizer reported that studies revealed a lung cancer association with Exubera. Even before this data, Pfizer divorced itself from its marketing obligations for the treatment under its agreement with Nektar Therapeutics, because sales fell short of the company’s expectations.

With the news of the lung cancer cases, Nektar decided to nix efforts to find another partner. Pfizer, in fact, has gone so far as to enter discussions with regulatory agencies to withdraw marketing authorization of Exubera. Eli Lilly and Novo Nordisk, which were both in the latter stages of development, also dropped out of the race to develop an improved inhaled insulin product.

The Case for Technoshpere Insulin

Mannkind, on the other hand, is wagering on Technosphere Insulin. The company believes that the technology improves the odds of quicker and more efficacious insulin delivery. The Technosphere platform stabilizes insulin into its monomeric form before release, which the body can readily use, explains Richard Anderson, corporate vp—office of the chairman. Insulin usually exists as a hexamer and must first be broken down into three dimers and finally individual molecules to have a physiological effect.

Current insulin analogs are designed to be hexamers that dissociate more quickly than regular insulin. When the Technosphere Insulin particles dissolve in the deep lung, however, the released insulin is already a mixture of dimers and monomers.

The fast kinetics of Technosphere Insulin is the main difference between this product and other inhaled insulin products that were in development, Anderson points out. “Several studies have shown that unlike others working in inhaled insulin who did find impaired lung function post treatment, we saw no change of lung function in our Technosphere Insulin treatment group compared to the group on standard of care.

“The second advantage is that patients who take insulin have been observed to gain weight,” Anderson continues. Study participants in Mannkind’s trials did not gain weight, he reports.

Additionally, preclinical evaluations including a two-year carcinogenicity study in rats showed that Technosphere Insulin was well tolerated with no indications of carcinogenic potential or cellular proliferation in the lungs.

Anderson is confident that Phase III data will be positive and show good efficacy. “There are currently four Phase III trials under way, three of which are pivotal.” He expects results from two in the third quarter and data from the remaining studies by year end, which is when Mannkind anticipates filing an NDA.

“Two-thirds of patients do not reach their glucose targets. If we can demonstrate significantly improved glucose control at meal time, that would certainly show an advantage.”

Regulatory Hurdles

Completion of these Phase III evaluations, though, may not signal the end of clinical development for Technosphere Insulin, Salares cautions. In light of Pfizer’s findings, the FDA could ask Mannkind to do an outcome study, she notes.

Pfizer reported that during Exubera’s clinical trial program, six of the 4,740 patients treated with Exubera developed lung cancer. To reveal such a rare cancer association, Mannkind would have to enlist thousands of people. To win the final go-ahead from the agency, Mannkind may also have to prove better overall survival as opposed to just improved efficacy.

Anderson reports that the company hasn’t been in discussions with the agency since the pre-NDA meeting, which was before the Pfizer reports.

Market Resistance

In the event that Mannkind does win the FDA over, the company will still be tasked with gaining approval among physicians and patients. “We continue to believe that Mannkind’s Technosphere Insulin represents a best-in-class product,” Salares comments. “However, we believe that the overall concerns related to inhaled insulin will overshadow its benefits.

“Before Pfizer made its announcement about the lung cancer association,” Salares states, “we were estimating a potential $1 billion market for Technosphere Insulin.” This was based on Leerink Swann’s assessment that the treatment is more than just insulin with an easier delivery method: i.e., inhalation.

Also, if Technosphere Insulin were to be targeted at patients currently only on oral noninsulin diabetese medication, which is 60% of the market, it would see a greater uptake than Exubera, which was reportedly aimed at patients already using inuslin injections.

Now, though, Mannkind will probably not be able to lock down a marketing ally in the short term, Salares says. Also, it has to battle against the general perception that inhaled insulin could increase the risk of lung cancer, downsizing its uptake to a niche market with peak sales of $125 million, she adds.

Even though Mannkind has another Technosphere product for diabetes in a Phase I trial and two cancer immunotherapies also in early-stage programs, the company has placed at least most of its eggs in the Technosphere Insulin basket. Since the consensus is that the product will most likely get the green light from the FDA, its eventual profitability will rest on a strong marketing team to sway the views of diabetes patients and their physicians.

Previous articleMethylation of Tumor-Suppressing Genes Increases as Women Age
Next articleScientists Link 350 Genetic Regions in Mice to Lymphoma