MannKind is seeking approval from U.S. regulators to market its inhaled insulin product AFRESA for treating diabetes, suggesting the biotech has learned from the past mistakes of a deeper-pocketed rival. The Valencia, California-based company submitted a New Drug Application to the U.S. Food and Drug Administration March 16 for its inhaled insulin product AFRESA to patients for treatment of adults with type 1 or type 2 diabetes mellitus for the control of hyperglycemia.

 

MannKind’s efforts come in the wake of the spectacular failure of Pfizer’s inhaled insulin product Exubera, once seen as a potential blockbuster. Pfizer stopped marketing Exubera  in October 2007 after the drug giant failed to achieve traction with doctors and mustered sales that fell far short of analysts’ expectations.

Doctors and analysts point to a number of reasons for Exubera’s market failure. Some of the blame they lay at Pfizer’s feet and the fact that the sales team handling it was trying to protect the giant Lipitor franchise from new generic competition at the same time. They also say that Pfizer made the mistake of focusing on seasoned endocrinologists who saw no upside in using inhaled insulin. “If you have low impact needles and very good regiments that work in my clinic or my hospital, why should I change what I do?” says Michael Schulman, an editor with ChangeWave Research, who noted doctors “made fun” of inhaled insulin.

 

But since the initial efforts to develop inhaled insulin began more than 10 years ago, notes others, development of pen devices and improvements in reducing the size of needles has largely eliminated the perceived benefit delivery of insulin through inhalation. “Most of us are comfortable with injectable insulin, especially in the new devices, so inhaled insulin and the whole concept had to be significantly better than what we have,” says Anastassios Pittas, an endocrinologist at Tufts Medical Center and associate professor of medicine and an associate professor of medicine at the Tufts University School of Medicine.

 

In addition, Exubera faced safety concerns. There were worries that the product could impair lung function. In April 2008, Pfizer issued a “Dear Doctor” letter alerting physicians to the fact that six of 4,740 Exubera users had developed lung cancer. In each of those cases, the patients had a history of smoking. At the time, MannKind was in advanced talks to partner its inhaled insulin, but decided to break off talks. “We were in some pretty late stage negotiations at that point. We pulled back,” says Matthew Pfeffer, vice president and CFO for MannKind. “We didn’t want to operate from a position of weakness.”

 

MannKind has sought to allay concerns about safety by performing additional safety tests and says its insulin product does not accumulate in the lung the way Exubera did. Studies have shown that the MannKind insulin was as effective as injectable insulin and its use showed no difference in lung function. But rather than pitching the convenience of inhaled insulin over the use of needles, MannKind is preparing to make a case for its product acting more like insulin in the body than other recombinant insulins.

 

“We think it’s a pretty dramatically different product in the sense that inhalation is not really what it’s all about in our case. It was for Exubera. Exubera was a product whose whole reason for being was to avoid injection,” Pfeffer says. “Ours just happens to be inhaled. The whole secret of the product is not that.”

That’s because like the body’s insulin, MannKind’s product is formulated as a single molecule or a monomer. All other recombinant insulins—including Exubera—are hexamers or polymers form from six molecules. The use of a hexamer allowed companies to stabilize the insulin, but MannKind says the result of this is that MannKind’s insulin acts more quickly and goes away more quickly than other man-made insulins. When the AFRESA particles hit the lung tissue, they immediately dissolve, releasing insulin monomers that rapidly enter the bloodstream. AFRESA achieves peak insulin levels within 12-14 minutes of administration, effectively mimicking the release of meal-time insulin observed in healthy individuals, but which is absent or impaired in patients with diabetes, the company says.

Pfeffer says now that the company has its late-stage clinical data and has filed its application to begin marketing the product, it has resumed discussions with potential partners for the product. “The discussions are very active and there’s a lot of interest,” he says. The world changes when you have positive phase III data and you have filed an NDA.” MannKind CEO Alfred Mann has set an internal target of a deal by the end of the third quarter.

 

There are 23.6 million people in the United States who have diabetes. Diabetes currently affects 246 million people worldwide and is expected to affect 380 million by 2025. Each year, a further 7 million people develop diabetes and 3.8 million people succumb to the disease. The question is if MannKind is successful in winning regulatory approval, will its use be relegated to a small percentage of the population of patients who can’t overcome their fear of needles or can the company convince the market its formulation offers benefits beyond convenience.

 

“The way I look at inhaled insulin in the future if any product is approved is as niche insulin,” says Tufts’ Pittas, who sees 2 to 3 percent of patients falling into that category. “If someone needs insulin and they absolutely will not take injectable insulin and willing to live with potential risk, that person would be a candidate for inhaled insulin. That can be a huge number—thousands of patients.