There are two secrets to why Afresa behaves the way it does. The first is the insulin's delivery platform—the Technosphere
particle. Described as "tiny sponges" by MannKind Chief Scientific Officer Peter Richardson, Technosphere particles are formed
of multiple small crystals of fumaryl diketopiperazine (FDKP), which under certain conditions become just the right size for
inhalation (approximately three to five microns in diameter). FDKP also has another property that makes it very useful for
pulmonary drug delivery: Put it in an acid solution, and particles spontaneously assemble. Put the particles in a base environment—such
as the human lung, with a pH of 7.3 or 7.4—and they dissolve. The particles have multiple surfaces; in photos, some Technosphere
particles look a bit like a rose in bloom, flaring out in dozens of "petals." Powdered human recombinant insulin adheres to
the particle's surfaces electrostatically, which means that the particle and drug do not interact chemically. Deep in the
lung, the Technosphere dissolves and the insulin is absorbed in the bloodstream with remarkable speed.
"Under the right conditions, FDKP forms a complex crystalline lattice which then forms the particles," says Richardson. "Someone
thought: 'What happens if we put drugs or peptides on them?' They found that peptides do tremendously well in adhering to
them. And because they're pH-sensitive, you have an opportunity for a direct delivery."
At this point, secret number two kicks in. Conventional insulin tends to form hexamers—structures consisting of six monomers—the
basic unit of insulin. Hexameric insulin cannot bind to insulin receptors, and has to be broken down before it's usable. Some
insulin analogs, such as Lilly's Humalog and Novo Nordisk's Novolog, are modified to prevent the formation of hexamers. This
makes them faster acting than traditional insulins, but because they are administered subcutaneously, they still take between
30 and 60 minutes to peak.
The manufacturing process for Afresa results in monomeric insulin. Pulmonary delivery and instant availability makes Afresa
faster than conventional fast-acting insulins. And that turns out to have many advantages for patients. In clinical trials,
Afresa provides superior postprandial glycemic control, as well as improved fasting glucose control. It can easily be synchronized
to meals, cutting chances of hypoglycemia and—very desirably—reducing the risk of weight gain.
"A surprise upside of this product was its effect on weight," says Richardson. "In Phase II, we began to see a difference
in the weight profile of patients on conventional insulin versus TI. Patients either stayed weight-neutral or lost weight
on TI. They didn't get as much hypoglycemia and didn't have to snack between meals. That's a major potential benefit."
In total, MannKind has conducted 44 clinical trials of Afresa on thousands of patients over 10 years. In Phase III, MannKind
rolled out a 3,000-patient series of trials. The first was a one-year study in 550 Type I patients, comparing TI against injectable
therapies and rapid-acting analogs given at mealtime. The second examined 700 Type II patients—those who are not necessarily
insulin-dependent, but use insulin to control their diabetes—and compared TI results to those of common, fixed-mixture, short-
and long-acting insulin analog therapies. The series wrapped up with a two-year study that analyzed pulmonary function in
2,500 patients with both types of diabetes. The successful trials and supporting product data led to Afresa's March 16 NDA
submission for the control of hyperglycemia in adults with Type I or II diabetes mellitus.