The enthusiasm for inhaled insulin has waned, to say the least, since Exubera was pulled off the market by Pfizer. Following the Exubera debacle, the development of two other inhaled insulins (AIR by Eli Lilly and Alkermes, and AERx by Novo Nordisk) was halted as well.

But please don't consider that the final word on inhaled insulin. There's a new product in Phase III clinical studies, called Afresa, and it may succeed where the others failed. The reason, says its developer, MannKind Corporation, is that it simply mimics the functioning of natural insulin better than injectable insulins. The fact that it happens to be inhaled is just a side convenience, whereas for Exubera, that was the whole point.

Afresa consists of "Technosphere" particles, which are tiny lattices of crystals that form spontaneously from a liquid, but only under acid conditions (pH below 7). Powdered human recombinant insulin is attached to the lattices electrostatically, after which the particles are dried to a powder and loaded into a inhaler device. When the particles are inhaled into the lungs, they encounter a basic (alkali) environment (pH of 7.3 or 7.4), which causes them to dissolve instantly back into a liquid. The released insulin is then transported from the lung alveoli to adjacent capillaries, sending the insulin to the bloodstream very, very rapidly. The remaining liquid is simply voided from the body.

What's critical here is the fact that peak insulin levels are achieved within 12 to 14 minutes after inhalation. This rapid insulin spike, which mimics the natural insulin spike in response to a meal, is what signals the liver to stop releasing glucose during the meal-time period. Even rapid-acting insulin analogs take 30 to 60 minutes just to begin acting after injection, and they typically peak at four hours. Consequently, there is no quick spike to send the signal to the liver, and endogenous glucose production by the liver is suppressed much more slowly.

Rapid-acting insulin analogs also continue to act for a total of eight hours, although natural post-prandial (after-eating) insulin secretion subsides within two to four hours. In fact, only 18 percent of a subcutaneous insulin injection is consumed by the body during a meal. The remainder continues to have an effect, called a tail, long after natural post-prandial insulin would have returned to basal levels. To avoid this tail, which can lead to low blood sugar, patients have two choices. They can either reduce their insulin dose, which prolongs their hyperglycemia, or they can eat snacks to avert potential hypoglycemia caused by the tail's continued action, which leads to weight gain. In contrast to injected insulin, 74 percent of Technosphere insulin is consumed during a meal. Consequently, patients using Afresa have not gained the weight usually associated with insulin use. In some cases, in fact, they have even lost weight.

The reason that injectable insulin is slower to act than Afresa is in part due to the fact that only monomers, or single insulin molecules, can bind to insulin receptors. In solution, however, monomers join together to form hexamers, which consist of six monomers in a single structure. To be used in the body, the hexamers must first dissociate into dimers, or two molecules, and then into monomers. This takes awhile, making injectable insulin slower to be absorbed.  Rapid-acting insulin analogs have been altered to block the formation of hexamers, thereby improving the speed of absorption. However, they still take between 30 and 60 minutes to peak, much slower than the natural post-prandial insulin release. The manufacturing process for Afresa, however, results in monomeric insulin, which can go right to work without taking the time to dissociate from hexamers into monomers.

The force behind Afresa, and MannKind, is Al Mann, a venerable billionaire who has already sunk a good portion of his fortune into Afresa. In 1979, after a series of inventions that led to very lucrative companies, Mann developed an insulin pump which was the genesis of yet another successful company:  MiniMed (now part of Medtronic). In 1997, he learned of an inhaled insulin, created by a firm called Pharmaceutical Discovery, that peaked in only 12 to 14 minutes and had a bioavailability of up to three times that of the other inhaled insulins. Afresa was born, and Mann is determined to see it grow up. Given his track record, the odds are in his favor.

Afresa is in the news again because the results of two Phase III clinical trials have just been presented at the European Association for the Study of Diabetes (EASD) annual meeting in Vienna. The first study shows that Afresa suppresses endogenous glucose production (EGP), which is the production of glucose by the liver, more rapidly than subcutaneous insulin lispro (Humalog) or Exubera. The study of 18 types 2s found that EGP suppression occurred earliest with Afresa, followed by insulin lispro and then Exubera. 

The second study showed that over four years of continuous treatment using Afresa as their only mealtime insulin, adult patients with type 2 diabetes achieved sustained glycemic control reflected by low A1c's, without significant changes in pulmonary function.

* * *

Sources:

MannKind

in-Pharma Technologist press release

Forbes

PharmExec

OnDrugDelivery