KEYSTONE, COLO. — Pfizer Inc.'s Exubera earned marketing approval to enormous fanfare in 2006 as the first inhaled insulin. Expectations were high for what was expected to be a blockbuster product. Yet Exubera was pulled from the market the next year, brought down not by safety issues, but because it was a spectacular commercial failure.
The Exubera flameout has not dissuaded other pharmaceutical companies from pursuing development of intranasal, buccal, oral, peritoneal, and even rectal insulins, according to Dr. Jay S. Skyler. He presented an update on many of these novel insulins and new delivery systems at the conference, which was sponsored by the University of Colorado, Denver, and the Children's Diabetes Foundation at Denver:
▸ Inhaled insulin. Afrezza, MannKind Corp.'s investigational inhaled insulin with fumaryl diketopiperazine, reaches peak plasma insulin concentrations in just 10 minutes, far faster than currently available rapid-acting insulins. And the Afrezza inhaler is no bigger than a thumb, in contrast to the bulky and awkward Exubera inhaler.
“Everybody criticizes Afrezza. They say, 'Exubera failed.' Well, it probably failed in the marketplace because of its delivery system and lack of pharmacokinetic advantages compared to existing insulins, whereas with Afrezza you get both the pharmacokinetic advantage and convenience of delivery,” said Dr. Skyler, professor of medicine, pediatrics, and psychology and former director of the division of endocrinology, diabetes, and metabolism at the University of Miami.
Afrezza is now under review by the Food and Drug Administration for possible marketing approval.
▸ Intraperitoneal insulin delivery. In the mid-1990s, Dr. Skyler and coworkers demonstrated that when insulin was delivered intraperitoneally, 51% of it was rapidly absorbed into the portal circulation and went straight to the liver.
The redesigned DiaPort percutaneously implanted peritoneal port system, under development by Roche, can be connected to an external insulin pump, according to two unpublished studies: In a recent 6-month study, patients who were randomized to standard insulin pump therapy with continuous subcutaneous insulin infusion gained an average of 1.5 kg, whereas those assigned to the DiaPort system experienced no change in body weight. And in another trial, episodes of recurrent severe hypoglycemia in patients using the DiaPort system were reduced sevenfold, compared with baseline, even though their hemoglobin A1c fell by nearly 2%.
“I think the peritoneal approach is one we need to seriously think about as we move into automated systems,” the endocrinologist said.
▸ Oral insulins. These agents' Achilles heel has been poor bioavailability, typically less than 1%. Proposed solutions include using liposomal coatings, absorption promoters, or protease inhibitors, and packaging the oral insulin in hydrogels or microspheres to stabilize it against degradation.
Oral insulins in the developmental pipeline that appear to achieve rapid peak plasma insulin concentrations include Emisphere Technologies' oral insulin (Diabetes Care 2010;33:1288–90) and Biocon's IN-105 oral insulin polymer (J. Diabetes Sci. Technol. 2009;3:568–84).
In contrast, Capsulin, under development by Diabetology Ltd., a U.K. company, has a far less impressive early plasma effect (Diabetes Obes. Metab. 2010;12:82–7).
“This one doesn't look like it's going anywhere as a rapid-acting insulin, but it might actually work as a basal insulin, given orally,” Dr. Skyler said.
Another product with a delayed effect is the oral insulin capsule being developed by Oramed Pharmaceuticals, an Israeli company. This product, known as ORMD 0801, is designed for intestinal absorption. Phase II studies have been completed in patients with type 2 diabetes.
▸ Novel basal insulins. Novo Nordisk A/S's ultralong-acting insulin degludec has a half-life in excess of 24 hours and can be detected in the circulation at least 96 hours post injection. It can be given once daily or three times per week, although Dr. Skyler suspects that many patients would have difficulty sticking to the latter schedule.
Insulin degludec achieves protracted absorption in subcutaneous tissue by utilizing a soluble multihexamer formation rather than the standard single hexamer formation. Insulin degludec will be studied in the pivotal phase III BEGIN and BOOST trials, which together will involve more than 10,000 patients and will be the largest-ever clinical trial program for insulin therapy in diabetes.
Eli Lilly & Co.'s insulin lispro protamine suspension has been studied with favorable results as part of a basal-bolus approach in patients with type 1 diabetes (Diabet. Med. 2010;27:563–9), as well as in insulin-naive patients with type 2 diabetes that is poorly controlled with oral agents (Diabet. Med. 2010;27:181–8). This insulin is already marketed in some parts of the world.
A French company, Flamel Technologies Inc., is developing FT-105, a basal insulin consisting of a vitamin E and glutamic acid polyaminoacid polymer linked to the insulin protein. When administered by subcutaneous injection, FT-105 aggregates into dense microparticles that take a long time to dissolve.