By Paul Thomas, Managing Editor
With the number of diabetes patients steadily rising, the race to replace conventional needles for insulin delivery becomes all the more important, and lucrative. Clear leaders are emerging, but there have been few real successes and many documented failures.
The holy grail is some kind of easy oral dosage, and many firms are pursuing tablet technologies which would allow active compounds to safely navigate the GI tract. Emisphere Technologies (Tarrytown, N.Y.) presented impressive results of early clinical trials at last year’s AAPS annual meeting on the use of its eligen technology to formulate synthetic compounds for transporting large molecules such as insulin across gastrointestinal membranes.
For insulin, the company developed six or seven suitable carriers before settling on just the right one, says Dr. Shingai Majuru, director of the company’s Pharmaceutics R&D. The company is now at the point of optimizing formulation, Majuru says, tweaking the compound so that it delivers the right amount of insulin and achieves desirable glucose levels.
The critical question is whether a pill equals or betters an injection for performance. Emisphere claims it has proven just that, with no adverse events in subjects over the course of two week trials. “We feel very confident in being able to bring this to market,” Majuru says. As of yet, Emisphere does not have a development partner for its insulin pill.
There is much work to be done before insulin can be effectively administered orally, says University of Texas-Austin’s Dr. Nicholas Peppas, a leading researcher in insulin delivery. Peppas’s work includes studies on the use of hydrogels to shield insulin from stomach acids.
Bioavailability is the key issue for oral delivery, Peppas says. “People don’t like to talk much about bioavailability, which indicates that perhaps they haven’t yet achieved the level that would be required,” he says. “Five to seven years ago, some of the pharmaceutical companies would say that an oral delivery system for insulin with a bioavailability of five to 10 percent would be satisfactory. Now they have raised the bar and are saying they would like something more like 50 percent. It’s difficult to convince the leaders of companies that they would be selling a product 50 percent of which would not be active.”
Bill Martineau, senior healthcare consultant with The Freedonia Group (Cleveland), predicts that we won’t see liquid or solid oral insulin products on the market until 2010 or beyond (chart, below). “It’s difficult to prove their efficacy,” he says. FDA approval, patient education and post-marketing surveillance will all be difficult, he says.
Transmucosal sprays and inhalables, which avoid the GI tract and speed absorption, might have a better chance, Martineau says. He sees inhalation forms of insulin as having potential due to their quick absorption and thinks they’ll be on the market by decade’s end, although there have been notable setbacks of late.
Pfizer and Aventis have been working with Nektar Therapeutics (San Carlos, Calif.) on an inhalable powder, Exubera, for adults with type 1 or type 2 diabetes. Exubera would be inhaled prior to eating and quickly absorbed, cutting down on spikes in glucose levels. The companies have filed for approval in Europe. Some patients in clinical trials, however, have developed coughs, which has led to concerns that the insulin may cause lung damage or reduce lung capacity, Martineau says. This will likely require two or three more years of clinical testing, he believes.
Eli Lilly and Co. (Indianapolis) continues the pursuit of alternative deliveries of its Humilin and Humalog, now focusing efforts on inhalable powder. It is entering Phase III trials with Cambridge, Mass. delivery firm Alkermes, Inc. on pulmonary delivery based upon a technology which actually increases particle size beyond the one to three micron size typical of inhalable powders. Alkermes’ AIR technology blends insulin and excipients into porous particles of 10 microns—like little whiffle balls—that tend not to get caught in the throat and, due to their size, require only a simple breath-activated inhaler to deliver to the lungs. Nypro, Inc. (Clinton, Mass.) does the injection molding for the handheld device.
|Working with Eli Lilly on an inhalable insulin powder, Alkermes, Inc. has expanded production at its Chelsea, Mass. facility.
The drug is made from a solution of excipients and insulin through a fairly standard spray drying process, says Alkermes’ VP of manufacturing Lloyd Johnston. Droplets of solution are atomized at the top of the dryer and also contacted with hot gas, evaporating the liquid and leaving the solid particles—the company adds a few proprietary twists to the process to produce their porousness—which are collected into bulk powder.
The powder is put into capsules that are blister-packed. Patients puncture the capsules with the spray device prior to inhaling.
Thus far, Alkermes has taken the lead on CMC (Chemistry, Manufacturing, and Control), while Lilly has led the clinical trials. Lilly has also pitched in to get the first line of Alkermes’ $40 million, 9,000 square foot Chelsea, Mass. plant up and ready for commercial production. Alkermes plans to build out additional lines as other products come to fruition.
“There is a great unmet need out there for diabetes treatments,” says Lilly global product spokesperson J. Scott MacGregor. “The inhalable insulin can fit in there to provide different treatment options.”
Freedonia’s Martineau isn’t sold just yet on Lilly’s inhaler. “The patient has to breathe just right to have adequate delivery,” he says. “I’m questioning how much more convenient it’ll be over injection.”
In fact, technology advances with needles and pen injectors may be sufficient to stave off alternative delivery methods of insulin, Martineau believes, particularly if the latest insulin analogs continue to reduce the required frequency of shots. He says injectables will dominate for the foreseeable future.
Becton, Dickinson and Co. (Franklin Lakes, N.J.) is leading the pack for the smallest needles around and advances in injection systems. Pen injectors are more popular in the Europe, but will eventually make greater inroads into the U.S. market, Martineau says. He likes the potential of Owen Mumford’s (Oxford, England) Autopen, which features a side-mounted trigger which requires less force than plunger mechanisms, regardless of dosage size or needle gauge, making it easier for children or the elderly to use.
Martineau also believes there is tremendous potential in drugs and therapies that go beyond diabetes and treat broader, more fundamental metabolic issues such as obesity. Lilly is also high on an injectible form of exenatide, a pre-insulin treatment for patients at the onset of Type 2 diabetes. The company, again working with Alkermes, filed a new drug application (NDA) last year.
Exenatide is a first in incretin mimetics, mimicking the body’s natural hormones, MacGregor says. In early testing, the drug has proven to reduce glucose levels and help patients lose weight. Lilly is also in Phase III trials of an oral form of ruboxistaurin, which addresses some of the vascular complications associated with high blood glucose.Insulin Demand by Dosage Formulation (in millions of dollars)
|Insulin Dosage Formulations
|Vials for injection
|Cartridges for injection
Courtesy of The Freedonia Group