Cambridge biotech company Alkermes Inc. said it plans to continue working with partner Eli Lilly and Co. on an inhalable form of insulin for diabetes patients, even though two other drug makers scrapped work on competing products in the past few months.
In October, Pfizer Inc. shelved its Exubera inhaled insulin product, despite spending close to $3 billion developing and marketing the product. The company said too few patients preferred using the device to giving themselves insulin injections. On Monday, Novo Nordisk A/S of Denmark halted development of its own version of inhalable insulin, AERx, after studying Pfizer's Exubera failure
"People had expected something that was simpler than an insulin pen, and they actually ended up with something that was much more complicated," said Mads Krogsgaard Thomsen, Novo Nordisk's chief science officer, in a conference call with analysts.
Doctors and patients said that Exubera was bulkier than injection needles and difficult to use. Thomsen said a breakthrough would be needed to persuade customers to switch to an inhalable version of insulin - something AERx could not deliver.
Some physicians have questioned the safety of inhalable insulin, saying it is unknown what effect the drug could have on the lungs.
Despite the doubts, Alkermes and Eli Lilly said they plan to go forward with their version of inhalable insulin, called Air Insulin.
David Broecker, chief executive of Alkermes, recently told investors that Air Insulin is "better and simpler than the Exubera device."
Rebecca Peterson, a spokeswoman for the company, said Air Insulin users will simply need to insert a capsule, press a button, and breathe. The device is also much smaller than Exubera. Alkermes also said it and Eli Lilly are hoping to produce medical data that highlight the device's benefits.
Air Insulin is currently in late-stage clinical trials for type 1 and type 2 diabetes, and results are expected this year. Tim Coulom, spokesman for Eli Lilly, said the company plans to file an application with the Food and Drug Administration in 2009 for permission to start marketing the device.
The company is not alone. Mannkind Corp., a biotech in Valencia, Calif., is also developing a palm-sized inhalable insulin system, called Technosphere. And Novo Nordisk executives said this week they still hope to develop a new generation of lung treatments for those with diabetes and other chronic diseases.
If successful, new diabetes drugs have the potential to generate billions of dollars in sales. In the United States alone, about 21 million people are thought to have diabetes. Many of them take insulin regularly to help control their blood-sugar levels. Typically, diabetes patients' blood-sugar levels are not regulated naturally because their pancreases does not make enough insulin or their cells do not use it properly. <<
As Novo Nordisk joins Pfizer in abandoning an inhaled insulin product, what are the implications for the future of targeting the lung for delivering protein therapeutics?
The promise of an alternative to insulin injections for diabetes management suffered another disappointment on 15 January when Novo Nordisk discontinued the development of its fast-acting inhaled insulin product AERx iDMS, which was in Phase III development. Just 3 months before, on 18 October, Pfizer withdrew Exubera, the first approved inhaled human insulin powder and lung delivery device.
Novo Nordisk's product, which was licensed from Aradigm, is another casualty of Exubera's failure to help create what some analysts predicted would be a US$5 billion annual market. Exubera, co-developed with the product originator Nektar Therapeutics, was supposed to revolutionize diabetes care through the easier management of patients' blood sugar levels, but the expected market success was not achieved.
Several possible causes for the failure have been highlighted. "Right from the beginning, I thought it was no major breakthrough," says Mayer Davidson, professor of medicine at the Charles R. Drew University in Los Angeles, USA, who was involved in early clinical trials for Exubera. "The instrument was bulky and not easy to use. You couldn't carry it in your purse and pull it out surreptitiously. Patients still required an injection of longer-acting insulin to maintain a basal level and, the way the FDA approved it, the patient had to go in for periodical lung function tests."
Furthermore, says Davidson, the patient still had to stick their fingers to measure their blood sugar. Those inconveniences negated its big advantage: reducing the burden of injections, which Davidson notes, have drastically improved thanks to advances such as small, easy-to-use and discrete injectable pens.
[v]According to pharmaceutical analyst Andrew Forman of WR Hambrecht and Co., an investment bank based in San Francisco, USA, the problems went beyond the product itself. "Pfizer screwed up on execution," he says, pointing to the company's poor marketing scheme and failure to have the packaging facilities ready at launch. "They didn't have enough inventory. People who would've loved to use it couldn't trust that they were going to be able to supply it."
Despite these setbacks, companies including MannKind and Alkermes are continuing development of their inhaled insulin products (Table 1), in the hope that their next-generation designs and novel approaches may allow them to succeed where Exubera failed. Even so, developing safe, effective, user-friendly inhaled therapeutics that outshine injections remains a tall order.
Table availble for viewing in link provided FYI...
"It is clear that it is not enough to merely replace insulin injections; a new therapy must provide a differentiated safety and efficacy profile over existing therapies," says Dick Anderson, Chief Financial Officer of California-based MannKind. The company's inhalable insulin device, Technosphere, is the size of a cell phone and trials show it delivers insulin quickly. "It closely matches the normal pattern of insulin secretion following a meal," says Anderson.
Perhaps one of the greatest challenges to using the lungs as a delivery route for peptides and protein-based drugs that are currently administered by injection is that dosing can be "rather unreliable," says Peter Byron, an aerosol drug delivery systems expert at the Virginia Commonwealth University School of Pharmacy, USA. "Many simple devices deliver rather more to the mouth than the lung. And given that people have different sized mouths and throats, delivery can be very variable."
To overcome these obstacles, developers are designing less cumbersome, more effective inhalers and testing a range of formulations including powders, crystals and liquids. For instance, Alkermes is developing an insulin inhaler that is smaller than the Exubera inhaler, and the powdered insulin particles it delivers are large but have a low density. "Unlike small particles, like Exubera, these are light and large — they flow better and disperse more readily," says Byron.
MannKind's Technosphere also uses powder, but instead of creating large, aerodynamically light particles, the drug contains an absorption enhancer. "By making it absorb faster, you can overcome bioavailability problems," says Byron. "The idea is good; the question is whether this enhancer is truly non-toxic."
The lungs are not the only alternative drug delivery route being considered for peptides and protein-based therapies that are currently delivered by injections. "Almost every part of the body probably provides a window," says Robert Langer, a bioengineer at the Massachusetts Institute of Technology, USA.
For example, Nastech Pharmaceutical Company, Washington, USA, is developing a nasal delivery system for calcitonin, a hormone given to women with osteoporosis to reduce bone loss. Several companies, including the Dutch pharmaceutical company Echo and New Jersey-based Johnson & Johnson, are working on ultrasound and electrical approaches for transdermal delivery. With its RapidMist device, which resembles inhalers used by asthmatics, the Canadian pharmaceutical company Generex focuses on buccal delivery, where absorption is limited to the mouth. In addition to an oral insulin spray, Generex is working on buccal sprays for morphine and fentanyl to treat breakthrough pain, and for low molecular weight heparin to treat deep-vein thrombosis.
According to Langer, it is difficult to determine how these approaches compare with the lungs as a delivery route because many are in the early stages of development. "A lot depends on how good the clinical results are, and that remains to be seen," he says. "I don't think there's a single technology or route that will be perfect for everybody. They all have benefits and you have to look at the issues — reproducibility, bioavailability, immunogenicity, cost — on a case-by-case basis."
Bioavailability is a gold standard for regulatory approval and therefore important for any new drug delivery system, according to William Calhoun, Vice Chair of research at the University of Texas Medical Branch, USA, and a consultant to the FDA's Endocrinologic and Metabolic Drugs Advisory Committee that considered Exubera. In the case of Exubera, the fact that the bioavailability of the drug was less than that of injected insulin didn't deter the Committee for two reasons: patients could take another dose to get the right amount, and it was used to cover peaks in blood sugar, not as a complete substitute for injected insulin.
The FDA's principal concern, says Calhoun, "was that there might be some abnormalities in lung function." In fact, data showed that the drug did cause modest impairment of lung function, although the abnormalities were not progressive.
The findings also highlight one of the challenges that developers of new drug delivery systems face: there might be a biological effect on the lung or another organ that is not part of the intended therapeutic effect of the drug. "If you're using the lung as a delivery system for lung diseases, the therapeutic target is the organ to which the drug is being delivered," says Calhoun. "But when the lung is simply a convenient delivery route, we're going to continue to have concerns about the potential unwanted therapeutic effects of agents that are delivered this way."
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