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In-PharmaTechnologist insulin series

Inhaled insulin delivery - which products will triumph?

By Kirsty Barnes , 25-Jan-2006

With the first non-injectable insulin to the world market predicted to earn $1.5 bn (€1.2 bn) a year, inhaled pulmonary delivery is winning the race, looking certain to trigger a bitter grapple between the big insulin players.

The big companies currently pioneering these new insulin delivery methods are >Pfizer, >Eli Lilly />Alkermes and >Novo Nordisk />Aradigm.

Leading the pack is Exubera, which Pfizer now owns after buying the rights off >Sanofi-Aventis for $1.3 bn this month.

Exubera is a fast-acting powdered insulin that is inhaled into the lungs before each meal, using a device the size of a torch. Both the formulation and device were developed by Nektar Therapeutics.

With a 2-3 year lead on other such products in clinical development, Exubera should make it to the market first and is expected to be a sure-fire blockbuster for Pfizer - although the road to approval has so far proved bumpy.

In clinical trials Exubera was as effective as injected insulin, however, it has been shown to cause a short-term decrease in lung function and concerns over the long-term affect of inhaling insulin into the lungs has led to ongoing delays in US Food and Drug Administration (FDA) approval of the product.

In September 2005, an FDA Advisory Committee finally recommended approval of Exubera for the treatment of adults with type 1 (insulin-dependent) and Type 2 diabetes (non-insulin-dependent).

However, in October, the FDA extended its original review period of the drug by three months while it considers additional data submitted on its potential to decrease users' lung capacity.

Although it is expected that Exubera will soon be approved and available on the market by the second quarter of this year, these approval delays have been good news for Eli Lilly, providing valuable catch-up time for its inhaled insulin product, the AIR Insulin system.

Eli Lilly is hot on the heels of Pfizer and has made inhaled insulin its lead project in a bid to claw back its market leadership that was stolen by Novo Nordisk last year.

The firm's AIR Insulin system has cleared Phase II trials and Lilly and its development partner Alkermes are now carrying out separate Phase III studies in both Type 1 and Type 2 diabetics.

The AIR Insulin device is smaller than the Exubera device, roughly the size of a marker pen, and has not yet shown the same questionable effects on lung function.

These two factors may provide Lilly's product with a marketing advantage upon its eventual launch, although it is still several years off approval and an FDA submission date for the product is yet to be announced.

Not wanting to be left behind, current top insulin player Novo Nordisk has also been developing its version of inhaled insulin with Aradigm, the AERx insulin Diabetes Management System (iDMS), and last year Novo acquired full development and marketing rights for the product.

The AERx system is the only inhaled insulin system currently in clinical trials that uses a liquid formulation, requiring the insulin to be refrigerated. It is also quite large - about the size of a paperback book.

These factors may disadvantage the product, although using a liquefied version of insulin and a battery-powered device, AERx can deliver more minutely metered doses of insulin, which may be a selling point for some patients.

However, the product has experienced a set-back, with Novo Nordisk placing its Phase III clinical trial of AERx on hold last year to re-examine dosages because it was found that the drug was leaving the body too quickly.

Novo Nordisk will officially announce if it will continue with the remaining Phase III trials on January 27. However, Novo's website is currently advertising for a clinical trial manager for "a phase 3a programme with several large efficacy and safety trials worldwide," believed to be for AERx.

If it does not bring this product to market, Novo has a lot to lose, as it could see its leadership in both the insulin and the insulin delivery device market slip away to its rivals.

Meanwhile, small drug delivery firm >MannKind is going it alone, developing yet another inhaled formulation of insulin, but without the support of a big drug company.

TI, currently in Phase III trials, is based on Mannkind's Technosphere drug delivery technology, and involves the inhalation of very small particles of an insulin formation into the lungs using Mannkind's proprietary inhaler device.

This system may be a dark horse in the running as it reputedly works faster than Pfizer, Lilly or Novo's products due to its unique drug-delivery formulation. In addition, the inhaler is small and fits into the palm of the patient's hand.

However Mannkind doesn't plan to file for FDA approval of T1 until mid-2008 and being a small company would need to form a partnership with a larger drug firm to market the product effectively.

Amidst all the hype, these non-injectable insulin products will no doubt prove popular, but at this stage will not totally replace insulin injections as the new products currently in development only use rapid-acting insulin and are only intended for use before meals.

They may also be unaffordable for many patients. According SG Cowen analyst Ian Sanderson, based on four treatments per day, inhaled insulin would cost $4 (€3.30) to $4.50 a day, compared with 85 cents to $1 for the injected version.

Dr Nancy Bohannon, who specialises in research in and treatment of diabetes in the US told In-PharmaTechnologist.com that she believes the new products may only cost double the currently injected products.

"However, patient uptake in the US will mainly depend on whether the government will provide any reimbursement for the new products," she said.

In addition to cost issues, the lungs aren't the most efficient entryway for insulin delivery, requiring 5-10 times the injected dose to achieve the same level of insulin in the body, and several questions, such as the long-term affect on the lungs and the effectiveness in smokers or people with a cold or other respiratory disorder, still need to be answered.

These factors leave room for other novel routes of delivery to also achieve success and several small biotech companies are preparing to take on the big companies with their inventions such as nasal spray, capsule, and transdermally delivered insulin.

Thus, while pulmonary delivered insulin should reach world markets first and Pfizer now looks set to cross the finishing line first, it may not be a case of winner takes all.

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