Inhalable insulin

Inhalable insulin was available from September 2006 to October 2007 in the United States as a new method of delivering insulin, a drug used in the treatment of diabetes, to the body. After the withdrawal of the only inhalable formulation, all currently available insulin formulations are administered by subcutaneous or intravenous injection.^[1]

The first such product to be marketed was Exubera, a powdered form of recombinant human insulin, delivered through an inhaler into the lungs where it is absorbed. ^[2][3][4] Once it has been absorbed, it begins working within the body over the next few hours. Type 1 diabetics still need to take a longer acting basal insulin by injection.^[5]

A systematic review concluded that inhaled insulin "appears to be as effective, but no better than injected short-acting insulin. The additional cost is so much more that it is unlikely to be cost-effective."^[6] In October 2007, Pfizer announced that it would be discontinuing the production and sale of Exubera due to poor sales.^[7] Several other companies are developing inhaled forms of the drug to reduce the need for daily injections among diabetics.

History

Insulin was introduced by Banting and Best from the University of Toronto in 1921 as an injectable agent. German researchers first introduced the idea of inhalable insulin in 1924.^[1] Years of failure followed until scientists realized they might be able to use new technologies to turn insulin into a concentrated powder with particles sized for inhalation.^[1]

This technology was developed so that the inhaled insulin can effectively reach the lung capillaries where it is absorbed.^[8] Nektar Therapeutics of San Carlos, California developed this technology that paved the way for pharmaceutical companies to begin testing and formulating inhalable insulin.^[1] Once concrete methods were developed, human tests began in the late 1990s.^[1] In January 2006, the U.S. Food and Drug Administration (FDA) approved the use of Exubera which is a form of inhalable insulin developed by Pfizer.^[2]

Approval and competing drug development

Exubera is the brand name of first formulation of inhalable insulin to receive the US FDA approval.^[2] It is manufactured by Pfizer in collaboration with Nektar Therapeutics and is licensed for use by both type 1 and type 2 diabetics. However in the UK its use in under the National Health Service "should not be recommended because it could not be proven to be more clinically or cost effective than existing treatments",^[5] except under special circumstances.^[9] In April 2006, the UK's National Institute for Health and Clinical Excellence issued a preliminary statement advising against the use of inhalable insulin on the grounds that the benefits of avoiding injections did not justify the higher cost of the new product. At that time, NICE recommended use of the new drug only in clinical trials.^[10]

Concerns have been expressed by the Institute for Safe Medication Practices about a serious risk of dosing errors when prescribing Exubera.^[11] Insulin is traditionally prescribed in international units, but Exubera is prescribed in milligrams. 1 mg of Exubera is equivalent to 3 units of insulin, however, the increment is not linear: 3 mg of Exubera is equivalent to 8 units of insulin and not 9 units as might be expected, and the prescriber is strongly advised to refer to the manufacturer's conversion table before prescribing. Furthermore, because of retention of blister contents, three consecutive doses of 1 mg blisters of Exubera results in a higher dose of insulin than a single 3 mg blister of Exubera, further complicating prescribing calculations.

Exubera is considered a short or rapid acting insulin. In clinical studies, Exubera reached peak concentration levels faster than some insulins administered by injection.^[2] Thus, this form of insulin would begin working within the body faster than those forms of injected insulin. Type 1 and 2 diabetics will still need an injection of longer acting insulin to maintain a basal level for a 24 hour period.^[5]

As of October 18, 2007, Pfizer has announced that it will no longer manufacture or market Exubera. According to Chairman and CEO Jeffrey Kindler this is because Exubera "failed to gain acceptance among patients and physicians."^[7]

At the time of Exubera's discontinuation, several other companies were pursuing inhaled insulin including Alkermes working with Eli Lilly and Company,^[12] MannKind Corporation,,^[13][14] and Aradigm working with Novo Nordisk. However, by March 2008, all of these products had been discontinued except for MannKind’s Afrezza product.^[15] As of March 2010 Afrezza was still under FDA review.^[16]

Lung cancer concerns

On April 9, 2008, Pfizer announced in its "Dear Doctor" letter that Exubera may have been associated with lung cancer: of the 4,740 patients who used Exubera in clinical trials, six have developed lung cancer as of April 2008, compared to only one of the 4,292 patients in the placebo group. The association was not statistically significant, and Pfizer maintained in its letter that "Exubera remains a safe and effective medication."

In a letter 18 June 2008, Pfizer informed UK doctors of the above mentioned six cases, noting that they all had a prior history of cigarette smoking and that they were planning to investigate further the "observed imbalance in diagnosed lung cases" with an international observational trial. Pfizer's letter also stated that Nektar had stopped searching for a new marketing partner and therefore Pfizer would withdraw its Marketing Authorisation around September 2008.

Pfizer patent infringement lawsuit

Novo Nordisk, a Danish diabetes pharmaceutical company, filed suit against Pfizer on August 1, 2006, claiming patent infringement.^[17][18] The lawsuit seeks both compensatory damages and injunctive relief. Novo sought a preliminary injunction preventing the release of Pfizer's planned September 2006 launch of the diabetes drug. A federal judge, however, delayed any decision on Novo Nordisk's request for injunctive relief until at least December 4, 2006 when a court hearing is scheduled in the case.^[19] Pfizer's answer contends that Novo wants to deny diabetics access to Exubera, the only FDA approved inhaled insulin, and interfere with the company's pharmaceutical business.^[20]

On December 14, 2006 a federal judge denied Novo Nordisk's request for a preliminary injunction to halt sales of Pfizer's inhaled insulin.^[21] The patent lawsuit, however, has not been dismissed, and Pfizer's legal defenses are preserved. The pharmaceutical companies are still litigating in court over their respective inhaled insulin patent claims, a process that could take some time to resolve.

MannKind's AFREZZA

On March 16, 2009 MannKind submitted an NDA for their inhalable insulin product, AFREZZA. The drug is an ultra rapid acting form of inhalable insulin with peak plasma concentrations that mimic physiologic mealtime response at 12–14 minutes. The drug has performed well in clinical trials and was originally scheduled for FDA approval on December 29, 2010. However, in December the FDA announced it needed an additional 4 weeks to complete its review. The company received a CRL on January 19, 2011, denying approval of Afrezza as "questions remain that preclude approval in its current form."^[22] MannKind also reported the FDA requires 2 additional clinical trials on its next-generation inhaler compared to the MedTone Inhaler to assess "performance characteristics, usage, handling, shipment and storage," updated safety information related to AFREZZA, as well as proposed user training and changes to the proposed labeling of the device, blister pack, foil wrap and cartons.^[23]

Aerogen and Dance Pharmaceuticals

January 2011: Aerogen in Galway, Ireland and Dance Pharmaceuticals in San Francisco, California have announced a drug-delivery partnership for the production of inhalable insulin.^[24]

History of the discovery

Seeds such as soybeans containing very high levels of protein can undergo desiccation, yet survive and revive after water absorption. A. Carl Leopold, began studying this capability at the Boyce Thompson Institute for Plant Research at Cornell University in the mid 1980s. He found soybeans and corn to have a range of soluble carbohydrates protecting the seed's cell viability.^[25] Patents were awarded to him in the early 1990s on techniques for protecting "biological membranes" and proteins in the dry state. Using the knowledge gleaned from studying the preservation of proteins in dry soybeans, Carl developed a method to preserve peptide hormones like insulin in the glassy state so that they can be pulverized into a powder and inhaled by diabetics as an alternative to self-injection^[26]

What Leopold, who has died, could not have foreseen is that his research on soybeans would lead to techniques that allowed insulin to be dried and later processed into an inhalable insulin, named Exubera by Pfizer.^[27]

Inhalable insulin and Alzheimer's disease

On 9/13/2011 it was announced that a form of inhalable insulin, aerosolized insulin, applied deep into the nostrils may delay the onset of Alzheimer's disease.^[28][29][30]

References

http://www.rttnews.com/Content/TopStories.aspx?Id=1509503&SM=1

Footnotes