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. Afrezza, a new inhalable insulin product was approved for sale in the United States by the FDA in June of 2014, however, and may become available.
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.
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."
In October 2007, Pfizer announced that it would be discontinuing the production and sale of Exubera due to poor sales. Several other companies are developing inhaled forms of the drug to reduce the need for daily injections among diabetics.
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. 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.
This technology was developed so that the inhaled insulin can effectively reach the lung capillaries where it is absorbed. Nektar Therapeutics of San Carlos, California developed this technology that paved the way for pharmaceutical companies to begin testing and formulating inhalable insulin.
Once concrete methods were developed, human tests began in the late 1990s. 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. In February 2007 Pfizer completed acquisition of the patents and related property concerning Exubera from sanofi-aventis.
Approval and competing drug development
Exubera is the brand name of first formulation of inhalable insulin to receive the US FDA approval. It was manufactured by Pfizer in collaboration with Nektar Therapeutics and is licensed for use by both type 1 and type 2 diabetics. 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", except under special circumstances.
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.
Concerns have been expressed by the Institute for Safe Medication Practices about a serious risk of dosing errors when prescribing Exubera. 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. 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.
As of October 18, 2007, Pfizer announced that it would no longer manufacture or market Exubera. According to Chairman and CEO Jeffrey Kindler this was because Exubera "failed to gain acceptance among patients and physicians."
At the time of Exubera's discontinuation, several other companies were pursuing inhaled insulin including Alkermes working with Eli Lilly and Company, MannKind Corporation, and Aradigm working with Novo Nordisk. However, by March 2008, all of these products had been discontinued except for MannKind’s Afrezza product which received FDA approval in June 2014.
Lung cancer concerns
On April 9, 2008, Pfizer announced 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 physicians of the 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.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. 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.
On December 14, 2006 a federal judge denied Novo Nordisk's request for a preliminary injunction to halt sales of Pfizer's inhaled insulin. 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.
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." 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.
In June, 2014, the FDA gave its approval for general public sale. Afrezza is FDA approved for both Type I and Type II adult diabetics, with a label restriction for patients having asthma, active lung cancer or COPD.
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.
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. 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
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.
Inhalable insulin and Alzheimer's disease
- Justin Gillis (January 28, 2006). "Inhaled Form of Insulin Is Approved". The Washington Post. Retrieved 2007-10-21.
- "FDA Approves First Ever Inhaled Insulin Combination Product for Treatment of Diabetes" (Press release). Silver Spring, Maryland: FDA. 2006-01-27.
- "Diabetes inhaler rejected for NHS - Insulin that can be inhaled rather than injected has been rejected by NHS advisers on grounds of cost". BBC News. 19 April 2006. - cost of £1,100 per person per year.
- Black C, Cummins E, Royle P, Philip S, Waugh N (2007). "The clinical effectiveness and cost-effectiveness of inhaled insulin in diabetes mellitus: a systematic review and economic evaluation". Health technology assessment (Winchester, England) 11 (33): 1–126. PMID 17767897.
- John Simons (19 October 2007). "How the Exubera debacle hurts Pfizer". CNNMoney. Retrieved 2007-10-21.
- "Inhalational Insulin Therapy". Insulin News.com. 2005. Archived from the original on 2007-09-30. Retrieved 2007-10-22.
- Portions of the 2008 Annual Report to Shareholders, Pfizer, 2008, archived from the original (PDF) on 2009
- "Diabetes (type 1 and 2), Inhaled Insulin - Final Appraisal Determination" (PDF). National Institute for Health and Clinical Excellence. 12 October 2006. Retrieved 2006-11-21.
- "Diabetes (type 1 and 2), Inhaled Insulin - Appraisal consultation document". National Institute for Health and Clinical Excellence. April 2006. Retrieved 2007-10-22.
- Institute for Safe Medication Practices (July 2006). "Insulin dosed in mg? A set up for errors!". Medication Safety Alert.
- "Alkermes Inc. AIR Inhaled Insulin System Human insulin inhalation powder Began Phase III trial to evaluate effectiveness in improving glucose control vs. injected premeal insulin in 400 patients 4/06 Type II diabetes". Bioworld Today. January 1, 2007. Retrieved 2007-10-22.
- "Technosphere Insulin - How it works". MannKind Corp. 2007. Archived from the original on 2007-10-20. Retrieved 2007-10-22.
- Pollack, Andrew (November 16, 2007). "Betting an Estate on Inhaled Insulin". The New York Times. Retrieved May 5, 2010.
- Lilly/Alkermes—RIP, AIR Insulin, Close Concerns, Inc. Company Watch, Diabetes Close Up #78, www.diabetescloseup.com.
- "FDA approves Afrezza to treat diabetes" (Press release). Silver Spring, Maryland: FDA. 2014-06-27.
- Aaron Smith (2006-08-02). "Novo Nordisk sues Pfizer over Exubera". CNNMoney. Retrieved 2014-07-21.
- "Novo-Nordisk A/S v. Pfizer, Inc. Exubera Patent Lawsuit". August 1, 2006. Archived from the original on 2006-12-11. Retrieved 2006-11-21.
- Peter Loftus (August 10, 2006). "Pfizer-Novo Nordisk patent hearing set for December". MarketWatch, Dow Jones. Retrieved 2006-11-21.
- "Novo-Nordisk A/S v. Pfizer, Inc. Exubera Patent Lawsuit: Pfizer’s Answer". August 22, 2006. Retrieved 2006-11-21.
- Chad Bray (December 14, 2006). "Judge denies motion to block sale of Pfizer's Exubera". MarketWatch, Dow Jones. Retrieved 2006-12-14.
- http://www.news.mannkindcorp.com/phoenix.zhtml?c=147953&p=irol-newsArticle&ID=1517413&highlight= MannKind Corporation Receives Complete Response Letter from the FDA for AFREZZA(R)
- Blackman SA, Obendorf RL, Leopold AC (September 1992). "Maturation Proteins and Sugars in Desiccation Tolerance of Developing Soybean Seeds". Plant Physiol. 100 (1): 225–230. PMC 1075542. PMID 16652951. doi:10.1104/pp.100.1.225.
- Ithaca journal: http://pqasb.pqarchiver.com/ithacajournal/access/1762528181.html?FMT=ABS&FMTS=ABS:FT&date=Mar+22%2C+2006&author=Andrew+Tutino&pub=The+Ithaca+Journal&edition=&startpage=A.1&desc=Cornell%27s+Leopold+sews+seeds+of+breakthrough
- Kolata, Gina (September 12, 2011). "Squirts of Insulin May Help Those With Early Alzheimer's". The New York Times.
- Healy, Melissa (September 13, 2011). "Insulin may slow Alzheimer's, study finds". Los Angeles Times.[dead link]
- 2011 Animation describing how Exubera functions