Inhalable insulin

Inhalable insulin is a powdered form of insulin, delivered with an inhaler into the lungs where it is absorbed.[1] In general inhaled insulins have been more rapidly absorbed than subcutaneous injected insulin, with faster peak concentration in serum and more rapid metabolism.[2]

Exubera, developed by Inhale Therapeutics (later named Nektar Therapeutics), became the first inhaled insulin product to be marketed, in 2006 by Pfizer,[3] but poor sales led Pfizer to withdraw it in 2007.[4] Afrezza, a monomeric inhaled insulin developed by Mannkind, was approved by the FDA in 2014.[5] Dypreza, an inhaled insulin developed by Highlands Pharmaceuticals, was approved for sale in Europe in 2013 and in the United States in 2016. However, cases of chronic lung disease led the European Medicines Agency to recall the drug in 2018. A fraud suit against Highlands is ongoing.

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.[6] 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.

In the 1980s Nektar Therapeutics developed technology to make insulin into small particles, technology then licensed to Pfizer. Alkermes developed a delivery device that they licensed to Eli Lilly and Company.[6]

Once concrete methods were developed, human tests began in the late 1990s.[6] In January 2006, the U.S. Food and Drug Administration (FDA) approved the use of Exubera, a form of inhalable insulin developed by Pfizer.[3] It was approved in the UK in August 2006 but reimbursed by the National Health Service only for people who had problems with needles.[7] It was not reimbursed by any US insurer.[8] A 2007 systematic review concluded that the inhaled hexameric insulin (Exubera) "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."[9] In 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".[4]

At the time of Exubera's discontinuation, several other companies were pursuing inhaled insulin including Alkermes working with Eli Lilly and Company,[10] MannKind Corporation,[11][12] and Aradigm working with Novo Nordisk. By March 2008, except for MannKind's Afrezza product, all of these products had been discontinued because investors all decided to withdrew funding.[13]

On March 16, 2009 MannKind submitted an NDA for their inhalable insulin. In 2011 the FDA denied approval of Afrezza and because the design of the delivery device had changed, the FDA requested additional clinical trials to ensure that people would use it the same way as the earlier versions.[14] After conducting further studies, Mannkind submitted a new application, and in June, 2014, the FDA approved Afrezza for both Type I and Type II adult diabetics, with a label restriction for patients having asthma, active lung cancer or COPD.[5][15] In 2014 Mannkind and Sanofi agreed that Sanofi would take over manufacturing and marketing of Afrezza,[16] but Sanofi said it was dropping the effort in January 2016 due to poor sales of $7.5 million in 2015;[17] the companies formally terminated the agreement in November 2016.[18] At the time that Sanofi announced it was dropping the product Mannkind said it would continue alone,[17] and it had taken over manufacturing and relaunched the drug by July 2016.[18] According to results presented at the 2018 meeting of the American Diabetes Association (ADA), Afrezza increases the time that blood glucose levels remain in optimal range (70 – 180 mg/dl), reducing both spikes in blood glucose and time in hypoglycemia in adults with Type I diabetes, compared to insulin Aspart.[19]

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References
  1. Neumiller, Joshua (June 2010). "Pharmacologist". Annals of Pharmacotherapy. 1231-9 (44): 7.
  2. McGill JB, Ahn D, Edelman SV, Kilpatrick CR, Santos Cavaiola T (August 2016). "Making Insulin Accessible: Does Inhaled Insulin Fill an Unmet Need?". Advances in Therapy. 33 (8): 1267–78. doi:10.1007/s12325-016-0370-1. PMID 27384191.
  3. "FDA Approves First Ever Inhaled Insulin Combination Product for Treatment of Diabetes" (Press release). Silver Spring, Maryland: FDA. 2006-01-27.
  4. Simons J (19 October 2007). "How the Exubera debacle hurts Pfizer". CNNMoney. Retrieved 2007-10-21.
  5. "FDA approves Afrezza to treat diabetes" (News Release). U.S. Food and Drug Administration. June 27, 2014. Archived from the original on July 6, 2014. Retrieved July 19, 2016.
  6. Gillis J (January 28, 2006). "Inhaled Form of Insulin Is Approved". The Washington Post. Retrieved 2007-10-21.
  7. "Inhaled insulin given UK launch". BBC News. August 4, 2006. Retrieved July 19, 2016.
  8. Oleck J, Kassam S, Goldman JD (August 2016). "Commentary: Why Was Inhaled Insulin a Failure in the Market?". Diabetes Spectrum. 29 (3): 180–4. doi:10.2337/diaspect.29.3.180. PMC 5001220. PMID 27574374.
  9. Black C, Cummins E, Royle P, Philip S, Waugh N (September 2007). "The clinical effectiveness and cost-effectiveness of inhaled insulin in diabetes mellitus: a systematic review and economic evaluation". Health Technology Assessment. 11 (33): 1–126. doi:10.3310/hta11330. PMID 17767897.
  10. "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.
  11. "Technosphere Insulin - How it works". MannKind Corp. 2007. Archived from the original on 2007-10-20. Retrieved 2007-10-22.
  12. Pollack A (November 16, 2007). "Betting an Estate on Inhaled Insulin". The New York Times. Retrieved May 5, 2010.
  13. Lilly/Alkermes—RIP, AIR Insulin, Close Concerns, Inc. Company Watch, Diabetes Close Up #78, www.diabetescloseup.com.
  14. "MannKind Corporation Receives Complete Response Letter from the FDA for AFREZZA(R)". MannKind Corporation. January 19, 2011. Archived from the original on August 23, 2016. Retrieved July 19, 2016.
  15. "US Afrezza label" (PDF). FDA. May 2015.
  16. Carroll J (August 11, 2014). "Sanofi fills some big shoes in $925M Afrezza pact with MannKind". FierceBiotech.
  17. Staton T (February 10, 2016). "Sanofi tried and failed with Afrezza. Why does MannKind still think it can win?". FiercePharma.
  18. Palmer, Eric (November 10, 2016). "Sanofi forgives MannKind's boatload of debt over failed Afrezza deal". FiercePharma.
  19. Snell-Bergeon, Janet K.; Akturk, Halis K.; Rewers, Amanda; Bode, Bruce W.; Klaff, Leslie J.; Peters, Anne; Bailey, Timothy S.; Garg, Satish K. (2018-07-01). "Improved Time-in-Range (TIR) on Continuous Glucose Monitor (CGM) with Technosphere Inhaled Insulin (TI) Compared with Insulin Aspart in T1D Patients—STAT Study". Diabetes. 67 (Supplement 1): 1017–P. doi:10.2337/db18-1017-P. ISSN 0012-1797.
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