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, ultra rapid-acting insulin developed by Mannkind, was approved by the FDA in 2014 and is the only inhaled insulin commercialized at the moment.[5]

History

Insulin was discovered by Sir Frederick G Banting, Charles H Best, and JJR Macleod from the University of Toronto in 1921 as an injectable agent.[6] German researchers first introduced the idea of inhalable insulin in 1924.[7] 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.[citation needed]

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.[7]

Once concrete methods were developed, human tests began in the late 1990s.[7] 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.[8] It was not reimbursed by any US insurer.[9] 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."[10] 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,[11] MannKind Corporation,[12][13] 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 withdraw funding.[14]

On March 16, 2009 MannKind submitted a new drug application for their inhalable insulin. In 2011 the FDA denied approval of Afrezza; because the design of the delivery device had changed, it requested additional clinical trials to ensure that people would use it the same way as the earlier versions.[15] 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][16] In 2014 Mannkind and Sanofi agreed that Sanofi would take over manufacturing and marketing of Afrezza,[17] but Sanofi said it was dropping the effort in January 2016 due to poor sales of $7.5 million in 2015;[18] the companies formally terminated the agreement in November 2016.[19] At the time that Sanofi announced it was dropping the product Mannkind said it would continue alone,[18] and it had taken over manufacturing and relaunched the drug by July 2016.[19] 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 (74 – 106 mg/dl), reducing both spikes in blood glucose and time in hypoglycemia in adults with Type I diabetes, compared to insulin Aspart.[20]

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. S2CID 25390720.
  3. ^ a b "FDA Approves First Ever Inhaled Insulin Combination Product for Treatment of Diabetes" (Press release). Silver Spring, Maryland: FDA. 2006-01-27.
  4. ^ a b Simons J (19 October 2007). "How the Exubera debacle hurts Pfizer". CNNMoney. Retrieved 2007-10-21.
  5. ^ a b "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. ^ "100 Years of Insulin". Diabetes UK.
  7. ^ a b c Gillis J (January 28, 2006). "Inhaled Form of Insulin Is Approved". The Washington Post. Archived from the original on 2018-04-29. Retrieved 2007-10-21.
  8. ^ "Inhaled insulin given UK launch". BBC News. August 4, 2006. Retrieved July 19, 2016.
  9. ^ 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.
  10. ^ 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.
  11. ^ "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.[dead link]
  12. ^ "Technosphere Insulin - How it works". MannKind Corp. 2007. Archived from the original on 2007-10-20. Retrieved 2007-10-22.
  13. ^ Pollack A (November 16, 2007). "Betting an Estate on Inhaled Insulin". The New York Times. Retrieved May 5, 2010.
  14. ^ Lilly/Alkermes—RIP, AIR Insulin, Close Concerns, Inc. Company Watch, Diabetes Close Up #78, www.diabetescloseup.com.
  15. ^ "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.
  16. ^ "US Afrezza label" (PDF). FDA. May 2015.
  17. ^ Carroll J (August 11, 2014). "Sanofi fills some big shoes in $925M Afrezza pact with MannKind". FierceBiotech.
  18. ^ a b Staton T (February 10, 2016). "Sanofi tried and failed with Afrezza. Why does MannKind still think it can win?". FiercePharma.
  19. ^ a b Palmer, Eric (November 10, 2016). "Sanofi forgives MannKind's boatload of debt over failed Afrezza deal". FiercePharma.
  20. ^ 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. S2CID 90171098.
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