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'''Inhalable insulin''' is a powdered form of [[insulin]], delivered with an inhaler into the lungs where it is absorbed.<ref name="A Review of Inhaled Technosphere Insulin">{{cite journal |last1=Neumiller |first1=Joshua |title=Pharmacologist |journal=Annals of Pharmacotherapy |date=June 2010 |volume=1231-9 |issue=44 |page=7 |url=https://www.researchgate.net/publication/44643382}}</ref> In general inhaled insulins have been more rapidly absorbed than [[Subcutaneous injection|subcutaneous injected]] insulin, with faster peak concentration in serum and more rapid metabolism.<ref name="McGill2016rev">{{cite journal | vauthors = McGill JB, Ahn D, Edelman SV, Kilpatrick CR, Santos Cavaiola T | title = Making Insulin Accessible: Does Inhaled Insulin Fill an Unmet Need? | journal = Advances in Therapy | volume = 33 | issue = 8 | pages = 1267–78 | date = August 2016 | pmid = 27384191 | doi = 10.1007/s12325-016-0370-1 | s2cid = 25390720 }}</ref>
'''Inhalable insulin''' is a powdered form of [[insulin]], delivered with an inhaler into the lungs where it is absorbed.<ref name="A Review of Inhaled Technosphere Insulin">{{cite journal |last1=Neumiller |first1=Joshua |title=Pharmacologist |journal=Annals of Pharmacotherapy |date=June 2010 |volume=1231-9 |issue=44 |page=7 |url=https://www.researchgate.net/publication/44643382}}</ref> In general inhaled insulins have been more rapidly absorbed than [[Subcutaneous injection|subcutaneous injected]] insulin, with faster peak concentration in serum and more rapid metabolism.<ref name="McGill2016rev">{{cite journal | vauthors = McGill JB, Ahn D, Edelman SV, Kilpatrick CR, Santos Cavaiola T | title = Making Insulin Accessible: Does Inhaled Insulin Fill an Unmet Need? | journal = Advances in Therapy | volume = 33 | issue = 8 | pages = 1267–78 | date = August 2016 | pmid = 27384191 | doi = 10.1007/s12325-016-0370-1 | s2cid = 25390720 }}</ref>


'''Exubera''', developed by Inhale Therapeutics (later named [[Nektar Therapeutics]]), became the first inhaled insulin product to be marketed, in 2006 by [[Pfizer]],<ref name="exubra_fda_approval"/> but poor sales led Pfizer to withdraw it in 2007.<ref name="cnn01"/> '''Afrezza''', a [[monomeric]] inhaled, ultra rapid-acting insulin developed by [[Mannkind]], was approved by the FDA in 2014 and is the only inhaled insulin comercialized at the moment. <ref name="fda.gov">{{cite web | url = https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm403122.htm | title = FDA approves Afrezza to treat diabetes|type=News Release|date=June 27, 2014|access-date=July 19, 2016|publisher=U.S. Food and Drug Administration | archive-url = https://web.archive.org/web/20140706163846/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm403122.htm | archive-date = July 6, 2014 }}</ref>
'''Exubera''', developed by Inhale Therapeutics (later named [[Nektar Therapeutics]]), became the first inhaled insulin product to be marketed, in 2006 by [[Pfizer]],<ref name="exubra_fda_approval"/> but poor sales led Pfizer to withdraw it in 2007.<ref name="cnn01"/> '''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.<ref name="fda.gov">{{cite web | url = https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm403122.htm | title = FDA approves Afrezza to treat diabetes|type=News Release|date=June 27, 2014|access-date=July 19, 2016|publisher=U.S. Food and Drug Administration | archive-url = https://web.archive.org/web/20140706163846/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm403122.htm | archive-date = July 6, 2014 }}</ref>
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== History ==
== 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.<ref>{{Cite web|title=100 Years of Insulin|url=https://www.diabetes.org.uk/research/research-impact/insulin#:~:text=Insulin%20was%20discovered%20by%20Sir,than%20a%20year%20or%20two.|url-status=live|website=Diabetes UK}}</ref> German researchers first introduced the idea of inhalable insulin in 1924.<ref name="washingtonpost01"/> 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|date=January 2022}}
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.<ref>{{Cite web|title=100 Years of Insulin|url=https://www.diabetes.org.uk/research/research-impact/insulin#:~:text=Insulin%20was%20discovered%20by%20Sir,than%20a%20year%20or%20two.|url-status=live|website=Diabetes UK}}</ref> German researchers first introduced the idea of inhalable insulin in 1924.<ref name="washingtonpost01"/> 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|date=January 2022}}
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At the time of Exubera's discontinuation, several other companies were pursuing inhaled insulin including [[Alkermes (company)|Alkermes]] working with [[Eli Lilly and Company]],<ref name="bioworldtoday01"/> [[MannKind Corporation]],<ref name="mannkind01"/><ref name="nyt01"/> 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.<ref name="diabetescloseup01"/>
At the time of Exubera's discontinuation, several other companies were pursuing inhaled insulin including [[Alkermes (company)|Alkermes]] working with [[Eli Lilly and Company]],<ref name="bioworldtoday01"/> [[MannKind Corporation]],<ref name="mannkind01"/><ref name="nyt01"/> 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.<ref name="diabetescloseup01"/>


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.<ref>{{cite web|url=http://investors.mannkindcorp.com/releasedetail.cfm?ReleaseID=792188|title=MannKind Corporation Receives Complete Response Letter from the FDA for AFREZZA(R)|date=January 19, 2011|access-date=July 19, 2016|publisher=MannKind Corporation|archive-url=https://web.archive.org/web/20160823032632/http://investors.mannkindcorp.com/releasedetail.cfm?ReleaseID=792188|archive-date=August 23, 2016|url-status=dead}}</ref> 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.<ref name="fda.gov"/><ref name=USlabel2015>{{cite web|title=US Afrezza label|url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/022472s009lbl.pdf|publisher=FDA|date=May 2015}}</ref> In 2014 Mannkind and Sanofi agreed that Sanofi would take over manufacturing and marketing of Afrezza,<ref>{{cite news|last1=Carroll|first1=John | name-list-style = vanc |title=Sanofi fills some big shoes in $925M Afrezza pact with MannKind|url=http://www.fiercebiotech.com/partnering/sanofi-fills-some-big-shoes-925m-afrezza-pact-mannkind|work=FierceBiotech|date=August 11, 2014}}</ref> but Sanofi said it was dropping the effort in January 2016 due to poor sales of $7.5 million in 2015;<ref name=why>{{cite news|last1=Staton|first1=Tracy | name-list-style = vanc |title=Sanofi tried and failed with Afrezza. Why does MannKind still think it can win?|url=http://www.fiercepharma.com/pharma/sanofi-tried-and-failed-afrezza-why-does-mannkind-still-think-it-can-win|work=FiercePharma|date=February 10, 2016}}</ref> the companies formally terminated the agreement in November 2016.<ref name=forgive>{{cite news|last1=Palmer|first1=Eric|title=Sanofi forgives MannKind's boatload of debt over failed Afrezza deal|url=http://www.fiercepharma.com/pharma/sanofi-forgives-mannkind-boatload-debt-over-failed-afrezza-deal|work=FiercePharma|date=November 10, 2016}}</ref> At the time that Sanofi announced it was dropping the product Mannkind said it would continue alone,<ref name=why/> and it had taken over manufacturing and relaunched the drug by July 2016.<ref name=forgive/> 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.<ref>{{Cite journal|last1=Snell-Bergeon|first1=Janet K.|last2=Akturk|first2=Halis K.|last3=Rewers|first3=Amanda|last4=Bode|first4=Bruce W.|last5=Klaff|first5=Leslie J.|last6=Peters|first6=Anne|last7=Bailey|first7=Timothy S.|last8=Garg|first8=Satish K.|date=2018-07-01|title=Improved Time-in-Range (TIR) on Continuous Glucose Monitor (CGM) with Technosphere Inhaled Insulin (TI) Compared with Insulin Aspart in T1D Patients—STAT Study|url=http://diabetes.diabetesjournals.org/content/67/Supplement_1/1017-P|journal=Diabetes|language=en|volume=67|issue=Supplement 1|pages=1017–P|doi=10.2337/db18-1017-P|s2cid=90171098|issn=0012-1797}}</ref>
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.<ref>{{cite web|url=http://investors.mannkindcorp.com/releasedetail.cfm?ReleaseID=792188|title=MannKind Corporation Receives Complete Response Letter from the FDA for AFREZZA(R)|date=January 19, 2011|access-date=July 19, 2016|publisher=MannKind Corporation|archive-url=https://web.archive.org/web/20160823032632/http://investors.mannkindcorp.com/releasedetail.cfm?ReleaseID=792188|archive-date=August 23, 2016|url-status=dead}}</ref> 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.<ref name="fda.gov"/><ref name=USlabel2015>{{cite web|title=US Afrezza label|url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/022472s009lbl.pdf|publisher=FDA|date=May 2015}}</ref> In 2014 Mannkind and Sanofi agreed that Sanofi would take over manufacturing and marketing of Afrezza,<ref>{{cite news|last1=Carroll|first1=John | name-list-style = vanc |title=Sanofi fills some big shoes in $925M Afrezza pact with MannKind|url=http://www.fiercebiotech.com/partnering/sanofi-fills-some-big-shoes-925m-afrezza-pact-mannkind|work=FierceBiotech|date=August 11, 2014}}</ref> but Sanofi said it was dropping the effort in January 2016 due to poor sales of $7.5 million in 2015;<ref name=why>{{cite news|last1=Staton|first1=Tracy | name-list-style = vanc |title=Sanofi tried and failed with Afrezza. Why does MannKind still think it can win?|url=http://www.fiercepharma.com/pharma/sanofi-tried-and-failed-afrezza-why-does-mannkind-still-think-it-can-win|work=FiercePharma|date=February 10, 2016}}</ref> the companies formally terminated the agreement in November 2016.<ref name=forgive>{{cite news|last1=Palmer|first1=Eric|title=Sanofi forgives MannKind's boatload of debt over failed Afrezza deal|url=http://www.fiercepharma.com/pharma/sanofi-forgives-mannkind-boatload-debt-over-failed-afrezza-deal|work=FiercePharma|date=November 10, 2016}}</ref> At the time that Sanofi announced it was dropping the product Mannkind said it would continue alone,<ref name=why/> and it had taken over manufacturing and relaunched the drug by July 2016.<ref name=forgive/> 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&nbsp;mg/dl), reducing both spikes in blood glucose and time in hypoglycemia in adults with Type I diabetes, compared to insulin Aspart.<ref>{{Cite journal|last1=Snell-Bergeon|first1=Janet K.|last2=Akturk|first2=Halis K.|last3=Rewers|first3=Amanda|last4=Bode|first4=Bruce W.|last5=Klaff|first5=Leslie J.|last6=Peters|first6=Anne|last7=Bailey|first7=Timothy S.|last8=Garg|first8=Satish K.|date=2018-07-01|title=Improved Time-in-Range (TIR) on Continuous Glucose Monitor (CGM) with Technosphere Inhaled Insulin (TI) Compared with Insulin Aspart in T1D Patients—STAT Study|url=http://diabetes.diabetesjournals.org/content/67/Supplement_1/1017-P|journal=Diabetes|language=en|volume=67|issue=Supplement 1|pages=1017–P|doi=10.2337/db18-1017-P|s2cid=90171098|issn=0012-1797}}</ref>


==References==
==References==

Revision as of 14:51, 9 January 2023

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.{{cite web}}: CS1 maint: url-status (link)
  7. ^ a b c Gillis J (January 28, 2006). "Inhaled Form of Insulin Is Approved". The Washington Post. 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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