Adrenocorticotropic hormone (medication) explained

Adrenocorticotropic hormone is used as a medication and as diagnostic agent in the ACTH stimulation test.

The form that is purified from pig pituitary glands is known as corticotropin^{[1] [2]} is a medication and naturally occurring polypeptide tropic hormone produced and secreted by the anterior pituitary gland.^[3]

The form that is made synthetically is tetracosactide, also known as synacthen,^[4] tetracosactrin and cosyntropin.^{[2] [3] [5]} It consists of the first 24 (of a total of 39) amino acids of ACTH and retains full function of the parent peptide.^[2] Tetracosactide stimulates the release of corticosteroids such as cortisol from the adrenal glands, and is used for the ACTH stimulation test to assess adrenal gland function.

Medical uses

Both corticotropin and tetracosactide have been used for diagnostic purposes to determine adrenocortical insufficiency, particularly in Addison's disease, via the ACTH stimulation test. However, as of 2015 the US label for corticotropin does not include diagnostic use.

Both corticotropin and tetracosactide have been used for therapeutic purposes. In the US the tetracosactide label is limited to diagnosis but the UK label provides for therapeutic uses.

In the US corticotropin is used to treat epileptic spasms in infants, acute exacerbations of multiple sclerosis in adults; acute episodes of psoriatic arthritis and rheumatoid arthritis and ankylosing spondylitis; in acute exacerbations or as maintenance therapy for collagen disorders like systemic lupus erythematosus and systemic dermatomyositis; for skin conditions like severe erythema multiforme and Stevens–Johnson syndrome; for serum sickness; for severe acute and chronic allergic and inflammatory processes involving the eye such as keratitis, iritis and iridocyclitis, diffuse posterior uveitis, choroiditis, optic neuritis, chorioretinitis, and anterior segment inflammation; sarcoidosis in the lungs; and to treat edema in certain nephrotic syndromes.

In the UK tetracosactide is used for short-term therapy in conditions for which glucocorticoids are usually used but for some reason should not be; some uses include use for people who do not respond to glucocorticoids or cannot tolerate them who have ulcerative colitis, Crohn's disease, juvenile rheumatoid arthritis, rheumatoid arthritis, or osteoarthrosis.

Contraindications

In the US the only contraindication for tetracosactide for diagnostic use is hypersensitivity to ACTH but in the UK, regulators placed contraindications for hypersensitivity to ACTH and additionally, for people with allergic disorders including asthma, acute psychosis, infectious diseases, peptic ulcer, refractory heart failure, Cushing's syndrome, treatment of primary adrenocortical insufficiency and adrenocongenital syndrome.

The same contraindications that were applied in the UK for diagnostic use of tetracosactide, apply for therapeutic use of both tetracosactide and corticotropin in the US and UK.

In addition, the US label for corticotropin for therapeutic uses includes contraindications for people who have recently had surgery, and people with scleroderma, osteoporosis, uncontrolled hypertension, or sensitivity to proteins of porcine origin; in addition the infection diseases systemic fungal infection, ocular herpes simplex, and infants who have congenital infections are specified. The label also notes that people taking corticotropin for immunosuppression should not be given live vaccines.

Adverse effects

People taking corticotropin or tetracosactide are more likely to get infections, and are at risk of hypothalamic-pituitary-axis (HPA) suppression and Cushing's syndrome.

Pharmacology

In the normal situation, ACTH is released from the pituitary gland at the base of the brain. It acts on the adrenal glands to stimulate the production of steroid hormones (glucocorticoids). If the adrenal glands are healthy, a single injection of tetracosactide results in a rise in blood cortisol concentrations in 30 minutes. If the adrenal glands appear not to be working then tetracosactide injection can be given to check whether the problem is due to diseased or damaged adrenals or due to lack of pituitary ACTH.

Tetracosactide stimulates the release of corticosteroids such as cortisol from the adrenal glands, and is used for the ACTH stimulation test to assess adrenal gland function.

Chemistry

The synthetic form consists of the first 24 (of a total of 39) amino acids of ACTH and retains full function of the parent peptide.^[2]

Society and culture

Approved forms

In the US, available forms of animal-derived corticotrophin have included:

• Corticotrophin derived from pituitary glands from pigs, in a gel formulation as well as in a zinc hydrochloride formulation, each first approved in the US in 1955 and subsequently discontinued.^{[6] [7]} In September 2015 ANI Pharmaceuticals and Merck & Co. agreed that ANI would purchase NDA 009854 and NDA 008975 and related trademarks and other assets related to these two versions of corticotrophin from Merck for $75M and ongoing royalties; the transaction closed in January 2016.^[8] As of November 2016 ANI was preparing its supplemental NDA to get approval to re-introduce this formulation;^[9] in 2015 ANI estimated that the US market for these products was about $1 billion per year, based on sales of Acthar gel.^[8]
• Corticotrophin, first approved in 1952 and subsequently discontinued; as of January 2017 this NDA was under control of Parkedale, a subsidiary of King Pharmaceuticals which is in turn a subsidiary of Pfizer.^{[10] [11]}
• Corticotrophin branded as "Acthar", was first approved in 1950 and was subsequently discontinued; as of January 2017 this NDA was under control of Sanofi.^[12]
• A corticotrophin was approved in 1957 under NDA 010831, was subsequently discontinued, and as of January 2017 was under control of Organics/Lagrange, a subsidiary of Abbvie via Abbott's acquisition of Solvay's drug business.^{[13] [14] [15]} A generic version under this NDA was approved under ANDA 088772 and was subsequently discontinued, and as of January 2017 was under the control of Actavis.^[16]
• A corticotrophin called H.P. Acthar Gel was approved in 1952 and as of January 2017 was under the control of Mallinckrodt.^[17] A repository version of H.P. Acthar gel was approved in 2010 and as of January 2017 was also under the control of Mallinkrodt.^{[18] [19]}

Synthetic forms were created as a replacement for the animal-derived products.^[20]

In the US, available forms of tetracosactide/cosyntropin, the synthetic form of corticotrophin, have been approved only for diagnostic uses,^[20] and have included:

• A branded version called Cortrosyn, which was created and developed by Organon and was approved by the FDA in 1970, and as of January 2017 was under the control of Amphastar Pharmaceuticals,^{[21] [22]} and there were three generic versions under ANDAs, one for Mylan approved in 2009,^[23] one for Sandoz/Novartis, approved in 2012,^[24] and another for Amphastar under ANDA 016750.^[21] This version is a powder that is reconstituted before use.^[25]
• A version of cosyntropin in solution (as opposed to powder) was developed by Sandoz/Novartis and was approved under the 505b(2) pathway in 2008; as of January 2017 it had been discontinued.^{[26] [27] [28]}

In the UK, available forms of tetracosactide/cosyntropin, the synthetic form of corticotrophin, have been approved for both therapeutic and diagnostic uses, and have included:

• A version branded Synacthen and provided in solution 250 mcg ampoules, for diagnostic uses, approved in 2008 and as of January 2017 controlled by Mallinckrodt.^[29]
• A version branded Synacthen, absorbed on to zinc phosphate, provided in milky white suspension, approved in 2008 and as of January 2017 controlled by Mallinckrodt.^[30]

Doping

As of 2007, it was widely reported that tetracosactide had been used as an illegal performance-enhancing drug by professional cyclists.^[31] It is known to be used as a doping agent to increase the secretion of glucocorticoids by adrenal glands.^[32]

Pricing

Mallinckrodt acquired the US rights to the animal-derived form via its acquisition of Questcor Pharmaceuticals in 2014. When Questcor acquired the drug in 2001 it sold for $40 a vial; within a year of the acquisition Questcor raised the price of the drug to $1,500 per vial and to $28,000 by 2013.^{[33] [34]} In 2013, Questcor acquired the US rights to a competing product, Synacthen Depot, from Novartis.^[34] In 2014 Mallinckrodt raised the price of Acthar further to $34,000.^{[35] [36]} The Federal Trade Commission and attorneys general from five states sued Mallinckrodt for anti-competitive behavior with regard to the acquisition of Synacthen Depot and the monopolistic pricing of Acthar, and in January 2017 the company settled, agreeing to pay $100 million and to license Synacthen Depot to a competitor.^[37] According to Kaiser Health News, Mallinckrodt responded by increasing its Congressional lobbying to $610,000, and its contributions to Congress members to $44,000, in the first quarter of 2017.^[38]

In Canada, Synacthen Depot's pricing increased by 2000% in 2015, causing some provincial single payer authorities to delist the drug from funded medications. The increase in the drug's price came after Mallinckrodt acquired Questcor and its drug portfolio, which included the worldwide rights to Synacthen Depot. Prior to the price increase, Mallinckrodt claims that the drug was manufactured at a loss. Some have claimed that the price increase is abusive.^[39] The drug had been priced at $33 but rose to $680 per vial. As an off-patent pharmaceutical, a similar drug, differing in formulation, available in Europe, made by a different manufacturer, sells for $8 per vial.^[40]

Research

Acthar gel has been proposed as a therapy to treat refractory autoimmune diseases^[20] and refractory nephrotic syndrome due to a variety of glomerular diseases.^[41]

Veterinary medicine

Both versions of the hormone are also used to perform the ACTH stimulation test to diagnose hypoadrenocorticism in dogs and sometimes cats.^{[42] [43] [44] [45]}

Notes and References

1. Book: Index Nominum 2000: International Drug Directory. January 2000. Taylor & Francis. 978-3-88763-075-1. 275–.
2. Book: Elks J . The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. 14 November 2014. Springer. 978-1-4757-2085-3.
3. Book: Morton IK, Hall JM . Concise Dictionary of Pharmacological Agents: Properties and Synonyms. 6 December 2012. Springer Science & Business Media. 978-94-011-4439-1. 84–.
4. Web site: BNF. NICE.
5. Book: Index Nominum 2000: International Drug Directory. January 2000. Taylor & Francis. 978-3-88763-075-1. 1005–.
6. Web site: NDA 009854: Purified corticotropin-zinc hydrochloride. FDA. 22 January 2017.
7. Web site: NDA 008975: Purified corticotrophin gel. FDA. 22 January 2017.
8. Web site: Form 8K, Exhibit 99.1: Press release: ANI Pharmaceuticals to Acquire Two NDAs from Merck for $75 Million. ANI Pharmaceuticals via SEC Edgar. September 21, 2015. See Form 8-K, filed 2015-09-21, index page
9. Web site: Form 8-K Exhibit 99.1: ANI Pharmaceuticals Reports Record Third Quarter Results and Year-To-Date 2016 Highlights and Narrows Full-year Guidance. ANI Pharmaceuticals via SEC Edgar. November 3, 2016. See 8-K index page
10. Web site: NDA 008317: ACTH (Corticotropin). FDA. 22 January 2017.
11. Web site: King Pharmaceuticals, Inc. Form 10-K, Annual report for the fiscal year ended December 31, 2007. SEC Edgar.
12. Web site: NDA 007504: Acthar (Corticotropin). FDA. 22 January 2017.
13. Web site: NDA 010831: Corticotropin. FDA. 22 January 2017.
14. News: Whalen J, Cimilluca D, McCracken J . Abbott to Buy Solvay Drug Unit for $7 Billion. Wall Street Journal. 28 September 2009.
15. Web site: Press Release - Lincoln International. Lincoln International. 23 January 2017. 14 August 2013. https://web.archive.org/web/20170202093905/http://www.lincolninternational.com/transactions/organics/. 2 February 2017. dead.
16. Web site: ANDA 088772: Corticotropin. FDA. 22 January 2017.
17. Web site: NDA 008372: H.P. Acthar Gel (Corticotropin). FDA. 22 January 2017.
18. Web site: NDA022432: H.P. Acthar Gel (Repository Corticotropin). FDA. 22 January 2017.
19. Web site: US Label: H.P. Acthar Gel (repository corticotropin) and (corticotropin). Mallinckrodt. First approved 1952. February 2015.
20. Gettig J, Cummings JP, Matuszewski K . H.p. Acthar gel and cosyntropin review: clinical and financial implications . P & T . 34 . 5 . 250–257 . May 2009 . 19561871 . 2697107 .
21. Web site: NDA016750: Cortrosyn (Cosyntropin). FDA. 22 January 2017.
22. Organon sold the rights to Cortrosyn to Amphastar in 2003, per Web site: Amphastar Pharmaceuticals S-1, Amendment 5. SEC Edgar. October 27, 2005.
23. Web site: ANDA 090574: Cosyntropin. FDA. 22 January 2017.
24. Web site: ANDA 202147:Cosyntropin . FDA. 22 January 2017.
25. Web site: US Cortrosyn (cosyntropin) label. FDA. 28 January 2021.
26. Web site: NDA 022028: Summary review. FDA. February 21, 2008.
27. Web site: NDA 022028: Cosyntropin solution. FDA. 22 January 2017.
28. Web site: US Label: Cosyntropin Injection. FDA. February 2008.
29. Web site: Synacthen Ampoules 250 micrograms per ml - Summary of Product Characteristics. UK Electronic Medicines Compendium. 23 January 2017. en. First approved 25 June 1998 under PL 43357/0001. June 8, 2016.
30. Web site: Synacthen Depot Ampoules 1mg/ml - Summary of Product Characteristics. Electronic Medicines Compendium. 28 January 2021. en. First approved 25 June 1998 under PL43357/0002. June 8, 2016. medicines.org.uk.
31. Book: Kimmage P . Rough Ride . Yellow Jersey Press . 2007 . 125 . tour 87 stage 14 . 978-0-224-08017-0 .
32. Chaabo A, de Ceaurriz J, Buisson C, Tabet JC, Lasne F . Simultaneous quantification and qualification of synacthen in plasma . Analytical and Bioanalytical Chemistry . 399 . 5 . 1835–1843 . February 2011 . 21170520 . 10.1007/s00216-010-4565-z . 28664950 .
33. News: Questcor Finds Profits, at $28,000 a Vial . Pollack A . 2012-12-29 . New York Times .
34. News: Staton T . Questcor's Acthar maneuvers land Mallinckrodt in hot water with FTC, state AGs. FiercePharma. June 18, 2015. en.
35. Web site: Pharma corp. hikes infant epilepsy drug price by 2,000%, from $33.05 per vial to $680 per vial . 16 November 2015 . 16 November 2015 .
36. News: Galeon D . Company Raises the Price of a Drug That Fights Infant Epilepsy by 85,000%. Futurism. 21 January 2017.
37. News: Johnson CY . Maker of $34,000-a-vial drug to pay $100 million for allegedly preventing competition. Washington Post. January 18, 2017.
38. http://khn.org/news/follow-the-money-drugmakers-deploy-political-cash-as-prices-and-anger-mount/ Follow The Money: Drugmakers Deploy Political Cash As Prices And Anger Mount
39. News: 2,000% price hike for infant seizure drug called 'absurd' . Crowe K . CBC News . 16 November 2015 .
40. News: Monday November 16th 2015 . 16 November 2015 . The National . CBC News .
41. Bomback AS, Tumlin JA, Baranski J, Bourdeau JE, Besarab A, Appel AS, Radhakrishnan J, Appel GB . 6 . Treatment of nephrotic syndrome with adrenocorticotropic hormone (ACTH) gel . Drug Design, Development and Therapy . 5 . 147–153 . March 2011 . 21448451 . 3063118 . 10.2147/DDDT.S17521 . free .
42. Lathan P, Moore GE, Zambon S, Scott-Moncrieff JC . Use of a low-dose ACTH stimulation test for diagnosis of hypoadrenocorticism in dogs . Journal of Veterinary Internal Medicine . 22 . 4 . 1070–1073 . 2008 . 18537878 . 10.1111/j.1939-1676.2008.0118.x .
43. News: Lyman R . Consider ACTH stimulation test when you suspect canine hyperadrenocorticism . dvm360.com . November 1, 2008 . January 23, 2017. July 4, 2018. https://web.archive.org/web/20180704182712/http://veterinarynews.dvm360.com/consider-acth-stimulation-test-when-you-suspect-canine-hyperadrenocorticism. dead.
44. Web site: ACTH Stimulation Test . Idexx. 23 January 2017. https://web.archive.org/web/20170202020508/http://www.idexx.com.tw/pdf/zh_tw/smallanimal/snap/cortisol/cortisol-acth-stimulation-protocol.pdf . 2017-02-02. dead.
45. News: Gallagher A . Demystifying Tests for Hyperadrenocorticism . Clinicians' Brief. November 2014. 2017-01-23 . https://web.archive.org/web/20141222040116/http://www.cliniciansbrief.com/sites/default/files/attachments/ASK_Demystifying%20Tests%20for%20HAC.pdf . 2014-12-22. dead.