Tiomolibdic acid explained

Tradename:Decuprate
Atc Prefix:A16
Atc Suffix:AX22
Index2 Label:anion
Cas Number:13818-85-4
Cas Number2:16330-92-0
Pubchem:4660425
Drugbank2:DB05088
Chemspiderid:21494208
Chemspiderid2:10619308
Unii:206J6X63BE
Unii2:91U3TGV99T
Kegg:D12485
Synonyms:Tetrathiomolybdic acid; choline salt: ATN-224, WTX101, ALXN1840
H:2
Mo:1
S:4
Smiles:S=[Mo](=S)(S)S
Stdinchi:1S/Mo.2H2S.2S/h;2*1H2;;/q+2;;;;/p-2
Stdinchikey:IEGNLZVDENYZEJ-UHFFFAOYSA-L

Tiomolibdic acid (trade name Decuprate) is a chelating agent under investigation for the treatment of cancer and of Wilson's disease,[1] a rare and potentially fatal disease in which the body cannot regulate copper. It is developed by Wilson Therapeutics and used in form of the salt bis-choline tetrathiomolybdate.

Wilson's disease is an autosomal recessive genetic disorder that is manifested by serious hepatic, neurologic or psychiatric symptoms. The disease is fatal if left untreated. It is estimated that 1 individual in every 30,000 to 100,000 worldwide has Wilson's disease.[2]

Bis-choline tetrathiomolybdate has been evaluated in clinical trials in patients with various forms of cancer[3] [4] [5] and has received orphan designation in the US and EU as a potential therapy against Wilson's disease.[6] [7]

Pharmacology

Mechanism of action

Tiomolibdic acid selectively forms highly stable complexes with copper and proteins. These complexes are then believed to be primarily excreted via the bile, restoring the normal excretion route of copper that is impaired in patients with Wilson's disease.[8] [9] [10]

The binding and excretion mechanism is stable; whereas many de-coppering agents form unstable complexes that are excreted via urine.[11]

Clinical trials

As of November 2014, a Phase 2, multi-centre, open-label study was recruiting newly diagnosed Wilson's disease patients 18 and older to evaluate the efficacy and safety of bis-choline tetrathiomolybdate administration over a 24-week period.[12]

As of 2016, tetrathiomolybdate had been tested in over 500 patients for up to seven years, primarily in oncology[13] [14] [15] [16] [17] [18] [19] and Wilson's disease,[20] [21] [22] [23] as well as some other clinical pathologies.[24] [25]

The data suggest that bis-choline tetrathiomolybdate can rapidly lower and control toxic free copper levels and improve clinical symptoms in Wilson's disease patients. The data also suggest that it is generally well tolerated, with the potential for a reduced risk of neurological worsening after initiation of therapy compared to existing therapies.

Dosing

Previous clinical studies with bis-choline tetrathiomolybdate in oncology patients have shown that it can lower and maintain copper levels using a once or twice daily oral dosing. This may be helpful since untreated Wilson's disease may lead to death within several years of the onset of symptoms,[26] and medication use should continue throughout the patient's lifespan. Patient compliance is crucial for clinical improvement, and it is a particular challenge for Wilson's disease patients taking de-coppering treatments.[27]

Society and culture

Names

Tiomolibdic acid is the recommended International nonproprietary name (INN).[28]

External links

Notes and References

  1. Web site: Tiomolibdic acid . National Center for Advancing Translational Sciences . 30 December 2021.
  2. Ala A, Walker AP, Ashkan K, Dooley JS, Schilsky ML . Wilson's disease . Lancet . 369 . 9559 . 397–408 . February 2007 . 17276780 . 10.1016/S0140-6736(07)60196-2 . 24663871 .
  3. Berenson JR, Boccia RV, Bashey A, Levine AM, Koc ON, Callahan JA, Mazar AP, Reich SD. 2006. Phase I Study of the [Cu, Zn] Superoxide Dismutase (SOD1) Inhibitor ATN-224 (Bis-Choline Tetrathiomolybdate) in Patients with Advanced Hematologic Malignancies Presentation at the Amer Soc Hematol 2006 Annual Meeting. Blood. 108. Abstract 2593.
  4. Lin J, Zahurak M, Beer TM, Ryan CJ, Wilding G, Mathew P, Morris M, Callahan JA, Gordon G, Reich SD, Carducci MA, Antonarakis ES . A non-comparative randomized phase II study of 2 doses of ATN-224, a copper/zinc superoxide dismutase inhibitor, in patients with biochemically recurrent hormone-naïve prostate cancer . Urologic Oncology . 31 . 5 . 581–8 . July 2013 . 21816640 . 3227793 . 10.1016/j.urolonc.2011.04.009 .
  5. Lowndes SA, Adams A, Timms A, Fisher N, Smythe J, Watt SM, Joel S, Donate F, Hayward C, Reich S, Middleton M, Mazar A, Harris AL . Phase I study of copper-binding agent ATN-224 in patients with advanced solid tumors . Clinical Cancer Research . 14 . 22 . 7526–34 . November 2008 . 19010871 . 10.1158/1078-0432.CCR-08-0315 . free .
  6. http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2013/03/WC500139536.pdf Public summary of opinion on orphan designation: Choline tetrathiomolybdate for the treatment of Wilson's disease
  7. http://www.accessdata.fda.gov/scripts/opdlisting/oopd/OOPD_Results_2.cfm?Index_Number=346511 Orphan Drug Designations and Approvals: choline tetrathiomolybdate
  8. Komatsu Y, Sadakata I, Ogra Y, Suzuki KT . Excretion of copper complexed with thiomolybdate into the bile and blood in LEC rats . Chemico-Biological Interactions . 124 . 3 . 217–31 . February 2000 . 10728780 . 10.1016/s0009-2797(99)00159-3 . 2000CBI...124..217K .
  9. McQuaid A, Mason J . A comparison of the effects of penicillamine, trientine, and trithiomolybdate on [35S]-labeled metallothionein in vitro; implications for Wilson's disease therapy . Journal of Inorganic Biochemistry . 41 . 2 . 87–92 . February 1991 . 2033396 . 10.1016/0162-0134(91)80002-y .
  10. Ogra Y, Ohmichi M, Suzuki KT . Systemic dispositions of molybdenum and copper after tetrathiomolybdate injection in LEC rats . Journal of Trace Elements in Medicine and Biology . 9 . 3 . 165–9 . October 1995 . 8605606 . 10.1016/S0946-672X(11)80042-8 . 1995JTEMB...9..165O .
  11. Říha M, Karlíčková J, Filipský T, Macáková K, Hrdina R, Mladěnka P . Novel method for rapid copper chelation assessment confirmed low affinity of D-penicillamine for copper in comparison with trientine and 8-hydroxyquinolines . Journal of Inorganic Biochemistry . 123 . 80–7 . June 2013 . 23563391 . 10.1016/j.jinorgbio.2013.02.011 .
  12. Web site: Wilson Disease Clinical Trials. Phase 2 Study in Newly Diagnosed Wilson Disease Patients with WTX101 (Tetrathiomolybdate). 2009. Wilson Disease Association. dead. https://web.archive.org/web/20150209193156/http://www.wilsonsdisease.org/wilson-disease-research/wilsondisease-clinicaltrials.php. 9 February 2015.
  13. Brewer GJ, Dick RD, Grover DK, LeClaire V, Tseng M, Wicha M, Pienta K, Redman BG, Jahan T, Sondak VK, Strawderman M, LeCarpentier G, Merajver SD . Treatment of metastatic cancer with tetrathiomolybdate, an anticopper, antiangiogenic agent: Phase I study . Clinical Cancer Research . 6 . 1 . 1–10 . January 2000 . 10656425 .
  14. Gartner EM, Griffith KA, Pan Q, Brewer GJ, Henja GF, Merajver SD, Zalupski MM . A pilot trial of the anti-angiogenic copper lowering agent tetrathiomolybdate in combination with irinotecan, 5-flurouracil, and leucovorin for metastatic colorectal cancer . Investigational New Drugs . 27 . 2 . 159–65 . April 2009 . 18712502 . 4171042 . 10.1007/s10637-008-9165-9 .
  15. Henry NL, Dunn R, Merjaver S, Pan Q, Pienta KJ, Brewer G, Smith DC . Phase II trial of copper depletion with tetrathiomolybdate as an antiangiogenesis strategy in patients with hormone-refractory prostate cancer . Oncology . 71 . 3–4 . 168–75 . 2006 . 17641535 . 10.1159/000106066 . 25861052 .
  16. Jain S, Cohen J, Ward MM, Kornhauser N, Chuang E, Cigler T, Moore A, Donovan D, Lam C, Cobham MV, Schneider S, Hurtado Rúa SM, Benkert S, Mathijsen Greenwood C, Zelkowitz R, Warren JD, Lane ME, Mittal V, Rafii S, Vahdat LT . Tetrathiomolybdate-associated copper depletion decreases circulating endothelial progenitor cells in women with breast cancer at high risk of relapse . Annals of Oncology . 24 . 6 . 1491–8 . June 2013 . 23406736 . 3707432 . 10.1093/annonc/mds654 .
  17. Pass HI, Brewer GJ, Dick R, Carbone M, Merajver S . A phase II trial of tetrathiomolybdate after surgery for malignant mesothelioma: final results . The Annals of Thoracic Surgery . 86 . 2 . 383–9; discussion 390 . August 2008 . 18640301 . 10.1016/j.athoracsur.2008.03.016 . free .
  18. Redman BG, Esper P, Pan Q, Dunn RL, Hussain HK, Chenevert T, Brewer GJ, Merajver SD . Phase II trial of tetrathiomolybdate in patients with advanced kidney cancer . Clinical Cancer Research . 9 . 5 . 1666–72 . May 2003 . 12738719 .
  19. Schneider BJ, Lee JS, Hayman JA, Chang AC, Orringer MB, Pickens A, Pan CC, Merajver SD, Urba SG . Pre-operative chemoradiation followed by post-operative adjuvant therapy with tetrathiomolybdate, a novel copper chelator, for patients with resectable esophageal cancer . Investigational New Drugs . 31 . 2 . 435–42 . April 2013 . 22847786 . 4418641 . 10.1007/s10637-012-9864-0 .
  20. Roberts EA, Schilsky ML . Diagnosis and treatment of Wilson disease: an update . Hepatology . 47 . 6 . 2089–111 . June 2008 . 18506894 . 10.1002/hep.22261 . American Association for Study of Liver Diseases (AASLD) . free .
  21. Brewer GJ, Askari F, Dick RB, Sitterly J, Fink JK, Carlson M, Kluin KJ, Lorincz MT . Treatment of Wilson's disease with tetrathiomolybdate: V. Control of free copper by tetrathiomolybdate and a comparison with trientine . Translational Research . 154 . 2 . 70–7 . August 2009 . 19595438 . 10.1016/j.trsl.2009.05.002 .
  22. Brewer GJ, Askari F, Lorincz MT, Carlson M, Schilsky M, Kluin KJ, Hedera P, Moretti P, Fink JK, Tankanow R, Dick RB, Sitterly J . Treatment of Wilson disease with ammonium tetrathiomolybdate: IV. Comparison of tetrathiomolybdate and trientine in a double-blind study of treatment of the neurologic presentation of Wilson disease . Archives of Neurology . 63 . 4 . 521–7 . April 2006 . 16606763 . 10.1001/archneur.63.4.521 . free .
  23. Brewer GJ, Hedera P, Kluin KJ, Carlson M, Askari F, Dick RB, Sitterly J, Fink JK . Treatment of Wilson disease with ammonium tetrathiomolybdate: III. Initial therapy in a total of 55 neurologically affected patients and follow-up with zinc therapy . Archives of Neurology . 60 . 3 . 379–85 . March 2003 . 12633149 . 10.1001/archneur.60.3.379 . free .
  24. Askari F, Innis D, Dick RB, Hou G, Marrero J, Greenson J, Brewer GJ . Treatment of primary biliary cirrhosis with tetrathiomolybdate: results of a double-blind trial . Translational Research . 155 . 3 . 123–30 . March 2010 . 20171597 . 10.1016/j.trsl.2009.09.009 .
  25. Vine AK, Brewer GJ . Tetrathiomolybdate as an antiangiogenesis therapy for subfoveal choroidal neovascularization secondary to age-related macular degeneration . Transactions of the American Ophthalmological Society . 100 . 73–6; discussion 76-7 . 2002 . 12545680 . 1358949 .
  26. Członkowska A, Tarnacka B, Litwin T, Gajda J, Rodo M . Wilson's disease-cause of mortality in 164 patients during 1992-2003 observation period . Journal of Neurology . 252 . 6 . 698–703 . June 2005 . 15742108 . 10.1007/s00415-005-0720-4 . 34212689 .
  27. Masełbas W, Chabik G, Członkowska A . Persistence with treatment in patients with Wilson disease . Neurologia I Neurochirurgia Polska . 44 . 3 . 260–3 . 2010 . 20625962 . 10.1016/s0028-3843(14)60040-2 .
  28. ((World Health Organization)) . International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 63 . WHO Drug Information . 24 . 1 . 2010 . 10665/74530 . free . World Health Organization .

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