Bis-choline tetrathiomolybdate

Bis-choline tetrathiomolybdate (or tiomolibdate USAN, trade name Decuprate), is a salt of tetrathiomolybdate (TTM, MoS42−) and choline currently under investigation as a therapy against Wilson's disease, a rare and potentially fatal disease in which the body cannot regulate copper. 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 undiagnosed and untreated. It is estimated that approximately 1 individual in every 30,000 worldwide have Wilson's disease, corresponding to approximately 15,000 individuals in the European Union and approximately 11,000 in the United States.[1]

Bis-choline tetrathiomolybdate
Clinical data
Trade namesDecuprate
Other namesCholine tetrathiomolybdate; ATN-224; WTX101
ATC code
  • none
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
Chemical and physical data
FormulaC10H28MoN2O2S4
Molar mass432.542 g/mol g·mol−1
3D model (JSmol)

Bis-choline tetrathiomolybdate has been evaluated in clinical trials in patients with various forms of cancer[2][3][4] and has received orphan designation in the US and EU as a potential therapy against Wilson's disease.[5][6]

Bis-choline tetrathiomolybdate is a de-coppering therapy in clinical development against Wilson's disease under the code name WTX101 by Wilson Therapeutics AB. Wilson Therapeutics was founded by HealthCap in 2012.

Mechanism of action

Tetrathiomolybdate has a unique mechanism of action through which it 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.[7][8][9]

The binding and excretion mechanism of WTX101 is stable; whereas many de-coppering agents form unstable complexes that are excreted via urine.[10]

Clinical trial results and studies in progress

As of 2016, tetrathiomolybdate had been tested in over 500 patients for up to seven years, primarily in oncology[2][3][4][11][12][13][14][15][16][17] and Wilson's disease,[18][19][20][21] as well as some other clinical pathologies.[22][23]

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.[19][20][21]

As of November 2014, a Phase 2, multi-centre, open-label study is 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.[24][25]

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.[3][4] This is an important finding, 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]

References
  1. Ala, A; Walker, A. P.; Ashkan, K; Dooley, J. S.; Schilsky, M. L. (2007). "Wilson's disease". The Lancet. 369 (9559): 397–408. doi:10.1016/S0140-6736(07)60196-2. PMID 17276780.
  2. 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.
  3. Lin, J; Zahurak, M; Beer, T. M.; Ryan, C. J.; Wilding, G; Mathew, P; Morris, M; Callahan, J. A.; Gordon, G; Reich, S. D.; Carducci, M. A.; Antonarakis, E. S. (2013). "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: Seminars and Original Investigations. 31 (5): 581–8. doi:10.1016/j.urolonc.2011.04.009. PMC 3227793. PMID 21816640.
  4. Lowndes, S. A.; Adams, A; Timms, A; Fisher, N; Smythe, J; Watt, S. M.; Joel, S; Donate, F; Hayward, C; Reich, S; Middleton, M; Mazar, A; Harris, A. L. (2008). "Phase I study of copper-binding agent ATN-224 in patients with advanced solid tumors". Clinical Cancer Research. 14 (22): 7526–34. doi:10.1158/1078-0432.CCR-08-0315. PMID 19010871.
  5. Public summary of opinion on orphan designation: Choline tetrathiomolybdate for the treatment of Wilson's disease, EMA/COMP/795268/2012, ATN-224, 18 February 2013.
  6. Orphan Drug Designations and Approvals: choline tetrathiomolybdate, U.S. Food and Drug Administration, 25 August 2011
  7. Komatsu, Y; Sadakata, I; Ogra, Y; Suzuki, K. T. (2000). "Excretion of copper complexed with thiomolybdate into the bile and blood in LEC rats". Chemico-Biological Interactions. 124 (3): 217–31. doi:10.1016/s0009-2797(99)00159-3. PMID 10728780.
  8. McQuaid, A; Mason, J (1991). "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. doi:10.1016/0162-0134(91)80002-y. PMID 2033396.
  9. Ogra, Y; Ohmichi, M; Suzuki, K. T. (1995). "Systemic dispositions of molybdenum and copper after tetrathiomolybdate injection in LEC rats". Journal of Trace Elements in Medicine and Biology. 9 (3): 165–9. doi:10.1016/S0946-672X(11)80042-8. PMID 8605606.
  10. Říha, M; Karlíčková, J; Filipský, T; MacÁková, K; Hrdina, R; Mladěnka, P (2013). "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. doi:10.1016/j.jinorgbio.2013.02.011. PMID 23563391.
  11. Brewer, G. J.; Dick, R. D.; Grover, D. K.; Leclaire, V; Tseng, M; Wicha, M; Pienta, K; Redman, B. G.; Jahan, T; Sondak, V. K.; Strawderman, M; Lecarpentier, G; Merajver, S. D. (2000). "Treatment of metastatic cancer with tetrathiomolybdate, an anticopper, antiangiogenic agent: Phase I study". Clinical Cancer Research. 6 (1): 1–10. PMID 10656425.
  12. Gartner, E. M.; Griffith, K. A.; Pan, Q; Brewer, G. J.; Henja, G. F.; Merajver, S. D.; Zalupski, M. M. (2009). "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. doi:10.1007/s10637-008-9165-9. PMC 4171042. PMID 18712502.
  13. Henry, N. L.; Dunn, R; Merjaver, S; Pan, Q; Pienta, K. J.; Brewer, G; Smith, D. C. (2006). "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. doi:10.1159/000106066. PMID 17641535.
  14. Jain, S; Cohen, J; Ward, M. M.; Kornhauser, N; Chuang, E; Cigler, T; Moore, A; Donovan, D; Lam, C; Cobham, M. V.; Schneider, S; Hurtado Rúa, S. M.; Benkert, S; Mathijsen Greenwood, C; Zelkowitz, R; Warren, J. D.; Lane, M. E.; Mittal, V; Rafii, S; Vahdat, L. T. (2013). "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. doi:10.1093/annonc/mds654. PMC 3707432. PMID 23406736.
  15. Pass, H. I.; Brewer, G. J.; Dick, R; Carbone, M; Merajver, S (2008). "A phase II trial of tetrathiomolybdate after surgery for malignant mesothelioma: Final results". The Annals of Thoracic Surgery. 86 (2): 383–9, discussion 390. doi:10.1016/j.athoracsur.2008.03.016. PMID 18640301.
  16. Redman, B. G.; Esper, P; Pan, Q; Dunn, R. L.; Hussain, H. K.; Chenevert, T; Brewer, G. J.; Merajver, S. D. (2003). "Phase II trial of tetrathiomolybdate in patients with advanced kidney cancer". Clinical Cancer Research. 9 (5): 1666–72. PMID 12738719.
  17. Schneider, B. J.; Lee, J. S.; Hayman, J. A.; Chang, A. C.; Orringer, M. B.; Pickens, A; Pan, C. C.; Merajver, S. D.; Urba, S. G. (2013). "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. doi:10.1007/s10637-012-9864-0. PMC 4418641. PMID 22847786.
  18. Roberts, E. A.; Schilsky, M. L.; American Association for Study of Liver Diseases (AASLD) (2008). "Diagnosis and treatment of Wilson disease: An update". Hepatology. 47 (6): 2089–111. doi:10.1002/hep.22261. PMID 18506894.
  19. Brewer, G. J.; Askari, F; Dick, R. B.; Sitterly, J; Fink, J. K.; Carlson, M; Kluin, K. J.; Lorincz, M. T. (2009). "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. doi:10.1016/j.trsl.2009.05.002. PMID 19595438.
  20. Brewer, G. J.; Askari, F; Lorincz, M. T.; Carlson, M; Schilsky, M; Kluin, K. J.; Hedera, P; Moretti, P; Fink, J. K.; Tankanow, R; Dick, R. B.; Sitterly, J (2006). "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. doi:10.1001/archneur.63.4.521. PMID 16606763.
  21. Brewer, G. J.; Hedera, P; Kluin, K. J.; Carlson, M; Askari, F; Dick, R. B.; Sitterly, J; Fink, J. K. (2003). "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. doi:10.1001/archneur.60.3.379. PMID 12633149.
  22. Askari, F; Innis, D; Dick, R. B.; Hou, G; Marrero, J; Greenson, J; Brewer, G. J. (2010). "Treatment of primary biliary cirrhosis with tetrathiomolybdate: Results of a double-blind trial". Translational Research. 155 (3): 123–30. doi:10.1016/j.trsl.2009.09.009. PMID 20171597.
  23. Vine, A. K.; Brewer, G. J. (2002). "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. PMC 1358949. PMID 12545680.
  24. Clinical trial number NCT02273596 for "Efficacy and Safety Study of WTX101 in Adult Wilson Disease Patients" at ClinicalTrials.gov
  25. "Wilson Disease Clinical Trials. Phase 2 Study in Newly Diagnosed Wilson Disease Patients with WTX101 (Tetrathiomolybdate)". Wilson Disease Association. 2009. Archived from the original on 2015-02-09.
  26. Członkowska, A; Tarnacka, B; Litwin, T; Gajda, J; Rodo, M (2005). "Wilson's disease-cause of mortality in 164 patients during 1992-2003 observation period". Journal of Neurology. 252 (6): 698–703. doi:10.1007/s00415-005-0720-4. PMID 15742108.
  27. Masełbas, W; Chabik, G; Członkowska, A (2010). "Persistence with treatment in patients with Wilson disease". Neurologia I Neurochirurgia Polska. 44 (3): 260–3. doi:10.1016/s0028-3843(14)60040-2. PMID 20625962.
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