Bis-choline tetrathiomolybdate

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Bis-choline tetrathiomolybdate (molecular structure).png
Clinical data
Legal status
  • Investigational
Identifiers
CAS Number 649749-10-0
ATC code none
ChemSpider 19906891
Synonyms Choline tetrathiomolybdate; Bis(choline)tetrathiomolybdate; ATN-224; WTX101
Chemical data
Formula C10H28MoN2O2S4
Molecular mass 432.542
  • OCC[N+](C)(C)C.[S-][Mo]([S-])(=S)=S.C[N+](C)(C)CCO
  • InChI=1S/2C5H14NO.Mo.4S/c2*1-6(2,3)4-5-7;;;;;/h2*7H,4-5H2,1-3H3;;;;;/q2*+1;;;;2*-1
  • Key:NEYVHGQOGHJAAD-UHFFFAOYSA-N

Bis-choline tetrathiomolybdate, or WTX101, 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 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 15,000 worldwide have Wilson's disease, corresponding to approximately 30,000 individuals in the European Union and approximately 20,000 in the United States.[1]

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 disease.[5][6]

Bis-choline salt of tetrathiomolybdate is a de-coppering therapy in clinical development against Wilson 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 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 2014, tetrathiomolybdate had been tested in over 500 patients for up to seven years, primarily in oncology[11][12][13][14][15][16][17][18][19][20] and Wilson's disease,[21][22][23][24] as well as some other clinical pathologies.[25][26]

Two noteworthy trends are supported by the data collected from these initial studies. Firstly, TTM more rapidly lowers copper levels than previously studied de-coppering agents. Secondly, the initial neurological deterioration frequently observed with de-coppering agents is noted in fewer Wilson disease patients when they are treated with TTM.[27][28][29]

As of November 2014, a Phase 2, multi-centre, open-label, study is recruiting newly diagnosed Wilson disease patients 18 and older to evaluate the efficacy and safety of bis-choline tetrathiomolybdate (WTX101) administration over a 24-week period.[30][31]

Dosing

Previous clinical studies with bis-choline salt of tetrathiomolybdate, or WTX101, in oncology patients have shown that bis-choline tetrathiomolybdate can lower and maintain copper levels using a once or twice daily oral dosing.[32][33] This is an important finding, since untreated Wilson's disease may lead to death within several years of the onset of symptoms,[34] 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 disease patients taking de-coppering treatments.[35]

References

  1. ↑ Ala A, Walker AP, Ashkan K, Dooley JS, Schilsky ML, 2007. "Wilson's disease". Lancet 369: 397-408.
  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 TM, Ryan CJ, Wilding G, Mathew P, Morris M, Callahan JA, Gordon G, Reich SD, Carducci MA, Antonarakis ES, 2011. "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-naive prostate cancer". Urologic oncology.
  4. ↑ 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, 2008. "Phase I study of copper-binding agent ATN-224 in patients with advanced solid tumors". Clin Cancer Res 14: 7526-7534.
  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 KT, 2000. "Excretion of copper complexed with thiomolybdate into the bile and blood in LEC rats". Chem Biol Interact 124: 217-231.
  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". J Inorg Biochem 41: 87-92.
  9. ↑ Ogra Y, Ohmichi M, Suzuki KT, 1995. "Systemic dispositions of molybdenum and copper after tetrathiomolybdate injection in LEC rats". Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements 9: 165-169.
  10. ↑ Riha M, Karlickova J, Filipsky T, Macakova K, Hrdina R, Mladenka P, 2013. "Novel method for rapid copper chelation assessment confirmed low affinity of D-penicillamine for copper in comparison with trientine and 8-hydroxyquinolines". J Inorg Biochem 123: 80-87.
  11. ↑ 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.
  12. ↑ 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, 2000. "Treatment of metastatic cancer with tetrathiomolybdate, an anticopper, antiangiogenic agent: Phase I study". Clin Cancer Res 6: 1-10.
  13. ↑ Gartner EM, Griffith KA, Pan Q, Brewer GJ, Henja GF, Merajver SD, Zalupski MM, 2009. "A pilot trial of the anti-angiogenic copper lowering agent tetrathiomolybdate in combination with irinotecan, 5-flurouracil, and leucovorin for metastatic colorectal cancer". Invest New Drugs 27: 159-165.
  14. ↑ Henry NL, Dunn R, Merjaver S, Pan Q, Pienta KJ, Brewer G, Smith DC, 2006. "Phase II trial of copper depletion with tetrathiomolybdate as an antiangiogenesis strategy in patients with hormone-refractory prostate cancer". Oncology 71: 168-175.
  15. ↑ Jain S, Cohen J, Ward MM, Kornhauser N, Chuang E, Cigler T, Moore A, Donovan D, Lam C, Cobham MV, Schneider S, Hurtado Rua SM, Benkert S, Mathijsen Greenwood C, Zelkowitz R, Warren JD, Lane ME, Mittal V, Rafii S, Vahdat LT, 2013. "Tetrathiomolybdate-associated copper depletion decreases circulating endothelial progenitor cells in women with breast cancer at high risk of relapse". Annals of Oncology.
  16. ↑ Lin J, Zahurak M, Beer TM, Ryan CJ, Wilding G, Mathew P, Morris M, Callahan JA, Gordon G, Reich SD, Carducci MA, Antonarakis ES, 2011. "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-naive prostate cancer". Urologic oncology.
  17. ↑ 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, 2008. "Phase I study of copper-binding agent ATN-224 in patients with advanced solid tumors". Clin Cancer Res 14: 7526-7534.
  18. ↑ Pass HI, Brewer GJ, Dick R, Carbone M, Merajver S, 2008. "A phase II trial of tetrathiomolybdate after surgery for malignant mesothelioma: final results". Ann Thorac Surg 86: 383-389; discussion 390.
  19. ↑ Redman BG, Esper P, Pan Q, Dunn RL, Hussain HK, Chenevert T, Brewer GJ, Merajver SD, 2003. "Phase II trial of tetrathiomolybdate in patients with advanced kidney cancer". Clin Cancer Res 9: 1666-1672.
  20. ↑ Schneider BJ, Lee JS, Hayman JA, Chang AC, Orringer MB, Pickens A, Pan CC, Merajver SD, Urba SG, 2012. "Pre-operative chemoradiation followed by post-operative adjuvant therapy with tetrathiomolybdate, a novel copper chelator, for patients with resectable esophageal cancer". Invest New Drugs.
  21. ↑ Roberts EA, Schilsky L, 2008. "Diagnosis and Treatment of Wilson Disease: An Update." "AASDL Clinical Practice Guidelines in Wilson Disease." Hepatology 47,6:2089-2111.
  22. ↑ Brewer GJ, Askari F, Dick RB, Sitterly J, Fink JK, Carlson M, Kluin KJ, Lorincz MT, 2009. "Treatment of Wilson's disease with tetrathiomolybdate: V. Control of free copper by tetrathiomolybdate and a comparison with trientine". Translational Research 154: 70-77.
  23. ↑ Brewer GJ, Askari F, Lorincz, MT, Carlson M, Schilsky M, Kluin KJ, Hedera P, Moretti P, Fink JK, Tankanow R, Dick RB, 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". Arch Neurol 63: 521-527.
  24. ↑ Brewer GJ, Hedera P, Kluin KJ, Carlson M, Askari F, Dick RB, Sitterly J, Fink JK, 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". Arch Neurol 60: 379-385.
  25. ↑ Askari F, Innis D, Dick RB, Hou G, Marrero J, Greenson J, Brewer GJ, 2010. "Treatment of primary biliary cirrhosis with tetrathiomolybdate: results of a double-blind trial." Translational Research 155: 123-130.
  26. ↑ Vine AK, Brewer GJ, 2002. "Tetrathiomolybdate as an antiangiogenesis therapy for subfoveal choroidal neovascularization secondary to age-related macular degeneration". Trans Am Ophthalmol Soc 100: 73-76; discussion 76-77.
  27. ↑ Brewer GJ, Askari F, Dick RB, Sitterly J, Fink JK, Carlson M, Kluin KJ, Lorincz MT, 2009. "Treatment of Wilson's disease with tetrathiomolybdate: V. Control of free copper by tetrathiomolybdate and a comparison with trientine". Translational Research 154: 70-77.
  28. ↑ Brewer GJ, Askari F, Lorincz MT, Carlson M, Schilsky M, Kluin KJ, Hedera P, Moretti P, Fink JK, Tankanow R, Dick RB, 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". Arch Neurol 63: 521-527.
  29. ↑ Brewer GJ, Hedera P, Kluin KJ, Carlson M, Askari F, Dick RB, Sitterly J, Fink JK, 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". Arch Neurol 60: 379-385.
  30. ↑ [1] "Efficacy and Safety Study of WTX101 in Adult Wilson Disease Patients". January 14, 2015.
  31. ↑ [2] "Wilson Disease Clinical Trials"."Phase 2 Study in Newly Diagnosed Wilson Disease Patients with WTX101 (Tetrathiomolybdate)".
  32. ↑ Lin J, Zahurak M, Beer TM, Ryan CJ, Wilding G, Mathew P, Morris M, Callahan JA, Gordon G, Reich SD, Carducci MA, Antonarakis ES, 2011. "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-naive prostate cancer". Urologic oncology.
  33. ↑ 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, 2008. "Phase I study of copper-binding agent ATN-224 in patients with advanced solid tumors". Clin Cancer Res 14: 7526-7534.
  34. ↑ Czlonkowska 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: 698-703.
  35. ↑ Maselbas W, Chabik G, Czlonkowska A, 2010. "Persistence with treatment in patients with Wilson disease". Neurologia i neurochirurgia polska 44: 260-263.

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