Bis-Choline Tetrathiomolybdate for Treating Wilson Disease

Abstract

Methods for treating Wilson Disease with bis-choline tetrathiomolybdate therapy are provided. The methods may include administering 15 mg or between 30 and 90 mg of bis-choline tetrathiomolybdate once daily to a patient exhibiting NCC corrected , alanine aminotransferase (ALT), hemoglobin, platelets, or neutrophils levels meeting specified criteria. The methods may include modifying treatment by decreasing or increasing the daily dose of bis-choline tetrathiomolybdate or discontinuing treatment for a period of time.

What is claimed: 
     
         1 . A method of treating Wilson Disease in a patient in need thereof, comprising administering 15 mg of bis-choline tetrathiomolybdate once every day, wherein the patient exhibits at least a 25% reduction in NCC corrected  at or after 24 weeks of administration as compared to the patient's NCC corrected  prior to administration. 
     
     
         2 . The method of  claim 1 , where the 15 mg of bis-choline tetrathiomolybdate is administered as a delayed-release dosage form. 
     
     
         3 . The method of  claim 2 , wherein the dosage form is an enterically coated tablet. 
     
     
         4 . The method of  claim 1 , wherein the bis-choline tetrathiomolybdate is administered to the patient in a fasted state. 
     
     
         5 . A method of treating Wilson Disease in a patient in need thereof, comprising administering 15 mg of bis-choline tetrathiomolybdate to the patient in a fasted state once every day. 
     
     
         6 . The method of  claim 5 , wherein the 15 mg of bis-choline tetrathiomolybdate is administered as a delayed-release dosage form. 
     
     
         7 . The method of  claim 5 , wherein the dosage form is an enterically coated tablet. 
     
     
         8 . A method of modifying bis-choline tetrathiomolybdate administration to a patient with Wilson Disease undergoing bis-choline tetrathiomolybdate treatment, said patient exhibiting one of more of:
 (1) an alanine aminotransferase (ALT) level at least twice that of the ALT level exhibited when starting bis-choline tetrathiomolybdate treatment;   (2) an alanine aminotransferase (ALT) level at least twice the upper limit of normal (ULN);   (3) a hemoglobin level of at least 30% lower than the hemoglobin level exhibited when starting bis-choline tetrathiomolybdate treatment;   (4) a platelet level of at least 30% lower than the platelet level exhibited when starting bis-choline tetrathiomolybdate treatment; and   (5) a neutrophils level of at least 30% lower than the neutrophils level exhibited when starting bis-choline tetrathiomolybdate treatment,   the method comprising: reducing the bis-choline tetrathiomolybdate dose wherein   if the patient was on a 15 mg once daily dose of bis-choline tetrathiomolybdate, reducing the dose to 15 mg bis-choline tetrathiomolybdate every other day;   if the patient was on a 30 mg once daily dose of bis-choline tetrathiomolybdate, reducing the dose to 15 mg bis-choline tetrathiomolybdate once daily;   if the patent was on a 45 mg once daily dose of bis-choline tetrathiomolybdate, reducing the dose to 30 mg bis-choline tetrathiomolybdate once daily;   if the patent was on a 60 mg once daily dose of bis-choline tetrathiomolybdate, reducing the dose to 45 mg bis-choline tetrathiomolybdate once daily;   if the patent was on a 75 mg once daily dose of bis-choline tetrathiomolybdate, reducing the dose to 60 mg bis-choline tetrathiomolybdate once daily; or   if the patent was on a 90 mg once daily dose of bis-choline tetrathiomolybdate, reducing the dose to 75 mg bis-choline tetrathiomolybdate once daily.   
     
     
         9 . The method of  claim 8 , said patient exhibiting an alanine aminotransferase (ALT) level of at least twice the upper limit of normal (ULN). 
     
     
         10 . The method of  claim 8 , said patient exhibiting a hemoglobin level of at least 30% lower than the hemoglobin level exhibited when starting bis-choline tetrathiomolybdate treatment. 
     
     
         11 . The method of  claim 8 , said patient exhibiting a platelet level of at least 30% lower than the platelet level exhibited when starting bis-choline tetrathiomolybdate treatment. 
     
     
         12 . The method of  claim 8 , said patient exhibiting a neutrophils level of at least 30% lower than the neutrophils level exhibited when starting bis-choline tetrathiomolybdate treatment. 
     
     
         13 . The method of  claim 8 , further comprising measuring at least one of said patient's:
 a) NCC corrected  level;   b) alanine aminotransferase (ALT) level;   c) hemoglobin level;   d) platelets level; and   e) neutrophils level.   
     
     
         14 . A method of administering bis-choline tetrathiomolybdate to treat a patient with Wilson Disease, said patient having exhibited an abnormal test result, the method comprising:
 (a) administering to said patient a first dose level comprising from about 15 to about 90 mg per day of bis-choline tetrathiomolybdate for a first time period, followed by   (b) administering a second dose level comprising at least about 15 mg per day less of bis-choline tetrathiomolybdate than the first dose level for a second time period.   
     
     
         15 . The method of  claim 14 , wherein the first dose level comprises about 15 mg per day of bis-choline tetrathiomolybdate and the second dose level comprises about 15 mg per two days of bis-choline tetrathiomolybdate. 
     
     
         16 . The method of  claim 14 , wherein the abnormal test result comprises an alanine aminotransferase (ALT) level (1) of at least twice that of a baseline ALT measured before bis-choline tetrathiomolybdate administration, or (2) greater than 80 IU/mL. 
     
     
         17 . The method of  claim 14 , wherein the abnormal test result comprises a hemoglobin level of at least 30% lower than a baseline hemoglobin level measured before bis-choline tetrathiomolybdate administration. 
     
     
         18 . The method of  claim 14 , wherein the abnormal test result comprises a platelet level of at least 30% lower than a baseline platelet level measured before bis-choline tetrathiomolybdate administration. 
     
     
         19 . The method of  claim 14 , wherein the abnormal test result comprises a neutrophil level of at least 30% lower than a baseline neutrophil level measured before bis-choline tetrathiomolybdate administration. 
     
     
         20 . The method of  claim 14 , wherein the abnormal test result comprises an alanine aminotransferase (ALT) level of at least five times higher that of a baseline ALT measured before bis-choline tetrathiomolybdate administration, further comprising:
 (c) discontinuing treatment for a third period of time between step (a) and step (b) until the patient exhibits an alanine aminotransferase (ALT) level less than two times the baseline ALT measured before bis-choline tetrathiomolybdate administration; and   wherein the second dose in step (b) is 15 mg every other day.   
     
     
         21 . The method of  claim 14 , wherein the abnormal test result comprises an alanine aminotransferase (ALT) level of at least 200 IU/mL, further comprising:
 (c) discontinuing treatment for a third period of time between step (a) and step (b) until the patient exhibits an alanine aminotransferase (ALT) level less than 80 IU/mL; and   wherein the second dose in step (b) is 15 mg every other day.   
     
     
         22 . The method of  claim 14 , wherein the abnormal test result comprises a hemoglobin level of less than 8 g/dL in the absence of bleeding:
 (c) discontinuing treatment for a third time period between step (a) and step (b) until the patient exhibits a hemoglobin level equivalent to the hemoglobin level measured before bis-choline tetrathiomolybdate administration; and   wherein the second dose in step (b) is 15 mg every other day.   
     
     
         23 . The method of  claim 14 , wherein the abnormal test result comprises a platelet level of less than 30,000 μL; further comprising
 (c) discontinuing treatment for a third time period between step (a) and step (b) until the patient exhibits a platelet level equivalent to the platelet level measured before bis-choline tetrathiomolybdate administration; and 
 wherein the second dose in step (b) is 15 mg every other day. 
 
     
     
         24 . The method of  claim 14 , wherein the abnormal test result comprises a neutrophils level of less than 1.0×10 3 /μL:
 (c) discontinuing treatment for a third time period between step (a) and step (b) until the patient exhibits a neutrophils level equivalent to the neutrophils level measured before bis-choline tetrathiomolybdate administration; and 
 wherein the second dose in step (b) is 15 mg every other day. 
 
     
     
         25 . The method of  claim 14 , further comprising measuring at least one of said patient's:
 a) NCC corrected  level;   b) alanine aminotransferase (ALT) level;   c) hemoglobin level;   d) platelets level; and   e) neutrophils level.   
     
     
         26 . The method of  claim 14 , wherein the bis-choline tetrathiomolybdate is administered as a delayed-release dosage form. 
     
     
         27 . The method of  claim 26 , wherein the dosage form is an enterically coated tablet. 
     
     
         28 . The method of  claim 14 , wherein the bis-choline tetrathiomolybdate is administered to the patient in a fasted state. 
     
     
         29 . The method of  claim 1 , wherein the patient has inadequate response to chelation therapy or zinc, failed to respond to chelation therapy or zinc, and/or has or is at risk for neurological symptoms. 
     
     
         30 . The method of  claim 5 , wherein the patient has inadequate response to chelation therapy or zinc, failed to respond to chelation therapy or zinc, and/or has or is at risk for neurological symptoms.