US 2011 01661 12A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/01661 12 A1 Zhang (43) Pub. Date: Jul. 7, 2011 (54) METHOD FOR STIMULATING PLATELET Publication Classification PRODUCTION (51) Int. Cl. A 6LX 3/573 (2006.01) (75) Inventor: Yanzhen Zhang, Sudbury, MA A63/496 (2006.01) (US) A6IP 7/02 (2006.01) A6IP35/00 (2006.01) (73) Assignee: Eisai, Inc., Woodcliff Lake, NJ A6IPL/I6 (2006.01) (US) A6IP3L/2 (2006.01) A6IP3L/04 (2006.01) (21) Appl. No.: 12/856,003 (52) U.S. Cl. ...................................... 514/171; 514/253.1 (57) ABSTRACT (22) Filed: Aug. 13, 2010 Provided are methods for increasing platelet response in a O O subject at risk for bleeding due at least in part to a low platelet Related U.S. Application Data count by administering to a subject with a low platelet count (60) Provisional application No. 61/234,153, filed on Aug. an effective amount of 1-(3-chloro-5-4-(4-chlorothiophen 14, 2009, provisional application No. 61/365,479, 2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl) filed on Jul.19, 2010. carbamoylpyridine-2-yl)piperidine-4-carboxylic acid. Patent Application Publication Jul. 7, 2011 Sheet 1 of 5 US 2011/O1661 12 A1 -H PLACEBO 500 ---0--- E55O15 mg *-i- E550120 mg 450 ----- ------. E5501 2.5 mg -...-a-...-. E5501 10 mg 4OO 350 3OO Patent Application Publication Jul. 7, 2011 Sheet 4 of 5 US 2011/O1661 12 A1 WEEK 1 WEEK 2 WEEK 3 WEEK 4 TIME FROM DATE OF LAST DOSE Figure 4 Patent Application Publication Jul. 7, 2011 Sheet 5 of 5 US 2011/O1661 12 A1 1.O O.9 O.8 O.7 O6 0.5 O4 O.3 0.2 O.1 O.O O 2 4 6 8 1 O 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 TIME FROM FIRST DAY OF ACTIVESTUDY DRUG (WEEKS) Figure 5 US 2011/01661 12 A1 Jul. 7, 2011 METHOD FOR STMULATING PLATELET least in part to a low platelet count. The methods generally PRODUCTION include administering to the Subject an effective amount of 1-(3-chloro-5-4-(4-chlorothiophen-2-yl)-5-(4-cyclohexy RELATED APPLICATIONS lpiperazin-1-yl)thiazol-2-yl)carbamoylpyridine-2-yl)pip 0001. This application is claims priority to U.S. Provi eridine-4-carboxylic acid, wherein the platelet response is sional Patent Application No. 61/234,153, filed Aug. 14, 2009 increased in less than 14 days. and U.S. Provisional Patent Application No. 61/365,479, filed 0005. In some embodiments, the method further provides Jul. 19, 2010. The contents of the foregoing applications are the step of detecting the platelet response within about 14 days, about 7 days, about 3 days or about 24 hours after hereby incorporated in their entirety. administration of 1-(3-chloro-5-4-(4-chlorothiophen-2- yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl) BACKGROUND OF THE INVENTION carbamoylpyridine-2-yl)piperidine-4-carboxylic acid. 0002 Thrombocytopenia is a potentially serious condi 0006. In some embodiments, the subject has an initial tion characterized by a deficiency of platelets in the circula platelet count of less than or about equal to 30,000/mmand tory system. It is associated with an increased risk of bleed the platelet response is increased in less than about 7 days to ing, particularly from Small capillaries, resulting in greater than or equal to about 50,0000/mm. thrombocytopenic purpura. The causes of thrombocytopenia 0007. In some embodiments, the subject has a response include decreases in platelet production in the bone marrow rate of at least about 10%, about 25%, about 50% or about and decreases in platelet survival in the blood. There are 80% over the initial platelet count at about 28 days after specific disease-related thrombocytopenias, such as immune administration of 1-(3-chloro-5-4-(4-chlorothiophen-2- (idiopathic) thrombocytopenic purpura (ITP) and thromb yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl) ocytopenias caused by the indirect effect of other diseases on carbamoylpyridine-2-yl)piperidine-4-carboxylic acid. the bone marrow, including malignancies and infections such as hepatitis. Currently, management of thrombocytopenia is 0008. In some embodiment, the subject has a response rate of at least about 5%, about 10%, about 25%, about 50%, about primarily based on platelet transfusion. Despite the effective 70%, about 90% or about 98% over initial platelet count at ness of transfusion, approximately 30% of transfusions are about 7 days after administration of 1-(3-chloro-5-4-(4- associated with serious complications, including alloimmu chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thia nization, febrile and allergic reactions, circulatory overload, acute pulmonary injury and bacterial or viral infections. In the Zol-2-yl)carbamoylpyridine-2-yl)piperidine-4-carboxylic 15 to 25% of patients who require repeated platelet transfu acid. sions, the platelet response is inadequate due to human leu 0009. In some embodiments, the subject has a sustained kocyte antigen (HLA) alloimmunization. Therefore, a safe platelet response of at least about 25%, about 30%, about thrombopoietic agent that can lessen or eliminate the need for 40%, about 50%, about 75% or about 77% after about 28 platelet transfusion would benefit patient health and could days. significantly lower health-care costs. 0010. In some embodiments, the platelet response is main tained for at least about 7 days, about 14 days, about 28 days, SUMMARY OF THE INVENTION about 2 months, about 3 months, about 4 months, about 5 months, about 6 months or about 7 months. In some embodi 0003. The present invention is based, at least in part, on the discovery that 1-(3-chloro-5-4-(4-chlorothiophen-2-yl)-5- ments, the platelet response is maintained indefinitely. (4-cyclohexylpiperazin-1-yl)thiazol-2-yl 0011. In some embodiments, the platelet response is increased by at least about 10%, by about 25%, by about 50% carbamoylpyridine-2-yl)piperidine-4-carboxylic acid): or by about 90% over the initial platelet count. 0012. In some embodiments, the platelet response is increased by between at least about 10,000/mm and about 400,000/mm. 0013. In some embodiments, the effective amount is an effective periodic dose. 0014. In some embodiments, the effective periodic dose is a once daily dose, a twice daily dose, a thrice daily dose, a dose administered every other day, a weekly dose or a monthly dose. 0015. In some embodiments, the effective periodic dose is has the ability to increase the platelet response in a rapid administered for about 1 month, about 2 months, about 3 manner when compared to conventional drugs, which may be months, about 4 months, about 5 months, about 6 months or useful in preparing Subjects that are at risk of bleeding due to about 7 months. a low platelet count for treatment that can induce bleeding. 0016. In some embodiments, the subject is in need of Accordingly, it is an object of the present invention to provide treatment that may induce bleeding. methods for rapidly increasing the platelet response in a Sub 0017. In some embodiments, the subject has a low platelet ject in order to prevent bleeding when the Subject undergoes count within at least about 1 month of treatment, within at a treatment that induces bleeding. least about 14 days of treatment, within at least about 7 days 0004. Accordingly, in some aspects, the present invention of treatment or at least about the time of treatment. provides method for rapidly stimulating the platelet response 0018. In some embodiments, the treatment comprises a in a subject at risk for bleeding or with active bleeding due at Surgery or administration of a therapeutic agent. US 2011/01661 12 A1 Jul. 7, 2011 0019. In some embodiments, the therapeutic agent com azin-1-yl)thiazol-2-yl)carbamoylpyridine-2-yl)piperidine prises chemotherapy, radiation therapy or a combination 4-carboxylic acid. In some embodiments, the platelet count is thereof. maintained indefinitely. 0020. In some embodiment, surgery comprises adminis tration of an anesthetic, administration of an epidural, a BRIEF DESCRIPTIONS OF THE DRAWINGS biopsy, a transplantation or dental work. 0039 FIG. 1 includes a graph illustrating the time-course 0021. In some embodiments, the dental work includes of platelet count increases above baseline over the 28 day dental cleaning. study period upon administration to the study Subject a pla 0022. In some embodiments, the subject has thrombocy cebo or E5501 in the amounts of 2.5 mg, 5.0 mg, 10 mg and topenia. 20 mg. 0023. In some embodiments, the subject further is in need 0040 FIG. 2 includes a graph illustrating the median of treatment for cancer, liver disease, vitamin B12 deficiency, platelet count (K/mm) from baseline for the Full Analysis a systemic viral infection, a systemic bacterial infection, sep Set (FAS) population over 18 weeks. sis, dengue fever or an immune disorder. 0041 FIG. 3 includes a graph illustrating the median 0024. In some embodiments, the liver disease is chronic platelet count (K/mm) from baseline for the Sufficient Expo viral hepatitis, nonalcoholic steatohepatitis, alcoholic liver sure population over 18 weeks. disease, liver failure or sepsis. 0025. In some embodiments, the thrombocytopenia is 0042 FIG. 4 includes a chart illustrating the time distri chronic immune (idiopathic) thrombocytopenic purpura, bution from the date of the last dose of E5501 in the rollover radiation-induced thrombocytopenia, chemotherapy-in study versus the incidence of recurrence of thrombocytope duced thrombocytopenia, HIV/AIDS-induced thrombocy 18. topenia, anemia-induced thrombocytopenia, thrombotic 0043 FIG.