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(12) Patent Application Publication (10) Pub. No.: US 2006/0084628A1 Pottage (43) Pub

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(12) Patent Application Publication (10) Pub. No.: US 2006/0084628A1 Pottage (43) Pub US 20060084628A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0084628A1 Pottage (43) Pub. Date: Apr. 20, 2006 (54) COMBINATION THERAPY FOR TREATING (52) U.S. C. ... 514/49; 514/220; 514/263.34; VRAL INFECTIONS 51.4/269 (75) Inventor: John Pottage, Madison, CT (US) Correspondence Address: (57) ABSTRACT CANTOR COLBURN, LLP SS GRIFFINROAD SOUTH BLOOMFIELD, CT 06002 A method of treating viral infections, particularly Hepatitis B (HBV) and Human Immunodeficiency Virus (HIV) infec (73) Assignee: Achillion Pharmaceuticals, New Haven, tions, by administering Elvucitabine and a second active CT agent to a patient Suffering viral infection is provided herein. The second active agent is, for example, an immunomodu (21) Appl. No.: 11/252,938 latory compound, an anti-viral agent, or a combination comprising one or more of the foregoing active agents. For (22) Filed: Oct. 18, 2005 example the anti-viral agent may be a tyrosine kinase Related U.S. Application Data inhibitor, a CCR5 inhibitor, a non-nucleoside reverse tran Scriptase inhibitor, a protease inhibitor, an integrase inhibi (60) Provisional application No. 60/620,023, filed on Oct. tor. Further provided herein are combination dosage forms 19, 2004. comprising Elvucitabine and a second active agent. The combination dosage may be administered once per day. The Publication Classification Elvucitabine may be administered less frequently than the (51) Int. Cl. second active agent. Packaged pharmaceutical compositions A 6LX 3L/7072 (2006.01) comprising Elvucitabine, a second active agent, and instruc A6 IK 3/55 (2006.01) tions for using the composition for treating a viral infection A6 IK 3/53 (2006.01) by administering Elvucitabine and the second active agent 46R 3/522 (2006.01) are also provided. Patent Application Publication Apr. 20, 2006 Sheet 1 of 10 US 2006/0084628A1 Idx I9InãIH «» Patent Application Publication Apr. 20, 2006 Sheet 2 of 10 US 2006/0084628A1 3 3 c S. S. S S 09 G OOO 007 O (/6ou) euSel (60u) euli? i 8 S.3 S.8 S S O2 08 O7 O O09 OOO O (I/60u) euSel (169U) eun Patent Application Publication Apr. 20, 2006 Sheet 3 of 10 US 2006/0084628A1 OZX99AA9IX93AAZIX09AA8XH90AA g9InãIH euese uoy (I/SLeo 0) unoo IIeo pood euA u!esueuo Patent Application Publication Apr. 20, 2006 Sheet 4 of 10 US 2006/0084628A1 gueseguog (I/SILeo 0I) SIEudonneNenosqv u e5uelo Patent Application Publication Apr. 20, 2006 Sheet 5 of 10 US 2006/0084628A1 lf) es CD c S. - 3 rt s c t M rol) O H C 07 09. O. O. O. G9 G2 (/6ou) euSel (/ 6v.0) oNW Patent Application Publication Apr. 20, 2006 Sheet 6 of 10 US 2006/0084628A1 s i s i 3 09 OO 09 O S'E 92 (16Oulu) euSel (/ 6vO) onw Patent Application Publication Apr. 20, 2006 Sheet 7 of 10 US 2006/0084628A1 C O O Cld N N O C o Cp o2 r CO G o S.s c 5 N C O CD S E S E rt - E Na O O b) t f m r C C /N 8H C C OOC OO O G9. 92 (f6au) euSeld (I/O) ONW Patent Application Publication Apr. 20, 2006 Sheet 8 of 10 US 2006/0084628A1 89InãIH Á?3|xo)oNÁ3e3Lg3ON „g<!--~~~~jouers ezkí Patent Application Publication Apr. 20, 2006 Sheet 9 of 10 US 2006/0084628A1 st .. CD C .C. EPs i EggE. E2se "e ever R E2. O O. O. O. O O O O (160u) uoeupueouoo Patent Application Publication Apr. 20, 2006 Sheet 10 of 10 US 2006/0084628A1 000Z OI9InãIAI 0 09 US 2006/0084628A1 Apr. 20, 2006 COMBINATION THERAPY FOR TREATING HBV and HIV infections. Typically about 300 mg of a VIRAL INFECTIONS reverse transciptase inhibitor must be administered daily for effective treatment of a viral infections, sometimes on a once CROSS REFERENCE TO RELATED per day dosing schedule, but more typically on a twice or APPLICATIONS three times per day dosing schedule. Because patients Suf 0001. This application claims priority to U.S. provisional fering from HBV or HIV often take a number of medica patent application No. 60/620,023, filed Oct. 19, 2004, tions, a reverse transcriptase inhibitor efficacious at lower which is hereby incorporated by reference in its entirety. dosages is urgently needed. A reverse transcriptase inhibitor that can be administered once daily or less frequently is FIELD OF THE INVENTION particularly desireable. 0002. A method of treating viral infections, particularly 0009 Elvucitabine is a nucleoside analog of the formula Hepatitis B (HBV) and Human Immunodeficiency Virus (HIV), by administering a low dose of Elvucitabine in combination with a second active agent to a patient Suffering viral infection is provided herein. The Elvucitabine dosage may be given BID, daily, once every 48 hours, or once SN weekly. Also provided herein are packaged pharmaceutical compositions comprising Elvucitabine and a second active 1. agent and instructions for treating a viral infection by N O. administering a low BID, daily, once/48 hour, or weekly dosage of Elvucitabine. Methods of improving patient com pliance with anti-viral therapy by providing a reverse tran HO scriptase inhibitor formulated for low dose administration in combination with a second active agent are also included (Elvucitabine) herein. 0010. The anti-viral properties of Elvucitabine have been BACKGROUND described previously in U.S. Pat. Nos. 5,621,120, 5,627, 160, 0003. Hepatitis B virus (HBV) infection is a major health and 5.839,881, and U.S. patent application Ser. No. 10/411, problem throughout the world. HBV is a causative agent of 929, filed Apr. 11, 2004, which are hereby incorporated by both an acute and chronic form of hepatitis. It is estimated reference for their teachings regarding the use of Elvucit that more than 200 million people worldwide are chronic abine for treating viral infections, including HBV and HIV carriers of HBV. infections, and for teachings regarding the chemical synthe 0004 HBV belongs to the family Hepadnaviridae, which sis of Elvucitabine. includes a number of related viruses that primarily infect 0011 Agents useful for treating viral infections, includ small rodents. All members of the hepadnavirus family have ing HBV and HIV infections, are often most effective when a number of characteristics in common Such as morphologi combined with additional anti-viral or immunomodulatory cal appearance, antigenic makeup and DNA size and struc agents. New combinations of anti-viral agents or anti-viral ture. Pathological findings following infection with the and immunomodulatory agents are therefore desirable. Such members of this family are quite similar. Studies show that combinations efficacious when administered at low dosages the replication and spread of the viruses of this family are are particularly desirable. The present invention fulfills this dependent upon the reverse transcriptase of an RNA inter need, and provides further related advantages. mediate. SUMMARY OF THE INVENTION 0005 HBV is a double-stranded DNA virus. Its DNA polymerase catalyzes both DNA-dependent and RNA-de 0012 A pharmaceutical composition comprising Elvucit pendent RNA synthesis. The life cycle of HBV involves the abine and a second active agent, wherein the second active enzyme reverse transcriptase in its DNA replication. agent is an immunomodulatory compound or an antiviral agent or a combination comprising one or more of the 0006 Although acute HBV infections are generally self foregoing active agents, is provided herein. In certain limiting, in many instances the disease can progress to the embodiments second active agent used in combination with chronic state. HBV infection also creates a risk to fulminant Elvucitabine is not interferon, a nucleoside or a nucleoside hepatitis. In addition, Hepatitis B viral infections are closely analog. associated with hepatocellular carcinoma. 0013. It has been discovered that Elvucitabine, a reverse 0007 AIDS is a generally fatal disease caused by a transcriptase inhibitor, is efficacious for treating viral infec human pathogenic retrovirus known as human immunode tions, including HIV and HBV infections, when adminis ficiency virus (HIV), which includes HIV-1 and HIV-2. tered at very low dosages. Elvucitabine is an effective Reverse transcriptase plays an essential role in the elabora anti-viral agent (including anti-HIV efficacy) when as little tion and life cycle of HIV and consequently, the progress of as about 2.5 mg to about 10 mg is administered once a day. the disease. Reverse transcriptase inhibitors are currently For some patients, including patients having an HIV or HBV used with other classes of anti-viral agents to slow and in infection, Elvucitabine may be effective when administered some cases halt the progress of HIV infection. as infrequently as one time per week. Thus pharmaceutical 0008 Reverese transcriptase inhibitors are preferred compositions comprising Elvucitabine and a second active therapeutics for treating certain viral infections, particularly agent, wherein the second active agent is an immunomodu US 2006/0084628A1 Apr. 20, 2006 latory compound or an antiviral agent or a combination and either a non-nucleoside reverse transcriptase inhibitor, comprising one or more of the foregoing active agents are such as efavirenz (SUSTIVA) or a protease inhibitor are provided herein. Dosage forms comprising at least 2.5 mg included herein. Elvucitabine, but less than 70 mg and preferably less than 7 mg Elvucitabine, and a second active agent are provided BRIEF DESCRIPTION OF DRAWINGS herein. 0.019 FIG. 1 illustrates a PK model of Elvucitabine. 0014 Methods of treating viral infections, including HIV and HBV infections, comprising administering about 2.5 mg 0020 FIG. 2 illustrates an example of individual fit using to about 10 mg Elvucitabine per day, or about 5 mg to about Pop PK analysis (IT2S). 20 mg Elvucitabine per 48 hour interval, or about 40 mg to 0021 FIG.
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