WO1994001125A1 - Composition and method of treating hepatitis b - Google Patents

Composition and method of treating hepatitis b Download PDF

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Publication number
WO1994001125A1
WO1994001125A1 PCT/US1993/006485 US9306485W WO9401125A1 WO 1994001125 A1 WO1994001125 A1 WO 1994001125A1 US 9306485 W US9306485 W US 9306485W WO 9401125 A1 WO9401125 A1 WO 9401125A1
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Prior art keywords
interferon
thymosin
α
immune system
composition
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PCT/US1993/006485
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French (fr)
Inventor
Kenneth E. Sherman
Original Assignee
Sherman Kenneth E
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22Hormones
    • A61K38/2292Thymosin; Related peptides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19Cytokines; Lymphokines; Interferons
    • A61K38/21Interferons [IFN]
    • A61K38/212IFN-alpha

Abstract

Compositions and methods of use for treating hepatitis B virus-infected mammals are disclosed. The compositions include one or more thymosins in combination with one or more interferons. Methods of treatment include use of thymosins together, or sequentially with interferon.

Description

COMPOSITION AND METHOD OF TREATING HEPATITIS B I. GOVERNMENT INTEREST This invention described herein may be manufactured, used and licensed by or for the Government for governmental purposes without the payment to us of any royalties thereon. II. RELATED APPLICATION This application is a continuation-in-part of U.S. Patent Application Serial No. 07/878,372, filed September 13, 1991 which in turn is a continuation-in-part of U.S. Patent Application Serial No. 07/759,544, filed September 13, 1991. III. FIELD OF INVENTION This invention relates generally to the pharmacological treatment of hepatitis B virus infection in patients. IV. DESCRIPTION OF THE RELATED ART Hepatitis B virus (HBV) infection is a serious worldwide problem that affects millions of patients. Consequences of infection include acute liver failure, cirrhosis with chronic liver failure, and an increased risk for the development of primary hepatocellular carcinoma. The incidence of acute HBV infection has been increasing in the United States. Among patients with acute hepatitis B infection, possible outcomes include death, resolution of disease, or development of a chronic infection state. The latter can be characterized histologically as a chronic active hepatitis, chronic persistent hepatitis, or an asymptomatic chronic carrier state. Alternately, the chronic process can be described in terms of molecular events as replicative vs.

non-replicative. Efforts aimed towards hepatitis B treatment have been underway for a number of years. Most interest recently has focused on the use of interferon alpha which has been studied in a number of controlled trials. Greenberg et. al. first reported on the inhibition of viral replication using leukocyte interferon. Several small trials after this demonstrated varying degrees of efficacy, (Lok et. al., 1984; Thomas HC et. al. 1985; Scully et. al., 1985) which was partially accounted for by the demographic characteristics of the population studied. Use of recombinant interferon alpha was first reported in 1983 (Smith et. al.). Recombinant interferon permits better standardization of dose and drug activity than is provided by the mixed interferon products previously utilized. The efficacy of therapy for HBV is measured in various ways depending on the study being examined. The first prospective, randomized, controlled trial utilizing recombinant interferon alpha came from a group at the National Institutes of Health. In this study 45 patients were randomized into three groups in which they were given 5 million units (M.U.) daily for 16 weeks, 10 M.U. q.o.d. for 16 weeks or controls which got no therapy (no placebo drug given). A treatment success was defined as sustained clearance of HBV DNA and DNA polymerase activity. The HBV DNA was measured by a probe hybridization assay. After 16 weeks, 4/16 (25%) of patients getting the 5 M.U. dose daily had negative HBV DNA. At 12 months 5/16 were HBV DNA negative and 3 converted to HBe antigen negative. At the 10 M.U. q.o.d. dosing schedule 6/15 became HBV DNA negative at 16 weeks and 7/16 (46%.7) at 12 months. Among untreated controls 2 (14.3%) cleared HBV DNA at 12 months. Female sex and high ALT correlated with interferon response. In a Chinese study using recombinant alpha interferon 2a Lok et. al. reported that only 8/54 (15%) sustained clearance of HBeAg, suggesting that this group may have lower response rates. It is not clear whether this is related to age of acquisition/duration of infection, presence of interferon antibodies or other factors. The response among whites was reportedly 42% in this study. Lai et. al. used recombinant interferon alpha 2a at a dose of 10 M.U. 3x/week for 12 weeks in HBsAg positive carrier Chinese children, this was compared to a placebo group, conversion of HBe antigen status to negative was rare (1/12) over 18 months in both groups. Other single agent therapies for hepatitis B that have been studied include Ara-A (vidarabine), Ara-AMP, acyclovir, Foscarnet, Levamisole and Thymosin alpha- 1. All these agents have shown some promise in small human and/or animal studies. Thymosin alpha- 1 (TA-1) was evaluated in 5 patients by Mutchnick et. al. (1991). In their study, 12 patients were initially randomized to receive TA-1, thymosin fraction 5 (a crude thymus extract) or placebo. Five patients ultimately received placebo and served as the control group. Four patients initially got thymosin fraction 5 but 2 were switched to TA-1 within 2 weeks because of side effects associated with the relatively impure extract. This switch resulted in 5 patients getting TA-1 for the majority of their treatment cycle. Among the placebo patients, 1/5 (20%) cleared HBV DNA during the study course. A post-hoc combination of the TA-1 and thymosin fraction 5 groups resulted in clearance of DNA in 6/7 patients in this group. This led to a larger, multicenter trial of TA-1 as monotherapy for hepatitis B which is currently underway. It is thus the object of this invention to disclose compositions and methods for the treatment of acute and chronic HBV infections in mammals comprising combination therapy with one or more thymosins and one or more interferons. This and other objects will become apparent by reference to the specification and to the appended claims.

DESCRIPTION OF THE INVENTION

A novel modality for treating HBV infection in mammals has been devised, comprising the administration to such mammals of one or more thymosins at doses which potentiate immune responses, in combination with

anti-viral doses of one or more interferons. By the term "thymosins" is meant any or all of the immune system potentiating polypeptides naturally occurring in the thymus gland or produced by chemical or recombinant means, or fragments derived from any of these polypeptides. By the term "mammals" is meant any mammalian subject, including human and animal patients, requiring treatment for hepatitis B infection. "Mammal" and "subject" are used interchangeably. The instant invention reveals that TA-1 combined with an interferon is better than placebo or better than interferon alone, in the treatment of replicative HBV infection. TA-1 had very high percentage of HBV DNA clearance in a small trial and should be confirmed in large prospective studies. Thymosin levels have been shown to be low in a histologically unclassified group of chronic hepatitis B carriers (Sherman et. al.), suggesting that this could be associated with an underlying immune defect that leads to the chronic carrier state. More specifically, this invention is directed to: 1. A method of treating a mammal infected with hepatitis B virus, comprising administering to said mammal an anti-viral effective amount of at least one interferon, concurrently or sequentially with administering said thymosin or thymosin fragment. 2. A method of Claim 1, wherein said interferon is selected from the group consisting of -, β- and 7- interferons. 3. A method of Claim 2, wherein said αr-interferon is interferon α-2b. 4. A method of Claim 1, wherein the step of administering said interferon comprises administering interferon produced by recombinant DNA technology. 5. A method of Claim 1, wherein said mammal is a human, said interferon is an α-interferon, and the amount of said interferon administered ranges between about one million and about ten million units of said interferon per administration. 6. The method of Claim 1, wherein said mammal is human, said thymosin is thymosin α-1, and said dose is about 1500 to about 1700 μg of said thymosin α-1. 7. A composition comprising a pharmaceutical dosage unit of a pharmaceutically acceptable carrier containing an immune system-potentiating amount of at least one member selected from the group consisting of thymosin and immune system-potentiating fragments of thymosin in combination with an anti-viral effective amount of at least one interferon, said pharmaceutical dosage unit being capable of promoting in vivo inactivation of hepatitis C virus when administered to mammals infected with said virus. 8. A composition of Claim 7, wherein said thymosin is selected from the group consisting of Thymosin Fraction Five and Thymosin α-1. 9. A composition of Claim 7, wherein said interferon is selected from the group consisting of α-, β-, and 7-interferons. 10. A composition of Claim 9, wherein said α-interferon is interferon α-2b. 11. A composition of Claim 10, wherein said interferon is recombinant interferon. 12. The composition of Claim 7, wherein said thymosin is Thymosin Fraction Five, the immune system-potentiating amount is a human immune

system-potentiating amount, and said pharmaceutical dosage unit is from about 900 to about 1200 mg/m2 body surface area of said human. 13. The composition of Claim 7, wherein said interferon is an αinterferon and said amount is between about 1 million and about 3 million units of said interferon. 14. The composition of Claim 7, wherein said thymosin is Thymosin α-1, said immune system-potentiating amount is a human immune system- potentiating amount, and said pharmaceutical dosage unit is from about 900 to about 1200 μg/m2 body surface area of said human. 15. The composition of Claim 7, wherein said thymosin is Thymosin α-1, and said pharmaceutical dosage unit contains about 1500 to about 1700 μg of Thymosin α-1. 16. An anti-hepatitis B formulation comprising an immune system- potentiating amount of at least one thymosin or an immune system-potentiating thymosin fragment in combination with an anti-viral effective amount of at least one interferon in a pharmaceutically acceptable carrier, for use in the

treatment of a mammal infected with hepatitis B virus. 17. The formulation of Claim 16, wherein said thymosin is selected from the group consisting of Thymosin Fraction Five and Thymosin α-1. 18. The formulation of Claim 16, wherein said interferon is selected from the group consisting of α-, β-, and γ-interferons. 19. The formulation of Claim 18, wherein said α-interferon is interferon α-2B. 20. The formulation of Claim 19, wherein said interferon is recombinant interferon. 21. The formulation of Claim 16, wherein said thymosin is Thymosin Fraction Five, said immune system-potentiating amount is a human immune system-potentiating amount, and said amount is from about 900 to about 1200 mg/m2 body surface area of said human. 22. The formulation of Claim 16, wherein said interferon is α- interferon and wherein said anti- viral effective amount is from about 1 million to about 3 million units of said interferon. 23. The formulation of Claim 16, wherein said thymosin is Thymosin α-1, said immune system-potentiating amount is a human immune system- potentiating amount, and said amount is from about 900 to about 1200 μg/m2 body surface area of said human. 24. The formulation of Claim 16, wherein said thymosin is Thuymosin α-1, and wherein said amount is about 1500 to about 1700 μg of Thymosin α- 1. STUDY OBJECTIVES A Phase II/III clinical trial can compare the efficacy of Thymosin alpha-1 plus interferon alfa-2b vs. placebo control group vs. interferon alfa-2b, for the treatment of chronic hepatitis B viral infection is proposed. The study should be a randomized, multicenter trial. Clinical, biochemical, serologic and histologic responses to the treatment arms can then be evaluated.

STUDY DESIGN OVERVIEW Adult patients (>age 18) with chronic hepatitis B should be randomized to one of three study arms. These are: 1) Thymosin alpha-1 1.6 mg SQ on Tuesdays and Fridays combined with recombinant interferon alfa-2b 5 M.U. SQ qd vs; 2) Interferon alfa-2b + Placebo Thymosin alpha-1 in the same dosing schedule as in "1" vs.; 3) Placebo Interferon + Placebo thymosin alpha-1 in the same time schedule as for "1". Treatment should be for 6 months with an additional 6 months follow-up to asses late response to therapy. Thymosin alpha-1 is manufactured by Alpha-1 Biomedicals, Inc. of Foster City, CA. Recombinant interferon alfa-2b is manufactured by Schering-Plough Corp., Kenilworth, N.J. CRITERIA FOR PATIENT SELECTION Adult patients eligible for care in the Department of Defense Medical System (DEERS) should be enrolled if they meet admission criteria and agree to participate. Patients must be a least 18 years old and able to provide informed consent. Both males and females are eligible for enrollment. Chronicity of hepatitis B is defined as presence of HBsAg for a period of a least 6 months prior to randomization. Alanine aminotransferase (ALT) must be elevated on two occasions at least 2 weeks apart in the 6 months prior to randomization. The mean ALT should be a least 1.3x the upper limit of normal for the local laboratory. Patients should have presence of HBV DNA on two occasions at least 1 month apart. HBeAg is not a requirement for entry, though this will be used as a screening tool to help identify potential candidates. A liver biopsy demonstrating features of chronic hepatitis will be required for all patients within 3 months of study randomization. Exclusion criteria include decompensated liver disease as defined by history of ascites, encephalopathy, or bleeding esophageal varices. Also excluded are patients with other forms of liver disease to include Wilson's disease, alpha-1 antitrypsin deficiency, primary biliary cirrhosis, alcoholic liver disease, autoimmune hepatitis, or other forms of viral hepatitis. Patients with HIV infection, confirmed with Western blot are also excluded. Patients with any malignancy other than curatively treated skin cancer or surgically cured in situ carcinoma of the cervix are not eligible. Patients who have serious underlying systemic/organ diseases like severe coronary artery disease, history of CVA or lupus are generally excluded. The Principal Investigator decides eligibility on a case by case basis for patients with potentially severe but stable non-liver associated conditions. Patients should not be pregnant during the course of treatment. Use of antiviral or immunosuppressive medication within 6 months or randomization is a temporary exclusion. Specific lab exclusions include: 1. Hemoglobin < 10 gm 2. Platelet count < 70,000/mm3 3. White blood cell count <3000/mm3 4. Absolute neutrophil count < 1000/mm3 5. Bilirubin > 4 mg/dl 6. Albumin < 3 gm/dl 7. ANA, ASMA, AMA, LKM-1 > 1:40 8. Creatinine < 1.8 AGENT ADMINISTRATION & PATIENT EVALUATION

Patients should be randomized to one of the three treatment arms. Block randomization should be performed utilizing a computer generated random number scheme. This should be performed for each site at a central location by a clinical pharmacist. Group I will receive TA-1 1.6 mg SQ on Monday and Friday + Interferon alfa-2b 5 M.U SQ qd. Group II will receive placebo TA-1 1.6 mg SQ on Mondays and Fridays + interferon alfa -2b 5 M.U. qd SW. Group 111 will receive placebo TA-1 on Mondays and Fridays + placebo interferon alfa-2b SQ qd. Total treatment course for all arms will be 26 weeks. Randomization will occur on the day the patient is scheduled to begin therapy. Patients should be taught to administer drug and keep records during the first week of drug treatment. Follow-up will be performed at 2 week intervals x 2 and then every 1 month thereafter. Responders will be followed for an additional 6 month thereafter. Responders will be followed for an additional 6 months on a monthly basis. Repeat liver biopsy will be performed on all patients between 6 and 12 months after initiation of therapy. The timing of laboratory evaluations on individual patients will be in accordance with medically acceptable practices. EVALUATION OF RESPONSE TO THERAPY Response to therapy is determined by evaluation of a series of parameters. These include Viral Nucleic Acid, Hepatitis B serologic markers of infection, Biochemical response in terms of liver enzymes and Histological improvement. 1. Viral DNA: Evaluation for hepatitis B DNA will be performed using a liquid phase molecular hybridization assay (Abbott Diagnostics, Illinois). Loss of DNA in the serum by this method will define response. 2. Serologic Markers: Markers of hepatitis B infection to be evaluated include HBsAg, HBeAg, anti-HBcIgm, anti MBc total (IgM =IgG). Loss of HBsAg and/or loss of HBeAg is defined as a serologic response. 3. Biochemical: Serum Alanine aminotransferase levels will be evaluated. Response in terms of ALT is defined as normalization of previously abnormal ALT. Partial response is defined as a 50% decrease in the baseline ALT level. 4. Histologic: Paired samples will be graded by a pathologist who is blinded to the treatment arm. Samples will be scored using the Histologic Activity. Index (HAI) as defined by Knodell et. al. Overall response rates will be determined using the following definitions: 1. Complete: Serum HBV DNA negative by the hybridization assay at the completion of therapy, and sustained for an additional 6 months. If HBeAg was positive at the onset of treatment, it must be negative at 12 months. 2. Partial: Persistence of HBeAg throughout treatment and follow-up period with negative HBV DNA. 3. Non-responser: Persistence of HBV DNA at 6 months. 4. Reactivation: Disappearance of HBV DNA at completion of therapy with recurrence by 12 months. Other appropriate laboratory tests to follow the course of treatment are listed in Example 1 below.

Thymosin therapy is preferably used in combination with interferon therapy, thereby combining the immune system potentiating effect of thymosins with the anti-viral effects of the interferons. An improved response rate at the currently used interferon doses would be beneficial, particularly in the light of dose-limiting side effects at higher doses of these proteins. An offshoot of this concept is the ability to achieve comparable efficacy with interferon plus thymosin at lower doses than would be required with interferon alone. Finally, patients unresponsive to thymosin alone or interfer alone may respond to combinations of these two groups of agents. In this combination therapy regimen, one or more interferons (for example, recombinant interferon α-2b, Intron-A, Schering-Plough, Kenilworth, New Jersey) is (are) administered subcutaneously to subjects, e.g., human patients, at doses ranging between about 1 MU and 10 MU along with or sequentially with one or more thymosins, preferably including THNα,, at a dose of about 900 to about 1200 μg/m2 body surface area. Although the example above speaks in terms of recombinant interferon α-2b, other anti-HCV-effective interferons such as α-, β- and 7-interferons, recombinant or naturally occurring, may be advantageously used in this

invention. This combination dose regimen is flexible, and depends on the clinical condition of the subject. Where subjects are refractory to the preferred dosage levels, these may be increased within the limits dictated by undesirable side effects. Typically, injections are made five times per week and continue until an acceptable response by the subject is realized. Tests to determine the effectiveness of the combination therapy may be the same as those described above for the described study objectives. In addition, histological examination of liver biopsy samples may be used as a second major criteria for evaluation. Knodell, R.G., et al., Hepatology. 1:431-5 (1981), whose Histological Activity Index (portal inflammation, piecemeal or bridging necrosis, lobular injury and fibrosis) provides a scoring method for disease activity. The following examples are provided merely to illustrate the invention, and are not to be construed in any way as limiting the scope of invention as set forth in the specification and claims.

EXAMPLE 1 Preparation of Injectable Formulation Pharmaceutical dosage units or 1 ml each are prepared from the ingredients shown in Table 1 below. 1 2 3 4 5

6

7

8 9

Figure imgf000018_0001

10 sodium phosphate dibasic, 11 2 mg/ml solution

12 sodium phosphate monobasic, 13 0.5 mg/ml solution

14 water for injection, U.S.P. 15

Claims

I Claim: A method of treating a mammal infected with hepatitis B virus, comprising administering to said mammal an anti-viral effective amount of at least one interferon, concurrently or sequentially with administering said thymosin or thymosin fragment. 2. A method of Claim 1 , wherein said interferon is selected from the group consisting of α-, β- and 7- interferons. 3. A method of Claim 2, wherein said α-interferon is interferon α-2b. 4. A method of Claim 1, wherein the step of administering said interferon comprises administering interferon produced by recombinant DNA technology. 5. A method of Claim 1, wherein said mammal is a human, said interferon is an α-interferon, and the amount of said interferon administered ranges between about one million and about ten million units of said interferon per administration. 6. The method of Claim 1, wherein said mammal is human, said thymosin is thymosin α-1, and said dose is about 1500 to about 1700 μg of said thymosin α- 1. 7. A composition comprising a pharmaceutical dosage unit of a pharmaceutically acceptable carrier containing an immune system-potentiating amount of at least one member selected from the group consisting of thymosin and immune system-potentiating fragments of thymosin in combination with an anti- viral effective amount of at least one interferon, said pharmaceutical dosage unit being capable of promoting in vivo inactivation of hepatitis C virus
when administered to mammals infected with said virus. 8. A composition of Claim 7, wherein said thymosin is selected from the group consisting of Thymosin Fraction Five and Thymosin α-1. 9. A composition of Claim 7, wherein said interferon is selected from the group consisting of α-, β~, and 7-interferons. 10. A composition of Claim 9, wherein said α-interferon is interferon α-2b. 11. A composition of Claim 10, wherein said interferon is recombinant interferon. 12. The composition of Claim 7, wherein said thymosin is Thymosin Fraction Five, the immune system-potentiating amount is a human immune system-potentiating amount, and said pharmaceutical dosage unit is from about 900 to about 1200 mg/m2 body surface area of said human. 13. The composition of Claim 7, wherein said interferon is an αinterferon and said amount is between about 1 million and about 3 million units of said interferon. 14. The composition of Claim 7, wherein said thymosin is Thymosin α-1, said immune system-potentiating amount is a human immune system- potentiating amount, and said pharmaceutical dosage unit is from about 900 to about 1200 μg/m2 body surface area of said human. 15. The composition of Claim 7, wherein said thymosin is Thymosin α-1, and said pharmaceutical dosage unit contains about 1500 to about 1700 μg of Thymosin α-1. 16. An anti-hepatitis B formulation comprising an immune system- potentiating amount of at least one thymosin or an immune system-potentiating thymosin fragment in combination with an anti-viral effective amount of at least one interferon in a pharmaceutically acceptable carrier, for use in the treatment of a mammal infected with hepatitis B virus. 17. The formulation of Claim 16, wherein said thymosin is selected from the group consisting of Thymosin Fraction Five and Thymosin α-1. 18. The formulation of Claim 16, wherein said interferon is selected from the group consisting of α-, β-, and 7-interferons. 19. The formulation of Claim 18, wherein said α-interferon is interferon α-2B. 20. The formulation of Claim 19, wherein said interferon is recombinant interferon. 21. The forumlation of Claim 16, wherein said thymosin is Thymosin Fraction Five, said immune system-potentiating amount is a human immune system-potentiating amount, and said amount is from about 900 to about 1200 mg/m2 body surface area of said human.
PCT/US1993/006485 1992-07-13 1993-07-09 Composition and method of treating hepatitis b WO1994001125A1 (en)

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Cited By (10)

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EP0731710A1 (en) * 1993-11-05 1996-09-18 Alpha 1 Biomedicals, Inc. Method and composition for treatment of patients having decompensated liver disease
WO1998046256A1 (en) * 1997-04-16 1998-10-22 Sciclone Pharmaceuticals, Inc. Treatment of hepatitis b infection with thymosin alpha 1 and famciclovir
US6199073B1 (en) 1997-04-21 2001-03-06 Ricoh Company, Ltd. Automatic archiving of documents during their transfer between a peripheral device and a processing device
US6200952B1 (en) 1993-06-02 2001-03-13 Sciclone Pharmaceuticals, Inc. Combination therapy method for treating chronic hepatitis B
US6288033B1 (en) 1998-09-25 2001-09-11 Sciclone Pharmaceuticals, Inc. Treatment of hepatitis B infection with thymosin alpha 1 in combination with lamivudine or in combination with lamivudine and famciclovir
US8466159B2 (en) 2011-10-21 2013-06-18 Abbvie Inc. Methods for treating HCV
US8492386B2 (en) 2011-10-21 2013-07-23 Abbvie Inc. Methods for treating HCV
US8716012B2 (en) 2009-05-08 2014-05-06 Sciclone Pharmaceuticals, Inc. Alpha thymosin peptides as vaccine enhancers
US8809265B2 (en) 2011-10-21 2014-08-19 Abbvie Inc. Methods for treating HCV
US8853176B2 (en) 2011-10-21 2014-10-07 Abbvie Inc. Methods for treating HCV

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CN103494769B (en) * 2013-10-08 2015-12-23 深圳翰宇药业股份有限公司 A COMPOUND situ gel depot injection preparation and a method of treating chronic hepatitis B

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6495521B2 (en) 1993-06-02 2002-12-17 Sciclone Pharmaceuticals, Inc. Combination therapy method for treating chronic hepatitis B
US6200952B1 (en) 1993-06-02 2001-03-13 Sciclone Pharmaceuticals, Inc. Combination therapy method for treating chronic hepatitis B
EP0731710A1 (en) * 1993-11-05 1996-09-18 Alpha 1 Biomedicals, Inc. Method and composition for treatment of patients having decompensated liver disease
EP0731710A4 (en) * 1993-11-05 1999-12-22 Alpha 1 Biomedicals Inc Method and composition for treatment of patients having decompensated liver disease
US5939423A (en) * 1997-04-16 1999-08-17 Sciclone Pharmaceuticals, Inc. Treatment of hepatitis B infection with thymosin alpha 1 and famciclovir
WO1998046256A1 (en) * 1997-04-16 1998-10-22 Sciclone Pharmaceuticals, Inc. Treatment of hepatitis b infection with thymosin alpha 1 and famciclovir
US6199073B1 (en) 1997-04-21 2001-03-06 Ricoh Company, Ltd. Automatic archiving of documents during their transfer between a peripheral device and a processing device
US6288033B1 (en) 1998-09-25 2001-09-11 Sciclone Pharmaceuticals, Inc. Treatment of hepatitis B infection with thymosin alpha 1 in combination with lamivudine or in combination with lamivudine and famciclovir
US8716012B2 (en) 2009-05-08 2014-05-06 Sciclone Pharmaceuticals, Inc. Alpha thymosin peptides as vaccine enhancers
US8492386B2 (en) 2011-10-21 2013-07-23 Abbvie Inc. Methods for treating HCV
US8680106B2 (en) 2011-10-21 2014-03-25 AbbVic Inc. Methods for treating HCV
US8685984B2 (en) 2011-10-21 2014-04-01 Abbvie Inc. Methods for treating HCV
US8466159B2 (en) 2011-10-21 2013-06-18 Abbvie Inc. Methods for treating HCV
US8809265B2 (en) 2011-10-21 2014-08-19 Abbvie Inc. Methods for treating HCV
US8853176B2 (en) 2011-10-21 2014-10-07 Abbvie Inc. Methods for treating HCV
US8969357B2 (en) 2011-10-21 2015-03-03 Abbvie Inc. Methods for treating HCV
US8993578B2 (en) 2011-10-21 2015-03-31 Abbvie Inc. Methods for treating HCV
US9452194B2 (en) 2011-10-21 2016-09-27 Abbvie Inc. Methods for treating HCV

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CN1087829A (en) 1994-06-15 application

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