Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
  • A61K38/2292—Thymosin; Related peptides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/19—Cytokines; Lymphokines; Interferons
  • A61K38/21—Interferons [IFN]
  • A61K38/212—IFN-alpha

Definitions

• 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.
• 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.
• Thymosin alpha- 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.
• 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.
• a novel modality for treating HBV infection in mammals comprising the administration to such mammals of one or more thymosins at doses which potentiate immune responses, in combination with
• thymosins 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.
• mammals 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 -, ⁇ - and 7- interferons. 3.
• a method of Claim 2 wherein said ⁇ r-interferon is interferon ⁇ -2b. 4.
• a method of Claim 1, wherein the step of administering said interferon comprises administering interferon produced by recombinant DNA technology.
• said mammal is a human, said interferon is an ⁇ -interferon, and the amount of said interferon administered ranges between about one million and about ten million units of said interferon per administration.
• 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.
• said thymosin is selected from the group consisting of Thymosin Fraction Five and Thymosin ⁇ -1.
• said interferon is selected from the group consisting of ⁇ -, ⁇ -, and 7-interferons. 10.
• a composition of Claim 9, wherein said ⁇ -interferon is interferon ⁇ -2b.
• a composition of Claim 10 wherein said interferon is recombinant interferon.
• the composition of Claim 7, wherein said thymosin is Thymosin Fraction Five, the immune system-potentiating amount is a human immune
• 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
• 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.
• liver disease 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.
• 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.
• 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.
• 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.
• patients unresponsive to thymosin alone or interfer alone may respond to combinations of these two groups of agents.
• one or more interferons for example, recombinant interferon ⁇ -2b, Intron-A, Schering-Plough, Kenilworth, New Jersey
• interferons for example, recombinant interferon ⁇ -2b, Intron-A, Schering-Plough, Kenilworth, New Jersey
• subjects e.g., human patients
• doses ranging between about 1 MU and 10 MU along with or sequentially with one or more thymosins, preferably including THN ⁇ , at a dose of about 900 to about 1200 ⁇ g/m 2 body surface area.
• 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.
• Histological Activity Index portal inflammation, piecemeal or bridging necrosis, lobular injury and fibrosis

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• 1993
  • 1993-07-09 WO PCT/US1993/006485 patent/WO1994001125A1/en not_active Ceased
  • 1993-07-09 AU AU46711/93A patent/AU4671193A/en not_active Abandoned
  • 1993-07-09 EP EP93917072A patent/EP0627930A4/de not_active Withdrawn
  • 1993-07-13 MX MX9304209A patent/MX9304209A/es active IP Right Grant
  • 1993-07-13 CN CN93116777A patent/CN1087829A/zh active Pending
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