WO1995012405A1 - Methode et composition pour le traitement de patients souffrant d'une maladie hepatique decompensee - Google Patents

Methode et composition pour le traitement de patients souffrant d'une maladie hepatique decompensee Download PDF

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Publication number
WO1995012405A1
WO1995012405A1 PCT/US1993/010619 US9310619W WO9512405A1 WO 1995012405 A1 WO1995012405 A1 WO 1995012405A1 US 9310619 W US9310619 W US 9310619W WO 9512405 A1 WO9512405 A1 WO 9512405A1
Authority
WO
WIPO (PCT)
Prior art keywords
hepatitis
patient
patients
virus
composition
Prior art date
Application number
PCT/US1993/010619
Other languages
English (en)
Inventor
Paul B. Chretien
Milton G. Mutchnick
Original Assignee
Alpha 1 Biomedicals, Inc.
The Board Of Governors Of Wayne State University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to DK94901265T priority Critical patent/DK0731710T3/da
Priority to KR1019960702942A priority patent/KR100298859B1/ko
Priority to PCT/US1993/010619 priority patent/WO1995012405A1/fr
Priority to MXPA94003453A priority patent/MXPA94003453A/es
Priority to SG1996006415A priority patent/SG64899A1/en
Priority to US08/313,160 priority patent/US5750501A/en
Priority to CA002175337A priority patent/CA2175337C/fr
Priority to DE69332982T priority patent/DE69332982T2/de
Application filed by Alpha 1 Biomedicals, Inc., The Board Of Governors Of Wayne State University filed Critical Alpha 1 Biomedicals, Inc.
Priority to PT94901265T priority patent/PT731710E/pt
Priority to ES94901265T priority patent/ES2194860T3/es
Priority to EP94901265A priority patent/EP0731710B1/fr
Priority to AU55920/94A priority patent/AU685413B2/en
Priority to JP5279386A priority patent/JPH07188049A/ja
Priority to MYPI94001152A priority patent/MY111342A/en
Publication of WO1995012405A1 publication Critical patent/WO1995012405A1/fr
Priority to NO961775A priority patent/NO961775D0/no
Priority to HK98114128A priority patent/HK1021685A1/xx

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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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the present invention relates to a method and composition for treating patients having hepatic decompensation.
  • Hepatic decompensation is liver failure which can result from chronic or chronic active infection of a patient by Hepatitis B virus.
  • ⁇ -interferon interferon alpha-2b
  • I ⁇ TRO ⁇ ® A interferon alpha-2b
  • Hepatitis B virus D ⁇ A was detectable in the patient's serum prior to transplantation
  • the recurrence of Hepatitis B infection has been virtually universal within one year following transplantation.
  • current medical practice precludes liver transplantation at many transplant centers in patients who have chronic Hepatitis B infection and who are serum positive for Hepatitis B virus DNA.
  • Thymosin a ( n ⁇ a. " )
  • Thymosin a-_ another drug which has been suggested for treatment of Hepatitis B in patients.
  • a method of treating a Hepatitis B patient having hepatic decompensation comprises administering Hepatitis B virus-reducing amounts of T ⁇ to a patient having decompensated liver disease, so as to render said patient serum negative (seronegative) for Hepatitis B virus DNA.
  • the invention further includes a composition for use in treating a Hepatitis B patient having hepatic decompensation, comprising a pharmaceutical dosage unit containing a Hepatitis B virus-reducing amount of ⁇ ot l t which pharmaceutical dosage unit can be administered to Hepatitis B-infected patient having decompensated liver disease, so as to render serum of said patient negative for Hepatitis B virus DNA.
  • Thymosin ⁇ - ! (“To-/ 1 ) can render Hepatitis B patients having decompensated liver disease serum negative for Hepatitis B virus DNA, thereby qualifying such patients for liver transplantation. This is surprising since the only approved drug for treatment of Hepatitis B, a- interferon, is contraindicated for use in patients with decompensated liver disease.
  • Thymosin a- ⁇ encompass not only native (i.e., naturally occurring) Tc ⁇ but also synthetic T ⁇ and recombinant Tot_ having the amino acid sequence of native T ⁇ x , amino acid sequences substantially similar thereto, or an abbreviated sequence from thereof, and their biologically active analogs (including muteins) having substituted, deleted, elongated, replaced, or otherwise modified sequences which possess bioactivity substantially similar to that of T ⁇ x .
  • Hepatitis B virus-reducing amounts of Thymosin are included within the dosage range of 0.4 - 4 mg.
  • Hepatitis B patients having decompensated liver disease are administered Thymosin a. until the patients are serum negative for Hepatitis B virus DNA, i.e., patients who become seronegative for Hepatitis B virus DNA in two consecutive monthly tests .
  • a test for serum Hepatitis B virus DNA can be any suitable test, for example a radioimmunoassay, such as is available from Abbott Laboratories.
  • Thymosin a. is administered by subcutaneous injection twice weekly in pharmaceutical dosage units within the range of about 1 - 4 mg (e.g., about 1.6 mg) .
  • pharmaceutical dosage units containing Thymosin a. may be formulated in any suitable manner for administration by any suitable route. Suitable routes of administration may include, but are not limited to, parenteral (including subcutaneous, intramuscular, intravenous and intradermal) , oral, and transdermal. Particularly preferred embodiments utilize parenteral administration.
  • ⁇ a_ is administered in separate pharmaceutical dosage units.
  • the pharmaceutical dosage units of the present invention include one or more pharmaceutically acceptable carriers and optionally other therapeutic ingredients.
  • the carrier(s) are "acceptable" in the sense of being compatible with the other ingredients of the dosage unit formulation and not deleterious to the recipient thereof.
  • the pharmaceutical dosage unit formulations may be prepared by any suitable methods.
  • Such methods may include the step of separately bringing into association the la. active ingredient with its carrier, which may comprise one or more ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association the T ⁇ ! active ingredient with liquid carriers or finely divided solid carriers or both.
  • Solid dosage unit formulations also may include the step of shaping the product .
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, containing a predetermined amount of the la. active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil- in-water liquid emulsion or a water-in-oil liquid emulsion, etc.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing, in a suitable machine, free-flowing powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent.
  • Molded tablets may be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may optionally contain anti- oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Suitable dosage units of Tot. can be administered to the patient daily, one or more times per day, e.g., two or three times per day, and doses can be administered one or more days per week, e.g., two, three, four, five, six or seven days per week.
  • Example 1 After the patient becomes serum negative for Hepatitis B virus DNA, the decompensated liver of the patient can be removed, and a healthy liver then can be transplanted into the patient.
  • the invention is further illustrated by the following examples, which are not intended to be limiting.
  • Patient 1 is a 48 year old physician who contracted hepatitis B surface antigen (HBsAg) positive hepatitis following a needle stick injury. Approximately 13 years later, liver biopsy showed chronic active hepatitis and cirrhosis. He suffered from significant fatigue. He had ascites and other manifestations of cirrhosis. Liver enzymes were elevated. Standard serologic studies were unusual in that Hepatitis B virus DNA, HBeAg, and HBsAg appeared negative. However, Hepatitis B virus DNA by the more sensitive PCR (polymerase chain reaction) assay was positive, as was Hepatitis B DNA testing of liver tissue obtained at biopsy. He was considered to have a mutant form of Hepatitis B virus infection.
  • HBsAg hepatitis B surface antigen
  • Hepatitis B infection so that he would be eligible for transplant, he was started on Thymosin alpha 1 at a dose of 1.6 mg subcutaneously twice weekly. After approximately 3 months, he reported less fatigue. After roughly 6 months, Hepatitis B DNA PCR was negative. He had a liver transplant and returned to work shortly after his transplant. At his latest clinic visit, he was feeling well without elevations of his aminotransferase enzymes.
  • Patient 2 was a 69 year old man with very far- advanced cirrhosis secondary to long-standing chronic Hepatitis B infection. His findings included jaundice, weakness, severe encephalopathy, hepato-renal syndrome with renal failure, and portal gastropathy secondary to increased portal vein pressure. He received Thymosin alpha 1 at a dose of 1.6 mg subcutaneously twice weekly under a compassionate use protocol in an attempt to cure his Hepatitis B virus infection so that he could received a liver transplant. He tolerated therapy well, and had no side effects, but died from gastric bleeding, renal failure, and encephalopathy after 3 1/2 weeks of therapy. Death was associated with complications of portal hypertension and cirrhosis, and not due to therapy with Thymosin alpha 1.
  • Example 3 Example 3
  • Patient 3 was a 53 year old man with chronic Hepatitis B infection, cirrhosis, and esophageal varices. He also had a hepato a, which recurred after a partial liver resection. Because of the limited amount of remaining normal hepatic tissue, another curative resection was not possible, and the patient's only hope for a cure was a transplant. However, he was not a candidate because of active infection with Hepatitis B.
  • Thymosin alpha 1 He was started on Thymosin alpha 1 at a dose of 1.6 mg subcutaneously twice weekly, with the intention of treating him for 26 weeks. He tolerated therapy well and had no adverse effects. However, his therapy was discontinued after 46 injections because of complications of the cirrhosis. He expired about three weeks after his last injection. His death was attributed to bleeding esophageal varices and hepatoma. His hepatologist did not believe that Thymosin alpha 1 contributed to his death.
  • the above three patients with cirrhosis and hepatic decompensation received Thymosin alpha 1 at a dose of 1.6 mg subcutaneously twice weekly for periods varying from 3.5 weeks to 6 months.
  • the intent of therapy was to cure chronic Hepatitis B virus infection so that the patient could be considered for transplant. None of the patients reported any adverse effects due to Tot. .
  • One of these patients had resolution of Hepatitis B virus infection while receiving Thymosin alpha 1, and later had a successful liver transplant, with no evidence of re ⁇ infection of the transplant by HBV.
  • HBV Hepatitis B virus
  • OHT liver
  • CANDIDACY FOR TRANSPLANTATION will be defined as liver failure evidenced by cirrhosis, and some combination of medical factors, as shown below.
  • Cirrhosis will be diagnosed on biopsy (where practical) or where a biopsy is contraindicated, the diagnosis will be made clinically and confirmed radiographically prothrombin time greater than 16 seconds (normal is 12 seconds) - total bilirubin greater than 2.5 mg% (normal is less than 1 mg%) serum albumin less than 3 mg% (normal is 3.5- 5.5 mg%) ascites unresponsive to medical management - past history of spontaneous bacterial peritonitis liver volume less than 1000 cc (normal is greater than 1400 cc) variceal hemorrhage - hepatic encephalopathy patient is willing and able to abstain from use of alcohol
  • end-stage liver disease qualifying patient for orthotopic liver transplant demonstrated serum HBV DNA by radioimmunoassay (Abbott Laboratories) , documented by 2 determinations at least 1 month apart, with or without elevation of serum transaminase levels, histologic evidence of hepatitis B and cirrhosis (preferably within 6 months) ; a liver biopsy will be performed if the patient presents a platelet count greater than 70,000 and a prothrombin time less than 3 seconds over control .
  • STUDY DESIGN This is a study to examine the role of Thymosin alpha 1 injections in achieving or accelerating the loss of serum HDV-DNA. Primary outcome measures are the proportion of patients losing serum HBV DNA during the study. At the time of entry, all study patients will have detectable levels of serum HBV DNA in a minimum 2 consecutive tests.
  • Simon Before being considered for OLT, each patient will participate in a study using the design described by Simon (Simon R. , "Optimal two-stage designs for Phase II clinical trials," Controlled Clinical Trials 10:1- 10 (1989)) . Simon's design tests the null hypothesis that the success probability has attained an "interesting target” against the alternative that is has attained a “desirable target”. "Success” is defined as a living patient who has lost viral DNA by one (1) year after study entry. The desirable target has been set at 0.30, i.e. a 30% success rate. An appropriate value for the uninteresting target depends upon estimation of the one-year of spontaneous loss of viral DNA in patients not treated with thymosin or another anti-viral agent. PATIENT MONITORING, MANAGEMENT, AND EVALUATION
  • Thymosin alpha 1 injection will be self- administered, twice weekly, by the subcutaneous route (a patient dose of 1.6 mg per injection)
  • Thymosin alpha 1 injection therapy in the clinical protocol will be described.
  • a liver biopsy will be performed if all of the following criteria are met: (a) the patient is not referred to transplant, (b) six (6) months subsequent to termination of thymosin therapy, and (c) if the patient presents a platelet count greater than 70,000 and a prothrombin time less than 3 seconds over control. Liver biopsy tissue will, wherever possible, be frozen in liquid Nitrogen for future analysis of HBV DNA by molecular hybridization assay.
  • HBV DNA by radioimmunoassay (Abbott Laboratories) will be performed at enrollment
  • routing clinical laboratory analyses will be performed at time of entry and every second week for the initial month of treatment, and will be performed monthly for the remainder of the period of therapy and follow-up.
  • TSH FTI serum protein electrophoresis autoimmune markers: ASMA, ANA, AMA hepatitis B serology: sAg/Ab, eAg/Ab, core Ag/Ab
  • CD4+, CD8+, ratio will be determined at time of entry, and at month 6 and month 12; and in the last month of follow-up (month 18)
  • Serum triglycerides and fractional cholesterol will be determined at the time of entry, and at month 12; and in the last month of follow-up. Progression to Liver Transplant

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Communicable Diseases (AREA)
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Abstract

On décrit une méthode pour traiter l'hépatite B chez des patients souffrant de décompensation hépatique. Cette méthode fait appel à une composition contenant des quantités de thymosine α1, que l'on administre à un patient souffrant d'une maladie hépatique décompensée, en une quantité suffisante pour provoquer une décroissance des virus responsables de l'hépatite B telle que le patient devienne séronégatif pour l'ADN viral de l'hépatite B.
PCT/US1993/010619 1993-11-05 1993-11-05 Methode et composition pour le traitement de patients souffrant d'une maladie hepatique decompensee WO1995012405A1 (fr)

Priority Applications (16)

Application Number Priority Date Filing Date Title
PT94901265T PT731710E (pt) 1993-11-05 1993-11-05 Composicoes contendo timosine alpha 1 destinadas ao tratamento de pacientes sofrendo duma doenca de figado descompensado
KR1019960702942A KR100298859B1 (ko) 1993-11-05 1993-11-05 대상부전성간질환을가진환자의치료방법및조성물
ES94901265T ES2194860T3 (es) 1993-11-05 1993-11-05 Composiciones que contienen timosina alfa 1 destinadas al tratamiento de pacientes que sufren una enfermedad hepatica descompensada.
SG1996006415A SG64899A1 (en) 1993-11-05 1993-11-05 Method and composition for treatment of patients having decompsated liver disease
US08/313,160 US5750501A (en) 1993-11-05 1993-11-05 Method and composition for treatment of patients having decompensated liver disease
CA002175337A CA2175337C (fr) 1993-11-05 1993-11-05 Methode et composition pour le traitement de patients souffrant d'une maladie hepatique decompensee
DE69332982T DE69332982T2 (de) 1993-11-05 1993-11-05 Thymosin-alpha-1 enthaltende zusammensetzungen zur behandlung von hepatitis b bei patienten mit dekompensierter lebererkrankung
DK94901265T DK0731710T3 (da) 1993-11-05 1993-11-05 Fremgangsmåde og præparat til behandling af patienter med inkompenseret leversygdom
PCT/US1993/010619 WO1995012405A1 (fr) 1993-11-05 1993-11-05 Methode et composition pour le traitement de patients souffrant d'une maladie hepatique decompensee
MXPA94003453A MXPA94003453A (es) 1993-11-05 1993-11-05 Metodo y composicion para el tratamiento de pacientes con hepatitis b que tienen descompensacion hepatica.
EP94901265A EP0731710B1 (fr) 1993-11-05 1993-11-05 Compositions contenant du thymosine alpha 1 destinees au traitement de patients souffrant d'une maladie hepatique decompensee
AU55920/94A AU685413B2 (en) 1993-11-05 1993-11-05 Method and composition for treatment of patients having decompensated liver disease
JP5279386A JPH07188049A (ja) 1993-11-05 1993-11-09 代謝不全肝疾患の患者の治療のための方法および組成物
MYPI94001152A MY111342A (en) 1993-11-05 1994-05-09 Method and composition for treatment of patients having decompensated liver disease
NO961775A NO961775D0 (no) 1993-11-05 1996-05-02 Fremgangsmåte og sammensetning for behandling av pasienter med dekompensert leversykdom
HK98114128A HK1021685A1 (en) 1993-11-05 1998-12-19 Thymosine alpha 1 containing compositions for the treatment of patients having decompensated liver disease

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PCT/US1993/010619 WO1995012405A1 (fr) 1993-11-05 1993-11-05 Methode et composition pour le traitement de patients souffrant d'une maladie hepatique decompensee
JP5279386A JPH07188049A (ja) 1993-11-05 1993-11-09 代謝不全肝疾患の患者の治療のための方法および組成物

Publications (1)

Publication Number Publication Date
WO1995012405A1 true WO1995012405A1 (fr) 1995-05-11

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PCT/US1993/010619 WO1995012405A1 (fr) 1993-11-05 1993-11-05 Methode et composition pour le traitement de patients souffrant d'une maladie hepatique decompensee

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JP (1) JPH07188049A (fr)
AU (1) AU685413B2 (fr)
WO (1) WO1995012405A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007134908A2 (fr) * 2006-05-19 2007-11-29 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Utilisation de thymosine alpha 1 pour le traitement de maladies immunologiques
CN1840177B (zh) * 2006-01-11 2011-04-06 成都圣诺科技发展有限公司 胸腺肽α1注射液及其制备方法
US8716012B2 (en) 2009-05-08 2014-05-06 Sciclone Pharmaceuticals, Inc. Alpha thymosin peptides as vaccine enhancers

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4079127A (en) * 1976-10-28 1978-03-14 Board Of Regents Of The University Of Texas Thymosin alpha 1

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4079127A (en) * 1976-10-28 1978-03-14 Board Of Regents Of The University Of Texas Thymosin alpha 1

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0731710A4 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1840177B (zh) * 2006-01-11 2011-04-06 成都圣诺科技发展有限公司 胸腺肽α1注射液及其制备方法
WO2007134908A2 (fr) * 2006-05-19 2007-11-29 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Utilisation de thymosine alpha 1 pour le traitement de maladies immunologiques
WO2007134908A3 (fr) * 2006-05-19 2008-04-03 Sigma Tau Ind Farmaceuti Utilisation de thymosine alpha 1 pour le traitement de maladies immunologiques
US8022036B2 (en) 2006-05-19 2011-09-20 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Use of thymosin alpha 1 for the treatment of immunological diseases
AU2007253527B2 (en) * 2006-05-19 2012-04-26 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Use of thymosin alpha 1 for the treatment of immunological diseases
KR101488224B1 (ko) * 2006-05-19 2015-02-04 시그마타우 인두스트리에 파르마슈티케 리우니테 에스.피.에이. 면역학적 질병의 치료를 위한 티모신 알파 1의 용도
US8716012B2 (en) 2009-05-08 2014-05-06 Sciclone Pharmaceuticals, Inc. Alpha thymosin peptides as vaccine enhancers

Also Published As

Publication number Publication date
AU685413B2 (en) 1998-01-22
AU5592094A (en) 1995-05-23
JPH07188049A (ja) 1995-07-25

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