WO1995011688A1 - Method for treating hepatitis b carriers with minimal disease - Google Patents

Method for treating hepatitis b carriers with minimal disease Download PDF

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Publication number
WO1995011688A1
WO1995011688A1 PCT/US1993/010343 US9310343W WO9511688A1 WO 1995011688 A1 WO1995011688 A1 WO 1995011688A1 US 9310343 W US9310343 W US 9310343W WO 9511688 A1 WO9511688 A1 WO 9511688A1
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WIPO (PCT)
Prior art keywords
thymosin
hepatitis
peptide
disease
serum
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PCT/US1993/010343
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English (en)
French (fr)
Inventor
Bruce F. Scharschmidt
John D. Baxter
David L. Horwitz
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Sciclone Pharmaceuticals
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.)
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Publication date
Priority to US07/833,468 priority Critical patent/US5308833A/en
Priority claimed from US07/833,468 external-priority patent/US5308833A/en
Application filed by Sciclone Pharmaceuticals filed Critical Sciclone Pharmaceuticals
Priority to EP93925097A priority patent/EP0728010A4/en
Priority to AU54542/94A priority patent/AU703480B2/en
Priority to KR1019960702207A priority patent/KR960705578A/ko
Publication of WO1995011688A1 publication Critical patent/WO1995011688A1/en
Priority to NO961685A priority patent/NO961685L/no

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    • 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

Definitions

  • This invention relates to treatment of disease resulting from infection with the hepatitis B virus ("HBV"). More particularly, this invention relates to treating minimal disease hepatitis B carriers using thymosin ⁇ -1, or using a biologically active fragment or analog of thymosin or-1.
  • HBV hepatitis B virus
  • HBV hepatitis B virus
  • the hepatitis B virus is a DNA virus. HBV is known to be transmissible through blood transfusions, contaminated hypodermic needles, and sexual contact, and from mother to child (vertical transmission). A large number of people are infected by unknown means.
  • a description of the hepatitis B virus and its modes of transmission, and of disease states associated with HBV infection, can be found in, e.g. , J.H. Hoofnagle (1990), New England Jour. Med. , Vol. 323, pp. 337-39; J.H. Hoofnagle (1990a), Vaccine, Vol.
  • hepatitis B virus Various clinically distinguishable disease states can be exhibited in persons infected with the hepatitis B virus, including chronic hepatitis and minimal disease hepatitis. About 50 % of persons infected with HBV show chronic inflammatory changes in the liver and, of those, about 50 % have histopathologic changes (termed "chronic active hepatitis") that can lead to fibrosis and ultimately to cirrhosis and progressive liver failure.
  • Carriers of HBV who do not have chronic inflammatory changes in the liver may develop chronic active hepatitis; and liver cancer develops in about 10 % to 30 % of persons infected with HBV. It has been estimated that approximately 4 million carriers of hepatitis B virus die each year from liver cancer or cirrhosis.
  • Patients having severe chronic active hepatitis are only a small percentage of the total population whose liver biopsy specimen is interpreted as showing chronic active hepatitis.
  • hepatitis B carriers manifest a "minimal disease" state, sometimes referred to as "asymptomatic" hepatitis.
  • a minimal disease carrier is a person who has detectable hepatitis B antigens or viral DNA in the serum, and yet has no clinically evident signs or symptoms of liver damage, or has, at most, only relatively slight clinically evident signs or symptoms of liver damage.
  • Minimal disease carriers may develop chronic active hepatitis, which can lead to cirrhosis with liver failure, as described above. Clinical progression is slower in asymptomatic hepatitis, and the factor or factors that contribute to development of active disease in patients initially presenting as minimal disease carriers are not at present known.
  • Thymosin ⁇ -1 is a 28 amino acid peptide. This peptide, originally isolated from calf thymus thymosin fraction 5, is one of several polypeptides present in thymosin fraction 5 which participate in the regulation, differentiation and function of thymic dependent lymphocytes (T-cells). The isolation, characterization and use of thymosin ⁇ -1 is described in, for example, U.S. Patent No. 4,079,127.
  • Thymosin ⁇ -1 has been shown to trigger maturational events in lymphocytes, to augment T-cell function, and to promote reconstitution of immune defects (T.L.K. Low et al. (1984), Thymus, Vol. 6, pp. 27-42). Thymosin has also been shown to cause increases in lymphocyte counts and enhance production of ⁇ -interferon in individuals suffering from chronic active hepatitis B (M.G. Mutchnick et al. (1991), Hepatology, Vol. 14, pp. 409-15).
  • M.G. Mutchnick et al. (1991) also describes the use of thymosin ⁇ -1 in treatment of chronic active hepatitis B, that is, in patients with evidence of liver injury on biopsy. Patients administered the peptide cleared hepatitis B virus DNA from serum and tested persistently negative for serum HBV DNA after treatment was terminated. No asymptomatic carriers without histopathological evidence of liver injury were included in this study.
  • thymosin ⁇ -1 and biologically active fragments and analogs of thymosin ⁇ -1, can be used to treat minimal disease hepatitis B infection. That is, administration of an appropriate amount of thymosin ⁇ -1 to a patient having minimal disease hepatitis B can result in a decrease in the patient in a parameter characteristic of minimal disease hepatitis B infection.
  • This invention provides a treatment of minimal disease hepatitis B infections.
  • this invention provides for use of thymosin ⁇ -1 (and of biologically active analogs and fragments of thymosin ⁇ -1) in compositions for treatment of minimal disease hepatitis B, that is for use in treatment of persons who may test seropositive for HBsAg and/or may test positive for HBV DNA in the serum, but who are asymptomatic and show no biochemical or histopathologic evidence of liver disease (or show only mild biochemical or histopathologic evidence of liver disease).
  • Treatment of such minimal disease carriers of hepatitis B virus can result in elimination of HBV from the subject, as evidenced by loss of HBV DNA from the serum, and can thereby render the subject no longer at risk of developing active hepatitis or liver cancer or of transmitting HBV to others.
  • the invention features treating minimal disease hepatitis B infection in a subject by administering to the subject a therapeutically effective amount of a composition that includes at least one peptide selected from the group consisting of thymosin ⁇ -1, a biologically active fragment of thymosin ⁇ -1, and a biologically active analog of thymosin ⁇ -1, in a pharmaceutically acceptable vehicle.
  • the peptide is thymosin ⁇ -1 and the composition is administered subcutaneously.
  • minimal disease hepatitis B is meant the disease state present in a carrier of hepatitis B, the carrier being identified as having hepatitis B serum antigens or as having HBV DNA in the serum, but having normal or slightly elevated serum enzyme levels, and no or only slight biochemical or histopathological evidence of liver disease.
  • the minimal disease state is readily understood and identifiable by a skilled practitioner.
  • Thimosin ⁇ -1 refers to the 28-mer described below, with or without the N-acetyl group, and is meant to include biologically active fragments of this sequence and biologically active analogs of the sequence (i.e. , deletion, substitution and addition mutants), which are substantially homologous to the peptide sequence shown below.
  • a peptide that is "substantially homologous" to thymosin ⁇ -1 is one in which at least about 30%, preferably at least about 85% to 90%, and most preferably at least about 95%, of the amino acids match over a defined length of the molecule, with the sequence depicted below.
  • a "biologically active" fragment or analog of thymosin ⁇ -1 is a fragment or analog of thymosin ⁇ -1 which retains a significant amount of the activity of the native molecule, . e. , which is capable of decreasing serum HBV DNA and/or hepatitis B surface antigen, as described further below.
  • treatment refers to either (i) the prevention of infection or reinfection (prophylaxis), or (ii) the reduction or elimination of indicators of minimal disease hepatitis B (therapy).
  • a “therapeutically effective amount” of thymosin ⁇ -1 is an amount of the peptide which has the capability of changing the measurable parameters of hepatitis infection. Since the patients included in the minimal disease category have normal liver enzyme biochemistry, the parameters that will normally be monitored are serum hepatitis B envelope antigen (HBeAg) and serum viral DNA (HBV DNA). Response is defined as a significant decrease of either of these parameters. An amount of peptide which has the ability of eliciting a response is considered a "therapeutically effective amount.” HBV DNA can be monitored using the spot hybridization assay described in M.G. Mutchnick et al. (1991), Hepatology, Vol. 14, pp. 409- 15, and in H.M. Lieberman et al.
  • HBV DNA in the blood can be measured using standard PCR technology. See, e.g. , U.S. Patent Nos. 4,683,202 and 4,683,194, incorporated herein by reference in their entirety. Serum HBeAg levels can be monitored using, for example, standard RIAs, as described in M.G. Mutchnick, M.G. et al. (1991), Hepatology, Vol. 14, pp. 409-15, or by standard ELISAs.
  • Thymosin ⁇ -1 is one of several peptides present in thymosin fraction 5 from the thymus gland.
  • the native molecule is a 28-mer, having the following amino acid sequence: Ac-Ser-Asp- Ala-Ala- Val-Asp-Thr-Ser-Ser-Glu- Ile-Thr-Thr-Lys-Asp-Leu-Lys-Glu-Lys-Lys-Glu-
  • Thymosin ⁇ -1 as well as fragments and analogs thereof, are easily synthesized using standard methods of peptide synthesis, known to those of skill in the art.
  • U.S. Patent Nos. 4,148,788 and 4,844,407 described the solution phase and solid phase synthesis, respectively, of thymosin ⁇ -1, and are incorporated herein by reference in their entirety. See also, J.D. Young, Solid Phase Peptide Synthesis, 2d ed. (Pierce Chemical Company 1984); and G. Barany et al. , The Peptides: Analysis, Synthesis, Biology, Vol. 2 (E. Gross and J.
  • Thymosin ⁇ -1 can also be isolated directly from appropriate tissue expressing thymosin ⁇ -1, using techniques readily known in the art. This is generally accomplished by first preparing a crude tissue extract which lacks cellular components and several extraneous proteins. The thymosin ⁇ -1 can then be further purified by, for example, column chromatography, HPLC, immunadsorbent techniques or other conventional methods well known in the art.
  • U.S. Patent No. 4,079,127 discloses a method for purifying thymosin ⁇ -1 from calf thymus and is incorporated herein by reference in its entirety.
  • thymosin ⁇ -1 and fragments or analogs thereof may be produced recombinantly using methods well known to those of skill in the art. See, e.g. , Sambrook, Fritsch & Maniatis, Molecular Cloning: A Laboratory Manual, 2d ed. (Cold Spring Harbor Laboratory Press 1989); and M.J. Gait, ed. (1984), Oligonucleotide Synthesis.
  • Thymosin ⁇ -1 can be administered to subjects diagnosed or suspected of having minimal disease hepatitis B infection.
  • the thymosin ⁇ -1 may be administered alone or in mixed with pharmaceutically acceptable vehicle or excipient.
  • the thymosin ⁇ -1 compositions are prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection may also be prepared.
  • the preparation may also be emulsified or the active ingredient encapsulated in liposome vehicles.
  • the active ingredient is often mixed with vehicles containing excipients which are pharmaceutically acceptable and compatible with the active ingredient.
  • Suitable vehicles are, for example, water, saline, dextrose, glycerol, ethanol, or the like, and combinations thereof.
  • the vehicle may contain minor amounts of auxiliary substances such as wetting or emulsifying agents or pH buffering agents.
  • auxiliary substances such as wetting or emulsifying agents or pH buffering agents.
  • composition or formulation to be administered will, in any event, contain a quantity of the peptide adequate to reduce or eliminate HBV DNA and/or HBsAg from the serum of the subject being treated.
  • injectable compositions are preferably administered by the subcutaneous route; intramuscular injection or intravenous injection can also be acceptable.
  • Injectable formulations will contain an effective amount of the active ingredient in a vehicle, the exact amount being readily determined by one skilled in the art.
  • the active ingredient may typically range from about 1 % to about 95 % (w/w) of the composition, or even higher or lower if appropriate.
  • the quantity to be administered can depend on such factors as the age, weight and degree of health of the subject to be treated.
  • an amount between about 600 and about 3000 ⁇ g of thymosin ⁇ -1 per square meter of body area will be administered; amounts between about 400 and about 3200 ⁇ g or between about 600 and about 1500 ⁇ g or between about 900 and about 1200 ⁇ g per square meter of body area may be effective.
  • Other effective dosages can be readily established by one of ordinary skill in the art through routine trials establishing dose response curves.
  • Additional formulations which are suitable for other modes of administration include suppositories and, in some cases, aerosol, intranasal, oral formulations, and sustained release formulations.
  • the vehicle composition will include traditional binders and carriers, such as, poly alkaline glycols, or triglycerides.
  • Such suppositories may be formed from mixtures containing the active ingredient in the range from about 0.5 % to about 10 % (w/w), and preferably from about 1 % to about 2 % .
  • Oral vehicles include such normally employed excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium, stearate, sodium saccharin cellulose, magnesium carbonate, and the like. These oral compositions may be taken in the form of solutions, suspension, tablets, pills, capsules, sustained release formulations, or powders, and contain from about 10 % to about 95 % of the active ingredient, preferably about 25 % to about 70 %.
  • Intranasal formulations will usually include vehicles that neither cause irritation to the nasal mucosa nor significantly disturb ciliary function.
  • Diluents such as water, aqueous saline or other known substances can be employed with the subject invention.
  • the nasal formulations may also contain preservatives such as, but not limited to, chlorobutanol and benzalkonium chloride.
  • a surfactant may be present to enhance abso ⁇ tion of the subject proteins by the nasal mucosa.
  • Controlled or sustained release formulations are made by incorporating the peptide into carriers or vehicles such as liposomes, nonresorbable impermeable polymers such as ethylenevinyl acetate copolymers and Hytrel ® copolymers, swellable polymers such as hydrogels, or resorbable polymers such as collagen and certain polyacids or polyesters such as those used to make resorbable sutures.
  • carriers or vehicles such as liposomes, nonresorbable impermeable polymers such as ethylenevinyl acetate copolymers and Hytrel ® copolymers, swellable polymers such as hydrogels, or resorbable polymers such as collagen and certain polyacids or polyesters such as those used to make resorbable sutures.
  • the peptides can also be presented using implanted mini-pumps, well known in the art.
  • the peptides may be formulated into compositions in either neutral or salt forms.
  • Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the active peptides) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed from free carboxyl groups may also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.
  • thymosin ⁇ -1 is administered from one to several times weekly for several weeks to several months. More preferably, the compositions are given one to seven times weekly, most preferably twice weekly, for at least about three to about twelve months or longer, most preferably for at least about six months.
  • the compositions can be given more frequently in earlier weeks and then less frequently in subsequent weeks (as, for example, daily for two weeks and then biweekly thereafter).
  • the progress of treatment can be monitored by measuring the presence of HBV DNA and/or HBeAg, as described above.
  • Example 1 This Example provides an illustrative protocol that can be used in a clinical trial of the efficacy of thymosin ⁇ -1 or any biologically active analog or fragment of thymosin ⁇ -1 in treatment of minimal disease hepatitis B.
  • the trial employs 33 patients in each of three groups. Criteria for selecting subjects for the trial
  • Candidates for inclusion in the trial are males and females between 18 and 64 years old at the time the trial is initiated; subjects are selected for inclusion using criteria designed to maximize safety and to ensure that a relationship can be established between the subjects' disease states and the treatment regimes.
  • HBsAg hepatitis B surface antigen
  • ALT serum alanine aminotransferase
  • Included subjects have a hematocrit ⁇ 30 % , platelet count > 80 x 10 9 /L, white blood cell count > 3 x 10 9 /!., and polymorphonuclear white cell count ⁇ 1.5 x 10 9 /L. Renal function is at least reasonably good as demonstrated by serum creatinine ⁇ 180 ⁇ mol/L. Prothrombin time is less than 5 seconds over control, serum albumin ⁇ 30 g/L, and bilinibin ⁇ 68 ⁇ mol/L; included subjects have no history of hepatic encephalopathy or bleeding esophageal varices. Liver biopsy of included subjects shows either "minimal change disease" or "chronic persistent hepatitis".
  • Candidates are excluded from the trial if they have any of several indications.
  • a candidate is excluded if he or she has any progressive decrease in serum HBV DNA level prior to initiation of the study, as indicated by a most recently determined serum HBV DNA level less than 50 % of the level from the preceding determination. Such a candidate may be included if, upon a further determination at least one month later, the serum HBV DNA level has stabilized.
  • a candidate is excluded if he or she has been treated using interferon or any other type of immunotherapy within one year prior to initiation of the study, or has been treated using adrenocorticoid steroids within six months prior to initiation of the study.
  • a candidate is excluded if there is evidence suggesting toxic hepatitis, alcoholic liver disease, Wilson's disease, primary biliary cirrhosis, hepatitis C, or presence of antibody to either of hepatitis C virus ("HCV"), hepatitis delta, hemochromatosis, or autoimmune hepatitis; or if he or she has HTV infection diagnosed by HTV seropositivity and confirmed by Western blot; or if she or he has concomitant or prior history of malignancy other than curatively treated skin cancer or surgically cured in situ carcinoma of the cervix; or if he or she has any active infectious process other than HBV that is not of a self-limiting nature, such as for example tuberculo
  • a candidate is excluded if he or she has any history of intravenous drug abuse within the 5 years prior to initiation of the trial; or if he or she is concomitantly using any drug known to be hepatotoxic.
  • a candidate is excluded if she is pregnant as documented by urine pregnancy test, and included female subjects must agree to practice birth control for the duration of the study.
  • a candidate is excluded if she of he is a poor medical or psychiatric risk, or has any non-malignant systemic disease that, in the opinion of the investigator, would make it unlikely that the candidate could complete the protocol or if, in the opinion of the investigator, there is any indication that the candidate would not comply with the conditions of the protocol.
  • Subjects preferably are recruited for the trial by screening a large population of candidates according to a scheme such as the following.
  • candidates are identified as suitable for treatment according to the invention by a pattern of criteria for minimal disease hepatitis B.
  • a preferred screening protocol includes first and second screening visits between four weeks and two months apart and, for cases where the criteria for inclusion are not clearly met in the first two visits, a third screening visit between four weeks and two months after the second visit.
  • a candidate for treatment meets the criteria set out above.
  • serum ALT for qualification of subjects preferably the level of serum ALT was no greater than 2.0 times the upper limit of normal at each of the first and second screening visits; or, alternatively, the mean of the serum ALT at the three screening visits was no greater than 2.0 times the upper limit of normal.
  • the determination must be positive on each of the first two screening visits; if the second visit HBV DNA level is less than 50 % the first visit level, then the level upon a third determination must be at least 50 % of the first in order for the candidate to be included.
  • Liver biopsy preferably is evaluated according to the so-called Knodell scale, described in Knodell et al. (1981), Hepatology, Vol. 4, no. 5, pp. 434 et seq.
  • the total Knodell score ("HAT or "histology activity index") for the majority of trial subjects having minimal disease hepatitis B as defined above will be ⁇ 4, more probably ⁇ 3 or ⁇ 2.
  • Candidates having HAI 4 or greater may not be properly classified as having minimal disease hepatitis B, as that expression is meant herein.
  • Treatment For the trial each subject will be assigned to one of three groups. Group 1 subjects receive Thymosin ⁇ -1 over a six months' treatment period, followed by six months of observation.
  • Group 2 subjects receive Thymosin ⁇ -1 over a twelve months' treatment period, followed by six months of observation.
  • Group 3 subjects are untreated, and will be observed for twelve months. Following the observation period, the HBV DNA status of Group 3 subjects is determined, and subjects that are still HBV DNA positive are randomly assigned to a six months' or twelve months' treatment period. That is, after the first twelve months' observation period Group 3 subjects are reassigned to one of three groups.
  • Group 3 A subjects (HBV DNA negative at twelve months) receive no treatment.
  • Group 3B subjects receive Thymosin ⁇ -1 over a six months' treatment period, followed by six months of observation.
  • Group 3B subjects receive Thymosin ⁇ -1 over a twelve months' treatment period, followed by six months of observation.
  • the subjects' liver function and hepatitis B markers are measured monthly during treatment periods, and each three months during observation periods.
  • each subject will have a liver biopsy at the end of the treatment period.
  • Thymosin ⁇ -1 will be administered by subcutaneous injection twice weekly at 1.6 mg per injection for all treated patients.
  • a range of 1.45 mg to 1.75 mg per injection can be expected to be safe and effective.
  • Virological response The principal measure of efficacy in the preferred trial is the subject's virologic response. Three indicia of virologic response may be used, namely:
  • the subjects' responses may be classified as:
  • Non-responder Reduction of serum HBV DNA of less than 50 % at the end of the trial;
  • Histological response the subject is classified according to histological response as a responder if there is improvement of at least 25 %, according to the method of and using the HAI index of Knodell et al. , in the histological grading of liver biopsy specimen, and loss of replicative HBV DNA forms or loss of hepatitis B core antigen in liver tissue on final biopsy; or as a non-responder if there is no significant improvement or worsening of the histological score.
  • Example 2 This example illustrates an alternative form of trial.
  • Candidates for inclusion in the trial have been hepatitis B surface antigen ("HBsAg") seropositive for at least 6 months prior to treatment, and have HBV DNA (as measured by PCR or any other standard DNA detection method) in the serum for at least 3 months prior to treatment.
  • HBV DNA as measured by PCR or any other standard DNA detection method
  • HCV hepatitis C virus
  • a pregnancy test for women of child bearing age Selected patients are randomized into two groups. Group 1 patients will receive thymosin ⁇ -1 treatment, and group 2 patients will receive a placebo. Group 1 patients are given thymosin ⁇ -1 at a dosage of 1600 ⁇ g/injection by the subcutaneous route twice weekly for 6 months. Group 2 patients receive placebo injections under the same regimen. All patients are seen at 2 and at 4 weeks from the start of the treatment, and thereafter at monthly intervals during the 6 month treatment period. The patients are monitored monthly for 6 months to two years after completion of treatment. Response to treatment is defined by loss of serum HBV DNA or serum HbeAg.
  • a responder is a patient is one in whom a decreased level of serum HBV DNA or of HBeAg is achieved and sustained during the 12 month study.
  • a nonresponder is one in whom no changes in either serum HBV DNA or HBsAg are shown at the conclusion of the study (12 months). Relapse status is given to patients who initially lose HBV DNA in their serum but regain the DNA by the conclusion of the study.
  • Group means are compared by Student's two-tailed t test. Changes in measurement between the inclusion values and subsequent time points are compared by Student's two-tailed paired t test or the Wilcoxon paired sample test. Patients are monitored for any significant side effects or allergic manifestations resulting from the treatment.
  • Example 3 For treatment of minimal disease hepatitis B, the sera of members of the population to be treated will be tested for presence of HBsAg and/or HBV DNA. Those who are seropositive for HBV infection may be further examined as appropriate, to determine both that treatment will not pose an unacceptably high risk of iatrogenic harm and that they are in fact minimal disease hepatitis B carriers. Liver biopsy may or may not constitute a part of the further examination; and further blood chemistry (such as analysis for ALT or other enzymes) may or may not constitute a part of the further examination. Diagnosed minimal disease hepatitis B carriers will then be treated according to the invention, using a dosage amount and dosage regime appropriate for the particular patient and for the particular Thymosin ⁇ -1 or analog or fragment that is being used.

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PCT/US1993/010343 1992-02-06 1993-10-28 Method for treating hepatitis b carriers with minimal disease WO1995011688A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
US07/833,468 US5308833A (en) 1992-02-06 1992-02-06 Method for treating hepatitis B carriers with minimal disease
EP93925097A EP0728010A4 (en) 1992-02-06 1993-10-28 METHOD FOR TREATING HEPATITIS B CARRIERS WITH A MINOR DISEASE
AU54542/94A AU703480B2 (en) 1992-02-06 1993-10-28 Method for treating hepatitis B carriers with minimal disease
KR1019960702207A KR960705578A (ko) 1992-02-06 1993-10-28 경증 질환을 가진 b형 간염 보균자의 치료방법(method for treating hepatitis b carriers with minimal disease)
NO961685A NO961685L (no) 1992-02-06 1996-04-26 Fremgangsmåte for behandling av hepatitt-B-bærere med minimal sykdom

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US07/833,468 US5308833A (en) 1992-02-06 1992-02-06 Method for treating hepatitis B carriers with minimal disease

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WO1995011688A1 true WO1995011688A1 (en) 1995-05-04

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TW (1) TW249755B (enrdf_load_stackoverflow)
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0731710A4 (en) * 1993-11-05 1999-12-22 Alpha 1 Biomedicals Inc METHOD AND COMPOSITION FOR THE TREATMENT OF PATIENTS WITH DECOMPENSATED HEPATIC DISEASE

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

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW224053B (enrdf_load_stackoverflow) * 1991-09-13 1994-05-21 Paul B Chretien
US5308833A (en) * 1992-02-06 1994-05-03 Sciclone Pharmaceuticals Method for treating hepatitis B carriers with minimal disease

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 EP0728010A4 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0731710A4 (en) * 1993-11-05 1999-12-22 Alpha 1 Biomedicals Inc METHOD AND COMPOSITION FOR THE TREATMENT OF PATIENTS WITH DECOMPENSATED HEPATIC DISEASE

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NO961685D0 (no) 1996-04-26
TW249755B (enrdf_load_stackoverflow) 1995-06-21
EP0728010A1 (en) 1996-08-28
NO961685L (no) 1996-04-26
SG64892A1 (en) 1999-05-25

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