WO2004056374A1

WO2004056374A1 - Use of glycyrrhizin for the treatment of standard therapy-resistant hepatitis c patients

Info

Publication number: WO2004056374A1
Application number: PCT/EP2003/014825
Authority: WO
Inventors: Kyozo Utsunomiya
Original assignee: Hpc Healthcare & Pharma Consulting Ag; Minophagen Pharmaceutical Co. Ltd.
Priority date: 2002-12-23
Filing date: 2003-12-23
Publication date: 2004-07-08
Also published as: AU2003300550A1; WO2004056374A8

Abstract

The invention relates to the use of glycyrrhizin and metabolites thereof for the treatment of standard therapy resistant Hepatitis C virus infections.

Description

Use of glycyrrhizin for the treatment of standard therapy-resistant Hepatitis C patients

Description

In Japan, glycyrrhizin extracted from the roots of the plant Glycyrrhiza glabra has been used for the treatment of chronic hepatitis for more than 20 years. Glycyrrhizin is a conjugate of a molecule of glycyrrhetinic acid and two molecules of glucuronic acid. Arase et al. (Cancer 79 (1997), 1494 - 1500) reported that in Japanese patients with chronic Hepatitis C, long-term treatment with two to seven times per week i.v. glycyrrhizin prevents the development of hepatocellular carcinoma when ALT normalized. The ALT lowering effect of glycyrrhizin was confirmed in European patients by van Rossum et al. (Am. J. Gastroenterol. 96 (2001 ), 2432 - 2437). The patients treated by van Rossum et al. were non- responders or persons unlikely to respond to interferon therapy. The treatment of patients which cannot be treated with current standard combination therapies, i.e. with IFN-σ and ribavirin, is neither disclosed nor suggested.

It has been demonstrated that after i.v. injection, glycyrrhizin is secreted into the bile and hydrolysed in the bowel by bacteria to become metabolized and reabsorbed into the systemic circulation.

Surprisingly it was found that glycyrrhizin and metabolites thereof, e.g. de- gluceronic acid, are effective in patients with Hepatitis C virus infections, particularly chronic or cirrhotic Hepatitis C infections, who cannot be treated with current standard therapies for the treatment of HCV infections. The term "standard therapy" particularly relates to a standard therapy with IFN-α and ribavirin and optionally amantadine, more particularly a standard therapy with IFN-α and ribavirin and amantadine for a sufficient period of time, preferably for at least 3 months. The results presented in the present application show that therapy with glycyrrhizin is effective for a group of Hepatitis C patients which are very difficult to treat and for which a previous therapy had not existed.

Treatment with IFN-α includes treatment with any form of IFN-α, e.g. PEGylated IFN-α, non-PEGylated IFN- , consensus IFN and others.

A first patient group which is subject to treatment with glycyrrhizin according to the present invention comprises patients who do not respond to a standard therapy. A non-response is preferably defined as a positive serum HCV-RNA and abnormal ALT values with an ALT value greater than 1 .5 ULN (Upper Limit of Normal as defined according to the respective method of determination) after standard therapy for at least 3 months.

A second patient group comprises patients who suffer from inacceptable side-effects in standard therapy. Such side effects include severe influenza-like symptoms, hematologic abnormalities, and neuro-psychiatric symptoms, and may lead to discontinuation of treatment in 20% of subjects.

A third patient group comprises patients who developed resistance to standard therapy.

A fourth patient group comprises patient who refuse standard therapy, particularly IFN-α treatment and/or patients who are precluded from standard therapy e.g. due to neuro-psychiatric problems, particularly depression. The present invention opens a new therapeutic potential for patients for which currently no therapy is available and thus represents a significant step in the field of HCV therapy.

Glycyrrhizin or metabolites thereof may be administered by known methods, e.g. by parenteral, oral, transdermal, rectal, nasal or pulmonal administration. Preferably, glycyrrhizin or metabolites thereof are administered by injection, e.g. intravenous, intramuscular or subcutaneous injection. Intravenous injection is particularly preferred. The daily dose is usually in a range of from 40 to 400 mg, preferably of from 80 to 240 mg for an adult human patient. Glycyrrhizin is administered for a time period of preferably at least 12 weeks, more preferably at least 24 weeks.

More preferably, glycyrrhizin is provided as an ampoule for injection containing a dosage of about 20 to about 100 mg of glycyrrhizin, e.g. the drug Stronger Neo-Minophagen C (SNMC, Minophagen Pharmaceutical, Tokyo, Japan). SNMC has a content of 2 mg glycyrrhizin, 1 mg of cysteine and 20 mg of glycine per ml in saline.

Response to glycyrrhizin therapy is preferably determined by reduction of ALT values, as indicated in the Example.

The invention is further explained by the following example.

Example

Data gathered in a clinical trial show a reduction of alanine transferase (ALT) values after 26 weeks of treatment with glycyrrhizin (daily dosage 100 ml SNMC) in 7 out of 8 patients who had not responded to prior standard treatment with IFN-α (IFN) and/or ribavirin (RIB) and/or amantadine.

In the following table the data are shown. 8 patients were non-responders to a standard therapy as indicated and received 26 weeks of treatment with SNMC. In 7 of the patients (patients 1 , 2, 3, 5, 6, 7 and 8) ALT levels decreased significantly. The ALT level remained constant in only 1 patient (patient 4).

Table I

Treatment With SNMC Of Hepatitis C Patients Not Responding To Standard Therapy

Patient Non-Responder to ALT Baseline ALT End of SNMC

Number Standard Therapv Treatment

1 Yes; IFN/RIB/Amantadine 140U/L 45 U/L

Yes; IFN/IFN/RIB/Amantadine 213U/L 155U/L

Yes; IFN/RIB/Amantadine 172U/L 49U/L

Yes; IFN/RIB/Amantadine 109U/L 117U/L

Yes; IFN 146U/L 42U/L

Yes; IFN/RIB 241 U/L 128U/L

Yes; IFN 209U/L 126 U/L

Yes; IFN/RIB 443U/L , 53 U/L

Claims

Clalms

1 . Use of glycyrrhizin or metabolites thereof for the manufacture of an agent for the treatment of a Hepatitis C patient who cannot be treated with a standard therapy with IFN-α and ribavirin and optionally amantadine.

2. The use of claim 1 for the treatment of a patient who does not respond to standard therapy.

3. The use of claim 1 for the treatment of a patient who suffers from side effects in standard therapy.

4. The use of claim 1 for the treatment of a patient who developed resistance for standard therapy.

5. The use of claim 1 for the treatment of a patient who refuses standard therapy and/or who is precluded from standard therapy.

6. The use of any one of claims 1 - 5 for the treatment of a patient with a chronic Hepatitis C virus infection.

7. The use of any one of claims 1 - 6 for the treatment of patients with a cirrhotic Hepatitus C virus infection.

8. The use of any one of claims 1 - 7 wherein the agent is for paranteral, oral, transdermal, rectal, nasal or pulmonal administration.

9. The use of claim 8 wherein the agent is for intravenous, intramuscular or subcutaneous injection.

0. The use of any one of claims 1 - 9 wherein the daily dose is in the range of from 40 to 400 mg.