Using polyethylene glycol-interferon-α (peg-ifn-α) and ribavirin for treatment of chronic hepatitis c

FIELD: medicine, hepatology.

SUBSTANCE: invention relates to treatment of chronic hepatitis C. Method involves administration in a patient α2A-interferon modified with polyethylene glycol (PEG)(conjugate PEG-IFN-α2A) in combination with ribavirin. Method provides the prolonged clearance of virus that promotes both activity with respect to cells proliferation and effective treatment of disease.

EFFECT: enhanced effectiveness of preparation.

2 cl, 1 tbl, 1 ex

 

The present invention relates to the treatment of chronic hepatitis C using the effective treatment of hepatitis C the number of conjugate PEG-IFN-α in combination with ribavirin.

Interferons (IFN) are naturally occurring proteins with antiviral, antiproliferative and immunoregulatory activity. It is established that in humans there are four different classes of interferons (Pestka and others, Ann. Rev. Biochem. 56, 727-777 (1987) and Emanuel and Pestka, J. Biol. Chem. 268, 12565-12569 (1993)). The family of IFN-α represents the predominant class of IFN produced by stimulated peripheral blood leukocytes (Pestka and others, in the above-mentioned place; Havell and others, Proc. Natl. Acad. Sci. USA 72, 2185-2187 (1975); Cavalieri and others, Proc. Natl. Acad. Sci. USA 74, 3287-3291 (1977)) and lymphoblastoid and myeloblastosis the cell lines (Familleti and others, Antimicrob. Agents. Chemother. 20, 5-9 (1981). The antiviral action of IFN-α achieved not only due to direct exposure to the virus, but also because of the effect on the target cells, resulting in protection against viral infection. Interferons can have actions on cancer and can affect the immune system, which is expressed, for example, that they activate macrophages and EC cells (natural killer cells) and intensify the expression of various important from the point and the view of the immune system components of the cell membrane. Details on obtaining interferon cDNA and its immediate expression, especially in E. coli, are the subject of numerous publications. For example, the preparation of recombinant interferons described in Nature 295, 503-508 (1982), Nature 284, 326-320 (1980), Nature 290, 20-26 (1981), Nucleic Acids Res. 8, 4057-4074 (1980), and also in EP 32134, EP 43134 and EP 211148.

For the treatment of chronic hepatitis C was proposed joint therapy with IFN-α and ribavirin (EP-A 707855), but such treatment is not always effective.

Thus, joint therapy with the use of conjugates of PEG-IFN-α and ribavirin may be more effective than joint therapy with IFN-α and ribavirin.

It was found that Pegylation of IFN-α leads to increased half-life in blood flow and residence time in the plasma, reduces immunogenicity, reduces the clearance and increases activity in vivo.

Therefore, in the present invention proposed the use of conjugates of PEG-IFN-α in combination with ribavirin for the preparation of drugs intended for the treatment of chronic hepatitis C. in Addition, in the present invention, a method for treatment of chronic hepatitis C in patients in need of such treatment, introducing effective against the situation of treatment of chronic hepatitis C is the number of conjugate PEG-IFN-α in combination with ribavirin.

The term "conjugate PEG-IFN-α" in the context of the present description refers to IFN-αobtained from any natural source (e.g., leukocytes, fibroblasts, lymphocytes) or product, which is its derivative (for example, cell lines), or IFN-α, produced by recombinant DNA. Details of the cloning of IFN-α and direct its expression, especially in E. coli, as described in many publications. The preparation of recombinant IFN-α described, for example, Goeddel, etc., Nature 284, 316-320 (1980) and Nature 290, 20-26 (1981), in EP 32134, 43980 and 211148. There are many types of IFN-αsuch as IFN-αI, IFN-α2; and their subtypes, including IFN-α2A, IFN-α2B, IFN-α2C and IFN-αII (also known as IFN-αII or ω-IFN-α), but are not limited to them. The term "IFN-αalso includes consensus IFN-αsupplied by the firm Amgen, or a mixture of natural and/or recombinant IFN-α. Preferred is the use of IFN-α2A. The production of IFN-α2A described in EP 43980 and EP 211148.

IFN-α kongugiruut with a polymer, such as polyalkyleneglycol (substituted or unsubstituted), for example, polyethylene glycol, getting conjugate PEG-IFN-α. The conjugation can be carried out using various linkers known in this field, in particular with the help of such linkers are described in the published is avkah for the European patent 0510356, 593868 and 809996. The molecular weight of the polymer, preferably polyethylene glycol, may be in the range from 300 to 70000 Yes, with IFN-α may(may) be konjugierte one or more, preferably one to three, the polymer (a). A preferred conjugate is PEG-IFN-α has the formula:

where R and R' denotes methyl, X denotes NH, and n and n' each separately or both equal to 420 or 520.

Ribavirin, ie 1-β--ribofuranosyl-1H-1,2,4-triazole-3-carboxamide described in the Merck Index, 11th edition, as compound No. 8199. Its production and preparation of a formulation based on it are described in the patent US 4211771.

According to the present invention, the conjugate is PEG-IFN-α and ribavirin administered to a patient suffering from a disease of chronic hepatitis C in amounts that in total (combined quantities) are effective to eliminate or at least weaken one or more signs or symptoms of chronic hepatitis C, including elevated alanine aminotransferase (ALT), a positive test for antibodies to HCV (hepatitis C virus), the presence of HCV, confirming a positive test for the presence of HCV RNA, clinical stigma of chronic liver disease and damage to the liver cells.

The dose of conjugate PEG-IFN-α joint therapy for this is in the invention is from about 33 to 540 µg / week regardless of body weight (effective dose) and is injected once or twice a week.

The dose of ribavirin in treating according to the present invention is approximately from 400 to 1200 mg per day (effective dose) for at least five days per week, preferably within seven days per week. If we assume that the weight of the patient is from 40 to 150 kg, the dose range is from 10 to 30 mg/kg of body weight per day. In a more preferred embodiment, the daily dose of ribavirin is 800-1200 mg This daily dose may be given once daily as a single dose or in divided doses twice or three times a day. The preferred mode of daily doses ribavirin is the introduction in divided doses twice a day.

According to the present invention ribavirin is administered to the patient together with the conjugate PEG-IFN-αthis means that the dose of the conjugate PEG-IFN-α introducing the same intervals, in which the patient receives doses of ribavirin, or in different periods of time. In one of the embodiments of the invention at least one daily dose of ribavirin introduced during the same week, when you enter at least one dose of conjugate PEG-IFN-α. In a more preferred embodiment, a large part of ribavirin doses administered during the same week, when you enter one or more doses of conjugate PEG-IFN-α. In another preferred is ariante implementation of all or substantially all of the dose of ribavirin administered for the same week when you enter one or more doses of conjugate PEG-IFN-α. Currently, the composition comprising the conjugate of PEG-IFN-α, are not effective when introduced orally, so the preferred method of introduction of the conjugate PEG-IFN-α is parenteral administration, preferably by subcutaneous (s.c.) or intramuscular (i.m.) the injection. Ribavirin may be administered orally in the form of a capsule or tablet in conjunction with parenteral introduction of conjugate PEG-IFN-α. Of course, can be considered and other routes of administration of both drugs, as soon as they are developed, for example, using a spray for nasal administration, transdermal administration, introduction by suppository, by dosing forms with the continuous release etc. Any form of administration must work within such period of time that the dose could be delivered without destruction of the active substance.

The effectiveness of treatment can be determined in controlled clinical experiments on the application of joint therapy compared with monotherapy and/or co-therapy with IFN-α and ribavirin. The effectiveness of joint therapy for easing the signs and symptoms of chronic hepatitis C and the frequency and severity of side effects is determined by the aligning with the results of previous monotherapy using IFN-α and/or co-therapy with IFN-α and ribavirin. To assess fit three groups of patients suffering from disease chronic hepatitis C. the Study can be conducted on any one or all three patient groups:

1. Patients previously untreated.

2. Patients who previously were treated with IFN-α and/or ribavirin or any other medicine, which later came a relapse.

3. Patients are not susceptible to treatment with IFN-α and/or ribavirin or any other medicine.

The effectiveness of joint therapy is determined by the extent to which weakened the previously described signs and symptoms of chronic hepatitis.

Example

Phase III randomized trial conducted in several centres, research on the effectiveness and safety of combination Targeted interferon-α2A and ribavirin versus REBETRON™ in the treatment of patients suffering from chronic HCV (CHC)

The main purpose of this study was to compare the efficacy and safety of combination PEG-IFN-α2A and ribavirin efficiency REBETRON [intron a + Rebetol (ribavirin, produced by Schering/ICN)] in the treatment of the SNA. Groups consisting of equal numbers of patients (330 patients)was administered for 48 weeks or a combination of PEG-IFN-α2A and RIBA is Wendy Erin, or REBETRON. The third group of patients (165 patients) was administered for 48 weeks PEG-IFN-α2A + placebo. The results obtained for the groups exposed monotherapeutic treatment were used to compare the safety and efficacy of treatment with a combination comprising PEG-IFN-α2A.

Dose of intron a was 4 Mio in 0.5 ml of solution and was injected subcutaneously (s.c.) three times per week (tiw) for 48 weeks.

The dose of PEG-IFN-α2A was 180 µg and it was injected s.c. once a week in combination with ribavirin or placebo for 48 weeks.

The dose of ribavirin and Rebetol was 1000 or 1200 mg per day depending on body weight and it was administered in divided doses. Patients with weight <75 kg (165 pounds), was administered 1000 mg / day (400 mg in the morning and 600 mg in the evening), while patients with weight ≥75 kg, was administered 1200 mg / day (600 mg in the morning and 600 mg in the evening).

The main performance criteria were combined prolonged virological [i.e., the number of HCV RNA not detected using AMPLICOR, RT - PCR analysis (sensitivity ≥100 copies/ml)] and biochemical (normalization of the concentration of ALT in serum) reaction after following the treatment period, when the processing has not been performed. For patients considered to be responders, they must have a normal asset is ity alanine aminotransferase (ALT) in serum after 68 and 72 weeks and they should not be detectable amounts of virus after 72 weeks from the beginning of the experiment.

Safety assessment conducted during the sampling period, at the beginning of the experiment, after 1, 2, 4, 6 and 8 weeks, and then every 4 weeks during the 48-week treatment period. The safety was assessed during the next 24-week period. Safety criteria included side effects, vital signs and lab results, and registration of cases of dose adjustment and premature failure of the treatment in terms of safety or tolerability.

In the group of patients consisted suffering from SNA men and women aged 18 years or above who were not previously treated with any form of IFN-α2A or ribavirin. The group included patients in whom it was possible to quantify the level of HCV RNA and which had a permanent abnormal ALT level and have a liver biopsy within 12 months confirming the presence of the SNA. Patients with other forms of liver disease - anemia, infected with the human immunodeficiency virus (HIV), carcinoma of the liver cells, which previously had been serious depression or other mental illness, heart disease, kidney disease, seizures, or severe retinopathy were excluded from participation in the experiment.

In clinical trials the period of treatment (48 weeks) preceded the sampling period to 35 days (the time from the first is tbore patients prior to the first injection test drug). Patients who met all eligibility criteria were randomly divided into three groups, with different mode of treatment.

Patients in all groups in which the 12 weeks has not been diagnosed with treatment response [defined as a decrease from baseline of their titer HCV RNA by at least one (1) unit decimal logarithm or decrease by at least 50% (or normalization) of their ALT levels in serum compared with the initial level], were considered as eresponder and treatment was stopped. Treatment of patients at 12 weeks satisfy the specified criterion, the reaction was stopped after 24 weeks if they have not had the level of HCV RNA, lower limit of detection (<100 copies/ml), or normal ALT levels. Patients excluded from the treatment group, were examined only from the point of view of safety of the treatment. All patients that met the specified criteria at the 12th and 24th week, were treated for 48 weeks. The main measure of effectiveness was the United viral and biochemical response (HCV RNA < 100 copies/ml and ALT normalization) after following the treatment period (24 weeks), when the processing has not been performed.

Currently known factors prolonged virological response when combined treatment using a combination of online is it And + Rebetol and estimation of the coefficients of prolonged virological response in monotherapy for 48 weeks with the use of PEG-IFN-α 2A (on the basis of the data obtained in phase II clinical trials) and the combination of PEG-IFN-α2A + ribavirin, are summarized in the table below:

1. The use of conjugates of PEG-IFN-α in combination with ribavirin for treatment of chronic hepatitis C, where the conjugate is PEG-IFN-α is a conjugate of PEG-IFN-α2A formula

where R and R' denotes methyl, X denotes NH, and n and n' each separately or both equal to 420 or 520.

2. The method of treatment of chronic hepatitis C, providing for the introduction of conjugate PEG-IFN-α in combination with ribavirin in amounts effective for the treatment of chronic hepatitis C, where the input conjugate PEG-IFN-α represents PEG-IFN-α2A formula

where R and R' denotes methyl, X denotes NH, and n and n' each separately or both equal to 420 or 520.



 

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1 tbl, 3 ex

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1 ex, 1 tbl

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2 cl, 2 tbl, 5 ex

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22 cl, 8 ex

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3 ex, 1 tbl

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EFFECT: improved preparing method, valuable medicinal properties of derivatives.

16 cl, 2 tbl, 14 ex

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