MXPA00011198A - Combination therapy comprising ribavirin and interferon alpha in antiviral treatment naive patients having g chronic hepatitis c infection - Google Patents
Combination therapy comprising ribavirin and interferon alpha in antiviral treatment naive patients having g chronic hepatitis c infectionInfo
- Publication number
- MXPA00011198A MXPA00011198A MXPA/A/2000/011198A MXPA00011198A MXPA00011198A MX PA00011198 A MXPA00011198 A MX PA00011198A MX PA00011198 A MXPA00011198 A MX PA00011198A MX PA00011198 A MXPA00011198 A MX PA00011198A
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- Prior art keywords
- weeks
- interferon
- hcv
- patients
- alpha
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Abstract
Use of ribavirin and interferon alpha to prepare pharmaceutical compositions for treating antiviral treatment naive patient having chronic hepatitis C infection to eradicate detectable HCV-RNA involving a combination therapy using a therapeutically effective amount of ribavirin and a therapeutically effective amount of interferon alpha for a time period of from 20 up to 50 weeks are disclosed.
Description
COMBINATION THERAPY THAT COMPRISES RIBAVIRINA E
ALPHA INTERFERENCE IN PATIENTS WHO HAVE NOT RECEIVED
ANTIVIRAL TREATMENT WHO HAVE INFECTION FOR HEPATITIS C
CHRONICLE
BACKGROUND OF THE INVENTION
The present invention relates to the uses of pbavinna and interferon alfa to prepare pharmaceutical compositions for the treatment of a patient who has not received antiviral treatment having chronic hepatitis C infection to eradicate detectable HCV RNA involving a combination therapy using a therapeutically effective amount of nbavirin and a therapeutically effective amount of interferon alpha for a period of about 20 to 50 weeks. Viral infection with chronic hepatitis C is a particularly insidious and slowly progressive viral disease that has a significant impact on the quality of life May eventually cause cirrhosis of the liver, decompensated liver disease and / or hepatocellular carcinoma
Interferon alfa monotherapy is commonly used to treat chronic hepatitis C infections. However, this treatment is not always effective and sometimes intolerable side effects related to dosing and duration of therapy occur. Nbavipna has been proposed as a treatment monotherapy for hepatitis infection
Chronic C (Thomas et al AASLD Abstracts, Hepatology Volume 20, number 4, part 2, number 440, 1994) However, it has been found that this monotherapy treatment is not effective Combination therapy of interferon alfa and pbavipna has been proposed in (Lai, et al Symposium to the 9th Biennial Scientific Meeting Asia Pacific Association for the Study of the Liver 1994), (Symposium for the 9th Biennial Scientific Conference of the Asian Pacific Association for the Study of the Liver, 1994), Treatment of combination with interferon alfa-2b and pbavipna to treat chronic hepatitis C in patients who have not achieved a sustained response to interferon alone (Swedish expepence J Hepatology, 1995,232 (Suppl 2) 17-21 Brouver JT, Nevens F, Michielsen P, et al, What options are left when hepatitis C does not respond to interferon? Placebo-controlled multicentre retreatment tpal on pbavipn monotherapy versus combination with interferon (What options are left when Does hepatitis C not respond to interferon? The placebo-controlled retreatment trial of the Benelux muiticentro on monotherapy of ribavinna against the combination with interferon, J Hepatol 1994,212 (Suppl 1) S17 Abstract WP2 / 08, Chemello L, Cavalletto L, BeARNrdinello E, et al, Response to pbavirin, to interferon and to a combination of both m patients with chronic hepatitis C and its relation to HCV genotypes (Response to nbavipna, to the interferon and to the combination of both in patients with chronic hepatitis C and their relationship with HCV J genotypes Hepatol 1994,212 (Suppl 1) S12 Abstract GS5 / 29, and The effect of interferon alpha and ribavipn combination therapy in naive patients with
chronic hepatitis C, (The effect of combination therapy of interferon alfa and nbavipna in patients who have not received treatment with chronic hepatitis C, J Hepatol 1995,23 (Suppl 2) 8-12 Reichard et al LANCET 1998,351, 83 -87, describe that more patients with chronic hepatitis C have a sustained virological response with a combination of interferon alfa-2b and nbavirin for 24 weeks than those who receive only interferon alfa-2b Reichard et al also describe that interferon alfa-2b alone It is sufficient to achieve a sustained response in those patients with serum HCV RNA values above 3 million copies / ml However, no one has described methods that use alpha interferon and pbavipna that can eradicate HCV RNA in any way long term, that are effective for patients who have not received antiviral treatment who have a specific infection by HCV genotype There is a definite need for a method patients who have not received antiviral treatment who have chronic hepatitis C infection with a combination of alpha interferon and pbavipna who eradicated HCV RNA in an effective manner, and in the long term
BRIEF DESCRIPTION OF THE INVENTION
The invention encompasses better uses of pbavipna and interferon alfa to prepare pharmaceutical compositions for treating a patient who has not received antiviral treatment who has chronic hepatitis C infection for
eradicate detectable HCV RNA involving combination therapy using a therapeutically effective amount of nbavipna and a therapeutically effective amount of interferon alpha for a period of about 20 to 50 weeks It has been found that if the patient who has not received antiviral treatment has an HCV genotype 1 infection, or if the patient who has not received antiviral treatment has an HCV genotype 1 infection, and a viral load greater than 2 million copies per ml of HCV RNA by quantitative PCR, then the administration The combination therapy is carried out for a period of 40-50 weeks, preferably 48 weeks. It has also been discovered that if the patient who has not received antiviral treatment has an HCV genotype 2 or 3 infection, then the administration of the therapy The combination is carried out over a period of 20-30 weeks, preferably 24 weeks. This invention involves the use of nbavipna for the manufacture of pharmaceutical compositions for treating a patient who has not received antiviral treatment having chronic hepatitis C infection to eradicate the detectable HCV RNA by a method comprising administering an effective amount of pbavipna in association with an effective amount of interferon alpha for a period of 20 to 50 weeks, and, wherein the patient who has not received antiviral treatment has an HCV genotype 2 or 3 infection, the administration of pbavirma in association with
interferon alfa is carried out for a period of 20-30 weeks, and, where the patient who has not received antiviral treatment has an HCV genotype 1 infection, the administration of pbavipna in association with interferon alfa is carried out for a period of 40 days. -50 weeks preferably 48 weeks The present invention involves the use of interferon alfa for the manufacture of a pharmaceutical composition for treating a patient who has not received antiviral treatment having chronic hepatitis C infection to eradicate HCV RNA by a method comprising administering an effective amount of alpha interferon alpha in association with an effective amount of pbavipna over a period of 20 to 50 weeks, and wherein the patient who has not received antiviral treatment has an HCV genotype 1 infection. The administration of pbavipna in association with interferon alfa is carried out for a period of 40-50 weeks, preferably 48 weeks and wherein the patient who has not received antiviral treatment has an HCV genotype 2 or 3 infection, the administration of pbavipna in association with interferon alfa is carried out for a period of 20-30 weeks, preferably 24 weeks. The present invention involves the use of both pbavipna and interferon alfa for the manufacture of pharmaceutical compositions to treat a patient who has not received antiviral treatment having chronic hepatitis C infection, to eradicate the detectable HCV RNA by a method comprising administering an effective amount of nbavipna in
association with an effective amount of alpha interferon for a period of 20 to 50 weeks, and wherein the patient who has not received antiviral treatment has an HCV genotype 1 infection and the administration of pbavipna in association with interferon alpha is carried out during a period of 40-50 weeks, preferably 48 weeks, and wherein the patient who has not received antiviral treatment having an HCV genotype 2 or 3 infection, administration of pbavipna in association with interferon alpha is carried out for a period of 20 days. -30 weeks preferably of 24 weeks The present invention involves the use of nbavipna for the manufacture of a pharmaceutical composition for treating a patient who has not received antiviral treatment having chronic hepatitis C genotypol infection to eradicate detectable HCV RNA by a method comprising administering an effective amount of pbavinna in association with an effective amount of alpha interferon for a period of 40-50 weeks, preferably 48 weeks The present invention also involves the use of interferon alfa for the manufacture of a pharmaceutical composition for treating a patient who has not received antiviral treatment having chronic hepatitis C genotype 1 infection to eradicate the detectable HCV RNA by a method comprising administering an effective amount of interferon alpha in association with an effective amount of pbavirin over a period of 40-50 weeks, preferably 48 weeks.
A preferred aspect of the present invention further encompasses the use of both nbavipna and interferon alfa for the manufacture of pharmaceutical compositions for treating a patient who has not received antiviral treatment having a chronic hepatitis C genotype 1 infection to eradicate HCV RNA. -1 by means of a method comprising administering an effective amount of pbavipna in association with an effective amount of interferon alpha for a period of 40-50 weeks, preferably 48 weeks. Therefore, another preferred aspect of the present invention also encompasses the use of both pbavipna and interferon alfa for the manufacture of pharmaceutical compositions for treating a patient who has not received antiviral treatment who has chronic hepatitis C genotype 1 infection, and a viral load greater than 2 million copies per milliliter of RNA of HCV-1 as HCV RNA is measured by quantitative PCR to eradicate RNA from HCV detectable by means of a method comprising administering an effective amount of pbavipna in association with an effective amount of interferon alpha over a period of 40-50 weeks, preferably 48 weeks. Another preferred aspect of the present invention further involves the use of pbavipna for the manufacture of a pharmaceutical composition for treating a patient who has not received antiviral treatment having chronic hepatitis C genotype 2 or 3 infection to eradicate the detectable HCV RNA by means of a method comprising administering
an effective amount of pbavipna in association with an effective amount of interferon alpha over a period of 20-30 weeks, preferably 24 weeks. The present invention also involves the use of interferon alfa for the manufacture of a pharmaceutical composition for treating a patient who does not has received antiviral treatment having genotype 2 or 3 infection of chronic hepatitis C to eradicate the detectable HCV RNA by means of a method comprising administering an effective amount of interferon alpha in association with an effective amount of pbavipna over a period of 20 hours. -30 weeks, preferably 24 weeks. The present invention further involves the use of both nbavipna and interferon alfa for the manufacture of pharmaceutical compositions to treat a patient who has not received antiviral treatment who has chronic hepatitis C genotype 2 or 3 infection to eradicate HCV RNA detectable by means of a method comprising administering an effective amount of pbavipna in association with an effective amount of interferon alpha over a period of 20-30 weeks, preferably 24 weeks. The alpha interferon administered is preferably selected from interferon alfa-2a, interferon alfa- 2b, a consensus interferon, a purified product of interferon alpha or a pegylated alpha-2a interferon or alpha-interferon-2b pegylated Most preferably, alpha interferon is selected from interferon alfa-2a, interferon alfa-2b, or a purified product of interferon
alpha and the amount of interferon alpha administered is 2 to 10 million IU per week on a weekly basis, TIW, QOD or target In a preferred embodiment, the interferon alpha administered is interferon-alpha-2b and the amount of interferon alpha is administered with 3 million Ul TIW AlteARNtively, interferon alpha administered is consensus interferon and the amount of interferon alpha administered is 1 to 20 micrograms per week on a weekly basis, TIW, QOD or target In another modality, the alpha interferon administered is an interferon pegylated alpha-2b and the amount of pegylated interferon alfa-2b administered is 0 to 2 0 micrograms / kilogram per week on a weekly, TIW, QOD or daily AlteARNtive basis, the alpha interferon administered is a pegylated interferon alfa-2a and the amount of pegylated interferon alfa-2a is around 20 to 250 micrograms / kilograms per week on weekly basis TIW, QOD or target The use of interferon alfa-2a or pegylated interferon alfa-2a or interferon alfa-2b or pegylated interferon alfa-2b is preferred. During the periods of 20-30 weeks and 40-50 weeks, the amount of pbavipna administered is 800 to 1200 mg per day, preferably 800, 1000 to 1200 mg per day, and the amount of interferon alfa-2a or interferon alfa-2b administered is around 2 to 10 million IU per week on a daily basis, weekly or TIW, QOD, most preferably 3 million Ul TIW
DETAILED DESCRIPTION OF THE INVENTION
Surprisingly, it has been found that in the case of patients who have not received antiviral treatment who have chronic hepatitis C infection and who have HCV genotype 1, or said patients who have not received treatment having HCV genotype 1 and a viral load greater than 2 million copies per milliliter of HCV RNA detected by quantitative PCR ("PCR"), combination therapy with a therapeutically effective amount of pbavipna and a therapeutically effective amount of interferon alpha for at least one period 20 to 30 weeks results in 10 times more in patients who have non-detectable HCV RNA in serum at least 24 weeks after the end of therapy, compared to monotherapy using only interferon alfa When combination therapy is extended to a period of 40 to 50 weeks, 2 or 3 times more patients have HCV RNA not detectable in serum at least 24 weeks after the end of the t era of combination compared to those treated with the combination therapy for 24 weeks and 8 to 9 times more patients having HCV RNA not detectable in serum at least 24 weeks after the termination of the combination therapy compared with those treated with alpha interferon monotherapy for 48 weeks See Tables 6, 14, 16 & 17, the sustained virological response rate found after using the combination therapy of the present invention depends on the HCV genotype and
of baseline viral load as measured by HCV / qPCR RNA as well as the treatment period of combination therapy for HCV genotype 1 See tables 13 and 15 The treatment period of combination therapy for Patients who have not received antiviral treatment who have HCV genotype 4, 5 and 6 infections are the same as patients who have not received aptiviral treatment and patients who have not received treatment who have chronic HCV genotype 1 The treatment period of combination therapy for patients who have not received antiviral treatment who have genotype 2 and / or 3 HCV is more reduced, mainly 20 to 30 weeks, preferably 24 weeks See tables 7, 13 &15 The term "interferon" "alpha" used herein refers to the protein family of highly homologous specific species that inhibit viral rep- ression and cell proliferation and modulate the immune response. The typical alpha interferons suitable include, but are not limited to, recombinant interferon alfa-2b such as the interferon Intro-A marketed by Schering Corporation, Kenilworth, NJ, the recombinant interferon alfa-2b, for example the interferon Roferon marketed by Hoffmann La Roche, Nutley, NJ, recombinant alpha-2C mterferon such as interferon alfa 2 Berofor marketed by Boehpnger Ingelheim Pharmaceutical, Ine, Ridgefield, CT, interferon alfa-n1, a purified mixture of natural alpha interferon such as Sumiferon, marketed by Sumitomo, Japan or as interferon alfa-n1 Wellferon (INS) marketed by Glaxo-Wellcome Ltd,
London, Great Britain, or a consensus alpha interferon such as that described in U.S. Patent Nos. 4,897,471 and 4,695,623 (especially Examples 7, 8 or 9 thereof) and the specific product marketed by Amgen, Ine, Newbury Park, CA, or interferon alfa-n3, a mixture of natural alpha interferons made by Interferon Sciences and marketed by Purdue Fredenck Co, Norwalk, CT under the trademark Alferon. The use of interferon alpha-2a or alpha 2b is preferred. alpha 2b, among all the interferons, has the widest approval worldwide for the treatment of chronic hepatitis C infection, it is the most preferred. The preparation of interferon alfa 2b has been described in the United States patent No 4, 530,901 Interferon alpha administered is selected from interferon alfa-2a, interferon alfa-2b, a consensus interferon, a purified product of interferon alfa or a pegylated interferon alfa-2a or pegylated interferon alfa-2b The therapeutically effective amount of interferon alfa -2a, interferon alfa-2b, or a purified interferon alfa administered in association with pbavipna is 2 to 10 million IU per week on a weekly basis, TIW, QOD or target The therapeutically effective amount of interferon-alpha-2b administered is 3 million Ul TIW When interferon alfa is administered in association with pbavipna it is consensus interferon, the therapeutically effective amount of
Interferon alfa administered is from 1 to 20 micrograms per week on a weekly basis, TIW, QOD or target The term "pegylated interferon alpha" as used herein means conjugates of interferon alpha, preferably interferon a? fa-2a and -2b , modified with polyethylene glycol The preferred polyethylene glycol-interferon alpha-2b conjugate is PEG12000-interferon alpha 2b The phrases "alpha-interferon conjugated with polyethylene glycol of molecular weight 12000" and "PEG12000-IFN alpha" used herein refer to conjugates such as that prepared according to the methods of the international application No. WO 95/13090 and containing urethane linkages between the interferon alpha-2a or -2b and polyethylene glycol groups with an average molecular weight of 12,000 pegylated interferon alpha, PEG12000- alpha 2b-interferon is available from the Schering Plow Research Institute, Kenilworth, NJ The preferred PEGi2ooo-αterferon alfa-2b is prepared by attaching a PEG polymer to the amino group epsilon. of a lysine residue in the IFN alpha-2b molecule A single molecule of PEG12000 is conjugated to the free amino groups of an IFN alpha-2b molecule by means of a urethane linkage. This conjugate is characterized by the molecular weight of the Fixed PEG12000 The PEG12000-IFN alpha-2b conjugate is formulated in the form of lyophilized powder for injection. The aim of the conjugation of IFN alpha with PEG is to improve the administration of the protein by significantly prolonging its plasma half-life and thus , produce a prolonged activity of IFN alpha
Other alpha-interferon conjugates can be prepared by coupling an interferon-alpha to a water-soluble polymer. A non-limiting list of such polymers include other polyalkylene oxide homopolymers such as polypropylene glycols, polyoxyethylenated polyols, copolymers thereof, and bulk codends. As an alterative to polymers based on polyalkylene oxide, non-antigenic materials such as dextran, polyvinylpyrrolidones, polyacrylamides, polyhydric alcohols based on carbohydrates and the like can be used. Such interferon alpha-polymer conjugates have been used. described in United States Patent No. 4,766,106, the patent of the United States
U.S. No. 4,917,888, European Patent Application No. 0 236 987, European Patent Applications Nos. 0510 356, 0 593 868 and 0 809 996
(pegylated interferon alfa-2a) and inte-national publication No WO 95/13090
Pegylated interferon alpha pharmaceutical compositions suitable for parenteral administration can be formulated with a suitable Ph-regulator, for example Tps-HCl, acetate or phosphate, for example Ph-regulator of sodium phosphate dibasic / sodium phosphate monobasic and pharmaceutically excipients acceptable (for example, sucrose), vehicles (for example, human plasma albumin), toxicity agent (for example NaCl), preservatives (for example NaCl), preservatives (for example thimerosal, cresol or beni co alcohol) and surfactants (for example example tween or po sorbates) in sterile water for injection Pegylated interferon alpha can be stored in the form of
powders ofilized with refrigeration at 2o - 8 ° C Reconstituted aqueous solutions are stable in storage at 2 ° to 8 ° C and used within 24 hours of reconstitution See, for example, US Pat. Nos. 4,492,537, 5,762,923 and 5,766,582 The reconstituted aqueous solutions can also be stored in syringes previously loaded with multiple doses such as those used for the administration of drugs such as insulin. Typical suitable syringes include provisions that comprise a pre-loaded bottle attached to a syringe similar to that of a syringe. plunger such as NOVELET Novo Pen marketed by Novo Nordisk, as well as recharged plunger syringes that allow for easy self-injection by the user. Other dispositions of syringes include a plunger syringe comprising a glass cartridge containing a diluent and powder. pegylated interferon alpha in a separate compartment When interferon alfa administered in association with pbavipna is a pegylated interferon alfa-2b and the amount of interferon alfa administered is 0 to 2 0 micrograms / kilogram per week on a weekly basis, TIW, QOD or target. When interferon alfa is administered in association with ribavipna it is a pegylated interferon alfa-2a and the amount of interferon alpha administered is 20 to 250 micrograms / kilogram per week on a weekly basis, TIW, QOD or target.
Ribavipna, 1-ß-Dr? Bofurans? L-1 H-1, 2,4-tr? Azol-3-carboxamide, available from ICN Pharmaceuticals, Ine, Costa Mesa, California, is described in the Merck index, Compound No. 8199, Decima First Edition Its manufacture and formulation is described in US Patent No. 4,211, 771. A person suffering from a chronic hepatitis C infection may exhibit one or more of the following signs or symptoms (a) High ALT (b) positive test for anti HCV antibodies, (c) presence of HCV demonstrated by a positive test to determine the presence of RNA, (d) clinical signs of chronic liver disease, (e) hepatocellular injury To practice the invention, it is administered Combination therapy of interferon alfa and pbavipna to the patient exhibiting one or more of the aforementioned signs in sufficient quantities to eliminate, or at least mitigate, one or more of the signs or symptoms. The formulations of interferon alfa, including the formulations of interf pegylated alpha are not effective when administered orally, so the preferred method for administering the formulations of interferon alpha or pegylated interferon alpha is by parenteral injection, preferably subcutaneous, IV, or IM pbavipna is administered to the patient in association with interferon alfa, that is, the dose of interferon alfa is administered during the same period in which the patient receives doses of pbavipna. pbavipna can be administered
orally in the form of capsules, tablets or liquid in association with the parenteral administration of pegylated interferon alpha. Of course, other types of administration of both drugs are also contemplated, as they are available, such as by nasal spray, transdermal, by means of suppositories, by way of Sustained Release Dosage, and Pulmonary Inhalation Any form of administration will work as long as appropriate dosages are administered without destroying the active ingredient. The term "patients who have not received antiviral treatment" in the context of the present invention means that patients they have never been treated with nvabipna or any kind of interferon, including, but not limited to an alpha interferon. The term "non-detectable ACV-RNA" in the context of the present invention means that there are fewer than 100 copies of HCV RNA per ml of patient's serum measured by PCR methodology Multicyclicative Quantitative Reverse Transcpptase HCV RNA is measured, preferably in the present invention, by the methodology which is then deciphered This methodology is referred to herein as HCV-RNA RNA is extracted from the patient's serum using an amount of guanidin-thiocyanate phenol-chloroform followed by the precipitation of ethanol-ammonium acetate. The precipitated RNA is centrifuged and the resulting pellet is dried in a Centpvap console (Labconco, Kansas City, Mo).
dry pellet is then resuspended in 30 micro-hours of a water-treated mixture of RNAsin (promega, corp, Madison, Wl) dithiothropol, and diethylpyrocarbonate. Samples are maintained at or below -20 ° C (preferably below -70). ° C) up to reverse transcription of RNA (RT) and PCR To convert the entire RNA sequence into cDNA in the RT reaction, random hexadeoxipbonucleotides (Pharmacia biotech, Piscataway, NJ) are used as primers for the first synthesis of cDNA chain Two aliquots of 3 micro-hours of resuspended sample are added to 3 micro-ters of random primers of 100 ng / μl and denatured at 70 ° C, then subjected to reverse transcription at 40 ° C for 1 hour using reverse transcpptase M -MLV (USB, Cleveland, OH) in standard pH regulator with a content of 5 mM MgC The volume of the final RT reaction is 26 μl The PCR is started immediately after reverse transcription Real Raise a modified version of the PCR method using heat-stable Taq polymerase to amplify the cDNA Seventy-five microchres of PCR mixture are added to the total volume of the RT reaction (26 μl) at a final concentration of gCb of 1 5 mM in a total volume of 101 μl Each sample of 101 μl is divided into 50 5 μl, and a layer of mineral oil is placed on the upper surface to prevent evaporation. The PCR cycle consists of fixing for 90 seconds, an extension for 90 seconds, and denaturation for 90 seconds, to
55 ° X, 74 ° C and 94 ° C, respectively Thermocycling samples are subjected to a final extension of 74 ° C for 10 minutes. 4 different cycle positions are used When loading the sample in duplicate, and dividing these samples even after of RT there are four tubes of a sample 5 Each of the four tubes will have a different number of cycles allowing sensitivity and accuracy in the quantification procedure The efficiency of the thermocycling will be evaluated by the successful amplification of a known number of copies of standards of RNA included in each group of 60 tubes We used 2 groups of initiators
for amplification, both for the untranslated region towards the 5 'end of the HCV genome Both of these groups of primers are highly conserved and all known subtypes of HCV are detected First group 1 upstream towards 5'-GTG GTC TGC GGA ACC GGT GAG T-3 ', downstream to 5'-TGC ACG GTC TAC GAG ACC TC-3' which produced a product of
190 bp Group 2 of initiators comment up to 5'-CTG TGA GGA ACT ACT GTC TTC-3 'downstream toward 5'-CCC TAT CAG GCA GTA CCA CAA-3' which produced a product of 256 bp The amplified cDNA is subjected to electrophoresis in 3% agarose gel and transferred to a nylon membrane. The target DNA is
detected by Southem blotting and immunostaining using a digoxigemna-labeled non-radioactive DNA probe These procedures are performed using automated instruments for PCR thermocycling, agarose gel electrophoresis, Southerm blot vacuum transfer,
hybridization, and immunostaining Each membrane contains a known number of copies and standards diluted in senes that are used to construct standard curves for the quantitative measurement of the sample bands. The originally standard curves are made from carefully diluted HCV RNA from transcribed clones. Studies of radioactive incorporation, gel electrophoresis, and OD 260 are performed on the transcripts to determine if they are of the expected length. After the production of the RNA transcripts, "mixed" standards of quantified clone standards are generated that represent better the heterogeneous nature of HCV, which could be found in a natural infection These mixtures are made by combining large amounts of serum or plasma from known infected individuals. The serum / plasma mixtures are calibrated with PCR, against the cloned transcripts after diluted in the known negative PCR fluids ally, the samples of the highest number of copies of the mixtures are checked against the Quantiplex cDNA nucleic acid detection system, from Chiron Ine (Emeryville, CA). These double-quantified mixtures are aliquoted and maintained at minus 70. ° C Dilutions of 5,000,000, 1, 000,000, 500,000, 100,000, 10,000, and 1000 copies / copiers milliliter are used in each experiment Each Southerm blot membrane is detected in a computer using an automated detector / densitometer, at intervals during development to determine when the standard curve is more linear They are measured
the resulting electronic images for the band area and means the band density All the readings are adjusted to integrate the band density and compared with the standard curve to obtain a numerical value of the viral copy number for each band The term "response sustained virological "as used in the context of the present invention means that there is no detectable HCV RNA in the serum of patients treated in accordance with the present invention for at least four weeks after the end of the combination therapy treatment. Preferably, the period of sustained virological response is at least one year "or more" after the end of treatment The following clinical protocols were performed Study 1
General design and curriculum The latter was a prospective group, multiple-center, randomized, double-blind and parallel The study compared treatment with INTRON® A plus pbavipna with treatment with INTRON® A plus placebo for 24 to 48 weeks in patients who had not received antiviral treatment with chronic hepatitis C compensated that they had not received previous treatment with any interferon including, but not limited to interferon alfa (INTRON® A, Roferon® A, consensus interferon, or Wellferon® therapy) and that they had not received previous treatment with
pbavipna Patients who had received prior treatment for hepatitis with any other antiviral drug or immunomodulatopo within the previous 2 years were also excluded from this study Patients who were chosen for chronic hepatitis C confirmed by positive serum HCV RNA, liver biopsy and laboratory tests Patients were randomly selected for treatment either INTRON® A with pbavipna or INTRON® A plus placebo The dose of INTRON® A was 3 million Ul SC TIW, the dose of pbavipna was 1000 or 1200 mg PO daily (based on weight) in two divided doses The assignments of the treatment group were performed in equal relationships through a central randomization center, Central Randomization Center The random selection procedure was designed to try to balance the treatment groups, within through sites, with respect to the presence or absence of cirrhosis in the biops ia of liver treatment, at HCV / qPCR RNA level and HCV genotype The treatment under study was administered for 24 to 48 hours The total study period was 48 or 72 weeks to determine the long-term effect of the treatment The duration Treatment was assigned at the time of the random selection During the follow-up of treatment and after treatment, biochemical (ALT), virological (HCV RNA) and histological (liver biopsy) tests were used to evaluate the nature and duration of the response to the treatment object of the study The main efficacy vapable
was the general response defined as the loss of HCV / qPCR RNA in serum (<100 copies / mL) as measured at 24 weeks after the end of therapy. In addition, a reduction in liver inflammation was also examined, Improvement in the post liver biopsy treatment as measured by the Knodell histology activity index (HAI) and ALT normalization was also examined as the endpoints of secuandapa efficacy. The safety of the treatments under study was assessed by monitoring the selected laboratory parameters and also recording and evaluating the presence of any adverse event
Treatment regimens There were four treatment regimens under study 1 INTRON® A 3 million Ul SC TIW plus pbavipna 1000 or 1200 g / day PO (orally) in two divided doses for 24 weeks, or 2 INTRON® A 3 million Ul SC TIW plus placebo comparing pbavipna PO in two divided doses over 24 weeks, or 3 - INTRON® A 3 million Ul SC SC plus nbavipna 1000 or 1200 mg / day PO in two divided doses over 48 weeks, or 4 - INTRON® To 3 million Ul SC TIW plus placebo comparing nbavipna PO in two divided doses for 48 weeks The treatments under study 1 and 2 were administered for 24 weeks, the treatments under study 3 and 4 were administered for 48 weeks The INTRON® A standard (interferon alfa-
2b, recombinant) regimen for hepatitis C were administered as a fixed dose of 3 million Ul TIW Each patient received instructions regarding the preparation and subcutaneous administration of INTRON® A pbavipna was administered twice daily, in the morning and in the evening The dose was determined according to the patient's body weight at the start visit Patients who weighed < 75 kg received 1000 mg daily in two capsules of 200 mg in the morning and three capsules of 200 mg in the afternoon Patients who weighed > 75 kg received 1200 mg daily in three 200 mg capsules in the morning and at night The random selection procedure was designed to balance the groups with respect to the following baseline characteristics • pretreatment liver histology (cirrhosis or absence of cirrhosis),. HCV-RNA / qPCR status in serum (HCV-RNA / qPCR
< 2,000,000 or HCV-RNA / qPCR > 2,000,000 copies / ml), and • HCV genotype (1 or other) Patients with mixed genotypes (including type 1) will be classified as type 1 for balance purposes
Efficacy The main objective of efficacy was the comparison of treatment groups 1 and 2 and 3 and 4 with respect to the response speed
sustained virological defined as the loss of serum HCV / qPCR RNA (detectable) measured at 24 weeks after the end of therapy at a non-detectable level or at a level of < 100 copies / ml The following secondary efficacy endpoints were also examined Secondary efficacy endpoints were • proportions of patients with normalization of ALT at 24 weeks of follow-up, • proportions of patients with an improvement in biopsy (categories I + II + lll combined scores), • changes from the baseline in the biopsy scores (categories I + II + III) combined scores), • response rates to the endpoint of treatment based on HCV-RNA / qPCR, • proportion of patients with normalization of ALT to the endpoint of treatment • response rates at 24 weeks of follow-up based on HCV-RNA / qPCR
Virology State of admission and change from admission The HCV-RNA / qPCR test in serum and the genotype test
HCV will be performed in a central laboratory. A positive HCV-RNA test was required in the baseline, only patients positive for HCV-RNA were involved. Repetition tests must be performed in the
weeks 4, 12 24 and if the patient was in the 48-week treatment groups in weeks 36 and 48 All patients had repeat tests scheduled for follow-up in weeks 12 and 24 The response was evaluated as follows Patient who present response A patient will be classified as responding to treatment at the given time if HCV-RNA / qPCR is negative (<100 copies per ml) at that time Patient who presented a sustained response A patient will be classified as one that responds to sustained treatment if the response is obtained in the patient at 24 weeks of follow-up Note that patients who do not meet this criterion, including patients who discontinued the medication before obtaining the required HCV-RNA / qPCR evaluations, will be classified as that do not respond to treatment Patient with a general response Based on both HCV-RNA / aCRP in serum and change in liver histology evaluate Knodel Inflammation Classification HAI A patient will be classified as a patient with a total response to treatment if at 24 weeks of follow-up, he / she is a patient who responds to sustained virological treatment and has normal ALT
Liver histology Liver biopsy was required within six months of patient registration and 24 weeks of follow-up for all patients Biopsies evaluation was performed by a single pathologist using histological activity classification Knodell The primary pathologist will not know the patient's identification, the treatment group, and the time the biopsy is performed with respect to the treatment (Pre- or Post-treatment). The efficacy of the study treatments will be classified by comparing the degree of inflammatory activity observed in the baseline with follow-up in week 24
Results Nine hundred twelve patients were enrolled in 42 centers in the United States and randomly selected for treatment with either INTRON® A plus pbavipna (N = 228) or INTRON® A plus placebo (N = 23) for 24 weeks or treatment either with INTRON® A plus pbavipna ("l + R") (N = 228) or INTRON A or more placebo ("l + P") (N = 225) for 48 weeks In general, 81% (734 / 912) of patients completed the treatment and 24 weeks of follow-up Eighty-nine percent
(203/228) of patients in week 24 of group I + R, 90% 8207/231) of patients in the L + P group of 24 weeks, 70% (159/228) of patients in
the group of R + R of 48 weeks, and 73% (165/225) of patients in group I + P of 48 weeks completed in the study Twenty percent (178/912) of patients discontinued during treatment 11% (25/228) in the 24-week R + R group, 10% (24/231) in the group of l + P of 24 weeks, 30% (69/228) in the group of R + R of 48 weeks, and 27% (60/225) in the group of l + P of 48 weeks An adverse event was the most frequent reason for a patient discontinued on treatment in all groups 8% [19/228] with 24 weeks of L + R, 9% [20/231] with 24 weeks of l + P, 20% [45/228] with 48 weeks of L + R, and 14% [32/225] with 48 weeks of L + P At least 96% of patients who finished treatment and continued with a Complete follow-up in the study Only 2 patients in the 24-week L + R group, 8 patients in the 24-week L + P group, 7 patients in the 48-week L + R group, and 4 patients in the L + R group. + P of 48 weeks discontinued treatment during follow-up The patient's weight and the characteristics of his baseline disease (HCV genotype and initial viral load) for all patients in study 1, are given to the chart a continuation gave HCV genotypes in the serum samples from a patient undergoing HCV-RNA / qPCR tests
TABLE 1 Body weight and characteristics of the baseline disease Will give study patients 1
l + R1 l + P2 l + R1 l + P 24 weeks 24 weeks 48 weeks 48 weeks
Weight (N = 228) (N = 231) (N = 228) (N = 225)
> 75kg 148 (65%) 157 (68%) 133 (58%) 153 (685)
< 75kg 80 (35%) 74 (32%) 95 (42%) 72 (32%)
Genotype3 HCV 1 164 (72%) 167 (72%) 166 (73%) 162 (72%)
2 29 (13%) 38 (17%) 37 (16%) 43 (19%) 3 28 (12%) 24 (10%) 23 (10%) 19 (8%) 4 6 (3%) 2 ( 09%) 1 (04%) 1 (04%) 5 0 0 1 (04%) 0 6 1 (04%) 0 0 0
HCV RNA / qPCR Copies / ml) Geometric mean 3,070,019 2,767,469 2,922,925 2,8199,324
= millions of 62 (27%) 74 (32%) 76 (33%) 63 (28%) copies / ml < million 166 (73%) 157 (68%) 152 (67%) 162 (72%) copies / ml Footnotes in table 1 1 I + R is Intron A + Ribavipna 2 I + P is Intron A + Placebo 3 The subgenotypes are classified under their respective genotype.
All the efficacy and safety presentations in this report are based on data for groups fully treated
Efficacy The objectives of this study can compare INTRON® A plus pbavinna with INTRON® A plus placebo with respect to the overall response rate at the virological response rate (based on HCV RNA (qPCR) for 24 and 48 weeks). Main efficacy for the study is the overall rate of response The conclusions of this efficacy are as follows The combination therapy of INTRON A plus pbavinna administered for 48 weeks increased the effectiveness of monotherapy with INTRON A for the treatment of hepatitis two to three times Chronic C in patients who have not received antiviral treatment Forty-eight weeks of INTRON A combination therapy plus pbavipna increased in the response rate at the end of treatment and decreased the rate of recidivism, which resulted in a virological response rate better sustained than during the 48 weeks of INTRON A + Placebo This improvement in efficacy included all aspects of the disease and resulted • Sustained eradication of detectable HCV RNA • Improvement in liver inflammation, • Normalization of ALT, • Improvement in Knodell HAI inflammation classification Sustained loss of HCV RNA in serum correlated with the improvement in or resolution of liver inflammation The results
demonstrated the correlation between sustained virological response, improvement in liver inflammation, normalization of ALT and improvement in HQL. The overall response rate at the end of follow-up is a combination of the loss of HCV RNA (qPCR) in serum and change in liver histology at the end of follow-up (24 weeks after the end of treatment) A patient was classified as a patient with a general response and HCV RNA (CRP) was negative at the post-treatment evaluation at week 24 and the Knodell HAI post-treatment inflammation classification (category I + ll + III) had improved if the post-treatment value had decreased by two or more units in relation to the pretreatment classification. The percentage of patients with sustained virological response over time to the ppmer RNA of the HCVA negative, the monitoring term of virological response (sustained, the histological response and the General response speeds are summarized in Tables 2, 3, 4 and 5
Sustained virological response of HCV RNA at the end of follow-up Sustained loss of HCV RNA at 24 weeks after the end of treatment The proportion of patients with eradication of HCV RNA in serum at 24 weeks after the end of treatment was two three times higher (41% v 16%) in the group of patients treated with
combination of INTRON® A plus pbavinna compared to those who received INTRON® A plus placebo Prolongation of combination therapy had the greatest effect on recidivism rates At 24 weeks after the end of treatment, the rates of recidivism for the 48 weeks of the combination therapy and for the 48 weeks of Intron A plus placebo were the same (12%). A longer treatment with the combination therapy (48 weeks and the reduced recidivism rates gave as a result higher sustained virological response rates Sustained virological response rates were also significantly higher at 48 weeks of combination therapy, compared to 24 weeks of combination therapy (38% vs 31%, p value = to 0 053) Extending the combination therapy from 24 to 48 weeks substantially increased the virological responses obtained in patients who initially had negative HCV RNA at weeks 12 and 24 Most patients who were patients with sustained virological response had RNA of HCV negative in week 4 As summarized in table 2, the sustained virological response was observed 81% (35/44) of the patients at 24 weeks of the combination therapy (l + R) at week 4 of the 24-week treatment and for 81% (36/45) of the patients in the 48 weeks of combination therapy at week 4 of the 48-week treatment Note that substantial portions of these
Patients in the combination therapy of 24 and 48 weeks who responded for the first time to week 12 became patients with sustained virological response In 42% of these patients in the combination therapy group of 24 weeks and 63% of those patients in the 48-week combination therapy group, these responses were sustained. In addition, 44% of the patients in the 48-week combination therapy treatment group who first obtained negative HCV RNA at week 24, achieved a sustained virological response None of the responses that occurred after week 24 were from patients with responses obtained in any of the treatment groups The number of patients with a response for the first time at weeks 12 and 24 who became responders virologic sustained 24 weeks after the end of treatment was greater for patients who received 48 weeks of combination therapy (Cons ulte table 2 below)
TABLE 2 Percentage of patients presenting sustained virological response with time determined at undetectable levels of HCV RNA for study 1
Table 3 summarizes the patient's response at the end of follow-up as indicated by HCV RNA in serum
TABLE 3 Term of HCV RNA from serum monitoring: proportion of patients with eradication of HCV RNA at 24 weeks after the end of treatment (TEQ)
Combination therapy significantly increased the virological response at the end of treatment compared to INTRON A monotherapy. See Table 3. The p values for the comparison of combination therapy during 48 weeks with INTRON A monotherapy for 48 weeks and comparisons of 24 weeks of combination therapy with 24 and 48 weeks of INTRON A monotherapy are each < 0.001. Extending the combination therapy from 24 to 48 weeks reduced the rate of
recidivism 50% (24% to 12%) in that way, making the 48-week combination therapy more effective than the 24-week combination (p = 0 053) Pre and post-treatment biopsies were available for 79% (179/228) and 69% (157/228) of patients treated with INTRON® A plus pbavipna for 24 and 48 weeks respectively and for 76% (176/231) and 70% (158/225) of those patients who received INTRON® A plus placebo for 24 and 48 weeks, respectively Table 4 summarizes the effect of treatment on liver inflammation for patients with both liver biopsy results pre- and post-treatment As with the sustained loss of HCV RNA replication, the proportion of patients with an improvement in liver inflammation was significantly higher (p <0.001) in patients receiving combination therapy compared to those who received INTRON® A monotherapy during 48 weeks The eradication of A RN of detectable HCV was highly correlated with serum normalization ALT 2 to 3 times more patients were normal ALT with combination therapy compared to monotherapy of INTRON A at the end of follow-up Among patients who fear ALT, normalized sustained, a The highest proportion of patients on the 48-week combination therapy were patients with sustained virological response compared with patients who received 24 weeks of
combination therapy and 24 weeks or 48 weeks of monotherapy with INTRON A.
TABLE 4 Liver histology at the end of follow-up: Improvement in liver histology 24 weeks after the end of treatment based on the Knodell HAI result (l + ll + lll).
Number (%) of patients "Condition of INTRON A + Ribavipna INTRON A + Placebo Value Pc patient AC 2 weeks 48 weeks 2 weeks 48 weeks (N = 179) a (N = 157) a (N + 176) 3 (N = 158) a Biopsy 102 (57%) 96 (61%) 77 (4%) 65 (41%) < 0 001 improvement at N = Number of patients with biopsy samples in pairs b Patients with both pretreatment and biopsy biopsies post-treatment c Fisher's exact test d change from pretreatment to aftercare in the result of the Knodell Histological index
(HAI) (sum of l + ll + lll) classified as a reduction of 2 or more of the pretreatment
General response When the study was designed, it was recognized that because liver biopsy is an invasive procedure, it would be unlikely that post-treatment liver biopsies would be obtained for all patients. Therefore, the protocol and statistical analysis plan specified that the analysis for general response would be based on data for all treated patients and will be estimated using a maximum likelihood method (MLE).
for patients whose general response condition could not be determined, ie, patients with negative HCV RNA and who are missing biopsy (post-treatment) evaluations. The protocol also specified that further analysis would be carried out on patients with biopsy results. both pre-treatment and post-treatment (ie patients with complete data) The overall response is a combination of sustained loss of detectable HCV RNA and improvement in liver histology at the end of follow-up. The overall response is summarized in Table 5 on the basis of in the following analyzes • estimated maximum likelihood (MLE), • patients with complete data (results for both pretreatment and posttreatment biopsy), • patients with missing data (either or both HCV / biopsy) treated as deficiencies
TABLE 5 Overall response rate
Data INTRON A + Ribavipna INTRON A + analyzed • Placebo A B C D Value p "
24 weeks 48 weeks 24 weeks 48 weeks B vs D
Estimated probability 26% 35% 5% 9% < 0001 maximum8 Patient with data 29% 41% 5% 11% < 0001 complete0 (52/179) (64/157) (8/170) (18/158) Treat what is missing as 23% 28% 28% 8% < 0001 deficiencies "(52/228) (64/228) (64/228) (18/225) to MLE based on logistic regression Logistic regression analysis of patients with complete biopsy data The p-value for A vs. D is < 0 001 and for A vs B is 0 096 b Fisher's exact test c Complete data = biopsy results for both pretreatment and posttreatment
(Logistic regression analysis) d Patients who lack virology or biopsy data or both were counted as not responding
As would be expected from individual results for treatment purpose on HCV RNA eradication at the end of follow-up and improvement in liver inflammation, the overall response rate in the 48-week treatment group with INTRON® A plus ribavipne was significantly greater (< 0.001), than the one observed in the 48-week treatment group with INTRON® A plus placebo. There was a statistically significant improvement in the overall response with the combination therapy treatment of 48 weeks compared to 48 weeks of monotherapy treatment with INTRON A as measured
by MLE and complete biopsy The overall response rates for 24 and 48 weeks of combination therapy treatment were significantly higher than with 24 and 48 weeks of monotherapy with INTRON A, respectively Logistic regression analysis was performed on all demographic variables and characteristics of the baseline disease The only statistically significant baseline patient characteristics and disease that predict the sustained response at the end of the follow-up were the genotype different from 1 and viral load from < 2 million For the number of viral copies (<2 million,> 2 million), the difference was statistically significant in favor of higher response rates in patients with < 2 million copies (table 6) When genotype and baseline virus load are combined, a response hierarchy is observed Patients with a genotype different from 1 and baseline virus load from < 2 million copies that received 24 and 48 weeks of combination therapy had the best response at the end of follow-up, sustained virological response for those patients with genotype 1 and > 2 million copies that had 48 weeks of combination therapy with INTRO A plus pbavipna was twice as good as those patients of the same type who had combination therapy for only 24 weeks (See table 6)
TABLE 6 Characteristics of the disease against sustained response: All patients treated.
Number (%) of patients Characteristics of the disease8 INTRON A + Ribavipna INTRON A + Placebo 24 weeks 48 weeks 24 weeks 48 weeks
HCV RNA / viral caroa < 2 million copies / ml 42% (26/62) 43% (33/76) 9% (7/74) 29% (18/63) > 2 million copies / ml 27% (44/166) 36% (54/152) 4% (6/157) 7% (11/162)
Genotype of HCV 1 16% (26/164) 28% (46/166) 2% (3/167) 7% (11/162) 1 Q Other Genotypes 69% (44/64) 66% (41/62) 16% (10/64) 29% (18/63)
Genotype / Baseline HCV RNA Other Genotypes < 2 million copies / ml 88% (14/16) 71% (15/21) 25% (5/20) 50% (10/20)
Other Genotypes > 2 million copies / ml 63% (30/48) 63% (26/41) 11% (5/44) 19% (8/43)
Genotype 1, = 2 million • J 5 copies / ml 26% (12/46) 33% (18/55) 4% (2/54) 19% (8/43)
Genotype 1, > 2 million 12% (14/118) 25% (28/111) 1% (1/113) 3% (3/119) copies / ml a At the beginning, patients were classified by number of viral copies of HCV ( = 2 million,> 2 million), genotype (1 or other), and cirrhosis (present or absent) as measured by HCV RNA / PCR
TABLE 7 Sustained virological response rates (%) by HCV genotype
INTRON A + Ribavinna INTRON A + Placebo
Genotype 24 weeks 48 weeks 24 weeks 48 weeks
1 16% (27/165) 28% (46/166) 21% (4/168) 7% (11/162) 2 83% (25/30) 68% (25/37) 18% (7/38) ) 35% (15/43) 3 57% (16/28) 65% (15/23) 8% (2/24) 16% (3/19)
4-6 40% (2/5) 50% (1/2) 0 0
Table 7 illustrates that sustained virological response rates for patients of each genotype with 48 weeks of combination therapy were higher than those treated with Intron A plus placebo for 24 and 48 weeks With the exception of patients with genotype 2 of the
HCV, the extension of the duration of combination therapy increased the proportion of patients with sustained virological responses (But see Table 15 for combined virological responses for Studies 1 and 2) Logistic regression analysis of sustained virological response showed that, in addition to the treatment group, the HCV genotype different from 1 and < 2 million copies of HCV baseline virus / ml significantly predicted sustained virological response (p <0 0111 value) Most notably, treatment with combination therapy for 48 weeks improved sustained virological response rates for patients from whom the slowest response rates were expected, namely those patients with HCV genotype 1 and more than 2 million
copies of HCV / ml virus These patients had sustained virologic response rates that were twice as high as those who had 24 weeks of treatment with the combination therapy. Significantly sustained virological response for patients with HCV genotype 1 who received 48 weeks of combination therapy was 1 75 times greater than that for those patients who received 24 weeks of combination therapy
Study 2 Through basically the same methodology as described above in Study 1, Study 2 was also conducted in 43 international sites (832 patients) using the following three treatment regimens The results are summarized below 1 INTRON® A 3 million Ul SC TIW plus pbavipna 1000 or
1200 mg / day PO in two divided doses for 24 weeks, or 2 INTRON® A 3 million IU SC TIW plus pbavipna 1000 to 1200 mg / day PO in two divided doses for 48 weeks, or 3 INTRON® A 3 million Ul SC TIW plus placebo matched the pbavipna PO in two divided doses over 48 weeks
Efficacy The main objective of efficacy is the sustained virological response as defined by the loss of detectable HCV RNA (qPCR) in serum measured at the end of follow-up (24 weeks after the end of treatment). A patient was classified as a patient with a response Overall, if HCV RNA (PCR) was negative in the 24-week post-treatment evaluation and the Knodell HAI post-treatment inflammation result (sum of categories l + ll + lll) had improved (decreased) by 2 or more units in relation to to the result of pretreatment The percentage of patients with sustained virological response over time to the first negative HCV RNA, the virological response at the end of follow-up, histological response, and general response rates are summarized in tables 9, 10, 11 and 12 The patient's body weight and baseline disease characteristics (HCV genotype and viral load) initial) for all patients in Study 2 are provided in Table 8 below
TABLE 8 Body weight and characteristics of the baseline disease for patients in Study 2
INTRON A, + Ribavirin INTRON A + Placebo
Body weight 24 weeks 48 weeks 48 weeks > 75kg 116 (42%) 129 (47%) 122 (44%) < 75kg 161 (58%) 148 (53%) 156 (56%)
Genotype of HCV 1 161 (58%) 159 (57%) 168 (60%) 2 27 (10%) 23 (8%) 21 (8%) 3 73 (26%) 74 (27%) 79 (28% ) 4 12 (4%) 16 (6%) 9 (3%) 5 1 (0.4%) 5 (2%) 1 (0.4%) 6 3 (1%) 0 0
HCV-RNA / PCR (copies / mi) geometric mean 2,229,797 2,064,959 2,351,824 < 2 million of 108 (39%) 115 (42%) 95 (34%) copies / mL > 2 million of 169 (61%) 162 (59%) 183 (66%) copies / mL
TABLE 9 Percentage of patients with sustained virological response over time for first levels of HCV RNA not detectable for Study 2
Time will give Intron A + Ribavipna Intron A + Placebo first HCV RNA not detectable (weeks) 24 weeks 48 weeks 48 weeks 4 84% (57/68) 83% (58/70) 72% (33/46) 12 47% (36/77) 69% (51/74) 34% (18/53) 24 12% (3/26) 45% (9/20) 10% (2/21)
As summarized in Table 9, the majority of patients who had sustained virological response had negative HCV RNA levels by week 4 of treatment, however, substantial proportions of patients in the combination therapy treatment groups of 24 and 48 weeks that were HCV RNA positive at week 4 responded for the first time at week 12, 47% of those in the 24-week treatment group and 69% of those in the 48-week treatment group had sustained response Importantly, 45% (9/20) of patients in the 48-week combination therapy treatment group who were first negative at week 24 had sustained virological response. None of the responses that occurred after week 24 were made sustained in none of the three treatment groups
Response of HCV RNA to the end of follow-up Sustained loss of HCV RNA 24 weeks after the end of treatment
The proportion of patients with HCV RNA eradication in the serum 24 weeks after the end of the combination therapy treatment was significantly higher in patients treated with the combination therapy of INTRON® A plus pbavipna compared to those receiving monotherapy with INTRON ® A Table 10 summarizes the patient's response at the end of follow-up as indicated by serum HCV RNA
TABLE 10 Serum HCV RNA at the end of follow-up: Proportion of patients with HCV RNA eradication at 24 weeks after the end of treatment (EQT) and follow-up period (EQFU)
Number (%) of patients INTRON A + pbavipna INTRON A + placebo A B C Value p 24 weeks 48 weeks 48 weeks B vs C1
(N = 277) (N = 277) (N = 278) EOT2 Negative 57% (157) 52% (145) 33% (93) < 0 001
Positive 42% (120) 42% (132) 65% (185) EOFU3 Sustained 35% (96) 43% (118) 19% (53) < 0 001
Recurrence 23% (23) 10% (27) 15% (41) Patients 42% (42) 48% (132) 66% (184) do not respond
1 Fisher's exact test for EOT comparisons, logistic regression for EOFU 2 EOT = Term of treatment P value for A vs C = < 0 001 and for A vs B is 0 348 3 EOFU = Term of follow-up Value P for A vs C = < 0 001 and for A vs B is 0 055 Table 10 illustrates that (1) combination therapies of 24 and 48 weeks significantly increased the sustained virologic response at the end of treatment compared to that for monotherapy with Intron A ( the p values are both <0 001) and (2) the increase in the duration of the combination therapy from 24 to 48 weeks had the greatest effect on recidivism rates (10% for 48 weeks vs. 23% for 24 weeks , the p-value is 0 055)
Liver histology at the end of follow-up in the hepatic histology 24 weeks after the end of treatment based on the results of Knodell's Histological Activity Index (HAI) (l + ll + lll)
Pretreatment and posttreatment biopsies were available for 74% (204/277) and 60% (167/277) of patients treated with INTRON® A plus pbavipna for 24 and 48 weeks, respectively, and for 69% (191/278 ) of those patients who received INTRON® A plus placebo Table 11 summarizes the effect of treatment on liver inflammation for patients with liver biopsy results from both
pretreatment as post-treatment As with the sustained loss of HCV RNA replication, the proportion of patients with improvement in liver inflammation was significantly higher (p <0.001) in patients receiving combination therapy for 48 weeks compared to those who receive monotherapy with INTRON® A for 48 weeks The extension of the combination therapy from 24 to 48 weeks also significantly increased the proportion of patients who had improvement in liver inflammation (value p = 0 046)
CUADR0 11
Liver histology at the end of follow-up Improvement in hepatic histology 24 weeks after the end of treatment based on the HAI result of Knodell (l + ll + lll)
Number (%) of pacients INTRON A + pbavipna INTRON A + placebo
Condition A B C Value pc
. , »24 weeks 48 weeks 48 weeks B vs C oei patient (N = 204) to (N = 167) to (N = 191) to meSad 53% (107) 63% (105) 39% (74) < 0 ° 01
a Number of patients with biopsies in pairs b Patients with both pretreatment and post-treatment biopsies
c Fisher's exact test. Value p for A vs C = 0.007 and A for A vs B is 0.046. d Change from pretreatment to after-treatment in the result of Knodell's Histological Index (HAI) (sum of l + ll + lll) classified as a decrease of 2 or more of the pretreatment.
General response The general response is summarized in table 12 based on the following analyzes: • maximum likelihood estimate (MLE); • patients with complete data (result for biopsy both pretreatment and aftercare); • patients with missing data (either or both HCV RNA / biopsy) treated as deficiencies.
TABLE 12 Overall response speed
INTRON A + INTRON A + ribavirin placebo ABC Data analyzed 24 weeks 48 weeks 48 weeks Estimated 37% 17% maximum probability 28% Patients with 30% data (62/204) 41% (68/167) complete biopsy0 17% ( 32/191)
Treat what is missing as 22% (62/277) 2% (68/277) 12% (32/278) deficiencies "
to MLE based on logistic regression Value p for B vs C = < 0 001 and for A vs C = < 0 002 and for A vs B is 0 043 b Fisher's exact test c Complete data = biopsy results for both pretreatment and aftercare P value for B vs C is < 0001, for A vs C is < 0 005 and for A vs B is 0 032 d Patients who lacked virology or biopsy data or both were counted as deficiencies As would be expected from individual results for the purpose of treatment on HCV RNA eradication at the end of follow-up and improvement in liver inflammation, the overall response rate in the INTRON A plus pbavipna group is significantly greater with a two-fold improvement over that observed with the INTRON A groups plus placebo for all assessment methods Logistic regression analysis was performed in all the demographic variables and characteristics of the baseline disease The only statistically significant baseline characteristic that predicts the sustained response at the end of the follow-up was a genotype different from 1
TABLE 13 Sustained virological response rates by HCV genotype for Study 2 patients
Intron A + pbavipna Intron A + placebo
Genotype 24 weeks 48 weeks 48 weeks 1 18% (29/161) 30% (48/159) 11% (19/168)
2 59% (16/27) 74% (17/23) 35% (8/23)
3 66% (48/73) 61% (45/74) 32% (25/79)
4-6 19% (3/16) 38% (8/21) 12% (1/8)
Combination therapy provided a higher sustained virological response rate for all genotypes compared to Intron A plus placebo The extension of the duration of combination therapy to 48 weeks increased the proportion of sustained virological response for all genotypes except the type 3 (See table 13 as well as table 15 for the combined virological response for studies 1 and 2) For viral copies number (<2 million, > 2 million), there was a numerical difference in favor of higher sustained virological response rates in patients with < 2 million copies (table 14) When the genotype and load of baseline virus are combined, a response hierarchy is observed. Those patients with genotype different from 1 and baseline virus load 2 million copies had the best response to the end of follow-up, those patients with genotype 1 and > 2 million copies that received the 48-week-plus treatment with
combination therapy had the most significant improvement in substantial virological response of all groups
TABLE 14 Characteristics of the disease against sustained virological response: All patients treated in Study No. 2
Number (%) of patients Characteristics of the most INTRON® A plus INTRON® A pbavipna disease placebo 24 weeks 48 weeks 48 weeks
HCV-RNA / qPCR < 2 million 47% 44% (48/108) 31% (15/49) copies / ml (54/115) > 2 million 28% (48/109) 40% 13% (24/183) copies / ml (64/102) Genotype of HCV 30% 18% (29/161) 11% (19/168) (48/159) ) 59% Other genotype 58% (67/116) 31% (34/110) (70/118) Genotype / RNA from baseline HCV / qPCR Other genot? Po /! 53% (28/53) 62% (34/55) 31% (15/49) million copies / ml Other genot? Po / > 2 62% (39/63) 57% (36/63) 31% (19/61) million copies / ml Genotype 1 and 5 2 36% (20/55) 33% (20/60) 30% (14 / 46) million copies / ml Genotype 1 and > 2 8% (9/106) 28% (28/99) 4% (5/122) million copies / ml
Table 14 illustrates that the extension of combination therapy to 48 weeks in general improved sustained virological response rates. The highest sustained virological response rates were observed with patients receiving combination therapy for 48 weeks with genotypes different from 1 and initial HCV levels of < 2 million copies / ml Importantly, for patients with genotype 1 and HCV levels > 2 million, sustained virological response rates with 48 weeks of combination therapy were more than three times higher than rates with only 24 weeks of combination
Conclusions about the efficacy for combined results for all patients in the 1 + 2 studies Combination therapy was significantly more effective than monotherapy with INTRON®A for the initial treatment of chronic hepatitis C The rates of sustained virological response in these patients have not received antiviral treatment were almost three times higher with 48 weeks of combination therapy compared to 48 weeks of monotherapy with Intron A and significantly higher with 48 weeks compared to 24 weeks of combination therapy sustained response could be explained by two treatment effects higher response rates at the end of treatment and decreased recidivism rates The net result of
both effects were the highest sustained response rate with 48 weeks of combination therapy compared to 48 weeks of monotherapy or a shorter regimen with combination This increase in efficacy with 48 weeks of combination therapy also included other response-mediated such as biochemical (ALT) and histological endpoints In fact, the sustained loss of HCV RNA in serum was highly correlated with other clinical endpoints - normalization of ALT and improvement in or resolution of liver inflammation. The loss of detectable HCV RNA at the end of follow-up was related to normalization of ALT in all treatment groups but was slightly higher with the combination therapy. Most combination therapy patients who had normal ALT were also Negative HCV RNA (83-87%) The increased duration of therapy had the greatest effect on recidivism rates. At the end of the follow-up, the recidivism rates for both 48-week combination and monotherapy treatment groups were lower than the recidivism rate of the 24-week combination therapy treatment group The combination of the high response at the end of the treatment resulting from 24 and 48 weeks of combination therapy compared with 48 weeks of monotherapy with Intron A and decreased recidivism rates resulted in response speeds
sustained highest sustained response rates were twice as high with 48 weeks of combination therapy compared to monotherapy with Intron A (48) (p <0 001) Sustained virological response rates were also higher with 48 weeks of combination therapy compared to only 24 weeks of (p = 0.008) The benefit of combination therapy remained regardless of the standard agents predicting the response to monotherapy with I TRON®A and combination therapy of 24 Weeks in patients who relapse At the beginning of these tests, patients were classified by the following characteristics of the HCV genotype disease (type I or other genotypes), HCV virus level extension (number of virus copies in serum < 2 million / ml or> 2 million / ml), and cirrhosis (present or absent) Logistic regression analysis of sustained virological response demonstrated that, in addition to the treatment, only the HCV genotype significantly predicted the sustained virological response Neither the level of pretreatment HCV virus nor the presence of cirrhosis seemed to influence the ability of previously untreated patients to achieve sustained virological response to combination therapy With 48 weeks of combination therapy, sustained response rates were consistently higher than those for 48 weeks of monotherapy with Intron A regardless of genotype and were generally higher than 24 weeks of combination therapy. As a group, patients infected with genotype I have been shown to respond less to
monotherapy with INTRON®A than patients infected with other genotypes Despite this, the sustained virological response rates for genotype I were approximately 3 times higher with 48 weeks of combination therapy compared to 48 weeks of monotherapy with Intron A and almost twice as high at 48 weeks compared to 24 weeks of combination therapy Combination therapy consistently produced higher sustained virological response rates in patients infected with other genotypes. Response rates with both 24 and 48 weeks combination therapy were higher than with 48 weeks of monotherapy with Intron A and in all genotypes except types 2 and 3 whose genotypes had the same response rate, ie approximately 64% at the end of 24 weeks as well as after 48 weeks of combination therapy, the extension of the duration of combination therapy to 48 Weeks increased the proportion of patients with sustained virological responses (See Table 15) Combination therapy was also more effective than 48 weeks of monotherapy with Intron A by producing sustained virological responses regardless of the level of virus in baseline Forty-eight weeks of combination therapy consistently produced sustained virological response rates higher at each level of virus infection than 48 weeks of monotherapy with Intron A Sustained response rates were similar for most virus levels in the treatment groups of combination therapy both
of 24 weeks as of 48 weeks, except with the highest virus levels (5- <6 and> 6x106 copies / ml) where the sustained response rates with the 48-week combination therapy groups were approximately twice higher than the 24-week combination therapy groups As mentioned above, patients with different genotypes of type I had higher sustained virological response rates than those with type I and a virus level < 2 million / ml was related to a better response rate than > 2 million / ml It was notable that the extension of the combination therapy treatment to 48 weeks improved the sustained response rates for patients from whom the lowest response rates were expected, namely, those with genotype I and >2 million copies of HCV RNA / ml The extension of combination therapy to 48 weeks in this group of patients produced rates of sustained virological response that were four times higher than those with only 24 weeks of combination therapy. demographic / history of the disease had a small effect on the outcome with combination therapy In contrast, considerably lower sustained response rates were observed with 48 weeks of monotherapy with Intron A in patients older than 55 years, > 75 kg or who were infected through
transfusion All had sustained response rates in the range of 10-12% The availability of biopsies in pairs was high compared to similar types of studies in patients with chronic hepatitis C As expected, pretreatment and posttreatment liver biopsies were not available for a proportion of patients for a variety of reasons. Nevertheless, biopsies were obtained in pairs of 71% of patients Improvement was observed in a significantly higher proportion of patients of combination therapy of 48 weeks compared with monotherapy patients. with 48-week Intron A at the end of follow-up (p <0 001) Twenty-four weeks of combination therapy were also significantly more effective than 48 weeks of Intron A monotherapy in improving liver inflammation. As noted above, the correlation with the virological response was maintained if the biopsies were evaluated by mej ora or average change of the baseline in the necroinflammation result, 64-69% of the patients had improvement in hepatic inflammation with average changes of the baseline from -3 8 to -5 0 The most substantial average change was in the monotherapy patients with 48-week Intron A As expected, patients with sustained virological response in all treatment groups experienced greater improvement in liver biopsy inflammation results than patients who remained positive HCV RNA, and although the degree of the
improvement was similar in all groups, the proportion of patients with virological response with histological improvement was at least twice as high with the combination therapy of both 24 and 48 weeks than with 48 weeks of monotherapy with Intron A The extension of the combination therapy resulted in higher average improvements in liver inflammation. It is also interesting to note that patients who relapsed from the 48-week combination therapy had a considerable average improvement in inflammation. The combined results are summarized in tables 15 to 20
TABLE 15 Combined virological response for Studies 1 and 2
Efficacy Lost of detectable HCV RNA at the end of treatment (EOT) and sustained virological response at the end of follow-up (EOFU) and percentage of patients responding
'Characteristics of patients (a) 66% male, 34% female, (b) average age 42 7 years, (c) HCV RNA levels of pretreatment average < 2 million copies / ml 66%, Super Quant, NGI, (d) genotype HCV 1 = 66% genotype 2 = 13%, genotype different from 1-3 = 13% EOT is the end of the treatment value PB vs D = < 0 001, value P A vs D is = < 0001 EOFU is the term of follow-up for 24 weeks, value P A vs B = 0 257, value P B vs D = < 0 001, value P A vs D = < 0 001 3 Sustained virological response at the end of follow-up, value P A vs B = 0008
4 The sustained virological response for genotypes 2 and 3 of HCV at the end of 24 weeks was approximately 64 5% and at the end of 48 weeks was approximately 65%
TABLE 16 Percentage of sustained virological response for all patients with HCV genotype 1
Intron A + Ribavinna Intron A + Placebo Patient 24 weeks 48 weeks 24 weeks 48 weeks
The sustained virological response for all patients with HCV genotype 1 treated for 24 and 48 weeks with the therapy of
The combination was statistically significantly higher than that observed for all patients with HCV genotype 1 treated with INTRON A plus placebo for 24 and 48 weeks The sustained virological response for patients with HCV genotype 1 with a baseline HCV viral load greater than 2 million copies / ml was statistically significantly higher than
24 and 48 weeks of combination therapy compared to INTRON A + Placebo for 24 and 48 weeks
TABLE 17 Sustained virological response by HCV genotype and baseline HCV RNA levels for Studies 1 and 2
Intron A + Ribavipna Intron A + Placebo Patients 24 weeks 48 weeks 24 weeks 48 weeks
Genotype 1 of HCV and levels of RNA DEL HCV line 32% 33% 4% 25% Basal of < 2 million copies / ml HCV Genotype 1 and HCV RNA levels of line 11% 27% baseline of > 2 million 1% 4
^ n copies / ml Other genotypes of HCV1 and RNA levels of HCV of 61% 64% 25% 36% Baseline of > 2 million Other HCV1 genotypes and RNA levels of the baseline HCV RNA of > 2 million 62% 61% 11% 10% copies The HCV genotypes 4/5/6 represent the 3% sustained response of patients for l + R 24% (24 weeks) and 38% (48 weeks) for I + P 0% (24 weeks) and 11% (48 1 weeks) The sustained response rate for 2 + 3 HCV genotypes is the same as the previous one
TABLE 18 Sustained virological response by baseline HCV RNA levels for all patients (Studies 1 and 2)
Patients Intron A + Ribavmna Intron A + Placebo 24 48 24 48 weeks weeks weeks weeks
Patients with HCV RNA levels of 44% 46% baseline < 2 million 9% 36% copies / ml Patients with HCV RNA levels of 27% 38% 4% 10% baseline > 2 million copies / ml
TABLE 19 Percentage of patients with sustained viral response over time for first levels of non-detectable HCV RNA for Studies 1 and 2
Time for Intron A + Ribavirin Intron A + Placebo first HCV RNA not detectable (weeks) 24 weeks 48 weeks 24 weeks 48 weeks
4 83% (92 111) 82% (94/115) 48% (10/21) 71% (47/66)
12 44% (66/149) 66% (91/137) 9% (3/32) 35% (29/84)
24 19% (8/42) 44% (20/45) 0% (0/22) 15% (6/39)
TABLE 20 ALT Response: Normalization of ALT in serum in all patients in Studies 1 and 2
INTRON A + Ribavirin INTRON A + Placebo? L tdreTÍn? 24 weeks 5 fi £ Value. "P value" A treatment (N = 505) weeks weeks weeks B vs D vs D (N = 505) (N = 231) (N = 503) Study 1 and 2 66% (329) 66% (334) 24% (56) 37% (185) < 0 001 0739
1 58% (133) 61% (138) 24% (56) 28% (62) < 0 001 < 0 001
2 71% (196) 71% (196) - 44% (123) < 0 001 < 0 001
End of follow-up Study 1 + 2b 36% (181) 44% (221) 11% (25) 24% (102) < 0 001 < 0 001
1 32% (72) 36% (83) 11% (25) 16% (35) < 0 001 < 0 001
2 39% (109) 50% (138) - 24% (67) < 0 001 < 0 001 a General association of Cochran-Mantet Haenszel for combined results, Fisher's exact test for multiple studies Combined results
Many modifications and variations of this invention can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. The specific embodiments described herein are offered by way of example only, and the invention should be limited only by the terms of the appended claims, together with the full scope of permitted equivalents for said claims
Claims (12)
1 - . 1 - The use of pbavipna for the manufacture of a pharmaceutical composition for treating a patient who has not received antiviral treatment having a chronic hepatitis C infection to eradicate detectable HCV RNA by a method comprising administering an effective amount of pbavipna in association with an effective amount of alpha interferon for a period of 20 to 50 weeks, and wherein the patient who has not received antiviral treatment has an HCV genotype 2 or 3 infection, administration of pbavinna in association with interferon alfa is carried out for a period of 20-30 weeks, preferably 24 weeks, and wherein the patient who has not received antiviral treatment has an HCV genotype 1 infection, the administration of pbavipna in association with interferon alfa is carried out for a period of 40 days. -50 weeks, preferably 48 weeks
2 - The use of interferon alfa for the manufacture of a pharmaceutical composition A method of treating a patient who has not received antiviral treatment who has a chronic hepatitis C infection to eradicate detectable HCV RNA by a method comprising administering an effective amount of alpha interferon alfa in association with an effective amount of pbavipna over a period of 20 to 50 weeks, and where the patient who has not received antiviral treatment has an HCV genotype 1 infection, the administration of pbavipna in association with interferon alfa is carried out for a period of 40-50 weeks, preferably 48 weeks and in which the patient who has not received antiviral treatment has an infection by genotype 2 or 3 of HCV, the administration of pbavinna in association interferon alfa is carried out for a period of 20-30 weeks, preferably 24 weeks
3 - The use of both pbavipna and alpha ipterferon alfa for the manufacture of pharmaceutical compositions for treating a patient who has not received antiviral treatment having chronic hepatitis C infection to eradicate detectable HCV RNA by a method comprising administering an effective amount of pbavipna in association with an effective amount of alpha-interferon during a period of 20 to 50 weeks, and where the patient who has not received anti-HIV treatment virus has an infection by HCV genotype 1, the administration of pbavipna in association with interferon alfa is carried out for a period of 40-50 weeks, preferably 48 weeks, and where the patient who has not received antiviral treatment has an infection due to Genotype 2 or 3 of HCV, the administration of pbavipna in association with interferon alfa is carried out during a pepod of 20-30 weeks, preferably 24 weeks
4 - Use in accordance with any previous claim, further characterized because the patient who has not received antiviral treatment is a patient who has an HCV genotype 1 infection and a viral load greater than 2 million copies per ml of quantitative PCR of HCV RNA
5 - The use according to any of claims 1, 2 or 3, further characterized because the patient has an HCV genotype 1 infection and a load viral load greater than 2 million copies per ml of HCV-1 RNA as measured by quantitative HCV RNA PCR and where the administration is carried out for a period of 40-50 weeks, preferably 48 weeks
6 - The use of both of pbavipna as interferon alfa for the manufacture of pharmaceutical compositions for treating a patient who has not received antiviral treatment having chronic hepatitis C genotype 1 infection to eradicate detectable HCV-1 RNA by a method comprising administering an effective amount of pbavipna in association with an effective amount of alpha interferon for a period of 40-50 weeks, preferably 48 weeks
7 - The use of both pbavipna and alpha interf They were for the manufacture of pharmaceutical compositions for treating a patient who has not received antiviral treatment having chronic hepatitis C genotype 2 or 3 infection to eradicate detectable HCV RNA by a method comprising administering an effective amount of pbavirin in association with an effective amount of alpha-interferon during a pepodo of 20-30 weeks, preferably 24 weeks
8 -. 8 - The use of both pbavipna and alpha interferon for the manufacture of pharmaceutical compositions for treating a patient who has not received antiviral treatment having chronic hepatitis C genotype 1 infection, and a viral load greater than 2 million copies per ml of HCV-1 RNA as measured by quantitative PCR of HCV RNA to eradicate detectable HCV RNA by a method comprising administering an effective amount of pbavipna in association with an effective amount of alpha-interferon HCV for a period of 40 hours. -50 weeks, preferably 48 weeks
9 -The use according to any of the preceding claims, further characterized in that the amount of pbavipna administered is 800 to 1200 mg per day. The use according to any of claims 1 to 9. , further characterized in that the interferon alpha administered is selected from interferon alfa-2a, interferon alfa-2b, a consensus interferon, a p purified interferon alpha product, a pegylated interferon alfa-2a or a pegylated interferon alfa-2b 11 - The use according to any of claims 1 to 9, further characterized in that the alpha interferon employed is an alpha-2b interferon and the amount of alpha interferon administered is 2 to 10 million Ul per week on a weekly basis, TIW, QOD or target 12. - The use according to any of claims 1 to 9, further characterized in that alpha interferon is alpha-2a interferon and the amount of alpha interferon administered is from 2 to 10 million Ul per week on a weekly basis, TIW, QOD or daily
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US09/079,566 | 1998-05-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA00011198A true MXPA00011198A (en) | 2001-07-31 |
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