SCH 503034, a Novel Hepatitis C Virus Protease Inhibitor, Plus Pegylated Interferon α-2b for Genotype 1 Nonresponders
2007; Elsevier BV; Volume: 132; Issue: 4 Linguagem: Inglês
10.1053/j.gastro.2007.01.041
ISSN1528-0012
AutoresChristoph Sarrazin, Roman Rouzier, Frank Wagner, Nicole Forestier, Dominique Larrey, Samir K. Gupta, Musaddeq Hussain, Amrik Shah, David L. Cutler, Jenny Zhang, Stefan Zeuzem,
Tópico(s)Hepatitis B Virus Studies
ResumoBackground & Aims: SCH 503034 is a novel and potent oral hepatitis C virus (HCV) protease inhibitor. In this phase Ib study, we assessed safety parameters and virologic response of combination of SCH 503034 plus pegylated (PEG) interferon (IFN) α-2b in patients with HCV genotype 1 infections who were previously nonresponders to PEG-IFN-α-2b ± ribavirin therapy. Methods: This was a multicenter, open-label, 2-dose level, 3-way crossover, randomized (to crossover sequence) study carried out in 3 medical centers in Europe. Adult patients received SCH 503034 200 mg (n = 14) or 400 mg (n = 12) 3 times daily orally and PEG-IFN-α-2b 1.5 μg/kg subcutaneously once each week. Patients received SCH 503034 as monotherapy for 1 week, PEG-IFN-α-2b as monotherapy for 2 weeks, and combination therapy for 2 weeks with washout periods between each treatment period. Results: Combination therapy with SCH 503034 and PEG-IFN-α-2b was well tolerated, with no clinically significant changes in safety parameters. Mean maximum log10 changes in HCV RNA were −2.45 ± 0.22 and −2.88 ± 0.22 for PEG-IFN-α-2b plus 200 mg and 400 mg SCH 503034, respectively, compared with −1.08 ± 0.22 and −1.61 ± 0.21 for SCH 503034 200 mg and 400 mg, respectively, and −1.08 ± 0.22 and −1.26 ± 0.20 for PEG-IFN-α-2b alone in the 200 mg and 400 mg SCH 503034 groups, respectively. Conclusions: SCH 503034 plus PEG-IFN-α-2b was well tolerated in patients with HCV genotype 1 nonresponders to PEG-IFN-α-2b ± ribavirin. These preliminary results of antiviral activity of the combination suggest a potential new therapeutic option for this hard-to-treat, nonresponder patient population. Background & Aims: SCH 503034 is a novel and potent oral hepatitis C virus (HCV) protease inhibitor. In this phase Ib study, we assessed safety parameters and virologic response of combination of SCH 503034 plus pegylated (PEG) interferon (IFN) α-2b in patients with HCV genotype 1 infections who were previously nonresponders to PEG-IFN-α-2b ± ribavirin therapy. Methods: This was a multicenter, open-label, 2-dose level, 3-way crossover, randomized (to crossover sequence) study carried out in 3 medical centers in Europe. Adult patients received SCH 503034 200 mg (n = 14) or 400 mg (n = 12) 3 times daily orally and PEG-IFN-α-2b 1.5 μg/kg subcutaneously once each week. Patients received SCH 503034 as monotherapy for 1 week, PEG-IFN-α-2b as monotherapy for 2 weeks, and combination therapy for 2 weeks with washout periods between each treatment period. Results: Combination therapy with SCH 503034 and PEG-IFN-α-2b was well tolerated, with no clinically significant changes in safety parameters. Mean maximum log10 changes in HCV RNA were −2.45 ± 0.22 and −2.88 ± 0.22 for PEG-IFN-α-2b plus 200 mg and 400 mg SCH 503034, respectively, compared with −1.08 ± 0.22 and −1.61 ± 0.21 for SCH 503034 200 mg and 400 mg, respectively, and −1.08 ± 0.22 and −1.26 ± 0.20 for PEG-IFN-α-2b alone in the 200 mg and 400 mg SCH 503034 groups, respectively. Conclusions: SCH 503034 plus PEG-IFN-α-2b was well tolerated in patients with HCV genotype 1 nonresponders to PEG-IFN-α-2b ± ribavirin. These preliminary results of antiviral activity of the combination suggest a potential new therapeutic option for this hard-to-treat, nonresponder patient population. See editorial on page 1611. See editorial on page 1611. The current standard of care for the serious public health problem represented by chronic hepatitis C is pegylated (PEG) interferon (IFN) α plus ribavirin. Among patients with genotype-1a/1b hepatitis C virus (HCV) infection, the most common genotype in North America, Europe, and Japan, treatment with PEG-IFN-α plus ribavirin results in sustained virologic response in only approximately 40% to 50%.1Zeuzem S. Buti M. Ferenci P. Sperl J. Horsmans Y. Cianciara J. Ibraniyi E. Weiland O. Noviello S. Brass C. Albrecht J. Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia.J Hepatol. 2006; 44: 97-103Abstract Full Text Full Text PDF PubMed Scopus (451) Google Scholar, 2Manns M.P. McHutchison J.G. Gordon S.C. Rustigi V.K. Shiffman M. Reindollar R. Goodman Z.D. Koury K. Ling M. Albrecht J.K. 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Early clearance of HCV RNA with valopicitabine (NM283) plus peg-interferon in treatment-naive patients with HCV-1 infection: first results from a Phase IIb trial.J Hepatol. 2006; 44: S271Abstract Full Text PDF Google Scholar, 15Roberts S. Cooksley G. Shaw D. Berns H.K. Brandl M.T. Fettner S.H. Hill G. Ipe D. Klumpp K. Mannino M. O'Mara E. Tu Y. Washington C.B. Interim results of a multiple ascending dose study of R1626, a novel nucleoside analog targeting HCV polymerase in chronic HCV patients.J Hepatol. 2006; 44: S269Abstract Full Text PDF Google Scholar The difficult-to-treat population that has not responded to current therapy may benefit most from these new developments. HCV is an enveloped, positive-strand RNA virus of approximately 9.6 kilobase. HCV infection of host hepatic cells triggers a series of intracellular signaling events through specific receptors that result in increased production of IFNs α and β, the central mediators of the host antiviral response. The expression of many genes is regulated by IFNs, and their products mediate viral and host functions that limit HCV replication. Furthermore, secreted IFN-β interacts with the IFN-α/β receptor to activate the Janus kinase/signal transducers and activators of transcription signaling pathway in infected cells and in neighboring uninfected tissue. Signaling through this pathway results in amplified IFN α/β production and limits cell-to-cell spread of virus.16Gale Jr, M. Foy E.M. Evasion of intracellular host defence by hepatitis C virus.Nature. 2005; 436: 939-945Crossref PubMed Scopus (549) Google Scholar Upon entry into a host cell, the RNA genome is translated to assemble a 3000-amino acid polyprotein that undergoes posttranslational processing by viral and host proteases to produce 10 different polypeptides.17Reed K.E. Rice C.M. 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Combination of a hepatitis C virus NS3-NS4A protease inhibitor and α interferon synergistically inhibits viral RNA replication and facilitates viral RNA clearance in replicon cells.Antimicrob Agents Chemother. 2004; 48: 4784-4792Crossref PubMed Scopus (84) Google Scholar make inhibition of the NS3 serine protease an attractive target for development of antiviral therapies. SCH 503034 may provide dual antiviral activity through direct suppression of viral replication and restored IFN activity. The NS3 serine protease has high substrate specificity because of a unique extended substrate-binding cleft. Rational inhibitor design resulted in discovery of SCH 503034, a novel peptidomimetic NS3 protease inhibitor. The ketoamide portion of SCH 503034 forms a specific, stable, covalent, and reversible complex with NS3 in vitro and has potent activity in the HCV replicon system. Furthermore, results of combining SCH 503034 and IFN-α-2b in the HCV replicon system suggested at least additive potency of the combination compared with either agent alone.22Malcolm B.A. Liu R. Lahser F. Agrawal S. Belanger B. Butkiewicz N. Chase R. Gheyas F. Hart A. Hesk D. Ingravallo P. Jiang C. Kong R. Lu J. Pichardo J. Prongay A. Skelton A. Tong X. Venkatraman S. Xia E. Girijavallabhan V. Njoroge G.F. SCH 503034, a mechanism-based inhibitor of hepatitis C virus NS3 protease, suppresses polyprotein maturation and enhances the antiviral activity of α interferon in replicon cells.Antimicrob Agents Chemother. 2006; 50: 1013-1020Crossref PubMed Scopus (285) Google Scholar These observations provided rationale for clinical investigation of combination therapy with SCH 503034 and PEG-IFN-α-2b in a phase Ib trial. Two initial dose levels of SCH 503034 were evaluated for safety and tolerability as monotherapy and in combination with PEG-IFN-α-2b in comparison with PEG-IFN-α-2b alone in 26 patients with chronic HCV infection who had previously not responded to treatment with PEG-IFN-α-2b ± ribavirin. Virologic response and pharmacokinetic parameters of the 2 agents in short-term monotherapy and combination therapy were also evaluated. The primary objective of this phase I study was to determine the safety and tolerability of SCH 503034 in combination with PEG-IFN-α-2b for patients with HCV genotype 1 who had previously failed to respond to PEG-IFN-α-2b (Peg-Intron; Schering-Plough Corporation, Kenilworth, NJ) ± ribavirin. Secondary objectives were to assess pharmacodynamic characteristics of this combination therapy with HCV viral load measurements, as well as to evaluate pharmacokinetic parameters for each component alone and in combination. A number of at least 10 patients for each protease inhibitor dose level were considered to be sufficient for assessment of safety, efficacy, and proof of concept in this phase I study. Patients of either sex and any race could be included in this study if they were 18 to 60 years of age, were willing to give written informed consent, and were willing to undergo multiple inpatient periods and outpatient visits during the study. Female patients had to be surgically sterile or of non-childbearing potential, and males had to practice acceptable methods of contraception. Female partners of male enrollees also had to practice acceptable methods of contraception, and all contraception had to have been practiced for 30 days before the dosing period, during all dosing periods, and for 30 days after discontinuation of dosing. Patients had to be serum positive for HCV RNA by quantitative polymerase chain reaction (PCR) assay, with ≥100,000 IU/mL RNA and be genotype 1a or 1b nonresponders to PEG-IFN-α-2b with or without ribavirin. Nonresponse was defined as achieving less than a 2-log10 decline in HCV RNA levels after at least 12 weeks of dosing with PEG-IFN-α-2b at 1.5 μg/kg/wk. Patients had to have alanine aminotransferase (ALT) and aspartate aminotransferase ≤5 times upper limit of normal, α-fetoprotein values within normal levels, negative screen for drugs with high potential for abuse, normal or clinically acceptable electrocardiogram (QTc value, <450 milliseconds (ms) for females and <430 ms for males), and evidence of compensated liver disease. Patients were required to meet the following criteria: hemoglobin ≥11 g/dL for females and ≥12 g/dL for males, white blood cells ≥4000/mm3, neutrophil count ≥1500/mm3, and platelets ≥100,000/mm3 and the following parameters within normal limits: direct bilirubin, indirect bilirubin, albumin, prothrombin time, activated partial thromboplastin time, and serum creatinine. Patients were excluded from the study if they met any of the following criteria: hemophilia or use of anticoagulant therapy; evidence of advanced liver disease (eg, known cirrhosis, history or presence of ascites, bleeding varices, encephalopathy); presence of organ transplant; known human immunodeficiency virus (HIV) or hepatitis B virus positivity based on recent tests for anti-HIV antibodies and hepatitis B surface antigen; or liver disease with a cause other than chronic hepatitis C. The significance of antinuclear antibodies, if present, was to be evaluated by investigators for individual patients to determine whether any interference with the protocol that would warrant exclusion from the study could be expected. The study was carried out in 3 medical centers in Europe. Approval by each center's institutional review board was obtained, and the study was conducted in conformance with Good Clinical Practices. All enrolled patients provided written informed consent. All investigational drugs were supplied by Schering-Plough Research Institute (Kenilworth, NJ). This phase I clinical trial was a randomized-to-sequence, open-label, 2-dose level, crossover study. Patients (n = 26) received 3 periods of dosing, consisting of administration of SCH 503034 monotherapy for 1 week, administration of PEG-IFN-α-2b monotherapy once weekly for 2 weeks, and administration of combination SCH 503034 plus PEG-IFN-α-2b for 2 weeks. The first 2 treatment periods were followed each by at least 2-week washout periods, and the third treatment period was followed by a 2-week follow-up period. Patients were randomized to determine the sequence of treatment periods by a computer program (Table 1). Based on the results of a previous dose-finding study, 2 dose levels of SCH 503034, 200 mg 3 times daily and 400 mg 3 times daily, were evaluated. PEG-IFN-α-2b was administered at 1.5 μg/kg once per week.Table 1Design of the 3-Way Crossover StudyNo. per SequencePeriod 1Period 2Period 34SCH 503034 7 daysPEG-IFN-α-2b 14 daysCombo Tx 14 days4PEG-IFN-α-2b 14 daysCombo Tx 14 daysSCH 503034 7 days5Combo Tx 14 daysSCH 503034 7 daysPEG-IFN-α-2b 14 days5SCH 503034 7 daysCombo Tx 14 daysPEG-IFN-α-2b 14 days4PEG-IFN-α-2b 14 daysSCH 503034 7 daysCombo Tx 14 days4Combo Tx 14 daysPEG-IFN-α-2b 14 daysSCH 503034 7 daysNOTE. Patients (n = 26) were randomized to receive 6 possible sequences of treatment at each dose of SCH 503034 (n = 14 at 200 mg 3 times daily; n = 12 at 400 mg 3 times daily).Combo Tx, combination therapy with PEG-IFN-α-2b and SCH 503034. Open table in a new tab NOTE. Patients (n = 26) were randomized to receive 6 possible sequences of treatment at each dose of SCH 503034 (n = 14 at 200 mg 3 times daily; n = 12 at 400 mg 3 times daily). Combo Tx, combination therapy with PEG-IFN-α-2b and SCH 503034. Safety and tolerability of study treatments were assessed by clinical laboratory tests, vital signs, physical examination, electrocardiograms, and occurrence of adverse events. Clinical laboratory tests were recorded on days −1, 3, 6, and 10 during combination therapy and monotherapy with PEG-IFN-α-2b and on days −1, 3, and 6 during SCH 503034 monotherapy and day 14 of the follow-up period. Urinalysis was performed on day −1 of each treatment period and the follow-up period. Electrocardiograms were performed at hours 0 and 1 on days −1, 1, 2, 3, 8, 9, and 10 during combination therapy periods and at hours 0 and 1 on days −1, 1, 2, and 3 during monotherapy with SCH 503034. In addition to outpatient visits, patients were confined to the hospital for the initial 8 days of the combination therapy and PEG-IFN-α-2b monotherapy treatment periods and for the initial 4 days during the SCH 503034 monotherapy treatment period to assess carefully the safety and tolerability as well as to optimize compliance. Complete blood counts and chemistry were obtained twice per week during dosing periods. The severity of adverse events was graded according to the National Cancer Institute Common Toxicity Criteria.23Cancer Therapy Evaluation Program. Common terminology criteria for adverse events v3.0 (CTCAE). Publish Date: December 12, 2003. Available at: http://ctep.cancer.gov. Accessed May 29, 2006.Google Scholar Investigators at each site assessed each adverse event as unlikely, possibly, or probably related to use of study drug. Blood samples for HCV RNA determinations and viral sequencing were collected daily during the different therapies. HCV RNA was measured by extracting total RNA from the sample and using an in-house real-time reverse-transcriptase (RT)-PCR assay with a lower limit of detection of 29 IU/mL. The amplification target was the 5′-untranslated region of the HCV genome. An internal RNA control was added to each sample to assess efficiency of RNA extraction and RT-PCR. Appropriate negative and positive controls were added in each assay run. During their hospital stay, patients were fed standard low-fat meals either 90 minutes before SCH 503034 dosing or 90 minutes after on days when pharmacokinetic sampling was not performed. On pharmacokinetic sampling days, patients underwent a 10-hour fast, except for water before sampling and during the 4-hour sampling period. During outpatient periods, patients were asked to attempt to keep the same schedule of meals and dosing and to record meal and dosing times in a diary. Blood samples for pharmacokinetic analyses of SCH 503034 were collected prior to dosing (0 hour) and at 0.5, 1, 1.5, 2, 4, 6, and 8 hours after the morning dose on day 1 of monotherapy treatment periods and on days 1 and 8 of combination therapy treatment periods. Blood samples for pharmacokinetic analyses of PEG-IFN-α-2b were collected beginning on day 1 of monotherapy and combination therapy treatment periods at hours 0, 12, 24, 48, 72, and 168. Plasma samples were assayed for SCH 503034 using a validated liquid chromatographic tandem mass spectrometric method with a limit of quantitation of 0.500 ng/mL. Serum PEG-IFN-α-2b concentrations were determined as previously described using a validated electrochemiluminescence assay (limit of quantification 50 pg/mL, and variability was 12% at 50 pg/mL).24Glue P. Rouzier-Panis R. Raffanel C. Sabo C. Gupta S.K. Salfi M. Jacobs S. Clement R.P. A dose-ranging study of pegylated interferon alfa-2b and ribavirin in chronic hepatitis C.Hepatology. 2000; 32: 647-653Crossref PubMed Scopus (247) Google Scholar The following pharmacokinetic variables were estimated for SCH 503034 using model-independent methods: maximum observed plasma concentration; time of observed maximum plasma concentration; area under the plasma concentration-time curve over the dosing interval (AUC [0-τ]); apparent total body clearance at steady state; and accumulation ratio. Serum concentration data were used to estimate AUC (0–168 hours) for PEG-IFN-α-2b. A total of 26 patients (17 males, 9 females) were randomized to 3 different treatment arms in the sequences described in Table 1. Fourteen patients received SCH 503034 therapy at the 200 mg 3 times daily dose level and 12 at the 400 mg 3 times daily dose level. Demographic and other baseline characteristics of these patients are shown in Table 2.Table 2Demographic and Baseline Characteristics of 26 Patients Who Received SCH 503034 at 2 Different Dose Levels in Combination With PEG-IFN-α-2bSCH 503034 200 mg TID (n = 14)SCH 503034 400 mg TID (n = 12)Sex, n (%) Female6 (43)3 (25) Male8 (57)9 (75)Race, n (%) White12 (86)12 (100) Black2 (14)0Age, y Mean (SD)44.5 (6.1)48.9 (9.1) Median44.050.5 Range34−5631−64Weight (kg) Mean (SD)77 (16)79.1 (15.3) Median7580.4 Range51.8−106.355.1−100.0Height, cm Mean (SD)173.4 (11.1)174.0 (11.6) Median75.080.4 Range152.0−186.0159.0−193.0BMI (kg/m2) Mean (SD)25.4 (3.2)25.9 (2.0) Median25.325.7 Range21.0−31.121.5−28.9ALT (U/mL) Mean8380 Range28−14841−144HCV RNA (Log IU/mL) Mean6.35.6 Range5.6−6.84.0−6.2ALT, alanine aminotransferase; BMI, body mass index. Open table in a new tab ALT, alanine aminotransferase; BMI, body mass index. SCH 503034 as monotherapy and in combination with PEG-IFN-α-2b was generally well tolerated. Headache, myalgia, rigor, and fever were the most common treatment-emergent adverse events reported during combination and PEG-IFN monotherapy treatment periods. A summary of treatment-emergent adverse events experienced by 10% or more of patients in any group is shown in Table 3. Consistent with adverse event profiles associated with PEG-IFN-α-2b monotherapy, the incidence of headache, rigor, and myalgia was higher during combination therapy than SCH 503034 monotherapy.Table 3Summary of Treatment-Emergent Adverse Events in 10% or More of Patients in Any Cohort That Received SCH 503034 Monotherapy, PEG-IFN-α-2b Monotherapy, or Combination TherapyAdverse eventsSCH 503034 200 mg TID 1 week, n = 12 (%)SCH 503034 200 mg TID + PEG-IFN-α-2b 2 weeks, n = 13 (%)PEG-IFN-α-2b 2 weeks, n = 24 (%)SCH 503034 400 mg TID 1 week, n = 11 (%)SCH 503034 400 mg TID + PEG-IFN-α-2b 2 weeks, n = 10 (%)Total, n = 26 (%)Subjects reporting any adverse event5 (42)13 (100)22 (92)2 (18)10 (100)25 (96)Subjects discontinuing because of an adverse event01 (8)2 (8)003 (12)Symptoms Application site disorders02 (15)1 (4)01 (10)3 (12) Fatigue01 (8)1 (4)02 (20)3 (12) Fever02 (15)3 (13)04 (40)8 (31) Headache3 (25)10 (77)14 (58)1 (9)8 (80)23 (88) Influenza-like symptoms01 (8)2 (8)01 (10)3 (12) Rigors06 (46)8 (33)1 (9)4 (40)14 (54) Weakness001 (4)01 (10)1 (4) Abdominal pain02 (15)1 (4)003 (12) Dyspepsia00001 (10)1 (4) Nausea02 (15)1 (4)003 (12) Vomiting02 (15)1 (4)1 (9)03 (12) Back pain002 (8)01 (10)3 (12) Myalgia07 (54)15 (63)07 (70)18 (69) Emotional lability00001 (10)1 (4) Strangury00001 (10)1 (4) Taste perversion00001 (10)1 (4)Signs Injection site inflammation02 (15)1 (4)01 (10)3 (12)Laboratory and electrocardiogram abnormalities Anemia2 (17)1 (8)0002 (8) Leukopenia02 (15)4 (17)005 (19) Neutropenia06 (46)5 (21)009 (35) QTc/QT prolongation001 (4)1 (9)1 (10)1 (4)NOTE. SCH 503034 monotherapy (200 mg TID or 400 mg TID); PEG-IFN-α-2b monotherapy (1.5 μg/kg/wk). Laboratory values outside the normal range were assessed as adverse events with the following definitions: anemia, hemoglobin values of <11 g/dL for females and <12 g/dL for males; leukopenia, white blood count <4000/mm3; neutropenia, neutrophil count <1500/mm3; QTc/QT prolongation ≥450 ms for female and ≥430 ms for male patients (Bazett's). Any clinically significant change from baseline was recorded as an adverse event.TID, 3 times daily. Open table in a new tab NOTE. SCH 503034 monotherapy (200 mg TID or 400 mg TID); PEG-IFN-α-2b monotherapy (1.5 μg/kg/wk). Laboratory values outside the normal range were assessed as adverse events with the following definitions: anemia, hemoglobin values of <11 g/dL for females and <12 g/dL for males; leukopenia, white blood count <4000/mm3; neutropenia, neutrophil count <1500/mm3; QTc/QT prolongation ≥450 ms for female and ≥430 ms for male patients (Bazett's). Any clinically significant change from baseline was recorded as an adverse event. TID, 3 times daily. Evaluation of blood chemistry, hematology, and urinalysis parameters revealed no clinically significant abnormalities and no pattern of abnormalities associated with treatments in this study. One instance (8% of patients) of grade 1 increase in ALT levels was observed during combination therapy with SCH 503034 200 mg and PEG-IFN-α-2b. No significant changes in vital signs or electrocardiogram data between baseline and treatment values were observed. One occurrence of anemia and 1 complex partial seizure were considered to be important or serious adverse events, which, however, were not considered by the investigator to be related to administration of study drugs. The patient with the partial seizure had a past history of similar events, which he did not disclose during screening for this study. In all, 3 patients discontinued treatment because of treatment-emergent adverse events (complex partial seizures during combination therapy in period 1; leukopenia and neutropenia during PEG-IFN-2b monotherapy in period 1; and neutrophil count decrease during PEG-IFN-α-2b monotherapy in period 2), and 1 patient discontinued treatment for reasons unrelated to the study. All 3 treatment arms were completed by 12 patients who received 200 mg 3 times daily SCH 503034 and 10 patients given 400 mg 3 times daily SCH 503034. Pharmacokinetic parameters for SCH 503034 on day 1 of monotherapy and on days 1 and 8 of combination therapy with PEG-IFN-α-2b are shown in Table 4. The AUC (0-τ) on day 1 of monotherapy and combination therapy of both dose groups are similar, which suggests that there was no interaction between SCH 503034 and PEG-IFN. Based on AUC measurements on day 1 and 8 of combination therapy, the mean accumulation ratios of SCH 503034 were 1.71 following 200 mg 3 times daily ther
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