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JOINT RAPPORTEURS

Assessment Report on the Applicants responses to the

D150 CHMP LOQ

OVERVIEW

VICTRELISBoceprevir

EMEA/H/C/0002332/000

Applicant: Schering-Plough

Rapporteur:

Co-Rapporteur:

EMA PTL:

Start of the procedure: 26 November 2010

Date of this JOINT D150 report: 4 May 2011

Deadline for CHMP comments 9 May 2011


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TABLE OF CONTENTS

1. RECOMMENDATION ................................................................................. 6

2. EXECUTIVE SUMMARY ............................................................................. 7

2.1. Problem statement ............................................................................................... 72.2. About the product ................................................................................................ 82.3. The development programme/Compliance with CHMP Guidance/Scientific Advice ......... 92.4. General comments on compliance with GMP, GLP, GCP ........................................... 102.5. Type of application and other comments on the submitted dossier............................ 10

3. SCIENTIFIC OVERVIEW AND DISCUSSION ............................................ 113.1. Introduction....................................................................................................... 113.2. Quality aspects .................................................................................................. 113.3. Non clinical aspects ............................................................................................ 133.4. Clinical aspects .................................................................................................. 20

4. ORPHAN MEDICINAL PRODUCTS ........................................................... 62

5. BENEFIT RISK ASSESSMENT .................................................................. 625.1. Conclusions ....................................................................................................... 68

6. LIST OF ISSUES TO BE FURTHER CLARIFIED AND COMMITMENTS ....... 696.1 Quality aspects ................................................................................................. 696.2 Non clinical aspects ........................................................................................... 716.3 Clinical aspects ................................................................................................. 71

7. SUMMARY OF PRODUCT CHARACTERISTICS (SMPC)............................ 73


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ADMINISTRATIVE INFORMATION

Invented name of the medicinal product: VICTRELIS

INN (or common name) of the activesubstance(s):

BOCEPREVIR

Applicant: Schering-Plough

Applied Indication(s): Treatment of chronic hepatitis C genotype 1

infection, in combination with peginterferon alphaand ribavirin, in adult patients with compensated

liver disease who are previously untreated or whohave failed previous therapy.

Pharmaco-therapeutic group(ATC Code):

Not yet assigned

Pharmaceutical form(s) and strength(s): 200 mg

Rapporteur contact person:

Co-Rapporteur contact person:

EMA Product Team Leader:

Names of the Rapporteur assessors(internal and external):

Names of the Co-Rapporteur assessors(internal and external):


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LIST OF ABBREVIATIONS

AE adverse eventALT alanine transaminase

ANC absolute neutrophil countaPTT Activated Partial Thromboplastin TimeAUC area under the concentration-time curveBMI body mass indexBND benzphetamine N-demethylaseCHC chronic hepatitis CCHMP Committee for Medicinal Products for Human UseCI confidence intervalCL/F apparent clearanceCmax maximum drug concentrationCSR clinical study reportCV coefficient of variation

CYP cytochrome P450DMC data monitoring committeeDNA deoxyribonucleic acidECOD 7-ethoxycoumarin O-deethylaseELISA enzyme linked immunosorbent assayEROD 7-ethoxyresorufin O-deethylaseESRD end-stage renal diseaseETR end of treatment responseEU European UnionFDA US Food and Drug AdministrationGCP Good Clinical PracticeGGT gamma glutamyl transferaseHCV hepatitis C virusHIV human immunodeficiency virusIFN interferonIFN interferon alfaITT intention-to-treatIU international unitsIV intravenous(ly)LOD limit of detectionMedDRA Medical Dictionary for Regulatory ActivitiesPCR polymerase chain reactionPD Pharmacodynamics

PEG-IFN pegylated interferonPEG-IFN2a peginterferon alfa-2aPEG-IFN2b peginterferon alfa-2bPR Peginterferon+RibavirinPK pharmacokineticsPT Prothrombin TimePROD 7-pentoxyresorufin O-dealkylaseRBV ribavirinRNA ribonucleic acidSAE serious adverse eventSC subcutaneous(ly)SOC Standard of Care=Peg-IFN+Ribavirin = Bitherapy

SVR sustained virologic responset1/2, absorption half-life


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t1/2,z elimination half-lifeTSH thyroid stimulating hormoneULN upper limit of normalUS United States of America

SCH 18908 RibavirinSCH 503034 BoceprevirSCH 534128 Diastereoisomer of boceprevir with S-configuration at the third carbon atom from the

ketoamide end of the moleculeSCH 534129 Diastereoisomer of boceprevir with R-configuration at the third carbon atom from the

ketoamide end of the moleculeSCH 54031 PEG-Intron, peginterferon alphaSCH 629144 Major circulating metabolite of boceprevir in monkeys and humansSCH 783004 Diastereoisomer of SCH 629144, formed from SCH 534129SCH 783005 Diastereoisomer of SCH 629144, formed from SCH 534128

SCH 783006 Diastereoisomer of SCH 629144, formed from SCH 534129SCH 783007 Diastereoisomer of SCH 629144, formed from SCH 534128


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1. RECOMMENDATION

Based on the review of the data on quality, safety and efficacy, the Rapporteurs consider that theapplication for VICTRELIS (Boceprevir), in the treatment of genotype 1 chronic hepatitis C infection inadult patients with compensated liver disease, could be approvable provided the SPC is revised in line

with Rapporteurs comments. Moreover, two main issues should be part of the annex II since it isconsidered compulsory to further substantiate the benefit/risk balance:

1- the clinical dossier so far does not allow to fully appreciate to what extent the management of thesubstantial incremental anemia induced by boceprevir on top of PR could per se negatively affect the

benefit-risk balance of boceprevir, having in mind that on the one hand ribavirin dose reduction couldpotentially alter the benefit and on the other hand the EPO use, through its safety profile (associated withrisk of PRCA and thrombosis events), could alter the risk.It is therefore considered compulsory that, in order to establish the most rational management of anemia,additional investigations be performed by the applicant to better understand the causes (and consequently

possible patient characteristics) and potential negative consequences of the management of the high rate

of anemia (as a result of the incremental risk with boceprevir) in patients receiving the tritherapy withboceprevir+ribavirin+peginterferon.In particular the MAH is required to present plans and protocols investigating the following:

a. the mechanism underlying the observed increase of anemia (and to a lesser extent neutropenia andthrombocytopenia) in patients co-administered boceprevir with PR standard of care, which is suggested

being the result of an additional suppressive effect on bone marrow hematopoietic processes.

b. the potential impact on efficacy of lowering the dose of ribavirin in the management of anemia. Inparticular the data generated should provide further insight into the impact on the most optimal treatmentregimen and duration and the characterisation of the potential patient population for which ribavirin dosereduction might be an option to manage the anemia.

c. the anemia management in patients treated for hepatitis C in the EU in the presence of boceprevirin clinical practice.

2. The applicant should be committed to dispel the current level of uncertainties on whether thosepatients with favourable factors (on treatment viral kinetics and/or IL28B) for interferon responsivenesscould still retrieve a significant benefit of adding boceprevir to the bitherapy. The design of the protocolaimed at addressing this issue and currently under reflexion at the applicant level should mandatorily bevalidated by the CHMP before the study starts and the timelines for submission of this draft protocolshould be shortened (beginning of September 2011 instead of December 2011) to avoid a lateimplementation of the study.


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2. EXECUTIVE SUMMARY

2.1. Problem statement

Hepatitis C virus (HCV) infection is one of the most important causes of chronic liver disease and agrowing global health concern.Worldwide, approximately 3% of the population is infected with HCV, which represents several millionsof people who are at risk of developing serious liver disease, including cirrhosis, liver failure andhepatocellular carcinoma.In Europe, the prevalence tends to vary from 0.5% in Northern European countries to 2% and higher inthe Mediterranean countries and in Eastern Europe.

Approximately 70% of newly infected HCV patients become chronic carriers; among them 20% willdevelop cirrhosis with a mean of 20 years. In patients with cirrhosis, the 5-year risk of hepaticdecompensation is approximately 15-20% and the risk of hepatocellular carcinoma 10%. End stage liver

disease due to HCV infection currently represents the major indication for liver transplantation indeveloped countries.

At least 6 major genotypesof HCV, each including multiple subtypes, have been identified worldwide.Genotype 1 accounts for most HCV infections globally, as well as in most European regions, with anoverall prevalence that is estimated above 60%. Infection with genotype 2 or 3 generally represents 20 to30% of all HCV infection.

The current standard of care for CHC consists of the combination of pegylated interferon-alfa (2aor 2b) and ribavirin.Treatment duration is generally 48 weeks for patients with genotype 1 or 4 and 24weeks for patients with genotype 2 or 3 but may vary depending on baseline viral load and initial virologicresponse to therapy. The primary treatment outcome is sustained viral response (SVR), which is defined asHCV viral undetectability using a sensitive PCR-based assay 24 weeks following completion of therapy.

There are several pejorative factors (for the disease evolution and) for the response to treatment.They may be virus related: notably infection by genotype 1 (majority of EU patients) is associated withvery limited response rates (40-50% SVR) as compared to the 80% response rates of genotype 2/3.

Moreover, patients co-infected with HIV-HCVviruses are known as exhibiting a more pejorative courseof the disease and have a lower response rate to the bitherapy.The degree of fibrosis (cirrhoticpatients are known as being difficult-to-treat patients) and the responseto prior course of bitherapy (null responders to a bitherapy are very poor response rate


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Boceprevir belongs to the new class of Direct Acting Antiviral agents (DAA) . After decades oftreatment only relying on the bitherapy with (Peg-)IFN+ribavirin, a lot of DAAs are currently in the

pipeline and offer perspectives of therapeutic improvement for the patients infected with a genotype 1, forwhich there is a critical room for improvement, as opposed to the genotype 2/3 (good responders to SOC).It is anticipated that the first generations drugs (including boceprevir) will one day be supersededby next generations approaching Applications status (with simplified dosing regimen, higherpotency and higher genetic barrier)as in field of HIV infection.

In parallel to the development of these new DAAs, a new significant finding has emerged from thescientific community as regards the likelihood of response to the SOC with the bitherapy Peg-IFN+ribavirin. It has recently been identified that a genetic polymorphism near the IL28B gene,encoding interferon--3, was strongly associated with the likelihood of response to SOC (Ge D, Fellay J,Thompson JT, Simon JS, Shianna KV, Urban TJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature2009; 461, 399-401.IL28B genomic-based treatment paradigms for patients with chronic hepatitis C infection: the future of personalized HCV

therapies. Clark PJ,Thompson AJ,McHutchison JG. Am J Gastroenterol. 2011 Jan;106(1):38-45).

Three different genotypes of this polymorphism were identified: CC, TT, and CT. The prevalence of thefavorable CC genotypevaried among racial groups, this genotype was seen to provide a stronger baseline

predictor of SVR within each racial group than viral load, HCV genotype, cirrhosis or any other knownpredictor of responsiveness to interferon-based therapy.

Still recently, a genetic variant leading to inosine triphosphatase (ITPA)deficiency has been associatedwith risk of ribavirin-related anemia during SOC. (Fellay J, Thompson AJ, Ge D, Gumbs CE, Urban TJ, Shianna KV, et al.ITPA gene variants protect against anaemia in patients treated for chronic hepatitis C. Nature 2010;464:405-408.Thompson AJ, Fellay J, Ge D,Urban T, Shianna K, Sulkowski M, et al. Genome wide analysis of patients from the IDEAL study identifies a causal role for ITPA genetic

variation in ribavirin-induced hemolytic anemia. Poster presented on April 15, 2010 at the Annual Meeting of the European Association for the

Study of the Liver (EASL), April 14-18, 2010; Vienna, Austria).

2.2. About the product

Boceprevir is a new antiviral agent, serine protease inhibitor, specifically designed to inhibit the HCVnonstructural protein 3 (NS3) protease and, thereby, inhibit viral replication in infected host cells. Themechanism of inhibition involves formation of a stable reversible covalent bond between the ketoamide of

boceprevir and the NS3 protease active site serine, which is the protease that mediates the cleavage of theHCV polyprotein to form the functional proteins essential for viral propagation. This mechanism isdistinct from those of currently approved therapies; thus, boceprevir represents a novel class of HCVinhibitors.

The proposed indication for Victrelis (boceprevir) is the treatment of chronic hepatitis C (HCV)genotype 1 infection, in combination with peginterferon alpha and ribavirin, in adult patients (18 years andolder) with compensated liver disease who are previously untreated or who have failed previous therapy.
http://www.ncbi.nlm.nih.gov/pubmed?term=%22Clark%20PJ%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Thompson%20AJ%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22McHutchison%20JG%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22McHutchison%20JG%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Thompson%20AJ%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Clark%20PJ%22%5BAuthor%5D


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The proposed treatment regimen is 800 mg of Boceprevir administered orally three times daily (TID) withfood.For the patients who are previously untreated, the therapeutic schema proposed is: peginterferon alpha and ribavirin for 4 weeks (Treatment Weeks 1 4). and addition of Victrelis 800 mg orally three times daily to peginterferon alpha and ribavirin regimen

at Treatment Week (TW) 5. Based on the patient's HCV-RNA levels at TW 8 and TW 24, thefollowing Response Guided Therapy (RGT) guidelines must be used to determine the duration oftreatment :

ASSESSMENT(HCV-RNA Results*)

ACTIONAt Treatment

Week 8At TreatmentWeek 24

Undetectable Undetectable Complete three medicines regimen at Treatment Week 28.

Detectable Undetectable

1. Continue all three medications until Treatment Week 28,and then

2. Administer peginterferon alpha and ribavirin untilTreatment Week 48.

Any Result Detectable Discontinue three medicines regimen.* In clinical trials, HCV-RNA in plasma was measured with a Roche COBAS TaqManassay with a limit of detection of9.3 IU/ml.

Patients who have failed previous therapy, the therapeutic schema proposed is: peginterferon alpha and ribavirin for 4 weeks (Treatment Weeks 1 4). and addition of Victrelis 800 mg orally three times daily to peginterferon alpha and ribavirin regimen

at Treatment Week (TW) 5. Based on the patient's HCV-RNA levels at TW 8 and TW 12, thefollowing Response Guided Therapy (RGT) must be used to determine the duration of treatment :

ASSESSMENT(HCV-RNA Results*)

ACTIONAt TreatmentWeek 8

At TreatmentWeek 12

Undetectable UndetectableContinue three medicines regimen until completion throughTreatment Week 36.

Detectable Undetectable

1. Continue all three medications until Treatment Week 36, andthen

2. Administer peginterferon alpha and ribavirin until TreatmentWeek 48.

Any Result Detectable Discontinue three medicines regimen.* In clinical trials, HCV-RNA in plasma was measured with a Roche COBAS TaqManassay with a limit of detection of9.3 IU/ml.

2.3. The development programme/Compliance with CHM P Guidance/Scienti f ic Advice

GMP:All relevant sites of drug product underwent GMP inspections by EEA/MRA authorities with asatisfactory outcome within the last 3 years.

The manufacturing site of the active substanceBoceprevir is covered by relevant declaration from theQualified Person of Victrelis batch release site.

Based on review of Quality dossier, no need has been identified for inspection request prior toauthorization. Nevertheless, a routine GMP and product specific inspection has been proposed by theEMA Compliance and Inspection Sector and endorsed by the CHMP in February 2011 for the

manufacturing facility Schering-Plough Ltd., 50 Tuas West Drive, SG-638413, Singapore.


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The applicant has made extensive efforts to reduce impurities as suggested by the scientific advice soughtwith EMA: the total of 11.5% at the time of scientific advice has been reduced to NMT 6.0%.Recommendations of the scientific advice have been well followed and implemented.

Regulatory advice on the phase 3 development program was obtained viaNationalAdvice from Swedenand France in 2008.

2.4. General comments on compli ance with GMP, GLP, GCP

2.5. Type of application and other comments on the submi tted dossier

Legal basis

The application is submitted in accordance with art 8 of directive 2001/83/EC for a new active substance,

i.e. a complete dossier with administrative, quality, pre-clinical and clinical data.

Accelerated procedure

In novembre 2010, the CHMP agreed to the applicants request for an accelerated assessment of theMarketing Application for boceprevir.

Conditional approval

N/A

Exceptional circumstances

N/A Biosimilar application

N/A

1 year data exclusivity

N/A

Significance of paediatric studies

N/A


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3. SCIENTIFIC OVERVIEW AND DISCUSSION

3.1. Introduction

3.2. Qual ity aspects

Drug substance

Boceprevir, the active substance of Victrelis, is a novel serine protease inhibitor specifically inhibiting thehepatitis C virus non-structural protein 3/4A protease. Boceprevir is a new chemical entity (NCE) not yetdescribed in any pharmacopoeia.

Boceprevir contains 5 chiral centres, four of them have a fixed stereochemical configuration controlledduring the synthesis and the last one is obtained as a mixture of 2 configurations R and S. Thus,Boceprevir is manufactured as an equal mixture of two diastereoisomers in an approximate amount of 1:1.

Boceprevir is hygroscopic, poorly soluble in water and a non ionisable substance therefore its solubility isnot pH dependant. In addition, Boceprevir is obtained as an amorphous substance and attempts to obtain itas a crystalline material have not been successful. This problem, in addition to the fact that a salt formdoes not exists, makes that purification of Boceprevir has represented a challenge to the applicant.Boceprevir powder is consistently obtained with a specific surface area of 3.0 to 9.4 m2/g.

Due to the presence of a diketoamide function, Boceprevir can exist in a gem diol form in presence ofwater. The gem diol form is in equilibrium with the active substance. Boceprevir is, in addition,

predisposed to tautomerisation leading to an enol form. The enol form co-exists with the 2diastereoisomers of Boceprevir in plasma and other biological fluids.

The manufacture of Boceprevir is described in details in three steps. The choice of starting materials is

well justified, their specifications and sources are sufficiently described in the dossier. Two intermediatesare isolated and controlled. For each steps, in-process controls are in place and critical control parameters(CPPs) have been identified. The applicant has performed characterisation studies that have served tooptimisation of the process and led to reproducible production of Boceprevir further supported by a greatnumber of batch results (44 batches). Proven acceptable ranges (PARs) have been established within thedefinition of ICH Q8. It is noted that design space is not claimed. The control strategy in place consists ofa combination of quality of starting materials, intermediates and raw materials together with established

process parameters and IPCs. Few clarifications have been raised on manufacture and controls in place.

Boceprevir has a complex impurity profile, purification by crystallisation or by preparativechromatography were not possible. In addition, some of related substances exist as diastereoiomers. Thus,four sets of impurities have been distinguished as group A, group B, dimers and group W related

compounds. Limits proposed for all the specified impurities are supported by levels present in preclinicalbatches. Unspecified impurities are in compliance with ICH thresholds for a daily intake exceeding 2g.The applicant has made efforts to reduce impurities during different phases of development. Thus, theactual results for total of related substances up to 11.5% in preclinical batches and 6.5% in clinical batcheshave been reduced to maximum 3.30 % in the last 23 batches produced by the intended commercial

process. Change in reagents of the third stage of manufacture has led to removal of some of brominatedimpurities present. The applicant has explained its limitations for further purification.

Specifications of Boceprevir include the important quality attributes of the drug substance and suitablemethods such as XRD to monitor the amorphous form, diastereoisomers content, specific surface area,four HPLC methods to monitor different impurities and two headspace GCs for residual solvents.Justification for lack of specification for few materials and solvents used in the process still remains to beclarified.


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Boceprevir is an unstable active substance as it is sensitive to light, heat, humidity in solid and acidic,basic, oxidative conditions in solution. Stability results provided justify a retest period of 24 monthswhen Boceprevir is packed in double LDPE bags, in presence of silica gel packs, placed in metal drumswith a precaution storage of store in refrigerator and keep protected from light.

Drug Product

VICTRELIS drug product is a hard capsule for immediate release. Each capsule consists in a yellowish-brown colored cap with the Merck MSD logo printed in red ink, and an off-white opaque body withproduct code ID 314 printed in red ink.

One dosage strength, containing 200 mg of boceprevir as drug substance, is proposed.

The formulation comprises the following excipients: microcrystalline cellulose, lactose monohydrate,pregelatinized starch, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate.

The drug product is packaged into unit dose blister cells thermoformed from clear Aclar/PVC film and

sealed with a peelable paper faced foil lidding.

The pharmaceutical development of Victrelis was guided by the defined Quality Target Product Profile.Development and optimization of the formulation is adequately documented. The choice and the level ofthe excipients are justified on grounds of solubility, processability and chemical compatibility.Formulation robustness has been challenged through raw material variability risk assessment andformulation characterization studies.Manufacturing process development program consisted in process characterization studies, completed byscale-up studies, to support robustness of the process. A systematic and risk-based approach was followedin order to establish linkages between inputs (raw materials, process parameters), intermediate attributes,and critical quality attributes. Principles of Quality by Design have been applied to some extent andscience-based risk management processes have been used to facilitate risk reduction. Extensive

development studies have been carried out in order to acquire better understanding of the manufacturingprocess and to define appropriate control strategy to produce a consistent product quality. Design ofexperiments were conducted with the purpose to optimise operating parameters and to test the robustnessof the process, not with the scope of process flexibility. Ranges explored were, indeed, very restricted. Theapplicant confirms that the intended commercial manufacturing process will be run at setpoint values andthat a design space is not claimed.During development, stability studies have been performed to address temperature excursions instorage/shipping conditions. Data support a cumulative time out of refrigeration (TOR) for drug product,from manufacture until final dispensing to the patient, of maximum 30 days at temperatures up to 25C,including excursions of up to 50C for a maximum of 3 days and down to -20C for maximum of 10 days.Bulk shipping studies have been performed to ensure that drug product remained within the desiredtemperature conditions and allowable excursions.

The drug product manufacturing site, in charge of manufacturing only, is Schering-Plough (Singapore)PTE Ltd.. Packaging is performed by Schering-Plough Labo N.V. (Belgium) or by Merck Sharp & DohmeB.V. (The Netherlands). Control and batch release are performed by Schering-Plough Labo N.V.(Belgium).

Manufacturing process is sufficiently described. Operating parameters are set with their target values andtheir proven acceptable ranges. Maximum hold time periods have been validated during manufacturing

process development.Adequate control strategy, comprised of raw material controls, process parameter controls, in-processcontrols, and finished product specifications for the critical quality attributes, is proposed.


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The manufacturing process for Victrelis will be validated at Schering-Plough Singapore PTE Ltd. prior tocommercialization. Validation protocol is enclosed. It has been adequately characterized and scaled to the

proposed commercial batch sizes at the commercial manufacturing site. Data provided is thus consideredsufficient to give confidence in the robustness and consistency of the process at the time of submission.

Excipients used for the formulation of Boceprevir capsules are all of Ph. Eur. quality and classical for the

intended dosage form.

Specifications proposed for drug product include the important quality attributes and suitable methods forthis dosage form while accounting of specific characters of Boceprevir drug substance. Degradants in drug

product, are those of Boceprevir and no new degradant has been identified. The applicant has accepted totighten slightly the acceptance criteria for groups of related substances as it appears clearly from batchresults and stability data that the formulation used stabilises Boceprevir drug substance.

Efficiency of the packing blisters made in Aclar/PVC/ Alu has been demonstrated in stability studies.Victrelis capsules have been shown stable when blisters have been exposed to an ICH photostabilitywithout secondary packaging.

Formal stability studies have been performed at 5 3C as long term storage condition and at 25C/60%RH as accelerated condition. Limited extrapolation can be accorded due to the long term storage conditionused and number of supportive batches. Based on this extrapolation, Victrelis capsules can be accordeda shelf life of 24 months-before patient use- with a precaution storage of store in refrigerator.Thepatient in-use period up to 3 months after dispensing from the pharmacy for Boceprevir capsules issupportedat temperatures below 30Cby the submitted studies and data.

Conclusions on the chemical, pharmaceutical and biological aspects

Based on the review of the data on quality, many of the questions raised have been resolved. However,few unresolved points remain and need to be addressed before final approval. It is assumed that answer to

questions 1, 7, 8, 12, 13, 14, 15, 16 and 18 does not need performing additional studies and therefore animmediate response is expected.

3.3. Non cli nical aspects

Pharmacology

Primary pharmacodynamicsThe Hepatitis C virus (HCV) is a (+)-stranded RNA virus whose genome encodes a single polyprotein ofabout 3000 amino acids. The resulting polyprotein undergoes both co- and posttranslational proteolytic

maturation by host- and virally encoded proteases. Boceprevir is a serine protease inhibitor, which inhibitsNS3, a viral protease which is involved in further cleavage of the viral polyprotein into downstreamnonstructural proteins. Boceprevir binds covalently, yet reversibly, to the NS3 protease active site serinethrough a ketoamide functional group, thereby inhibiting the cleavage of the viral polyprotein intofunctional units, thereby inhibiting HCV replication.Due to the lack of robust viral cell/culture systems, activity of boceprevir was investigated in repliconassays and biochemical enzyme assays with recombinant NS3-NS4A (NS4A is a cofactor required by NS3for viral activity). In a chromogenic assay with recombinant proteases, it was shown that SCH 534128 isthe active diastereomer and SCH 534129 the inactive, and that there is rapid interconversion between thetwo diastereomers. In replicon assays with the human hepatoma cell line Huh7 transfected with RNA

based on HCV genotype 1b, IC50 was 200 900 nM and IC90 was 400 1400 nM. In the presence ofhuman serum, IC50 was 500 nM. In an enzyme assay, Ki was 14 nM for genotype 1a and 1b, and 39 nMand 25 nM for genotypes 2a and 3a respectively. In vitro studies showed that mutations emerge at


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concentrations up to 10 M. Mutations are therefore expected to emerge at human exposures if bocepreviris used as monotherapy.In replicon assays, boceprevir induced an up to 6-12 fold increase in IC90 after 8-10 passages and an up to8-48 fold increase after approximately 30 passages. Resistance-associated variants (RAVs) in repliconcells were observed at positions V36, Q41, F43, T54, Q86, S122, A150, R155, A156, V170, E176. Asecond mutation generally increased fold change above that induced by a single mutation. A156Tconferred the highest level of resistance (increase in IC90 80-fold), but also significantly reduced repliconfitness. In a replicon assay, the combination of boceprevir at 6xIC90 (2.5 M) and interferon alpha at1xIC90 (1 IU/ml) reduced resistance from 0.14% to 0.005% of the cell population.In HCV samples from Phase 1 and 2 patients (genotype 1 non-responders), RAVs were observed at

positions V36, T54, V55, R155, A156, V158, V163, V170. Among patients from Phase 3 clinical trials,the most detected RAVs were V36M, R155K and T54S for genotype 1a and T54A, T54S, V170A, A156Sand V55A for genotype 1b. Overall, post-baseline RAVs were detected in 15% of the subjects. The overall

percentage was similar among treatment failure subjects and treatment nave subjects and for shortertreatment (response-guided therapy) and standard treatment. 53% of patients who did not achievesustained virologic response (SVR) had RAVs. More subjects with poor interferon response had RAVs(41%) compared to interferon responsive subjects (6%).

HCV replication is rapid and virus production recovers quickly when inhibition of the NS3 enzyme isremoved. Therefore, it is assumed that potent and durable suppression of HCV replication in vivowilldepend on maintaining plasma trough concentrations (Cmin) at levels IC90. The applicant concludesthat the Cmin has to be 200 ng/ml (approximately 400 nM). Based on in vitro studies, this estimate israther low. Furthermore, clinical pharmacokinetic data show that in a large part of the patient populationCmin of 200 ng/ml was not even achieved. Moreover, this value represents the total fraction, as a result ofwhich the freely available, non-protein-bound fraction is even lower. However, based on clinical

pharmacokinetic data, higher dosing would not seem to increase Cmin substantially, and therefore a higherCmin seems not likely achieved. Ultimately, the clinical response is the most important and clinical data

point towards a significant effect of boceprevir in combination with peginterferon alpha and ribavirincompared to peginterferon alpha and ribavirin alone. Likely, the combination with peginterferon alpha andribavirin contributes significantly to the efficacy.

The activity of boceprevir was not investigated in animal studies. This is endorsed; robust in vitro cellculture systems are lacking and animal models for hepatitis C are not readily available, exceptchimpanzees, and activity measurements in chimpanzees are not expected to add significantly to clinicaldata.Boceprevir showed minimal cytotoxicity in several human cell lines (CC50 was 80 - >100 M).

Secondary pharmacologyCross reactivity of boceprevir with an extensive panel of proteases, other enzymes and receptors wasinvestigated in vitro. Only cathepsin L was inhibited by boceprevir to a substantial extent. This isconsidered not likely to have a relevant impact. Cathepsin L is only one of a large family of proteases, it isinvolved in nonspecific protein breakdown and most likely there will still be sufficient proteolytic

pathways.

Safety pharmacologyThe main criticism regarding the cardiovascular safety pharmacology programme is that theconcentrations tested in vitro were too low with regard to the clinical plasma levels. Nonetheless, a

prolongation of the Purkinje action potential reaching 40 ms was observed at 0.5 Hz. In that context, it isdifficult to accept that boceprevir is unlikely to prolong QT interval since no significant effect on hERG

potassium channel has been observed in a study performed at concentrations in the range of the clinicalCmax.The in vivo model was Cynomolgus monkey. At the top dose, an increase in heart rate was observedwithout any effect on QT interval. However, the Cynomolgus model is not a good model, as compared todog for example, to investigate the potential effects of a drug on the ECG pattern, due in particular to the

high and rapidly changing heart rate of these animals. Therefore it is not surprising that no effect could bedetected during the in vivo studies. In addition, the monkey-to-human Cmax ratio ranged actually from 0.5to 4.1 in the aforementioned study.


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The major human metabolite SCH 629144 was not tested. The applicant considers that due to the presenceof the main metabolite in monkeys, its potential cardiotoxicity was evaluated during the in vivo studies.For the same reasons as above, this is not convincing at all.A thorough QT/QTc study performed according to ICH E14 in human volunteers was negative, but thedata show a tendency to QT interval prolongation within acceptable limits with increasing boceprevirdoses. Taking into account that the pharmacokinetics of boceprevir is highly variable and complex, andthat the patients may present some pathophysiological conditions (e.g. electrolytic disturbances) that may

potentate a potential drug-related effect on cardiac physiology, there are some concerns regarding theresults obtained in in vitroand in vivocardiovascular safety pharmacology studies.Overall, there is some doubt concerning the potential effects of boceprevir on QT prolongation, in

particular in subjects presenting with low heart rates. Therefore, the positive findings observed in vitroarereported in SPC 5.3 to give adequate information to the prescriber, and a warning is included in SPC 4.4.In addition, it is still considered necessary to amend the RMP to monitor events possibly related to effectson the cardiovascular system.

Pharmacodynamic drug interactionsIFN and boceprevir showed additivity of effect in a replicon system. It was shown in vitro that IFN

decreased emergence of resistance to boceprevir. The interaction with ribavirin was not investigatedpreclinically. However, the combination of boceprevir with peginterferon- and ribavirin is investigatedclinically. No relevant pharmacodynamic interactions were observed with HIV protease inhibitorsatazanavir, lopinavir and ritonavir.

Pharmacokinetics

Both non-validated and validated LC-MS/MS methods have been used for the detection of boceprevir, itsindividual diastereomers SCH 534128 and SCH 534129, and its major metabolite SCH 629144 (collectivedesignation for SCH 783007, SCH 783005, SCH 783006, and SCH 783004) in plasma. Regarding thetotal recovery of the analytical methods in plasma (and serum), no explanation is provided with regard tothe greatly varying recoveries (between QCL, QCM and QCH) within the studies. This should be clarified

further.

Absorption was generally rapid in all species. After oral administration, the bioavailability of boceprevirwas moderate in male mice, rats, and dogs (34%, 26%, and 30%, respectively) but was low in fasted malemonkeys (4%). Subsequent studies in rats and male monkeys showed that the bioavailability of both SCH534128 and SCH 534129 was similar. In monkeys, the bioavailability increased under fed conditions (10-13%). The half-life of boceprevir is short, ranging from 1 to 5 h in the pre-clinical species and humans. Inaddition, the half life of the active diastereomer SCH 534128 ranged from 1 to 4 h in rat and monkey and~2 h in humans. No information was provided on the half-life in other pre-clinical species.From TK data obtained after a single dose, gender-related differences in systemic exposure were evidentin rodents with females more exposed than males given the same boceprevir dose (up to 3-fold in miceand rats). In addition, there was some inter-study variability regarding the exposure levels measured for a

given dose and in a given sex, particularly at high dose levels. A time-related effect on the kinetics ofboceprevir was observed in mice only, with a decrease in exposure levels probably related to the inductionof cytochrome P450 enzymes.Animals were treated once daily in the pre-clinical repeated dose studies and humans were treated two orthree times a day (every 8 to 12 hours) in the clinical studies. In addition, the ratio of the twodiastereomers is species dependent. In mice, the steady state SCH 534128:SCH 534129 ratio was 1.2:1and the ratio in male mice was greater than the ratio in female mice. The steady state SCH 534128:SCH534129 ratio was 1:1 in rat plasma. In monkey, the SCH 534128:SCH 534129 ratio was approximately1:5.9 in plasma at steady state. The ratio of diastereomer concentrations in humans at steady-state was2.2:1 (SCH 534128:SCH 534129).Therefore, the comparison of the kinetic parameters is hampered.Exposure values in juvenile rats were higher than exposure values in adult rats on a restricted diet; butlower than exposure values in adult rats fed ad libitum. However, based on the comparison of exposure

data obtained in adult and juvenile male rats under fed conditions, it cannot be excluded that thepharmacokinetics in juveniles are different than that in adults and may be caused by not fully expressed


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liver metabolic enzymes in the juvenile. It is expected that off-label use will take place in juveniles.Therefore, the applicant should state in the SPC that contradicting findings were observed in juvenile ratscompared to adult rats, in a perspective of a future use in paediatric patients.

Boceprevir is moderately bound to plasma proteins in all species, and was shown to cross the placenta inpregnant rats. In rats administered radiolabeled boceprevir, the highest radioactivity levels were measured

in the liver, bladder, kidneys, prostate gland, other endocrine tissues (adrenal, harderian, and salivaryglands), and bone marrow. The results did not indicate a specific binding of drug-related radioactivity tomelanin-containing tissues, and there was no gender-related difference in the tissular distribution profile.Only bladder, liver, kidney, bone marrow, endocrine glands and reproductive organs containedquantifiable levels of radioactivity at 8 h post-dose. All tissues, except bone marrow, were belowquantifiable limits after 24 h. Based on the provided distribution data, the fact that patients are treatedevery 8 h hours and similar half-lives in rat and humans, accumulation in humans can be expected in bonemarrow and endocrine glands. Effects on bone marrow were not specifically investigated in the pre-clinical toxicity studies. However, no toxicity was observed in bone marrow and blood after 6 monthsrepeated dosing in rat.

Boceprevir undergoes extensive metabolism in all tested species. In vitro, human liver microsomes

converted approximately 99% of boceprevir to metabolites, and at least 31 metabolites were produced. Invivo, the percentage of drug excreted unchanged was weak and the number of produced metabolites wasof the same order. The metabolism of boceprevir involves mainly oxidation and/or reduction, andhydrolysis reactions. Two main pathways can be described. The first involves the reduction of boceprevirto SCH 629144 (4 stereoisomers SCH783005, SCH783007, SCH783006, SCH783004) and is catalysed bythe cytosolic aldo-keto reductase (AKR) family of enzymes, more precisely AKR1C2 and 1C3 isoforms.AKR1C3 preferentially metabolised SCH 534128 to SCH 783007 and AKR1C2 preferentiallymetabolised SCH 534129 to SCH 783004. Metabolising data indicate that the formation of the differentSCH 629144 diastereomers is different between the different species with more SCH 783006 in ratcompared to the other pre-clinical species and humans. Exposure to SCH 629144 increased as the dose of

boceprevir was increased. AKR1C2 and 1C3 are expressed in the liver and in hormone-associated tissues(prostate, uterus, mammary gland, testes). Therefore, this metabolic pathway would take place in both

hepatic and extra-hepatic tissues, which could explain why PK parameters are not modified in patientswith hepatic insufficiency. Regarding the potential auto-inhibition of this pathway, only data showing that

boceprevir has no inhibitory potential for AKR1C3 were provided. Therefore, the applicant is requested toprovide boceprevir inhibition data for AKR1C2 or clinical data showing the absence of effects on theendocrine hormone metabolism.The second pathway involves the CYP3A4 and CYP3A5 isoenzymes, mainly responsible for theformation of oxidized metabolites. Another metabolite, SCH 503034-K (M0BA), is a hydrolytic cleavage

product and also a low-level impurity in the drug substance whose formation depends on the presence ofSLS (sodium lauryl sulphate) in the formulation. In humans dosed with boceprevir as capsule, thecirculating levels of SCH 503034-K relative to parent drug were lower than levels that may raise a safetyconcern. Therefore, this metabolite was clinically not relevant.Qualitatively, the metabolites detected in humans were also detected in mice, rats, and monkeys.

However, quantitatively, significant inter-species variability was noted. This is notably the case of themajor human metabolite SCH 629144, whose AUC represented 2-7%, 47-93% and 620-760% of the AUCof boceprevir in rats, mice and monkeys, respectively in toxicity studies. In humans, this figure amountedto 440% at the recommended dose. Therefore, SCH 629144 is a minor metabolite in the rat. This speciesis thus to be considered as not fully relevant for humans.

In all species, the main route of excretion was via the faeces, as a combination of biliary excretion ofmetabolites and excretion of unabsorbed drug. In rats, a limited fraction of an oral dose (3%) underwententerohepatic circulation. In lactating rats, boceprevir-related radioactivity was rapidly excreted intomaternal milk. No information was provided concerning the precise composition of radioactivity as foundin rat milk samples. Consequently, the SPC mentions that a risk to the newborn/infant cannot be excludedand that breast-feeding must be discontinued prior to initiation of therapy in patients who will beadministered boceprevir


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Boceprevir is an inducer of CYP2B and 3A in mice, but not in other species including humans. A study onhuman liver microsomes showed that it is rather a competitive inhibitor of CYP3A4/5 at concentrations inthe range of that reached in patients.Boceprevir was shown to be both a P-glycoprotein and a weak BCRP substrate, therefore this should bereported in SPC 5.2 and a warning about a likely interaction with inhibitors of these transporters should beincluded in SPC 4.5. Regarding the inhibitory potential for transporters, it can be concluded that

boceprevir is not expected to significantly inhibit MRP2 and BCRP at therapeutic concentrations.Nevertheless, it was shown to be a P-glycoprotein inhibitor in vitro and the applicant committed toperform a clinical drug-drug interaction study with digoxin to determine the clinical relevance. In addition,it was also shown to be an OATP1B1 inhibitor, but additional data is requested since a positive controlwas not used to warrant the reliability of the in vitromodel used.In an enzyme induction study with three batches of human hepatocytes, boceprevir did not causesignificant induction of CYP1A2, CYP3A4 and CYP2B6. As these enzymes are sensitive indicators foractivation of the AhR, PXR and CAR receptors, and activation of these receptors can also result in theinduction of some of the UGT enzymes, the potential that boceprevir will cause significant induction ofUGT enzymes is low.

Toxicology

The observed max. non-lethal oral acute doses in rat, dog and monkey were resp. 2000, 300 and 1000mg/kg.

Repeat-dose toxicity and carcinogenicity studies have identified the liver as a target organ in mice andrats. In mice treated for up to 3 months, uncorrelated minimal to mild increases in transaminases (ALAT,ASAT) and focal neutrophilic infiltrates were noted. The safety margins for the occurrence of focalneutrophilic infiltrates in the liver, seen only after 3-month dosing, reach 1.4 in males and 4.8 in females

based on NOAELs of 500 and 600 mg/kg/day, respectively. In the mouse carcinogenicity study, there wasan increased incidence of hepatocellular adenomas at the high-dose level (650 mg/kg/day, corresponding

to a mouse-to-human exposure ratio of 5.8). Based on the fact that the incidence of hepatocellularadenomas was increased in only one tissue, one gender, and one species, without findings suggestingincreased malignancy, without any impact on mortality, and considering also the negative results obtainedin genotoxicity studies (notably the mouse bone marrow micronucleus assay), the applicants position thatthis poses no clinical concern is shared. Non-neoplastic liver findings reported in the carcinogenicity studyconsisted in accumulation of pigment staining positive for lipofuscin in liver macrophages at 250mg/kg/day, and single cell necrosis of hepatocytes at high dose levels (500 mg/kg/day in males, 650mg/kg/day in females). In rats, uncorrelated minimal to mild increases in ALAT and ASAT in both sexesand multinucleated hepatocytes in males were observed. The latter effect was noted in 3-month and 6-month studies without any safety margin based on a NOAEL of 15 mg/kg/day. It is described as species-and gender-specific by the applicant, which is not fully endorsed. In fact, it may be viewed as species- butnot gender-specific because multinucleated hepatocytes were also reported in a dose-related manner infemale rats included in the carcinogenicity study. There was no safety margin for this finding, however no

physiological consequences was noted in the affected animals. The occurrence of multinucleatedhepatocytes has been characterized as an adaptative response in rats.

Repeat-dose toxicity and carcinogenicity studies also highlighted the male reproductive tract as a targetorgan in male rats.In 3- and 6-month studies, the histopathological findings consisted in Sertoli cell vacuolation, spermatiddegeneration, atrophy of seminiferous tubules in the testes, presence of cellular debris in the epididymides,hypospermia in the epididymides. It correlated with decreased weights of the epididymides and testes, andwith macroscopic findings of small epididymides and testes. In the 6-month study, the NOAEL for thesefindings reached 15 mg/kg/day meaning that there is no safety margin for these effects. The applicant

suggests that these findings may be reversible based on the results of a 3-month study (no.04124) showinga trend towards functional recovery in the testes that was observed during a 2-month post-dose interval. Of


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note, this is the only repeat-dose toxicity study performed in adult animals where a recovery period wasincluded. Similar effects were reported in the juvenile rat toxicity study, and they were not reversible. Inthe carcinogenicity study, non-neoplastic lesions were also noted on the male reproductive tract, and werequalitatively similar to that reported in the aforementioned studies.The applicant performed a 1-month study in adult rats showing that the occurrence of these findings isdose- and time-dependent, and suggesting initiation of testicular toxicity on the first dose and continual

progression of boceprevir-induced changes following daily dosing. There was no impact on serum LH,FSH and testosterone levels, and an additional study showed that boceprevir is devoid of agonistic andantagonistic activity the estrogen receptor alpha and androgen receptors, respectively, thus discarding ahormonal mechanism. The applicant concludes that the Sertoli cell is probably the primary target and thatthus inhibin B is a valid marker for this effect in clinical studies. The overall non-clinical and clinical datasuggest that the testicular toxicity observed in rats only is not likely to be relevant for humans. However,no definitive mechanism is proposed to support the assumption that the testicular findings are rat-specific.

In monkeys treated for up to 12 months, no target organ could be identified. A dose-dependent increase inaPTT was observed, but it was not associated with clinical observations, changes in other clinical

pathology parameters suggestive of haemorrhage, and gross pathology or histopathology evidence of

haemorrhage. It is agreed that the effect on APTT of boceprevir seen in monkeys is probably not animportant risk factor for humans. In fact, such a prolongation in aPTT was not reported in clinical studies.

Boceprevir was not genotoxic in an ICH-compliant battery of in vitroand in vivotests.Two-year carcinogenicity studies were conducted in mice and rats. In addition to the liver and testicular/epididymidal lesions described above, gall bladder discolouration occurred in mice withouthistopathologic correlate, inflammation, tumor formation, evidence of concretions, or long-term impact togall bladder integrity. No gall bladder finding was reported in monkeys, therefore this effect is consideredlikely specific to mice. Overall, boceprevir was shown to be devoid of carcinogenic potential in malemice, and in male and female rats. Hepatocellular adenomas were noted in female mice, but are notconsidered clinically relevant (see above).

Boceprevir altered the fertility of female rats (mated to untreated males), that was related to increased pre-and post-implantation losses. This effect was shown to be reproducible and reversible. The underlyingmechanism remains unknown, but is not hormone-related as shown in an investigative study. Bocepreviralso altered the fertility of male rats (mated to untreated males), and this can be reasonably attributed itstoxic effects on the male reproductive organs. In both male and female rats, the NOAEL for the effects onfertility amounted to 75 mg/kg/day, thus corresponding to a lack of safety margin for males and a weakone (1.0 to 1.9) for females.Embryo-fetal toxicity studies showed that boceprevir is devoid of embryotoxic or teratogenic potential in

both rats and rabbits at maternotoxic dose levels.The peri-post-natal toxicity study showed decreased body weight of F1 rat offsprings that was limited tothe pre-weaning period in the group dosed at 150 mg/kg. No other treatment-related effect on the

development of F1 pups/ offsprings was reported. It should also be considered that boceprevir is to be co-administered with ribavirin, whose SPC states that lactation is contra-indicated because of the potential foradverse reactions in breast-fed infants.The main target organs identified in juvenile rats were the testes / epididymides and the thyroid. Whereastesticular/ epididymidal toxicity was expected based on the data previously available in more mature rats,this is not the case for the occurrence of reversible and reproducible follicular thyroid hyperplasia. The

phenobarbital-like mechanism proposed by the applicant to explain the thyroid effects is not clearlyestablished. At the present time, MAA is sought for use of boceprevir in adults. Regarding the thyroidfindings, more data may be requested at a later time in case of an application to extend the indication to

paediatric patients.

All boceprevir-related impurities are considered qualified at the proposed acceptance criteria level based

on the level of impurity tested in the qualification repeat-dose and genotoxicity tests, the level of impurity


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tested when normalized for human dose on an mg/kg basis, and/or by virtue of the impurity also being ametabolite present in non-clinical species.

Standard immunotoxicity endpoints including white blood cell counts, differentials lymphoid organweights, lymphoid tissue histopathology and bone marrow cellularity were assessed in general toxicitystudies and did not indicate a need for specific inmmunotoxicity or antigenicity studies to be conducted.

Boceprevir showed no effect on red blood cell osmotic fragility in human blood and no effect on APTT(activated partial thromboplastin time) in cynomolgus monkey blood.

In rats, the combination of ribavirin with boceprevir did not increase the toxicity of boceprevir in a 3-month study. Administration of diflunisal, ritonavir and ribavirin caused more toxicity in a 3-month studyin rats with thymus, adrenal gland, kidneys and thyroid glands as targets. Co-administration of boceprevir,ribavirin and ritonavir increased dose normalized exposure to boceprevir at steady state approximately 2 to6-fold (in females) or 4 to 9-fold (in males). This increase is considered to be due to the net boost effect ofritonavir. The combination of PEG-Intron and ribavirin with boceprevir showed mild effects which wereonly attributable to PEG-Intron and ribavirin.

Ecotoxicity/environmental risk assessment

The PECSURFACEWATERvalue determined in the phase I risk assessment exceeds the action limit value by a1200-fold factor. Therefore, it is agreed that boceprevir should enter into phase II Tier A risk assessment.However, the environmental risk assessment could not be finalised because most studies are notcompleted at this stage. Therefore, the study report on log Kow and the study reports related to the phaseII assessment should be provided as soon as available.

Discussion on non-clinical aspects

Boceprevir is expected to be effective in combination with interferon alpha and ribavirin. However,mutations causing decreased susceptibility are expected to emerge at human exposures.

The analysis of the results obtained in pharmacokinetic and toxicokinetic studies highlights considerableinter-species variability, and even inter-study variability within the same species, at various levels of thekinetics of boceprevir (e.g., diastereoisomers ratios, absorption, systemic exposure, metabolism, hepaticenzymatic induction/inhibition). Therefore, significant inter- and intra-individual variability is to beexpected in patients. Attention will thus have to be paid to the conditions of administration, to patientswith enzymatic deficiencies, and to potential drug-drug interactions.

Anaemia was frequently reported as a treatment-related effect in humans. An in vitro assay in human

blood did not provide any evidence of a haemolytic potential for boceprevir. In spite of the lack ofinvestigations for such a potential with metabolites, further studies in non-clinical species are notconsidered necessary since i) anaemia was not reported in mice, rats and monkeys, and ii) bone marrowsmears performed in the 6- and 12-month monkey studies did not show any treatment-related effect.

Overall, the toxicological profile of boceprevir could be acceptable.

Conclusion on non-clinical aspects

There are no major objections against a marketing authorisation from a non-clinical point of view. Somequestions still remain to be addressed.


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3.4. Cl in ical aspects

Tabular overview of clinical studies


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Phase Study IDstudy centres

Study Posology Design Treatment Population Primary Endpoint Major findings

II P03523SPRINT 1

67 sites

800 mg TID Randomizedplacebo-controlleddose-rangingmulti-sitedouble blind

Peg/Rvb -48WPeg/Rvb/Boc -28WLI+Peg/Rvb/Boc -28WPeg/Rvb/Boc -48WLI+Peg/Rvb/Boc -48W---Peg/Rvb/Boc -48WPeg/Rvb low/Boc -48W

Nave patients

598 subjects

Efficacy (SVR) - SVR :Peg/Rvb :37.5%Peg/Rvb/Boc28: 54.2% (=16.7)LI+Peg/Rvb/Boc28: 56.3% (=18.8)Peg/Rvb/Boc48: 67% (=29.5)LI+Peg/Rvb/Boc48:74.8% (=37.3)

- EPO use :Peg/Rvb :33%Peg/Rvb/Boc28: 56%LI+Peg/Rvb/Boc28: 66%Peg/Rvb/Boc48: 80%LI+Peg/Rvb/Boc48:87%

II P03659RESPOND 1

30 sites

100 mg TID200 mg TID400 mg TID800 mg TID

Randomizedplacebo-controlleddose-rangingmulti-sitedouble blind

Peg/Rbv/Boc 400/800Peg/Boc 100Peg/Boc 200Peg/Boc 400Peg/Rbv/Boc 400Peg/Boc 800

Non-responders

357 subjects

Safety and effectivedose range

As recognized by the applicant in thesummary of clinical efficacy, results aredifficult to interpret due to significantchanges in the study design.

LongTermphase II

P05063 800 mg TID ongoing,multicenter,long-termfollow-upstudy

None Subjects whoparticipated in aPhase 1, 2, or 3clinical study inwhich

boceprevir was

administered.

604 subjectsfrom P03523,P03659,P04487 andP04531 studies

Durability of the SVRLong term Safety

Natural history of HCV

- High percent of RAVs returns to Wildtype within 2 years

III P05216SPRINT 2

800 mg TID Randomizedplacebo-controlled

Two cohorts with 3arms (1 with whitesubjects and 1 with

Nave patients

1099 subjects

Efficacy (SVR) - SVR :LI+Peg/Rbv : 37.7%LI+RGT : 63.3% (=25.6)


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149 sites multi-sitedouble blind

black subjects) :LI+Peg/Rbv -44WLI+RGT1LI+Peg/Rbv/Boc -44W

LI+Peg/Rbv/Boc : 66.1% (=28.4)

- EPO use :LI+Peg/Rbv : 24%LI+RGT : 43%LI+Peg/Rbv/Boc : 43%

III P05101RESPOND 2

78 sites

800 mg TID Randomizedplacebo-controlledmulti-sitedouble blind

LI+Peg/Rbv -44WLI+RGT2LI+Peg/Rbv/Boc -44W

Non-responders

404 subjects

Efficacy (SVR) - SVR :LI+Peg/Rbv : 21.3%LI+RGT: 58.6% (=37.4)LI+Peg/Rbv/Boc : 66.5% (=45.2)

- EPO use:LI+Peg/Rbv : 21%LI+RGT : 41%LI+Peg/Rbv/Boc : 46%

LI: lead in phase Peg+Rbv during 4 weeks1RGT : response guided therapy (Peg/Rbv/Boc during 24 weeks, patients with undetectable HCV-RNA at TW 8 completed therapy at TW 28 and entered follow-up, while those with detectable

HCV-RNA at TW 8 received an additional 20 weeks o f placebo plus PR, for a total treatment duration o f 48 weeks.)2RGT : response guided therapy (Peg/Rbv/Boc during 32 weeks, patients with undetectable HCV-RNA at TW 8 completed therapy at TW 32 and entered follow-up, whi le those with detectable

HCV-RNA at TW 8 received an additional 12 weeks o f placebo plus PR, for a total treatment duration o f 48 weeks.)


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Pharmacokinetics

Boceprevir is administered as an equal mixture of two diastereoisomers i.e SCH 534128 an activediastereoisomer and SCH 534129 an inactive diasteroisomer. Because of the low solubility in water andlow permeability, boceprevir is considered as a class 4 compound according to the BiopharmaceuticClassification System.

Absolute bioavailability has not been determined since no IV formulation was available. The datasupported that the bioavailability of a capsule formulation containing 3% SLS was substantially improved.The bioavalaibility of boceprevir is increased by 40-60% when administered with food. The meal type i.ehigh fat or low-fat and the timing of meal administration did not seem to notably affect this increase in

bioavailability. The recommendation in the SPC to take the drug with food is supported.

The apparent volume of distribution was not determined since no IV formulation was available. Theplasma protein binding was approximately 80%. Over the range of concentrations resulting from the dosesinvestigated in the clinical studies i.e 0-5000 ng/ml, the decrease in plasma protein binding was 8%.

A study with14

C boceprevir showed that a mean total of 88.2% (range 85%-91.6%) of the radioactivedose was recovered in the urine (mean 9.3%) in feces (mean 78.9%) over 168 hrs after a singleadministration dose of 800mg. Approximately 3% and 8% of the dosed radiocarbon were eliminated asunchanged boceprevir in urine and feces respectively.

Plasma boceprevir concentrations declined in a biphasic manner. The mean terminal half-life bocepreviracross the studies seems to be variable. In most studies the mean half-life was short ~2-4 hr whereas insome studies it was much longer ~10 hr. The mean half-life of the active diastereoisomer was found to beranging from 1.5 to 5 hrs across doses and studies.

The AUC values across the clinical studies and doses suggest that the plasma clearance of the inactivediastereoisomer SCH 534129 was greater than that of the active diastreoisomer SCH 534128. The ratio of

diastereoisomer concentrations in humans varies with time approaching a steady-state ratio of about 2:1(active:inactive diastereoisomer).

Based on in vitro data studies, the metabolism in humans appears to be primarily via isoforms of AKR(AKR1C2 and AKR1C3) and to a minor extent via CYP3A4/5-mediated oxidation. The metabolism of the2 diastereoisomers by both AKR1C3 and AKR1C2 leads to the formation of ketone reduced metabolitesin the form of stereoisomers quantifiable in the plasma: the active diastereoisomer SCH 534128 ismetabolized into SCH 783007 (M28) and SCH 783005 and the inactive diastereoisomer SCH 534129 ismetabolized into SCH 783004 (M31) and SCH 738006 (M30). All these 4 ketone-reduced metabolites areinactive as protease inhibitor. The minor pathway of metabolism via CYP3A4/5 was responsible for the

production of a large variety of hydroxylated and oxidized metabolites.

Another minor metabolite (MOBA) is a hydrolytic cleavage product resulting from the hydrolysis ofboceprevir in the presence of SLS and acidic medium in the stomach.

In plasma (pooled 2 hrs and 6 hrs), the metabolic profiling following a single 800 mg dose of 14Cboceprevir showed that SCH 783007 (M28), SCH 783004 (M31) and SCH 783006 (M30) are the main 3major ketone reduced metabolites quantifiable in plasma. The exposure to the sum of these 3 metaboliteswas approximately 2.5-fold greater than that of boceprevir. MOBA was 4 % of the circulatingradiocarbon. After a 800 mg tid dosing the plasma exposure to SCH 629144 was 4 to 5.4 fold higher thanthat of boceprevir.

Following a tid 800 mg dosing, the mean Cmax of SCH 629144 i.e the sum of M28, M30 and M31 wasapproximately 5100 ng/ml. The median Tmax ranged between 3 to 4 hrs and the mean half-life was 2.7hours.


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For boceprevir and the active diastereoisomer SCH 534128 steady-state exposure increases in a less thandose-proportional manner from 200 mg to 800 mg. At doses greater than 800 mg, the exposure does notincrease notably.

After multiple dose administration, accumulation is minimal for both boceprevir and the activediastereoisomer SCH 534128 and steady-state is reached after approximately 1 day of t.i.d dosing.

The range of interindividual variability measured at steady-state (800 mg tid for 14 days) expressed asCV was 11-32% for AUC, 21-35% for Cmax and 27-57% for Cmin in Caucasian and Japanese subjects.The intraindividual variability was not determined.

HCV-infected subjects were found to have similar PK profiles to healthy subjects.

The PK of boceprevir was investigated in subjects with end stage renal disease undergoing dialysis. Themean PK parameters indicated that ESRD and dialysis did not affect the PK of boceprevir.

In subjects with various degrees of stable chronic hepatic impairment, there was a trend toward an

increase in the mean boceprevir Cmax and AUC with the decrease in liver function, especially in thesevere group. The boceprevir ratio estimates for mild, moderate and severe hepatic impaired subjectscompared with healthy subjects were 91%, 114% and 149%for AUC0-tand 100%, 107% and 161%forCmaxrespectively.The applicant has proposed that BOC be contraindicated in patients with a Child-Pugh score > 6 i.e withmoderate and severe hepatic impairment. However, this contra-indication seems rather justified by theneed to co-administer BOC to pegylated IFN-Ribavirin for which moderate and severe hepaticimpairments are currently part of the contra-indication than justified by the impact of hepatic impairmenton the BOC PK parameters. A specific contra-indication to boceprevir could appear excessive especiallyin view of the limited impact of the moderate hepatic impairment on the BOC PK parameters.This issue deserves some attention insofar as patients with decompensated liver disease are currently beingtreated off label with Pegylated IFN+Ribavirin despite the contra-indication to obtain HCV RNA

undetectability before transplant. Physicians might be inclined to increase the likelihood of achievingHCV RNA undetectability by adding BOC to the tritherapy.Awaiting for other approaches, notably DAA combinations, physicians have to face with very challengingsituations in clinical practice and formal contra-indication might amount denying the difficulties of theirdaily life practice.

Race and weight were not shown to affect the PK of boceprevir. Gender slightly affected the clearance(19% decrease in females) and the absorption rate (16% increase in males). These effects were notconsidered to be clinically significant.

Drug-drug interaction studies

The interaction programme was rather limited.

All clinical studies were conducted in healthy volunteers, with multiple doses study design whenappropriate. As a limitation of these interaction studies, most of them were performed with a boceprevirdose not corresponding to the recommended 800 mg TID.

- Effect of AKR inhibitors (AINS diflunisal or ibuprofen) seems moderate on boceprevir concentrations.However, with ibuprofen, boceprevir plasma exposure is not altered in a significant manner whereas withdiflunisal, boceprevir plasma exposures tend to increase. As part of the CHMP D120 LOQ, the Applicantwas asked to discuss these conflicting results and their clinical relevance. The limitations of theinvestigations were acknowledged and overall given the limited use of AKR inhibitor in clinical practice,

no mention was to be made in the SPC.


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- The combination of boceprevir 400 mg TID with ritonavir 100 mg BID has been studied compared toboceprevir 400 mg TID. Ritonavir affects the elimination of SCH629144 (110% increase in AUC). Giventhat an increased exposure was expected by the applicant when boceprevir was combined with ritonavir(as reflected in their tested dose reduction adjustment), the findings of study P04624 can be regarded assomewhat conflicting with such an assumption insofar as a significant decrease in boceprevir plasmaexposure and notably Cmin, which decreases about 48 %, was observed. As part of the D120 LOQ, theapplicant was asked to clarify and further discuss the potential consequence of the co-administration ofritonavir and boceprevir.

This issue is of importance since new therapeutic options are particularly awaited for treating HIV-HCVco-infected patients well admitted as being a more pejorative population (in terms of natural course of thedisease and response to the biotherapy) as compared to mono-infected patients. Reassurance should beobtained as regards the use of the drug with boosted Protease Inhibitors. Co-administration with boostedProtease Inhibitors should be performed to check the applicants assumption of a lack of significant effectwith ritonavir, which is currently regarded as disputable in view on the impact on BOC Cmin. Theapplicant is asked to complete the interaction programme with exploration of drug-drug interaction withwidely used boosted PIs, notably darunavir/rtv and atazanavir/rtv. In response to the D120, the Applicant

has committed to perform clinical studies with boosted protease inhibitors i.e. atazanavir/ritonavir,darunavir/ritonavir and lopinavir /ritonavir. Results from theses studies will allow clarifying the net effectof ritonavir on boceprevir plasma exposure.

- Ketoconazole leads to a two-fold increase in boceprevir AUC. Therefore, the proposed recommendationin the SPC, that no dosage adjustment is required with ketoconazole, is not endorsed. The Applicant wasasked to discuss at the D120 the clinical relevance of such PK variations and halving the dose of

boceprevir was to be considered. In its response the applicant discuss the lack of clear relationshipbetween Cmin and boceprevir adverse events.

Furthermore, since the CYP3A4 pathway is marginally involved in boceprevir metabolism, themechanism behind this increase should be discussed and the respective role of P-gp and CYP3A4

inhibition should be precisely assessed. This may be of importance so as to define which inhibitors may beof concern: CYP3A4 or P-gp inhibitors. Finally, At D120 the Applicant was asked to discuss to whatextent the results observed with ketoconazole should apply to other azol antifungals, i.e. itraconazole,voriconazole and posaconazole.Overall, the Rapporteurs have considered that attention should be alerted on a potential alteration of the

boceprevir safety profile in case of co-administration with ketoconazole and azoles in general.

- Tenofovir was not found to have a significant effect on boceprevir concentrations, and vice versa.

- Efavirenz having drug-metabolizing enzyme inducing properties decreased AUC of boceprevir by 19%and Cmin by 44%. These results together with the absence of complete elucidation of elimination

pathways should lead to contra-indicated combination with potent inducers. This refers also to P-gp

inducers. The applicant was asked to discuss at the D120.It was admitted that efavirenz is a moderaterather than a potent CYP3A4 inducer as compared to rifampicin, phenobarbital or carbamazepine and theSPC statement was revised accordingly.

- As expected, midazolam AUC is increased by 5-fold after addition of boceprevir. Therefore, in theproposed SPC, the Applicant contra-indicates the combination of boceprevir with midazolam per os andrecommends a caution with midazolam IV.

- Effect of boceprevir on oral contraceptive drugs is rather complex: boceprevir increased drospirenoneexposure substantially. Drospirenone metabolism only involves CYP3A4 to a minor extent. Therefore, theobserved interaction with boceprevir is unexpected. As indicated in the study report, boceprevir may affectother metabolic pathways, however it remains unclear which one. As part of the D120, the applicant statedthat a study was being conducted with boceprevir and a combination oral contraceptive containingnorethindrone and ethinylestradiol to identify if the effect on drosperinone is likely to be unique.


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- No significant effect on PEG interferon was observed with boceprevir.

- With clarithromycin, the design of the study cannot allow drawing any conclusion.

Overall to further substantiate interaction profile of boceprevir and in particular its inhibitory potency onCYP3A4 and P-gp, additional studies are required which are of particular relevance for the future use ofthe drug in clinical practice notably with:- Methadone- immunosuppressive drugs administered in transplants patient which are CYP3A substrate (ciclosporinand tacrolimus),- and drugs which are P-gp substrate

As part of the D120 the applicant provided clarification on the PK and DDI that may help finalising therecommendation for physicians in sections 5.2 and 4.5. Furthermore the applicant commits to performadditional relevant interaction studies (anti-HIV drugs, contraceptive drugs).

PharmacodynamicsBoceprevir is the first representative of protease inhibitor in the HCV treatment. Boceprevir inhibits NS3

protease at low nanomolar concentrations. The inhibitory concentration (IC50 and IC90) values forboceprevir were approximately 200 nM (n=25) and 400 nM (n=25), respectively, in a 72-hour assay. In50% human serum, the replicon IC50 value for boceprevir was 500 nM.

Boceprevir had minimal cytotoxic effects.

In a phase 1 study (P03516) in which boceprevir was administered as monotherapy, a concentration-response analysis was performed. The results indicated that the maximal decrease in HCV-RNAconcentrations correlated best with Cmin.

Based on the results of the PK-PD results, the in vitro IC50 and IC90 and the Cmin concentrationsobtained with the different studied dosing regimens, the selection of 800 mg tid dosing appearsreasonable.

Evaluation of varying combinations of boceprevir and interferon alfa-2b that produced 90% suppressionof replicon RNA showed additivity of effect; no evidence of synergy or antagonism was detected.

The replicon assay highlighted 6 major resistance mutation to Boceprevir: V36M, T54A, R155K, V170A,A156T and A156V.A selection pressure-based method employed to analyze sequence data from the Phase 2 boceprevir trial innonresponders identified two other mutations: V55A and V158I.

Resistance-associated amino acid variants (RAVs) at baseline were detected in 6% of the patients inlongterm (34/556) and update (66/1020) studies. RAVs at baseline were observed in the same way in SVR

patients (6% in longterm study, 6% in update study) and non-SVR patients (6% in longterm study and 7%in update study) which suggests a low impact of baseline RAVs on SVR.

Baseline RAVs were observed more frequently in patients with genotype 1a (32/352, 9% in longtermstudy and 53/656, 8% in update) than genotype 1b (1/196, 1% in longterm and 13/359, 4% in update).SAVs were detected at baseline in 186/556 (33%) patients in the longterm study.

Among the subjects treated with Boceprevir, post baseline RAVs were observed in 42% in the longtermstudy (236/556) and 15% in the update analysis (156/1020).

The majority of the resistances wereobserved in Non-SVR patients (234/296, 79% in longterm study and 155/343, 45% in updateanalysis)and less than 1% of the patient who achieved SVR presented a resistance.


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RAVs emergence were similar in RGT arm and no RGT treatment arm (52%, 82/158 in RGT arm and52%, 74/142 in BOC/PR48 weeks) which casts doubt on the hypothesis that RGT would minimize the

presuure of selection.

In the longterm study, the prevalence of baseline mutation were similar in patients previously nonresponder (4%) and in naive patients (8%) but post baseline mutations were more observed in patientswho previously failed to treatment by SOC (79% RAVs) than in naive patients (18% RAVs).

In both study, the most frequently detected post-baseline RAVs were V36M (52% in longterm study and46% in update), T54S (67% in longterm study and 24% in update) and R155K (64% in longterm studyand 51% in update).

In the update analysis, poor interferon responders had a higher proportion of RAVs (68%) compared to theoverall subjects (52%) and Black subjects presended more detectable RAVs (64%) than non black patients(53%).

The 2 years of follow up data of the longterm study suggest that post baseline RAVs may return to wildtype over time (88.7% of the V36M mutation, 63.7% of the T54S, 69.7% of the R155K return to wild typewithin 2 years).

As part of the D120 the applicant was asked to further substantiate the impact on SVR of baseline RAV.

The data although limited were reassuring on the lack of significant impact.

Finally, as a particular limitation of the resistance analysis, clonal analysiswas only performed in phase 1study of boceprevir. Based on these limited data and as expected when referring to the data from other

ketoamide NS3 inhibitors, linked RAV combinations were observed at V36M+T54S, V36A+R155K,T54S+R155K or T54S+A165S. In his response to D120, the applicant was committed to compensate forthe limitation of its original analysis by assessing linkage of multiple RAVs in phase 3.


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Clinical efficacy

The Boceprevir clinical developmentprogram mainly comprised 5 clinical studies:- Phase II dose-controlled trials (P03523/SPRINT 1 in treatment nave patients and

P03659/RESPOND 1 in treatment experienced patients,)- Phase III trials (P05216/SPRINT 2 in treatment nave patients and P05101/RESPOND 2 in treatmentexperienced patients).

- A long term follow up trial (P05063)including all the subjects who participated in a Phase 1, 2, or 3clinical study in which boceprevir was administered is on-going at this time. The goals of this study are toexamine the durability of SVR, the long-term safety after boceprevir treatment and the natural history ofresistance-associated variants over time. Patients were off treatmentin this long term study.

Phase II dose selection development programme:

The first phase 2 study (P03659)was initiated in September 2005 in previous treatment experienced

subjects (including relapse, partial responder and null responder subjects).This phase II dose ranging study had a complex 7-arms design to meet the multiple objectives of:

- determining the most effective dose and treatment duration of BOC (100 mg TID, 200 mg TID, 400mg TOD or 800 mg TOD) in non responders patients,

- determining whether ribavirin is mandatory to enhance the efficacy of pegIFN and BOC, and- evaluating the safety of BOC.

In view of the poor anti-HCV activity due to the low dose of Boceprevir and the important development ofresistance in the group without ribavirin, the Data review Advisory Board took the decision to switch allcontinuing subjects to tritherapy with boceprevir 800mg TID.

The multiple amendments of this study made its results difficult to interpret. Nevertheless lessonswere used to design the subsequent phase II in treatment nave patients:

- notably that ribavirin was compulsory to protect the antiviral agents- study P03659 also demonstrated a dose-related antiviral activityof boceprevir. It was observed that800 mg TID of boceprevir in combination with PegIntron resulted in the most rapid time to the first HCV-RNA negative samples. The mean time in weeks to achieve the first negative HCV-RNA sample duringtreatment with 800 mg TID boceprevir was the shortest (4.9 weeks) when compared with the lowerdoses of 100 mg, 200 mg, and 400 mg TID (16.3, 8.4, 7.8 weeks, respectively).Predicted Cmin of boceprevir were observed to exceed the IC90 of the compound for the virus (200ng/mL) at a dose of 400 mg TID, with the greatest number of predicted concentrations exceeding thistarget in the 800 mg TID dose group. In addition, preliminary pharmacokinetic data in healthy volunteerswho received 800 mg TID and 1200 mg TID suggest that further dose escalation to 1200 mg TID willnot increase trough concentrations.


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Preliminary Scatter Plot of Individual Predicted Boceprevir Cmin vs Dose

Overall , the support of the dose selection i s limited (der ived from one phase I I study the interpretation

of whi ch being jeopardized by several amendments). The adequacy of the dose is ul timately to be judged

on the basis of the eff icacy/safety data derived fr om the phase II I studies.

The second phase 2 study (P03523) was initiated in January 2007 in treatment nave HCV infected

subjects with a genotype 1. The BOC 800 mg TID dose was directly selected for this phase II study.The study compared standard-of-care PEG2b (1.5 g/kg) plus ribavirin (800 to 1400 mg/day) for 48weeks to five treatment arms containing boceprevir 800 mg TID. The five treatments included standard ofcare plus boceprevir for 28 or 48 weeks, with and without a 4-week lead-in with P/R (Part 1), andexploration of PEG2b plus low-dose ribavirin (400 to 1000 mg/day)plus boceprevir for 48 weeks (Part2).

Again, this phase II had a complex design with the ambitious multi-objectivesof exploring:- different treatment durations of the tritherapy (28 vs 48 weeks),- interest of the Lead in (LI) phase(4 weeks with the bitherapy Pegylated IFN+ribavirin before theaddition of the boceprevir). The LI phase presents the theoretical advantage of allowing the introduction ofthe antiviral agent once the steady state of ribavirin has been reached, i.e. under the optimal condition forthe DAA (to best protect the DAA against functional monotherapy and to reduce the pre-existing variantsfor limiting the pressure of selection).Whether or not the lead in phase was compulsory for this DAA, was specifically assessed in thisphase II study with comparative arms with or without lead in phase.Of note, it is thought that some drugs might afford achieving maximal viral suppression without the LI and

despite pre-existing variants- a lower dose of ribavirinto minimize the risk of anemia due to the tritherapy with boceprevir


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As regards the primary efficacy analysis derived from this phase II study in treatment nave patients, theSustained virologic response (SVR) and relapse rate are described below:

All BOC arms showed statistically significant increased in SVR rate as compared to SOC. A considerable30-37% increase in SVR rate was observed in patients adding BOC to SOC for 48 weeks as compared toSOC therapy (as a reminder, a 20% increase was targeted by the Applicant). SVR rate was increased by17-19% when BOC is added to SOC for 28 weeks.As a matter of fact, the higher SVR rate observed in BOC arms was driven by a higher EOT in all BOCarms and by a lower relapse rate for the 48 weeks BOC arms only.

As regards the treatment dur ation:These data suggest that 28 weeks tritherapy may not be sufficient enough to eliminate variants in a

substantial proportion of patients.Nevertheless, rapid virological response might help discriminate patients that can benefit from shortertreatment duration without maximizing relapse, as highlighted in the table below:

c: Undetectable HCV-RNA at or before 4 weeks of P/R for Arm 1; undetectable HCV-RNA at or before 4 weeks ofboceprevir (TW 4 for Arms 2, 4, 6, and 7 and TW 8 for Arms 3 and 5).

It appears from these data that 48 weeks treatment regimen would be the most protective approach even inpatients with RVR. Relapse rates for the 48-week boceprevir arms in Part 1 were significantly lowercompared to P/R control (Arm 4 vs P/R control: P=0.008; Arm 5 vs P/R control: P=0.0002).

Emergence of the concept of Response Gui ded Therapy

When the response rates in these two arms were examined looking at subsets of subjects based on thetime each subject first achieved undetectable HCV-RNA, it was identified that subjects who attainedundetectable HCV-RNA by TW 8 had relatively similar SVR rates in both arms. For late responders,subjects with detectable HCV-RNA at TW 8, the SVR rates in the 48-week arm were superior to that inthe 28-week arm.

Based on these data, the concept of a treatment duration tailored to the early kinetics of virologicresponse has emerged (i.e. the Response Guided Therapy/RGT). This concept was then formallytested in the two phase III studies.


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As regards the comparati ve data with lead in vs no lead in phaseThe data derived from this study speak in favour of a lead in phase. As illustrated in the above tables,the lead in phase was indeed associated with higher SVR and lower relapses as compared to thecorresponding no lead in phase arms.

Finally, results from the low dose ribavirin arm argue in disfavour of this strategy. Full doseribavirin appears to be critically needed to reduce relapse rate and to achieve SVR also in the setting oftritherapy with BOC.

Phase III development programme:

The two pivotal phase 3 study [in treatment nave patients (P05216/SPRINT 2) and in treatmentexperienced patients (P05101/RESPOND 2] initiated in August 2008 were designed taking intoaccount the findings from the phase II studies.

Of note, although the phase III study in treatment nave patients can be regarded as being furtherconsolidated by the phase II study in the same population (and with the 800 mg TID dose), the same doesnot apply to the phase III study in treatment experienced patients since the corresponding phase II couldnot be interpreted due to several amendments.

1. As regards their designs:

For both phase III studies, the main following aspects of their design can be underlined:

- double blind(although the significant rate of dysgueusia with boceprevir (see safety assessment) mighthave to some extent given some insight to the boceprevir containing arms).

- multi-centersstudies with centers from US, EU, Canada and South Africa [P05101 : 78 sites: USA (44),Europe (27), Canada (8), South America (1) / P05216 : 149 sites: USA (82), Europe (49), Canada (11),South America (7)]

- the control arm was the current established standard-of-care (SOC), Pegylated Interferon+Ribavirin for 48 weeks

In both phase III studies (as we

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