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Masiviera EPAR FINAL ... 7 Westferry Circus Canary Wharf London E14 4HB United Kingdom An agency of the European Union Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7523 7455 E-mail

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Text of Masiviera EPAR FINAL ... 7 Westferry Circus Canary Wharf London E14 4HB United Kingdom An agency of...

  • 7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom

    An agency of the European Union Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7523 7455 E-mail [email protected] Website www.ema.europa.eu

    22 May 2014 EMA/CHMP/327108/2014 Committee for Medicinal Products for Human Use (CHMP)

    Assessment report

    Masiviera

    International non-proprietary name: MASITINIB

    Procedure No.: EMEA/H/C/002659/0000

    Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted.

  • Assessment report EMA/CHMP/327108/2014 Page 2/71

    Product information

    Name of the medicinal product:

    Masiviera

    Applicant:

    AB Science 3, Avenue George V 75008 Paris FRANCE

    Active substance:

    Masitinib mesylate

    International Nonproprietary Name/Common Name:

    MASITINIB

    Pharmaco-therapeutic group (ATC Code):

    Antineoplastic agents, protein kinase inhibitors (L01XE22)

    Therapeutic indication:

    Masiviera in combination with gemcitabine is indicated for the first-line treatment of non-resectable locally advanced or metastatic pancreatic cancer in adult patients presenting with: - specific genetic biomarker (GBM) (population 1) - pain (population 2). Adult patients eligible for Masiviera treatment should present with pain estimated as strictly higher than 20 mm / 100 mm on a visual analogue scale.

    Pharmaceutical form:

    Film-coated tablet

    Strengths:

    100 mg and 200 mg

    Route of administration:

    Oral use

    Packaging:

    bottle (HDPE)

    Package size:

    30 tablets

  • Assessment report EMA/CHMP/327108/2014 Page 3/71

    Table of contents

    1. Background information on the procedure .............................................. 7 1.1. Submission of the dossier ...................................................................................... 7 1.2. Manufacturers ...................................................................................................... 9 1.3. Steps taken for the assessment of the product ......................................................... 9 1.4. Steps taken for the re-examination procedure ....................................................... 10

    2. Scientific discussion .............................................................................. 10 2.1. Introduction....................................................................................................... 10 2.2. Quality aspects .................................................................................................. 11 2.2.1. Introduction .................................................................................................... 11 2.2.2. Active substance ............................................................................................. 11 2.2.3. Finished medicinal product ................................................................................ 13 2.2.4. Discussion on chemical, and pharmaceutical aspects ............................................ 16 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 16 2.2.6. Recommendation for future quality development ................................................. 16 2.3. Non-clinical aspects ............................................................................................ 16 2.3.1. Introduction .................................................................................................... 16 2.3.2. Pharmacology ................................................................................................. 17 2.3.3. Pharmacokinetics............................................................................................. 18 2.3.4. Toxicology ...................................................................................................... 21 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 26 2.3.6. Discussion on non-clinical aspects...................................................................... 26 2.3.7. Conclusion on the non-clinical aspects ................................................................ 29 2.4. Clinical aspects .................................................................................................. 29 2.4.1. Introduction .................................................................................................... 29 2.4.3. Pharmacodynamics .......................................................................................... 34 2.4.4. Discussion on clinical pharmacology ................................................................... 34 2.4.5. Conclusions on clinical pharmacology ................................................................. 35 2.5. Clinical efficacy .................................................................................................. 35 2.5.1. Dose response study ........................................................................................ 35 2.5.2. Main study ...................................................................................................... 36 2.5.3. Discussion on clinical efficacy ............................................................................ 48 2.5.4. Conclusions on the clinical efficacy ..................................................................... 48 2.6. Clinical safety .................................................................................................... 49 2.6.1. Discussion on clinical safety .............................................................................. 56 2.6.2. Conclusions on the clinical safety ....................................................................... 58 2.7. Pharmacovigilance .............................................................................................. 58 2.8. Risk Management Plan ........................................................................................ 58 2.9. User consultation ............................................................................................... 61

  • Assessment report EMA/CHMP/327108/2014 Page 4/71

    3. Benefit-Risk Balance ............................................................................. 61

    4. Recommendations ................................................................................. 63

    5. Re-examination of the CHMP opinion of 23 January 2014 ..................... 64

  • Assessment report EMA/CHMP/327108/2014 Page 5/71

    List of abbreviations

    AE Adverse events

    ALT Alanine aminotransferase

    ANC Absolute neutrophil count

    AST Aspartate aminotransferase

    AUC Area under Curve

    BE Bioequivalence

    CI Confidence Interval

    Cl Clearance

    Cl/F apparent clearance

    CL/F Total clearance

    CLr renal clearance

    Cmax Maximum concentration

    CNS Central nervous system

    CR Complete response

    Ct Cycle Threshold

    CYP Cytochrome p450

    DCt Delta Ct

    ECG Electrocardiogram

    ECOG Eastern Cooperative Oncology Group

    EGFR Human epidermal growth factor

    EMA European medicine agency

    F Bioavailability

    FGFR3 fibroblast growth factor receptor 3

    HR Hazard ratio

    KPS Karnofsky Performance Status

    M+G Masitinib + gemcitabine

    mITT modified Intent To Treat

    M-RECIST Modified Response Evaluation Criteria In Solid Tumours

    NA Not applicable or not assessable

    NOAEL No observable adverse effect level

    OS Overall Survival

    PD Progressive disease

    PDGF Platelet-derived growth factor

    PDAC pancreatic ductal adenocarcinoma

    PDGFR Platelet-derived growth factor receptor

  • Assessment report EMA/CHMP/327108/2014 Page 6/71

    PFS Progression Free Survival

    P+G Placebo + gemcitabine

    P-gp Permeability glycoprotein

    PK Pharmacokinetics

    PK/PD Pharmacokinetics/Pharmacodynamics

    PP Per Protocol

    PR Partial Response

    QoL Quality of Life

    QLQ-C30 Quality of Life Questionnaire C30

    RECIST Response Evaluation Criteria In Solid Tumours

    RNA Ribonucleic acid

    RT-PCR reverse transcription polymerase chain reaction

    SAE Serious adverse events

    SD Stable Disease

    t1/2 half life

    TKI Tyrosine Kinase Inhibitor

    Tmax Time to maximum concentration

    TTP Time to progression

    ULN Upper limit of normal

    VAS Visual analogue scale

    Vd Volume of distribution

    WT Wild Type

  • EMA/CHMP/327108/2014 Page 7/71

    1. Background information on the procedure

    1.1. Submission of the dossier

    The applicant AB Science submitted on 30 August 2012 an application for Marketing Authorisation to the European Medicines Agency (EMA) for Masiviera, through the centralised procedure falling within the Article 3(1) and point 4 of Annex of Regulation (EC) No 726/2004. The eligibility to the centralised procedure was agreed upon by the EMA/CHMP on 17 November 2011.

    Masiviera was designated as an orphan medicinal product EU/3/09/684 on 28 October 2009. Masiviera was designated as an orphan medicinal