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Assessment Report for Otezla

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Assessment Report for Otezla 20 November 2014 EMA/CHMP/476353/2014 Committee for Medicinal Products for Human Use (CHMP) Assessment report Otezla International non-proprietary name: apremilast Procedure No. EMEA/H/C/003746 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. 30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact An agency of the European Union © European Medicines Agency, 2015. Reproduction is authorised provided the source is acknowledged. Administrative information Name of the medicinal product: Otezla Applicant: Celgene Europe Limited 1 Longwalk Road Stockley Park UxbridgeUB11 1DB United Kingdom Active substance: apremilast International Nonproprietary Name/Common apremilast Name: Pharmaco-therapeutic group Immunosuppressant (ATC Code): (L04AA32) Therapeutic indications: Psoriatic arthritis Otezla, alone or in combination with Disease Modifying Antirheumatic Drugs (DMARDs), is indicated for the treatment of active psoriatic arthritis (PsA) in adult patients who have had an inadequate response or who have been intolerant to a prior DMARD therapy (see section 5.1). Psoriasis Otezla is indicated for the treatment of moderate to severe chronic plaque psoriasis in adult patients who failed to respond to or who have a contraindication to, or are intolerant to other systemic therapy including cyclosporine, methotrexate or psoralen and ultraviolet-A light (PUVA). Pharmaceutical form: Film-coated tablet Strengths: 10 mg, 20 mg and 30 mg Route of administration: Oral use Packaging: Blister (PVC/aluminium foil) EMA/CHMP/476353/2014 Page 2/189 Package sizes: 4 x 10 mg + 4 x 20 mg + 19 x 30 mg tablets 56 x 30 mg tablets and 168 x 30 mg tablets EMA/CHMP/476353/2014 Page 3/189 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 2. Scientific discussion .............................................................................. 10 2.1. Introduction....................................................................................................... 10 2.2. Quality aspects .................................................................................................. 13 2.2.1. Introduction .................................................................................................... 13 2.2.2. Active Substance ............................................................................................. 13 2.2.3. Finished Medicinal Product ................................................................................ 15 2.2.4. Discussion on chemical, pharmaceutical and biological aspects .............................. 17 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 17 2.2.6. Recommendation(s) for future quality development ............................................. 17 2.3. Non-clinical aspects ............................................................................................ 18 2.3.1. Introduction .................................................................................................... 18 2.3.2. Pharmacology ................................................................................................. 18 2.3.3. Pharmacokinetics............................................................................................. 32 2.3.4. Toxicology ...................................................................................................... 40 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 58 2.3.6. Discussion on non-clinical aspects...................................................................... 60 2.3.7. Conclusion on the non-clinical aspects ................................................................ 68 2.4. Clinical aspects .................................................................................................. 68 2.4.1. Introduction .................................................................................................... 68 2.4.2. Pharmacokinetics............................................................................................. 72 2.4.3. Pharmacodynamics .......................................................................................... 80 2.4.4. Discussion on clinical pharmacology ................................................................... 86 2.4.5. Conclusions on clinical pharmacology ................................................................. 89 2.5. Clinical efficacy .................................................................................................. 89 2.5.1. Dose response studies...................................................................................... 89 2.5.2. Main studies ................................................................................................... 90 2.5.3. Discussion on clinical efficacy .......................................................................... 140 2.5.4. Conclusions on the clinical efficacy ................................................................... 147 2.6. Clinical safety .................................................................................................. 148 2.6.1. Discussion on clinical safety ............................................................................ 177 2.6.2. Conclusions on the clinical safety ..................................................................... 179 2.7. Pharmacovigilance ............................................................................................ 180 2.8. Risk Management Plan ...................................................................................... 180 2.9. Product information .......................................................................................... 185 2.9.1. User consultation ........................................................................................... 185 3. Benefit-Risk Balance............................................................................ 185 4. Recommendations ............................................................................... 188 EMA/CHMP/476353/2014 Page 4/189 List of abbreviations AAR Apremilast Subjects as Randomized/Re-randomized AAT Apremilast Subjects as Treated 20%/50%/70% improvement per the American College of ACR 20/50/70 Rheumatology response criteria ACR-N American College of Rheumatology N index Treatment group comprising subjects initially randomized to APR 20 BID / APR 30 BID apremilast 20 or 30 mg BID APR 20 BID EE / APR 30 BID EE Treatment group comprising subjects in the APR 20 BID / APR 30 BID treatment groups who entered early escape at Week 16 APR 20 BID Treatment group comprising subjects in the APR 20 BID / NEE / APR 30 APR 30 BID treatment groups who did not enter early escape at BID NEE Week 16 APR Apremilast BASDAI Bath Ankylosing Spondylitis Disease Activity Index BID Twice daily BOCF Baseline observation carried forward BSA Body surface area cAMP Cyclic adenosine monophosphate CASPAR Classification Criteria for Psoriatic Arthritis CDAI Clinical Disease Activity Index DAS28(CRP) 28 Joint Disease Activity Score using CRP as acute phase reactant DIP Distal interphalangeal DMARD Disease-modifying antirheumatic drug DSC Differential scanning calorimetry DVS Dynamic vapor sorption ESR Erythrocyte sedimentation rate EULAR European League Against Rheumatism FACIT-Fatigue Functional Assessment of Chronic Illness Therapy – Fatigue Subscale FAS Full analysis set FT-IR Fourier Transform InfraRed GC Gas chromatography EMA/CHMP/476353/2014 Page 5/189 GRAPPA Group of Research and Assessment of Psoriasis and Psoriatic Arthritis HAQ-DI Health Assessment Questionnaire – Disability Index HPLC High-performance liquid chromatography ICH The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use IR Infrared LOCF Last observation carried forward LS Least-squares MASES Maastricht Ankylosing Spondylitis Enthesitis Score MCID Minimal clinically important difference MCS Mental component summary(SF-36v2) MMRM Mixed-effects model for repeat measures MTX Methotrexate NMR Nuclear magnetic resonance NRI Nonresponder imputation NSAID Nonsteroidal anti-inflammatory drug PASI Psoriasis area and severity index PASI-50 50% or greater improvement in Psoriasis Area and Severity Index score PASI-75 75% or greater improvement in Psoriasis Area and Severity Index score PBO/20 EE / PBO/30 EE Treatment group comprising subjects initially randomized to placebo who entered early escape and were re-randomized to apremilast 20 or 30 mg BID at Week 16 PBO/20 XO / PBO/30 XO Treatment group comprising subjects initially randomized to placebo who were re-randomized to apremilast 20 or 30 mg BID at Week 24 PCS Physical component summary PD Pharmacodynamic PDE4 Phosphodiesterase 4 PGA Patient’s (Subject’s) Global Assessment Ph. Eur. European Pharmacopoeia PK Pharmacokinetic(s) EMA/CHMP/476353/2014 Page 6/189 PP Per protocol PsA Psoriatic arthritis PsARC Psoriatic Arthritis
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