18 May 2017 EMA/349863/2017 Committee for Medicinal Products for Human Use (CHMP) CHMP assessment report Spherox Common name: spheroids of human autologous matrix-associated chondrocytes Procedure No. EMEA/H/C/002736/0000 30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5520 Send a question via our website www.ema.europa.eu/contact An agency of the European Union Administrative information Name of the medicinal product: Spherox Applicant: CO.DON AG Warthestr. 21 14513 Teltow GERMANY Spheroids of human autologous matrix- Active substance: associated chondrocytes Common Name: Spheroids of human autologous matrix- associated chondrocytes Other drugs for disorders of the musculo- Pharmaco-therapeutic group skeletal system (M09AX02) (ATC Code): Repair of symptomatic articular cartilage Therapeutic indication: defects of the femoral condyle and the patella of the knee (International Cartilage Repair Society [ICRS] grade III or IV) with defect sizes up to 10 cm2 in adults. Pharmaceutical form: Implantation suspension Strength: 10–70 spheroids/cm² Route of administration: Intraarticular use Packaging: Applicator Pre-filled syringe Package sizes: 1 to10 sterile tubes with up to 2 applicators CHMP assessment report EMA/349863/2017 Page 2/125 each + 1 syringe per applicator and 1 to 10 sterile tubes with 1 pre-filled syringe each +1 indwelling cannula or 1 filter stem per pre-filled syringe CHMP assessment report EMA/349863/2017 Page 3/125 Table of contents 1. Background information on the procedure ............................................ 10 1.1. Submission of the dossier ................................................................................... 10 1.2. Steps taken for the assessment of the product ...................................................... 11 2. Scientific discussion .............................................................................. 12 2.1. Problem statement ............................................................................................. 12 2.1.1. Disease or condition ........................................................................................ 13 2.1.1. Clinical presentation, diagnosis ......................................................................... 13 2.1.2. Management ................................................................................................... 14 2.2. Quality aspects .................................................................................................. 15 2.2.1. Introduction.................................................................................................... 15 2.2.2. Active substance ............................................................................................. 15 2.2.3. Finished Medicinal Product ................................................................................ 21 2.2.4. Discussion on chemical, pharmaceutical and biological aspects.............................. 26 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 28 2.2.6. Recommendation(s) for future quality development ............................................. 28 2.3. Non-clinical aspects ............................................................................................ 28 2.3.1. Introduction.................................................................................................... 28 2.3.2. Pharmacology ................................................................................................. 29 2.3.3. Pharmacokinetics ............................................................................................ 31 2.3.4. Toxicology ...................................................................................................... 32 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 34 2.3.6. Discussion on the non-clinical aspects ................................................................ 34 2.3.7. Conclusion on the non-clinical aspects ............................................................... 35 2.4. Clinical aspects .................................................................................................. 35 2.4.1. Introduction.................................................................................................... 35 2.4.2. Pharmacokinetics ............................................................................................ 39 2.4.3. Pharmacodynamics .......................................................................................... 39 2.4.4. Discussion on clinical pharmacology ................................................................... 41 2.4.5. Conclusions on clinical pharmacology ................................................................. 42 2.5. Clinical efficacy .................................................................................................. 43 2.5.1. Dose response studies ..................................................................................... 43 2.5.2. Main studies ................................................................................................... 44 2.5.3. Discussion on clinical efficacy ............................................................................ 91 2.5.4. Conclusions on the clinical efficacy .................................................................... 98 2.5.5. Discussion on clinical safety .............................................................................. 98 2.5.6. Discussion on the clinical safety ...................................................................... 106 2.5.7. Conclusions on the clinical safety .................................................................... 107 2.6. Risk Management Plan ...................................................................................... 108 CHMP assessment report EMA/349863/2017 Page 4/125 2.7. Pharmacovigilance ........................................................................................... 109 2.8. New Active Substance ...................................................................................... 109 2.9. Product information .......................................................................................... 109 2.9.1. User consultation .......................................................................................... 109 2.9.2. Labelling exemptions ..................................................................................... 109 2.9.3. Additional monitoring ..................................................................................... 110 3. Benefit-Risk Balance ........................................................................... 110 3.1. Therapeutic Context ......................................................................................... 110 3.1.1. Disease or condition ...................................................................................... 110 3.1.2. Available therapies and unmet medical need ..................................................... 111 3.1.3. Main clinical studies ....................................................................................... 111 3.2. Favourable effects ............................................................................................ 111 3.3. Uncertainties and limitations about favourable effects ........................................... 113 3.4. Unfavourable effects ......................................................................................... 113 3.5. Uncertainties and limitations about unfavourable effects ....................................... 114 3.6. Effects Table .................................................................................................... 114 3.7. Benefit-risk assessment and discussion ............................................................... 116 3.7.1. Importance of favourable and unfavourable effects ............................................ 116 3.7.2. Balance of benefits and risks .......................................................................... 118 3.8. Conclusions ..................................................................................................... 118 4. Recommendations ............................................................................... 118 CHMP assessment report EMA/349863/2017 Page 5/125 List of abbreviations 2D Two-dimensional 3D Three-dimensional ACI Autologous chondrocyte implantation ACL anterius cruciatum Ligamentum ACT Autologous chondrocyte transplantation ACT3D Autologous chondrocyte transplantation with a 3-dimensional chondrocyte product ACT3D-CS Spherox ADME Absorption, distribution, metabolism, excretion ADR Adverse Drug Reaction AG Corporation (Aktiengesellschaft) AE Adverse Event ALP Alcaline phosphatase AMG Arzneimittelgesetz (German Medicines Act) approx. Approximately AST Aspartate aminotransferase ATC Anatomical Therapeutic Chemical ATMP Advanced Therapy Medicinal Product BL Baseline BMI Body Mass Index BMP-2/4 Bone morphogenic protein 2/4 BrdU Bromdesoxyuridin BVOT Belgische Vereniging voor Orthopedie en Traumatologie (Belgian Society of Orthopaedics and Traumatology) CAT Committee for Advanced Therapies (at the EMA) CBMP Cell-Based Medicinal Products CCI Characterised chondrocyte implantation CE Conformitee European CEP Chondrocyte Expressed Protein CHMP Committee for Medicinal Products for Human Use CI Biopsy Biopsy out of native cartilage for cell isolation