22 January 2015 EMA/83337/2015 Committee for Medicinal Products for Human Use (CHMP) Assessment report Sivextro International non-proprietary name: tedizolid phosphate Procedure No. EMEA/H/C/002846/0000 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 5520 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. Table of contents 1. Background information on the procedure .............................................. 9 1.1. Submission of the dossier ..................................................................................... 9 1.2. Manufacturers ................................................................................................... 10 1.3. Steps taken for the assessment of the product ...................................................... 10 2. Scientific discussion .............................................................................. 12 2.1. Introduction ...................................................................................................... 12 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, and pharmaceutical aspects ........................................... 20 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 20 2.2.6. Recommendation(s) for future quality development ............................................. 20 2.3. Non-clinical aspects ............................................................................................ 20 2.3.1. Introduction.................................................................................................... 20 2.3.2. Pharmacology ................................................................................................. 21 2.3.3. Pharmacokinetics ............................................................................................ 23 2.3.4. Toxicology ...................................................................................................... 25 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 33 2.3.1. Discussion on non-clinical aspects ..................................................................... 34 2.3.2. Conclusion on the non-clinical aspects ............................................................... 34 2.4. Clinical aspects .................................................................................................. 34 2.4.1. Introduction.................................................................................................... 34 2.4.2. Pharmacokinetics ............................................................................................ 36 2.4.3. Pharmacodynamics .......................................................................................... 40 2.4.4. Discussion on clinical pharmacology ................................................................... 47 2.5. Clinical efficacy .................................................................................................. 49 2.5.1. Dose response studies ..................................................................................... 50 2.5.2. Main studies ................................................................................................... 52 2.5.3. Discussion on clinical efficacy ............................................................................ 80 2.5.4. Conclusions on the clinical efficacy .................................................................... 82 2.6. Clinical safety .................................................................................................... 82 2.6.1. Discussion on clinical safety ............................................................................ 101 2.6.2. Conclusions on the clinical safety .................................................................... 102 2.7. Pharmacovigilance ........................................................................................... 102 2.8. Risk Management Plan ...................................................................................... 102 2.9. Product information .......................................................................................... 106 2.9.1. User consultation .......................................................................................... 106 Assessment report EMA/83337/2015 Page 2/110 3. Benefit-Risk Balance ........................................................................... 106 4. Recommendations ............................................................................... 110 Assessment report EMA/83337/2015 Page 3/110 List of abbreviation Abbreviation Definition 14C radiolabelled carbon-14 ABSSSI acute bacterial skin and skin structure infections AE adverse event ANC absolute neutrophil count AUC area under the curve AUC0-∞ AUC from Hour 0 extrapolated to infinity based on the apparent terminal rate constant AUC0-24 AUC from Hour 0 to Hour 24.I BCRP breast cancer resistance protein BMI body mass index CA-MRSA community-acquired methicillin-resistant Staphylococcus aureus CDAD Clostridium difficile associated disease CE Clinically Evaluable CE-PTE Clinically Evaluable at PTE Cfr chloramphenicol-florfenicol resistance CFU/g log10 CHMP Committee for Medicinal Products for Human Use CI confidence interval CL clearance CL/F apparent clearance CLSI Clinical and Laboratory Standards Institute cMITT Clinical modified ITT CQAs Critical Quality Attributes cSSTI complicated skin and soft tissue infections CYP Cytochrome P450 dL deciliter Assessment report EMA/83337/2015 Page 4/110 Abbreviation Definition EC European Commission ECDC European Centre for Disease Prevention and Control ECG electrocardiogram eGFR estimated glomerular filtration rate EIE erythema plus induration or oedema EMA European Medicines Agency EOT end of therapy EU European Union FA free acid TR-701/FA is used when reference is made to both the disodium salt (TR-701) and the free acid form (TR-701 FA) of the study drug. fAUC/MIC The area under the unbound concentration-time curve to MIC ratio FDA Food and Drug Administration FT-IR Fourier transform infrared spectroscopy g gram GC Gas Chromatography GI gastrointestinal h hour HDPE high density polyethylene HPLC High-performance liquid chromatography IC50 median (50%) inhibitory concentration ICH International Conference on Harmonisation ICP-MS Inductively coupled plasma mass spectrometry IR Infrared Spectroscopy ISE Integrated Summary of Efficacy ITT Intent-to-Treat IV intravenous KF Karl Fischer L litre Assessment report EMA/83337/2015 Page 5/110 Abbreviation Definition LFU late follow up LLN lower limit of normal MAA Marketing Authorisation Application MAO monoamine oxidase ME Microbiologically Evaluable mg milligram mMITT Microbiological Modified Intent to Treat MHRA Medicines and Healthcare Regulatory Agency MI myocardial infarction MIC minimum inhibitory concentration MITT Modified Intent to Treat mL millilitre mm millimetre MPS mitochondrial protein synthesis MRSA methicillin-resistant Staphylococcus aureus MSSA methicillin-susceptible Staphylococcus aureus n number of patients in the specific category N number of patients in the analysis set NI non-inferiority NMR nuclear magnetic resonance spectroscopy NOAEL no observed adverse effect level OAT organic anion transporter OCT organic cation transporter PD primary pharmacodynamics P-gp P-glycoprotein Ph. Eur. European Pharmacopoeia PIP Pediatric Investigation Plan PK pharmacokinetics Assessment report EMA/83337/2015 Page 6/110 Abbreviation Definition popPK population pharmacokinetics PSE pseudoephedrine PSM phenol-soluble modulins PT Preferred Term PVC polyvinyl chloride PVdC polyvinylidene chloride PTE post therapy evaluation PVL Panton-Valentine leukocidin toxin QTc QT interval corrected for heart rate QTcF QT interval corrected for heart rate using Fridericia’s formula QTPP Quality Target Product Profile RBC red blood cell RH Relative Humidity SA substantially abnormal SAE serious adverse event SAP statistical analysis plans SD standard deviation SmPC Summary of Product Characteristics SOC system organ class SSTIs skin and soft tissue infections TEAE treatment-emergent adverse event TOC test of cure TR-700 tedizolid; microbiologically active moiety of TR-701 or TR-701 FA prodrug TR-701 disodium phosphate salt prodrug of TR-700 TR-701 FA tedizolid phosphate; free acid phosphate prodrug of TR-700 TR-701/FA TR-701 FA or TR-701 TYR30 tyramine dose required to cause a 30 mmHg increase in systolic blood pressure μCi microcurie Assessment report EMA/83337/2015 Page 7/110 Abbreviation Definition µg microgram UV/VIS ultraviolet/visible spectroscopy WBC white blood cell WFI water for injection XPRD X-Ray Powder Diffraction Assessment report EMA/83337/2015 Page 8/110 1. Background information