17 September 2020 EMA/CHMP/522273/2020 Committee for Medicinal Products for Human Use (CHMP) Assessment report Orfadin International non-proprietary name: nitisinone Procedure No. EMEA/H/C/000555/II/0071 Note Variation assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us An agency of the European Union Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 © European Medicines Agency, 2020. Reproduction is authorised provided the source is acknowledged. Table of contents 1. Background information on the procedure .............................................. 6 1.1. Type II variation .................................................................................................. 6 1.2. Steps taken for the assessment of the product ......................................................... 7 2. Scientific discussion ................................................................................ 8 2.1. Introduction......................................................................................................... 8 2.1.1. Problem statement ............................................................................................ 8 2.1.2. About the product .............................................................................................. 8 2.1.3. The development programme/compliance with CHMP guidance/scientific advice ........ 9 2.1.4. General comments on compliance with GCP ........................................................ 10 2.2. Non-clinical aspects ............................................................................................ 10 2.2.1. Introduction .................................................................................................... 10 2.2.2. Pharmacology ................................................................................................. 10 2.2.3. Ecotoxicity/environmental risk assessment ......................................................... 12 2.2.4. Discussion on non-clinical aspects...................................................................... 12 2.2.5. Conclusion on the non-clinical aspects ................................................................ 12 2.3. Clinical aspects .................................................................................................. 13 2.3.1. Introduction .................................................................................................... 13 2.4. Clinical efficacy .................................................................................................. 14 2.4.1. Dose response study ........................................................................................ 14 2.4.2. Main study ...................................................................................................... 19 2.4.3. Discussion on clinical efficacy ............................................................................ 59 2.4.4. Conclusions on the clinical efficacy ..................................................................... 63 2.5. Clinical safety .................................................................................................... 64 2.5.1. Discussion on clinical safety .............................................................................. 77 2.5.2. Conclusions on clinical safety ............................................................................ 79 2.5.3. PSUR cycle ..................................................................................................... 80 2.6. Risk management plan ........................................................................................ 80 2.7. Update of the Product information ........................................................................ 83 2.7.1. User consultation ............................................................................................. 83 3. Benefit-Risk Balance.............................................................................. 83 3.1. Therapeutic Context ........................................................................................... 83 3.1.1. Disease or condition ......................................................................................... 83 3.1.2. Available therapies and unmet medical need ....................................................... 83 3.1.3. Main clinical studies ......................................................................................... 84 3.2. Favourable effects .............................................................................................. 84 3.3. Uncertainties and limitations about favourable effects ............................................. 85 3.4. Unfavourable effects ........................................................................................... 85 3.5. Uncertainties and limitations about unfavourable effects ......................................... 86 3.6. Effects Table ...................................................................................................... 86 3.7. Benefit-risk assessment and discussion ................................................................. 87 3.7.1. Importance of favourable and unfavourable effects .............................................. 88 3.7.2. Balance of benefits and risks ............................................................................. 88 3.7.3. Additional considerations on the benefit-risk balance ........................................... 88 3.8. Conclusions ....................................................................................................... 88 4. Recommendations ................................................................................. 88 List of abbreviations ADR: adverse drug reaction AE: Adverse Events AKU: alkaptonuria AKUSSI: Alkaptonuria Severity Score Index ALP: alkaline phosphatase ATC: Anatomical, Therapeutical, Chemical BP: Blood Pressure BQA: benzoquinone acetic acid Cav: concentration average CHMP: Committee for Medicinal Products for Human Use CI: Confidential Interval Cmax: concentration maximum CRF: Case Report Form CSP: clinical study protocol DEXA: Dual energy X-ray absorptiometry eGFR: estimated glomerular filtration rate FAH: Fumarylacetoacetate hydrolase FAS: Final Analysis Set FPEN: Penetration Factor GCP: Good Clinical Practice HAQ: Health Assessment Questionnaire HGA : homogentisic acid HGD: homogentisate 1,2-dioxygenase HPP: 4-Hydroxyphenylpyruvate HPPD: 4-Hydroxyphenylpyruvate dioxygenase HT-1: hereditary tyrosinemia type 1 LLOQ: Lower Limit of Quantitation Log Kow: Octanol/Water partitioning coefficient LS: Least Square MAR : missing at random MCMC: Markov-Chain Monte Carlo MMRM: Mixed effect model repeat measurement MNAR : missing not at random MRI: Magnetic Resonance Imaging PBT: Persistent, Bioaccumulative and Toxic PECsw: Predicted Environmental Concentration surface water p-HGA : plasma concentration of HGA PT: Preferred Term QoL: Quality of Life REML: Restricted maximum likelihood method SA: Scientific Advice SAE: Serious Adverse Event SAP: Statistical Analysis Plan SE: standard error SF36: Short Form Health Survey SmPC: Summary of Product Characteristics SOC: Standard Organ Class (SOC) u-HGA: urine concentration of HGA u-HGA24: urine concentration of HGA in 24h. ULN: Upper Limit of Normal WHO: World Health Organization WOMAC: Wester Ontario and McMaster Universities Arthritis 1. Background information on the procedure 1.1. Type II variation Pursuant to Article 16 of Commission Regulation (EC) No 1234/2008, Swedish Orphan Biovitrum International AB submitted to the European Medicines Agency on 10 February 2020 an application for a variation. The following variation was requested: Variation requested Type Annexes affected C.I.6.a C.I.6.a - Change(s) to therapeutic indication(s) - Addition Type II I and IIIB of a new therapeutic indication or modification of an approved one Extension of indication to include treatment of adult patients with alkaptonuria (AKU) for Orfadin; as a consequence, sections 4.1, 4.2, 4.4, 4.6, 4.8, 5.1 and 10 of the SmPC are updated. The Package Leaflet is updated in accordance. Version 5.2 of the RMP has also been submitted accordingly and includes an update in accordance with GVP Module V Revision 2. The variation requested amendments to the Summary of Product Characteristics and Package Leaflet and to the Risk Management Plan (RMP). Information on paediatric requirements Not applicable Information relating to orphan market exclusivity Similarity Pursuant to Article 8 of Regulation (EC) No. 141/2000 and Article 3 of Commission Regulation (EC) No 847/2000, the MAH did not submit a critical report addressing the possible similarity with authorised orphan medicinal products because there is no authorised orphan medicinal product for a condition related to the proposed indication. MAH request for additional data exclusivity The MAH requested consideration of its application in accordance with Article 10(5) of Directive 2001/83/EC - one year of data exclusivity for a new indication. Scientific advice The MAH seeks Scientific advice at the CHMP. 1.2. Steps taken for the assessment of the product The Rapporteur appointed by the CHMP was: Rapporteur: Daniela Melchiorri Timetable Actual dates Submission date 10 February 2020 Start of procedure: 29 February 2020 CHMP Rapporteur