28 March 2019 EMA/250839/2019 Committee for Medicinal Products for Human Use (CHMP) Assessment report Pixuvri International non-proprietary name: pixantrone Procedure No. EMEA/H/C/002055/R/0046 Note 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 Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 An agency of the European Union © European Medicines Agency, 2019. Reproduction is authorised provided the source is acknowledged. Status of this report and steps taken for the assessment Current Description Planned Actual Date Need for step¹ date discussion² Start of procedure: 03 Dec 2018 03 Dec 2018 CHMP and PRAC Rapporteurs Joint Assessment 03 Jan 2019 07 Jan 2019 Report CHMP and PRAC members comments 07 Jan 2019 11 Jan 2019 Updated CHMP and PRAC Rapporteurs Joint 10 Jan 2019 17 Jan 2019 Assessment Report PRAC endorsed relevant sections of the 17 Jan 2019 17 Jan 2019 assessment report³ Request for supplementary information 31 Jan 2019 MAH responses to (RfSI) received on 05 Mar 2019 06 Mar 2019 CHMP and PRAC Rapporteurs' joint assessment 13 Mar 2019 15 Mar 2019 report PRAC endorsed relevant sections of the 14 Mar 2019 15 Mar 2019 assessment report CHMP and PRAC members comments 18 Mar 2019 21 Mar 2019 Updated CHMP and PRAC Rapporteurs joint 21 Mar 2019 22 Mar 2019 assessment report Opinion 28 Mar 2019 5 Apr 2019 ¹ Tick the box corresponding to the applicable step – do not delete any of the steps. If not applicable, add n/a instead of the date. ² Criteria for PRAC plenary discussion: interim results/outcome of the SOB that is a non-interventional PASS study challenging the benefit/risk balance of the product; new imposed non-interventional PASS resulting from the annual renewal (annex II condition); divergent positions between the Committees (CHMP and PRAC Rapp and CHMP and PRAC members) on specific aspects with significant impact on the B/R and any other situation at the discretion of the PRAC rapporteur. Criteria for CHMP plenary discussion: interim results/outcome of the SOB challenging the benefit/risk balance of the product; fulfilment of all SOBs; new imposed PASS/PAES resulting from the annual renewal (annex II condition); divergent positions between the Committees (CHMP and PRAC Rapp and CHMP and PRAC members) on specific aspects with significant impact on the B/R and any other situation at the discretion of the CHMP rapporteur. ³ Sections related to data on non-interventional PASS imposed as an SOB, Risk Management Plan (safety concerns, Pharmacovigilance plans, Risk minimisation Measures), sections on issues originating from parallel/recent PSUR or signal assessment, additional monitoring, pharmacovigilance inspections and Assessment report EMA/250839/2019 Page 2/107 preliminary conclusions on the benefit/risk balance. Declarations The assessor confirms that proprietary information on, or reference to, third parties or products are not included in this assessment, unless there are previous contracts and/or agreements with the third parties. (Non-Clinical/Clinical/Pharmacovigilance) The assessor confirms that reference to ongoing assessments or development plans for other products is not included in this assessment report. …………………………… Assessment report EMA/250839/2019 Page 3/107 Table of contents 1. Background information on the annual renewal ...................................... 5 2. Overall conclusions and benefit-risk balance .......................................... 5 2.1. Specific Obligations (SOBs) ................................................................................... 5 2.2. Benefit-risk Balance ............................................................................................. 5 3. Recommendations ................................................................................. 14 4. EPAR changes ....................................................................................... 14 Annex: Rapporteurs’ assessment comments on the renewal .................... 16 5. Specific Obligations ............................................................................... 17 5.1. Specific Obligations adopted with the initial marketing authorisation......................... 17 5.2. Outstanding Specific Obligations – status report for period covered .......................... 17 5.3. Other clinical studies of relevance ........................................................................ 91 5.4. Overall conclusion on Specific Obligations ............................................................. 96 6. Additional scientific data provided relevant for the assessment of the benefit/risk balance .................................................................................. 96 6.1. Quality .............................................................................................................. 96 6.2. Non-clinical ....................................................................................................... 96 6.3. Clinical pharmacology ......................................................................................... 96 6.4. Clinical efficacy .................................................................................................. 97 6.5. Clinical safety .................................................................................................... 97 6.6. Pharmacovigilance inspections ........................................................................... 101 6.7. Discussion ....................................................................................................... 101 7. Risk management plan ........................................................................ 101 7.1. Overall conclusion on the RMP ........................................................................... 107 8. Changes to the Product Information ................................................... 107 Assessment report EMA/250839/2019 Page 4/107 1. Background information on the annual renewal The European Commission issued on 10 May 2012, a conditional marketing authorisation (MA) for Pixuvri This implied that, pursuant to Article 14(7) of Regulation (EC) No 726/2004 and Article 5 of Commission Regulation (EC) No 507/2006, the marketing authorisation holder (MAH) has to complete ongoing studies, or to conduct new studies, as listed in Annex II.E of the MA, the so-called Specific Obligations (SOBs). These data form the basis of the renewal of the conditional MA. A conditional MA is valid for one year and may be renewed annually upon request by the MAH. Therefore, pursuant to Article 14 (7) of Regulation (EC) No 726/2004 and Article 6(2) of Commission Regulation (EC) No 507/2006, the MAH CTI Life Sciences Limited, submitted to the Agency on 30 November 2018 an application for renewal of the conditional MA for Pixuvri. The expiry date of the MA is 14 May 2019. The period covered by this annual renewal is 1 September 2017 to 31 August 2018. The application contained a justification in support of the possible granting of a marketing authorisation no longer subject to specific obligations. 2. Overall conclusions and benefit-risk balance 2.1. Specific Obligations (SOBs) Compliance of SOB data submitted During the period covered by this annual renewal data on the SOBs have been submitted that overall are compliant in terms of adherence to deadlines. Updated list of specific obligations (SOBs) None remaining. 2.2. Benefit-risk Balance During the period covered by this annual renewal, new data have been reported from the trial conducted as part of the SOBs. These data are considered comprehensive in the sense of the CMA regulation, as well as supportive of the positive benefit-risk of Pixuvri in the approved indication. Treatment of patients with relapsed DLBCL is challenging. If treatment with the currently most effective regimen in the first line (R-CHOP) fails to provide cure, the probability of achieving long-term disease suppression or cure with second or further lines of treatment is low. A potentially curative second line treatment is salvage chemotherapy followed by autologous stem cell transplantation (ASCT). However, significant associated toxicities preclude proceeding for a substantial fraction of patients, with comorbidities or advanced age, to this procedure. Recently, two CAR-T cell immunotherapies (Yescarta and Kymriah) were authorised in the EU for patients with relapsed or refractory DLBCL after two or more lines of systemic therapy which are intended for patients with sufficient disease control to await the manufacturing times and who are able to tolerate the conditioning regimen. The use of these products is associated with life-threatening and in some cases even fatal toxicities, excluding the patient population for whom ASCT is not an option. Assessment report EMA/250839/2019 Page 5/107 Pixuvri was approved in 2012 as monotherapy for the treatment of adult patients with multiply relapsed or refractory aggressive Non-Hodgkin B-cell Lymphomas (NHL) with palliative intent approach as a third or fourth line treatment. With the results from study PIX306 the benefit of pixantrone in patients who had received prior treatment with rituximab would be corroborated and the requirement to convert a conditional MA into a full MA (that is, without specific obligations) fulfilled. The MAH has now provided results from study