European Medicines Agency Doc.Ref.: EMA/CHMP/279276/2010 CHMP ASSESSMENT REPORT FOR Revolade International Nonproprietary Name: eltrombopag Procedure No. EMEA/H/C/001110 Assessment Report as adopted by the CHMP with all information of a commercially confidential nature deleted 7 Westferry Circus, Canary Wharf, London, E14 4HB, UK Tel. (44-20) 74 18 84 00 Fax (44-20) 74 18 86 13 E-mail: [email protected] http://www.ema.europa.eu TABLE OF CONTENTS Page 1. BACKGROUND INFORMATION ON THE PROCEDURE.........................................3 1.1 Submission of the dossier ........................................................................................................ 3 1.2 Steps taken for the assessment of the product.......................................................................... 4 2 SCIENTIFIC DISCUSSION...............................................................................................5 2.1 Introduction.............................................................................................................................. 5 2.2 Quality aspects......................................................................................................................... 6 2.3 Non-clinical aspects................................................................................................................. 8 2.4 Clinical aspects ...................................................................................................................... 20 2.5 Pharmacovigilance................................................................................................................. 72 2.6 Overall conclusions, risk/benefit assessment and recommendation ...................................... 75 2/79 1. BACKGROUND INFORMATION ON THE PROCEDURE 1.1 Submission of the dossier The applicant GlaxoSmithKline Trading Services Ltd. submitted on 04 December 2008 an application for Marketing Authorisation to the European Medicines Agency (EMEA) through the centralised procedure for Revolade, which was designated as an orphan medicinal product EU/3/07/467 on 03 August 2007. Revolade was designated as an orphan medicinal product in the following indication: treatment of idiopathic thrombocytopenic purpura. The calculated prevalence of this condition was between 1 and 4 in 10,000 persons in the European Union, which, at the time of designation, corresponded to between about 50,000 and 199,000 persons. The applicant applied for the following indication: treatment of previously treated patients with chronic idiopathic thrombocytopenic purpura (ITP) to increase platelet counts and reduce or prevent bleeding. The legal basis for this application refers to: Article 8.3 of Directive 2001/83/EC, as amended - complete and independent application Information on Paediatric requirements Pursuant to Article 7 of Regulation (EC) No 1901/2006, the application included an EMEA Decision P/207/2009 for the following condition: • Idiopathic thrombocytopenic purpura (ITP) on the agreement of a paediatric investigation plan (PIP). The PIP is not yet completed. 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 application contained a critical report addressing the possible similarity with authorised orphan medicinal products. Protocol Assistance: The applicant received Protocol Assistance from the CHMP on 24 March 2006. The Protocol Assistance pertained to clinical aspects of the dossier. Licensing status: Revolade has been given a Marketing Authorisation in the United States of America on 20 November 2008 (US tradename Promacta). The Rapporteur and Co-Rapporteur appointed by the CHMP were: Rapporteur: Gonzalo Calvo Rojas Co-Rapporteur: Ian Hudson 3/79 1.2 Steps taken for the assessment of the product • The application was received by the EMEA on 04 December 2008. • The procedure started on 24 December 2008. • The Rapporteur's first Assessment Report was circulated to all CHMP members on 30 March 2009. The Co-Rapporteur's first Assessment Report was circulated to all CHMP members on 17 March 2009. • During the meeting on 20-23 April 2009 the CHMP agreed on the consolidated List of Questions to be sent to the applicant. The final consolidated List of Questions was sent to the applicant on 23 April 2009. • The applicant submitted the responses to the CHMP consolidated List of Questions on 22 May 2009. • The Rapporteurs circulated the Joint Assessment Report on the applicant’s responses to the List of Questions to all CHMP members on 8 July 2009. • During the CHMP meeting on 20-23 July 2009, the CHMP agreed on the first List of Outstanding issues to be addressed in writing by the applicant. • The applicant submitted the responses to the First CHMP List of Outstanding Issues on 24 August 2009. • The Rapporteurs circulated the Joint Assessment Report on the applicant’s responses to the first List of Outstanding Issues to all CHMP members on 10 September 2009. • During the CHMP meeting on 21-24 September 2009, the CHMP agreed on the second list of outstanding issues to be addressed in writing by the applicant. • The applicant submitted the responses to the CHMP second List of Outstanding Issues on 02 October 2009. • The Rapporteurs circulated the Joint Assessment Report on the applicant’s responses to the second List of Outstanding Issues to all CHMP members on 07 October 2009. • During the CHMP meeting on 19-22 October 2009, the CHMP agreed on the third list of outstanding issues to be addressed in writing by the applicant. • The applicant submitted the responses to the CHMP third List of Outstanding Issues on 16 November 2009. • During a meeting of an Expert group on 01 December 2009, experts were convened to address questions raised by the CHMP. • The Rapporteurs circulated the Joint Assessment Report on the applicant’s responses to the third List of Outstanding Issues to all CHMP members on 02 December 2009. • During the meeting on 14-17 December 2009, the CHMP, in the light of the overall data submitted and the scientific discussion within the Committee, issued a positive opinion for granting a Marketing Authorisation to Revolade on 17 December 2009. The applicant provided the letter of undertaking on the follow-up measures to be fulfilled post-authorisation on 15 December 2009. • The CHMP adopted a report on similarity of Revolade with Nplate on 25 June 2009. • The CHMP opinions were forwarded in all official languages of the European Union, to the European Commission, which adopted the corresponding Decision on 11 March 2010. 4/79 2 SCIENTIFIC DISCUSSION 2.1 Introduction Chronic idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by autoantibody-induced platelet destruction and reduced platelet production, leading to a low peripheral blood platelet count (<150,000/μL). The epidemiology of ITP shows an overall incidence of ITP among adults from 1.6 to 3.0 per 100,000 person years of observation. Prevalence estimates range from 2.1 to approximately 36.4 per 100,000 persons. The estimated adult prevalence is 24.6 per 100,000 persons. The exact aetiology of ITP is unknown and the diagnosis of ITP remains one of exclusion. The clinical hallmark of the disease is an increased, pathological tendency to bleed, spontaneously or after minimal trauma. Routine diagnostic tools are blood count, peripheral blood film, patient history, physical examination and prompt response to high-dose corticosteroids Disease management decisions in patients with chronic ITP are based primarily on platelet count and severity of bleeding. The goal of treatment is to elevate platelet counts to a safe range (≥50,000/μL to 250,000/μL) to minimise the risk of bleeding. Medical treatment to elevate platelet counts to a safe range is recommended if patients’ platelet count is below 30,000/μL or if bleeding symptoms are present. Currently immunoglobulins (anti-D and IVIg) are used for the treatment of ITP. Additional drugs to treat chronic ITP include corticosteroids, azathioprine, cyclophosphamide, or vincristine. Based on the literature, first-line treatment with intravenous immunoglobulins or corticosteroids results in normal or sufficient platelet counts in about 70% of patients with chronic ITP. IVIg typically provides a temporary elevation of platelet counts within up to 5 days and for an average duration of 3-4 weeks. Corticosteroids will induce a response within up to two weeks, although the effect is often not sustained upon dose reduction or cessation of treatment, and long-term administration of corticosteroids is limited by the development of side effects. Furthermore, corticosteroid-treated patients are at increased risk of infections. Second-line therapy typically involves splenectomy. Two- thirds of patients with ITP who undergo splenectomy will achieve a normal platelet count, which is often sustained with no additional therapy. Patients who do not have a complete response can still expect some improvement in platelet counts (e.g. partial response) or transient increases in platelet count. When adult patients fail to first and second line therapies, they are considered as chronic refractory ITP. The actual percentage of patients defined as having refractory ITP varies from 11% to 35%. Romiplostim (Nplate), a recombinant protein that increases platelet production through activation of the thrombopoietin receptor (TPO-R), was authorised in the EU in February 2009. This application seeks marketing authorization