NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE SINGLE TECHNOLOGY APPRAISAL OF VIDAZA® (AZACITIDINE) MANUFACTURER/SPONSOR SUBMISSION OF EVIDENCE 20 MARCH 2009 1. Description of technology under assessment 1.1. Give the brand name, approved name and, where appropriate, therapeutic class. For devices please provide details of any different versions of the same device. Name: Vidaza® (azacitidine). Pharmacotherapeutic group: Pyrimidine analogue. It is a first-in-class epigenetic therapy that is believed to exert its disease-modifying effect through its incorporation into RNA and DNA, resulting in DNA hypomethylation and direct cytotoxicity in abnormal haematopoietic cells in the bone marrow.1,2 ATC code: L01BC07. 1.2. Does the technology have a UK marketing authorisation/CE marking for the indications detailed in this submission? If so, please give the date on which authorisation was received. If not, please state current UK regulatory status, with relevant dates (for example, date of application and/or expected approval dates). The European Commission granted a marketing authorisation valid throughout the EU for Vidaza to Celgene Europe Ltd on 17 December 2008. Azacitidine was designated as an orphan medicinal product (EU/3/01/084) on 6 February 2002 for the treatment of myelodysplastic syndromes (MDS). 1.3. What are the (anticipated) indication(s) in the UK? For devices, please provide the (anticipated) CE marking, including the indication for use. The licensed indication is as follows: Azacitidine is indicated for the treatment of adult patients who are not eligible for haematopoietic stem cell transplantation with: • Intermediate-2 and high-risk MDS according to the International Prognostic Scoring System • Chronic myelomonocytic leukaemia with 10–29% marrow blasts without myeloproliferative disorder 2 • Acute myeloid leukaemia (AML) with 20–30% blasts and multilineage dysplasia, according to the World Health Organization classification.1 1.4. To what extent is the technology currently being used in the NHS for the proposed indication? Include details of use in ongoing clinical trials. If the technology has not been launched, please supply the anticipated date of availability in the UK. Azacitidine is currently being used in the NHS as part of a Named Patient Programme which was initiated in February 2006. Celgene-sponsored ongoing trials assessing azacitidine are outlined in Table 1.1. Table 1.1. Celgene-sponsored trials Status Phase Location Title Recruiting Phase I USA A Phase I, open label, dose-escalation study to evaluate the safety, pharmacokinetics and pharmacodynamics of oral azacitidine in subjects with MDS and AML Recruiting Phase I USA A Phase I, open label, dose-ranging study to evaluate the pharmacokinetics and safety of azacitidine administered subcutaneously and as different oral formulations in subjects with MDS, AML, lymphoma and multiple myeloma Recruiting Phase I USA A Phase I, open label, multicentre, parallel group study to assess the pharmacokinetics and safety of subcutaneous azacitidine in adult cancer patients with and without impaired renal function AML: acute myeloid leukaemia; MDS: myelodysplastic syndromes Celgene is supporting international investigator-initiated trials assessing azacitidine alone or in combination with other therapies in MDS, AML and myelofibrosis. The anticipated launch date of azacitidine in the UK is between March and July 2009. 1.5. Does the technology have regulatory approval outside the UK? If so, please provide details. As of 21 January 2009, azacitidine has regulatory approval in the countries and regions described in Table 1.2. 3 Table 1.2. Countries in which azacitidine has regulatory approval Country Date of Indication authorisation USA 19/05/2004 Treatment of patients with the following MDS subtypes: RA or RARS (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), RAEB, RAEB-T and CMML. 26/01/2007 Approved for intravenous administration (same indication). 21/08/2008 Approval of overall survival supplement. South 27/01/2006 Treatment of MDS. Korea Switzerland 24/02/2006 Treatment of high-risk MDS such as refractory bicytopenias or pancytopenias with or without ringed sideroblasts (RCMD, RCMD-RS) or RAEB. Israel 09/07/2006 Treatment of patients with the following MDS subtypes: RA or RARS (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), RAEB, RAEB-T and CMML. Philippines 27/09/2006 Treatment of patients with MDS and their subtypes. Hong Kong 25/03/2007 Treatment of patients with the following MDS subtypes: RA or RARS (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), RAEB, RAEB-T and CMML. Lebanon 20/08/2007 Treatment of patients with the following MDS subtypes: RA or RARS (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), RAEB, RAEB-T and CMML. Thailand 10/10/2007 Treatment of patients with the following MDS subtypes: RA or RARS (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), RAEB, RAEB-T and CMML. Turkey 10/10/2007 Treatment of high-risk MDS, such as refractory bicytopenia or pancytopenia with or without ringed sideroblasts (RCMD, RCMD-RS) or RAEB type I and type II (RAEB-1 and RAEB-2), which is defined according to the WHO classification of MDS. Argentina 09/11/2007 Treatment of patients with the following MDS subtypes: RA or RARS (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), RAEB, RAEB-T and CMML. EU 17/12/2008 Treatment of adult patients who are not eligible for haematopoietic stem cell transplantation with: • Intermediate-2 and high-risk MDS according to the IPSS • CMML with 10–29% marrow blasts without myeloproliferative disorder • AML with 20–30% blasts and multilineage dysplasia, according to the WHO classification. AML: acute myeloid leukaemia; CMML: chronic myelomonocytic leukaemia; IPSS: International Prognostic Scoring System; MDS: myelodysplastic syndromes; RA: refractory anaemia; RAEB: refractory anaemia with excess blasts; RAEB-T: refractory anaemia with excess blasts in transformation; RARS: refractory anaemia with ringed sideroblasts; RCMD: refractory cytopenia with multilineage dysplasia; RCMD-RS: refractory cytopenia with multilineage dysplasia and ringed sideroblasts; WHO: World Health Organization 4 1.6. Is the technology subject to any other form of health technology assessment in the UK? If so, what is the timescale for completion? Azacitidine will be subject to an assessment by the Scottish Medicines Consortium. The timelines of the assessment have not been finalised. 1.7. For pharmaceuticals, what formulation(s) (for example, ampoule, vial, sustained-release tablet, strength(s) and pack size(s) will be available? Formulation: Vidaza (azacitidine) 25 mg/ml powder for suspension for injection. Azacitidine will be available in glass vials containing 100 mg of azacitidine as a white lyophilised powder. The powder is reconstituted with water for injections (4 ml) prior to use.1 Pack size: 1 vial of 100 mg azacitidine. ************************************************************************************************* ************************************************************************************************* ************************************************************************************************* ********************** 1.8. What is the proposed course of treatment? For pharmaceuticals, list the dose, dosing frequency, length of course and anticipated frequency of repeat courses of treatment. The recommended starting dose for the first treatment cycle, for all patients regardless of baseline haematology laboratory values, is 75 mg/m2 of body surface area, injected subcutaneously, daily for seven days, followed by a rest period of 21 days (28-day treatment cycle).1 It is recommended that patients be treated for a minimum of six cycles. Treatment should be continued for as long as the patient continues to benefit or until disease progression.1 Patients should be monitored for haematological response/toxicity and renal toxicities; a delay in starting the next cycle or a dose reduction may be necessary.1 5 1.9. What is the acquisition cost of the technology (excluding VAT)? For devices, provide the list price and average selling price. If the unit cost of the technology is not yet known, please provide details of the anticipated unit cost, including the range of possible unit costs. The acquisition cost of azacitidineis £321 per vial (25 mg/ml powder for injection). 1.10. What is the setting for the use of the technology? Azacitidine treatment should be initiated and monitored under the supervision of a physician experienced in the use of chemotherapeutic agents.1 1.11. For patients being treated with this technology, are there any other aspects that need to be taken into account? For example, are there additional tests or investigations needed for selection, or particular administration requirements, or is there a need for monitoring of patients over and above usual clinical practice for this condition? What other therapies, if any, are likely to be administered at the same time as the intervention as part of a course of treatment? Laboratory tests Liver function tests and serum creatinine should be determined prior to initiation of therapy and prior to each treatment cycle. Complete blood counts should be performed prior to initiation of therapy and as needed to monitor response and toxicity, but at a minimum, prior to each treatment cycle.1 Method of administration