22 April 2021
`EMA/308711/2021
`Committee for Medicinal Products for Human Use (CHMP)
`
`Assessment report
`
`Onureg
`
`International non-proprietary name: azacitidine
`
`Procedure No. EMEA/H/C/004761/0000
`
`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, 2021. Reproduction is authorised provided the source is acknowledged.
`
`
`
`CELGENE 2142
`APOTEX v. CELGENE
`IPR2023-00512
`
`

`

`Table of contents
`
`1. Background information on the procedure .............................................. 6
`1.1. Submission of the dossier ..................................................................................... 6
`1.2. Steps taken for the assessment of the product ........................................................ 7
`
`2. Scientific discussion ................................................................................ 8
`2.1. Problem statement ............................................................................................... 8
`2.1.1. Disease or condition .......................................................................................... 8
`2.1.2. Epidemiology .................................................................................................... 8
`2.1.3. Biologic features, Aetiology and pathogenesis ....................................................... 8
`2.1.4. Clinical presentation, diagnosis and stage/prognosis .............................................. 9
`2.1.5. Management ..................................................................................................... 9
`2.2. Quality aspects .................................................................................................. 12
`2.2.1. Introduction.................................................................................................... 12
`2.2.2. Active Substance ............................................................................................. 12
`General information .................................................................................................. 12
`Manufacture, characterisation and process controls ....................................................... 13
`Specification ............................................................................................................ 14
`Stability................................................................................................................... 14
`2.2.3. Finished Medicinal Product ................................................................................ 15
`Description of the product and Pharmaceutical development .......................................... 15
`Manufacture of the product and process controls .......................................................... 16
`Product specification ................................................................................................. 16
`Stability of the product .............................................................................................. 17
`Adventitious agents .................................................................................................. 17
`2.2.4. Discussion on chemical, pharmaceutical and biological aspects.............................. 17
`2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 17
`2.2.6. Recommendations for future quality development ............................................... 18
`2.3. Non-clinical aspects ............................................................................................ 18
`2.3.1. Introduction.................................................................................................... 18
`2.3.2. Pharmacology ................................................................................................. 18
`2.3.3. Pharmacokinetics ............................................................................................ 19
`2.3.4. Toxicology ...................................................................................................... 20
`2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 28
`2.3.6. Discussion on non-clinical aspects ..................................................................... 29
`2.3.7. Conclusion on the non-clinical aspects ............................................................... 31
`2.4. Clinical aspects .................................................................................................. 31
`2.4.1. Introduction.................................................................................................... 31
`2.4.2. Pharmacokinetics ............................................................................................ 41
`2.4.3. Pharmacodynamics .......................................................................................... 44
`2.4.4. Discussion on clinical pharmacology ................................................................... 52
`2.4.5. Conclusions on clinical pharmacology ................................................................. 54
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`2.5. Clinical efficacy .................................................................................................. 55
`2.5.1. Dose response study........................................................................................ 55
`2.5.2. Main study ..................................................................................................... 56
`2.5.3. Discussion on clinical efficacy ............................................................................ 79
`2.5.4. Conclusions on the clinical efficacy .................................................................... 83
`2.6. Clinical safety .................................................................................................... 83
`2.6.1. Discussion on clinical safety .............................................................................. 90
`2.6.2. Conclusions on the clinical safety ...................................................................... 91
`2.7. Risk Management Plan ........................................................................................ 91
`2.8. Pharmacovigilance ............................................................................................. 91
`2.9. Product information ............................................................................................ 92
`2.9.1. User consultation ............................................................................................ 92
`
`3. Benefit-Risk Balance ............................................................................. 92
`3.1. Therapeutic Context ........................................................................................... 92
`3.1.1. Disease or condition ........................................................................................ 92
`3.1.2. Available therapies and unmet medical need ....................................................... 92
`3.1.3. Main clinical studies ......................................................................................... 94
`3.2. Favourable effects .............................................................................................. 94
`3.3. Uncertainties and limitations about favourable effects ............................................. 95
`3.4. Unfavourable effects ........................................................................................... 96
`3.5. Uncertainties and limitations about unfavourable effects ......................................... 96
`3.6. Effects Table ...................................................................................................... 97
`3.7. Benefit-risk assessment and discussion ................................................................. 98
`3.7.1. Importance of favourable and unfavourable effects .............................................. 98
`3.7.2. Balance of benefits and risks ............................................................................ 98
`3.7.3. Additional considerations on the benefit-risk balance ........................................... 98
`3.8. Conclusions ....................................................................................................... 98
`
`4. Recommendations ................................................................................. 99
`
`
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`
`
`List of abbreviations
`
`
`
`Abbreviation or Specialist Term
`ADR
`AE
`AESI
`ALT
`AML
`ANC
`AST
`AUC
`AUCss
`BMI
`BSC
`CCR
`CHMP
`CI
`Clcr
`Cmax
`Cmax,ss
`CMML
`CR
`CRF
`CRi
`CSR
`CYP
`DFS
`DNA
`DS
`ECOG
`EEA
`EFS
`ELN
`EMA
`EP
`EQ-5D-3L
`ER
`EU
`EU-27
`FAB
`FACIT-F
`FDA
`FLT3
`G-CSF
`GCP
`GO
`HDC
`HMA
`HR
`HRQoL
`HSCT
`ICF
`ICH
`IDH
`
`Explanation
`Adverse drug reaction
`Adverse event
`Adverse event of special interest
`Alanine aminotransferase
`Acute myeloid leukemia
`Absolute neutrophil count
`Aspartate aminotransferase
`Area under the curve
`Area under the concentration curve at steady state
`Body mass index
`Best supportive care
`Conventional care regimens
`Committee for Human Medicinal Products
`Confidence interval
`Creatinine clearance
`Maximum concentration
`Peak plasma concentration at steady state
`Chronic myelomonocytic leukemia
`Complete remission
`Case report form
`Complete remission with incomplete blood count recovery
`Clinical study report
`Cytochrome P450
`Disease-free survival
`Deoxyribonucleic acid
`Differentiation syndrome
`Eastern Cooperative Oncology Group
`European Economic Area
`Event-free survival
`European LeukemiaNet
`European Medicines Agency
`Eosinophilic pneumonia
`European Quality of Life-Five Dimensions-Three Levels
`Exposure-response
`European Union
`European Union of 27 member states
`French-American-British (classification system)
`Functional Assessment of Chronic Illness Therapy – Fatigue
`Food and Drug Administration
`fms-like tyrosine kinase 3
`Granulocyte colony-stimulating factor
`Good Clinical Practice
`Gemtuzumab ozogamicin
`Histamine dihydrochloride
`Hypomethylating agent
`Hazard ratio
`Health-related Quality-of-Life
`Hematopoietic stem cell transplantation
`Intended commercial formulation
`International Council for Harmonisation
`Isocitrate dehydrogenase
`
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`IPSS
`ISS
`ITD
`ITT
`IV
`IVRS
`IWG
`KIR
`LDAC
`LFS
`MA
`MDS
`MedDRA
`MID
`mITT
`MM
`MRD
`NCCN
`NDA
`OS
`PD
`PK
`PML
`PT
`QD
`RA
`RAEB
`RAEB-T
`RARS
`RBC
`RFS
`RNA
`SAP
`SBP
`SC
`SCE
`SCP
`SCS
`SMQ
`SOC
`SPA
`TEAE
`UK
`US
`WBC
`WHO
`
`
`
`
`
`
`
`
`
`
`
`
`International Prognostic Scoring System
`Integrated Summary of Safety
`Internal tandem duplication
`Intent-to-treat
`Intravenous
`Interactive Voice Response System
`International Working Group
`Killer-cell immunoglobulin-like receptor
`Low dose-cytarabine
`Leukemia-free survival
`Marketing authorisation
`Myelodysplastic syndromes
`Medical Dictionary for Regulatory Affairs
`Minimally important difference
`Modified intent-to-treat
`Multiple myeloma
`Minimal residual disease
`National Comprehensive Cancer Network
`New Drug Application
`Overall survival
`Pharmacodynamic
`Pharmacokinetics
`Progressive multifocal leukoencephalopathy
`Preferred term
`Once daily
`Refractory anaemia
`Refractory anaemia with excess blasts
`Refractory anaemia with excess blasts in transformation
`Refractory anaemia with ringed sideroblasts
`Red blood cell
`Relapse-free survival
`Ribonucleic acid
`Statistical Analysis Plan
`Summary of Biopharmaceutical Studies
`Subcutaneous
`Summary of Clinical Efficacy
`Summary of Clinical Pharmacology
`Summary of Clinical Safety
`Standard MedDRA query
`System organ class
`Special Protocol Assessment
`Treatment-emergent adverse event
`United Kingdom
`United States
`White blood cell
`World Health Organization
`
`
`
`
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`
`1. Background information on the procedure
`
`1.1. Submission of the dossier
`
`The applicant Celgene Europe Limited submitted on 30 April 2020 an application for Marketing Authorisation to
`the European Medicines Agency (EMA) for Onureg, through the centralised procedure. As this application
`concerns active substance(s) already authorised via the centralised procedure, 'automatic' access was granted
`by the CHMP on 26 March 2020.
`
`During the procedure, the applicant was changed to Bristol-Myers Squibb Pharma EEIG.
`
`The legal basis for this application refers to:
`
`Article 8.3 of Directive 2001/83/EC - complete and independent application.
`
`The application submitted is composed of administrative information, complete quality data, non-clinical and
`clinical data based on applicants’ own tests and studies and/or bibliographic literature substituting/supporting
`certain test(s) or study(ies).
`
`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 applicant did submit a critical report addressing the possible similarity with authorised orphan
`medicinal products.
`
`New active substance status
`
`The applicant indicated the active substance azacitidine contained in the above medicinal product to be
`considered as a known active substance.
`
`Scientific advice
`
`The applicant received the following Scientific Advice from the CHMP on the Quality development relevant for
`the indication subject to the present application:
`
`Date
`
`Reference
`
`SAWP co-ordinators
`
`31 January 2019
`EMEA/H/SA/4006/1/2018/I
`The <Scientific Adv
`
`Ms Audrey Sultana, Prof. Dieter Deforce
`
`The Scientific Advice pertained to the following quality aspects:
`
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` Adequacy of the data presented to support the proposed batch size for commercial production of the
`intended commercial formulation.
`
`1.2. Steps taken for the assessment of the product
`
`The Rapporteur and Co-Rapporteur appointed by the CHMP were:
`
`Rapporteur: John Joseph Borg
`
`Co-Rapporteur: Fátima Ventura
`
`
`
`The application was received by the EMA on
`
`The procedure started on
`
`The Rapporteur's first Assessment Report was circulated to all CHMP
`members on
`
`30 April 2020
`
`21 May 2020
`
`10 August 2020
`
`
`
`The Co-Rapporteur's first Assessment Report was circulated to all CHMP
`members on
`
`10 August 2020
`
`The PRAC Rapporteur's first Assessment Report was circulated to all
`PRAC members on
`
`18 August 2020
`
`The CHMP agreed on the consolidated List of Questions to be sent to
`the applicant during the meeting on
`
`17 September 2020
`
`The applicant submitted the responses to the CHMP consolidated List of
`Questions on
`
`21 December 2020
`
`The Rapporteurs circulated the Joint Assessment Report on the
`responses to the List of Questions to all CHMP members on
`
`The PRAC agreed on the PRAC Assessment Overview and Advice to
`CHMP during the meeting on
`
`01 February 2021
`
`11 February 2021
`
`The CHMP agreed on a list of outstanding issues in writing and/or in an
`oral explanation to be sent to the applicant on
`
`25 February 2021
`
`The applicant submitted the responses to the CHMP List of Outstanding
`Issues on
`
`22 March 2021
`
`The Rapporteurs circulated the Joint Assessment Report on the
`responses to the List of Outstanding Issues to all CHMP members on
`
`07 April 2021
`
`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 Onureg on
`
`The CHMP adopted a report on similarity of Onureg with Dacogen,
`Rydapt, Mylotarg, Vyxeos liposomal, Xospata and Daurismo on
`(Appendix 1)
`
`22 April 2021
`
`22 April 2021
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`2. Scientific discussion
`
`2.1. Problem statement
`
`2.1.1. Disease or condition
`
`Onureg was proposed to be indicated as maintenance therapy in adult patients with acute myeloid
`leukaemia (AML) who achieved complete remission (CR) or complete remission with incomplete blood count
`recovery (CRi) following induction therapy with or without consolidation treatment and who are not
`candidates for, including those who choose not to proceed to, hematopoietic stem cell transplantation
`(HSCT).
`
`2.1.2. Epidemiology
`
`In the EU, the occurrence of newly diagnosed AML was estimated at approximately 18,000 cases annually
`(Rodriguez-Abreu, 2007) with age-adjusted incidence of 3.7 per 100,000 annually (4.0 per 100,000 for males
`and 3.4 per 100,000 for females) (Visser, 2012). Based on the incidence data and the total European Union of
`27 member states (EU-27) population, 42,795 new diagnoses of myeloid malignancies occur in the EU-27
`annually, including 18,376 cases of AML (43%). The complete AML prevalence proportion as of 01 Jan 2003
`was 11.0 per 100,000 persons with an estimated 54,619 cases in the EU-27 in 2008. Based on this, the
`estimated prevalence of AML in Europe is approximately 1.1 per 10,000 persons (Visser, 2012). In the US, it
`is estimated that 21,430 new AML cases and 10,920 deaths would have occurred in 2019 (Siegel, 2019). The
`age-adjusted incidence of AML in the US is 4.3 per 100,000 annually in the US (Shallis, 2019). Overall, the
`incidence of AML increases with age with median age at diagnosis of 68 years and median age at death of 72
`years and the age adjusted incidence for those older than 65 years being 20.1 per 100,000 person-years
`compared with 2.0 per 100,000 person-years for individuals younger than 65 (Visser, 2012; SEER cancer
`statistics review, 1975-2015; Shallis, 2019). The proportion of males:females diagnosed with AML is 1.6:1 with
`an age-adjusted incidence of 5.42 and 3.47 per 100,000 person-years, respectively (Shallis, 2019).
`
`In Europe, the annual incidence of AML in adults is 5 to 8 cases per 100.000 individuals with a mortality rate
`of 4 to 6 cases per 100.000. (1) The median age at diagnosis is 67 years, but the incidence increases by age
`with a projected incidence of 15 to 25 cases per 100.000 in patients who are 70 years of age or older.
`
`2.1.3. Biologic features, Aetiology and pathogenesis
`
`AML is a rare, heterogeneous, and aggressive hematologic malignancy characterized by rapid progression of
`the disease and symptoms and is uniformly fatal if not treated.
`
`Acute myeloid leukaemia is a form of leukaemia, characterised by infiltration of proliferative, clonal, abnormally
`differentiated, and occasionally poorly differentiated haematopoietic cells of myeloid lineage in the bone
`marrow, blood, and other tissues.
`
`Factors that influence prognosis in AML include both patient-related factors and disease-related factors, with
`age at diagnosis being the most significant patient-related factor and genetic risk category being the most
`influential disease-related factor (Döhner, 2017; Shallis, 2019).
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`Cytogenetic and molecular genetic risk categorization are major prognostic factors for determining relapse and
`OS outcomes and form the basis for the European LeukemiaNet (ELN) genetic risk stratification (Döhner, 2017;
`NCCN-AML, 2019). Likewise, the presence of complex or monosomal karyotypes in AML is an important
`prognostic factor associated with extremely poor prognosis (Döhner, 2017; NCCN-AML, 2019).
`
`The risk stratification criteria outlined by the ELN are used to determine which patients should be considered
`for allogeneic HSCT. In general, patients with favorable risk receive postinduction consolidation therapy and
`are generally not referred for transplantation unless there is evidence of conventional chemotherapy failure. In
`contrast, patients with adverse risk are known to have poor outcome despite intensive chemotherapy and are
`generally referred for HSCT if remission is achieved, a suitable donor is available, and the patient does not
`have serious comorbidities. The incidence of adverse genetics increases with age, so that they are frequently
`encountered in older patients who more often have comorbidities and poor performance status, and thus are
`not candidates for intensive remission induction therapy and HSCT. Therefore, prognosis for AML is generally
`inferior for older patients, resulting in less discriminatory relevance of molecular risk markers (Döhner, 2017).
`
`Minimal residual disease (MRD) is an important prognostic factor to monitor after diagnosis and following
`remission as the presence of MRD identifies patients at high risk of disease recurrence and short survival. The
`ELN recommendations include a proposal for a response category based on MRD status since despite
`morphologic remission, patients frequently have evidence of persisting MRD as assessed by flow cytometric
`(multiparameter flow cytometry [MFC]) or quantitative molecular methods that include real-time quantitative
`PCR (RT-qPCR), digital PCR, and next-generation sequencing-based technologies. Minimal residual disease can
`be assessed at early time points, for example, following induction and consolidation to assess remission status
`and determine kinetics of disease response, and sequentially beyond consolidation to detect impending
`morphologic relapse. (Döhner, 2017).
`
`2.1.4. Clinical presentation, diagnosis and stage/prognosis
`
`AML is a heterogeneous disease; the classification is based on morphologic, cytogenetic, molecular, and
`immunophenotypic features, which, along with baseline patient characteristics such as age and performance
`status (PS), influence outcome and treatment recommendations (4). Among these, baseline cytogenetic risk
`constitutes one of the most significant prognostic markers of disease outcome (5). Age is the most prominent
`patient-specific risk factor, and cytogenetics the most disease-specific risk factor.
`
`In AML, leukaemic blasts replace normal blood cells in bone marrow and peripheral blood, which leads to
`anaemia, neutropenia, and thrombocytopenia. This is associated with symptoms of fatigue, shortness of breath,
`disturbed wound healing, infections and bleedings. If left untreated, AML results in death within a few weeks
`to months.
`
`Long-term survival in adult patients with AML is only 35% to 40% for patients ≤60 years of age, and drops to
`5% to 15% in patients who are >60 years of age. (6) The majority of patients with AML will have relapsed
`disease within 3 years.
`
`2.1.5. Management
`
`The usual treatments for newly diagnosed AML patients without serious comorbidities include intensive
`chemotherapy to induce remission (induction chemotherapy). Intensive induction chemotherapy typically
`consists of cytarabine in combination with an anthracycline. In order to deepen the level of remission through
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`eradication of residual leukemia, patients typically receive consolidation chemotherapy. There is no consensus
`regarding the optimal approach to the number of cycles of consolidation therapy.
`
`The therapeutic approaches for patients who can tolerate intensive therapy are usually divided into two phases:
`induction of remission and post-remission (consolidation) therapy. Although patients can achieve CR and
`disease control after induction, patients who do not receive post remission consolidation therapy are more likely
`to relapse, usually within 6 to 9 months. Post remission therapy is recommended for patients younger than 60
`years old and for older patients who are fit for intensive therapy.
`
`For patients who cannot tolerate intensive induction therapy, combinations of low intensity therapy with novel
`agents such as venetoclax and glasdegib has shown improved responses and/or survival.
`
`Allogeneic HSCT is the only potentially curative treatment for patients with AML. However, HSCT is not a feasible
`treatment option for many patients, and the frequency of patients undergoing HSCT decreases with increasing
`age due to the increased prevalence of comorbidities and poor organ function limiting the benefit-risk
`assessment of the procedure. Despite treatment with consolidation chemotherapy, and even HSCT, relapse
`rates after these therapies remain high and contribute to the poor outcomes in AML. Salvage therapy following
`relapse is limited, particularly for patients who are not candidates for transplant. Intensive chemotherapy can
`offer the highest CR rates; however, its application is limited by tolerability, in particular, the high treatment-
`related mortality and short remission duration.
`
`Maintenance therapy conducive to long-term tolerable drug administration could potentially prolong remission
`
`and survival in the post‐consolidation setting, particularly in those with intermediate risk and high-risk disease
`
`as well as those who do not proceed to transplant. Despite the approval of several maintenance therapies for
`AML, given the lack of convincing benefit, maintenance therapy with these agents is globally not considered
`standard of care. Effective maintenance therapy could provide an important therapeutic approach to treatment
`of patients with AML, a disease associated with short survival and a high unmet medical need.
`
`Current salvage therapy at time of relapse is inadequate, particularly for subjects not eligible for transplant.
`Duration of first Complete Remission (CR) is an important predictor of outcome, with longer duration of first
`CR associated with better survival. Therefore, maintaining patients in CR is an important therapeutic goal in
`AML. As most patients will relapse, effective maintenance treatment for patients who do attain remission may
`play a role in preventing relapse and prolonging OS, especially in those for whom HSCT is not feasible.
`
`Maintenance Therapies Approved in the European Union:
`
`- Rydapt (midostaurin) was approved in the EU in 2017 as maintenance therapy for newly diagnosed patients
`with AML with FLT3 mutation, in first remission following midostaurin in combination with standard daunorubicin
`and cytarabine induction and high-dose cytarabine consolidation chemotherapy, based on a Phase 3 trial
`(RATIFY; Stone, 2017). In this study, 717 newly diagnosed patients with FLT3 mutant AML aged 18 to 59 years
`old, were randomized to receive standard chemotherapy (induction and consolidation) in combination with
`either the FLT3 inhibitor midostaurin (N = 360) or placebo (N = 357). Patients who achieved remission after
`consolidation therapy entered the maintenance phase and received midostaurin (N = 120) or placebo (N = 85)
`for an additional 12 months. The primary endpoint was OS, measured from time of randomization to death.
`Both OS and event-free survival (EFS) were significantly longer in patients treated with midostaurin compared
`with placebo (hazard ratio [HR] = 0.78; p = 0.009 for OS and 0.002 for EFS). Although there was a significant
`increase in OS, the specific contribution of maintenance midostaurin is not certain, as the maintenance portion
`of the study was neither randomized nor powered to determine the effect of midostaurin in maintenance setting.
`Additionally, the inclusion of midostaurin with induction treatment prior to maintenance, did not allow for
`determination of the independent effect of maintenance therapy. And lastly, midostaurin is targeted against
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`FLT3 mutant AML and therefore, it’s use is limited to this patient population, which comprises 30% of AML
`cases (Kindler, 2010).
`
`- Ceplene (histamine dihydrochloride [HDC]), in combination with IL-2, was approved in the EU/EEA in 2010
`as maintenance therapy for adult patients with AML in first remission based on an open label randomized Phase
`3 study (Brune, 2006). The study enrolled patients ≥ 18 years old with de novo or secondary AML with verified
`CR following induction and consolidation chemotherapy. A total of 320 patients were enrolled; 261 patients in
`first remission and 59 patients in subsequent remission. Patients were randomized 1:1 to receive either HDC/IL-
`2 for 10 consecutive 3-week cycles or no treatment (control) for a total of 18 months or until
`relapse/discontinuation. Median age was 55 years old (18 to 81) and 54 years old (18 to 84) in the HDC/IL-2
`and control arms, respectively. The primary efficacy endpoint was duration of leukemia-free survival (LFS).
`The study demonstrated significant improvement in LFS (HR = 0.71; p = 0.01) particularly in the subgroup of
`patients in first CR (HR = 0.69; p = 0.01) but not for patients in subsequent CR (HR = 0.79; p = 0.4); however,
`OS was not significantly improved neither in the overall population (p = 0.2) nor in the subgroups of patients
`in first or subsequent CR (p = 0.2 and > 0.5, respectively). The results of this study may have been confounded
`by the fact that 18% of patients enrolled were beyond first remission and 21% were enrolled > 6 months after
`achieving CR. Also, the study was not powered for differences in OS. In addition, the efficacy of HDC/IL-2 as
`maintenance in patients older than 60 years old has not been fully demonstrated.
`
`In summary, while both treatments have been approved in the maintenance setting in the EU, Rydapt and
`Ceplene have not been adopted by ELN for use in AML. This is due to limitations in the data as well as challenges
`to the use of the agents (e.g., patient population, study design limitations and side effects).
`
`The injectable form of azacitidine – Vidaza (azacitidine), is approved in the European Union (EU) for the
`treatment of adult patients who are not eligible for hematopoietic stem cell transplant (HSCT) with:
`
`-
`
`-
`
`intermediate-2 and high-risk MDS according to the International Prognostic Scoring System (IPSS),
`
`chronic myelomonocytic leukaemia (CMML) with 10-29% marrow blasts without myeloproliferative
`disorder,
`
`- Acute myeloid leukemia (AML) with 20-30% blasts and multi-lineage dysplasia, according to WHO
`classification,
`
`- AML with >30% marrow blasts according to the World Health Organization (WHO) classification.
`
`About the product
`
`Onureg is an oral formulation of azacitidine. Azacitidine is a DNA methyltransferase inhibitor and epigenetic
`modifier.
`
`Azacitidine is incorporated into DNA and RNA following cellular uptake and enzymatic biotransformation to
`nucleotide triphosphates. Incorporation of azacitidine into the DNA of cancer cells, including acute myeloid
`leukemia cells, modified epigenetic pathways through the inhibition of DNA methyltransferases, reduction of
`DNA methylation, and alteration of gene expression, including re-expression of genes regulating tumor
`suppression, immune pathways, cell cycle, and cell differentiation.
`
`Incorporation of azacitidine into the RNA of cancer cells, including leukemic cells, inhibited RNA
`methyltransferase, reduced RNA methylation, decreased RNA stability, and decreased protein synthesis. Anti-
`leukemic activity of azacitidine was demonstrated by reduction of cell viability and induction of apoptosis in
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`Assessment report
`EMA/308711/2021
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`Page 11/101
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`acute myelogenous leukemia (AML) cell lines in vitro. In vivo, azacitidine decreased tumor burden and increased
`survival in leukemic tumor models.
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`Pharmacotherapeutic group: Antineoplastic agents, Antimetabolites, Pyrimidine analogues
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`Onureg is indicated as maintenance therapy in adult patients with acute myelogenous leukemia (AML) who
`achieved complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following
`induction therapy with or without consolidation treatment, and who are not candidates, including those who
`choose not to proceed to, hematopoietic stem cell transplantation (HSCT).
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`The proposed starting dose is 300 mg orally, once daily (QD) for the first 14 days of each 28-day cycle.
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`In the case of disease relapse during therapy with 5% to 15% blasts in peripheral blood or bone marrow, in
`conjunction with clinical assessment, the dosing schedule indicates that it may be extended from 14 days to
`21 days of repeated 28-day cycles.
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`Type of Application and aspects on development
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`This submission is a complete and independent application.
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`2.2. Qua