CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`209606Orig1s000
`
`RISK ASSESSMENT and RISK MITIGATION
`REVIEW(S)
`
`
`
`
`
`
`

`

` Division of Risk Management (DRISK)
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`Office of Surveillance and Epidemiology (OSE)
`Center for Drug Evaluation and Research (CDER)
`
`NDA
`209606
`August 30, 2017
`2017-16; 2017-18
`Till Olickal, Ph.D., Pharm.D.
`Elizabeth Everhart, MSN, RN, ACNP
`Cynthia LaCivita, Pharm.D.
`June 27, 2017
`Review to determine if a REMS is necessary
`Enasidenib
`Idhifa
`Celgene
`Isocitrate dehydrogenase-2 inhibitor
`50 mg and 100 mg tablets
`100 mg once daily until disease progression or unacceptable toxicity
`
`
`Application Type
`Application Number
`PDUFA Goal Date
`OSE RCM #
`Reviewer Name(s)
`Acting Team Leader
`Division Director
`Review Completion Date
`Subject
`Established Name
`Trade Name
`Name of Applicant
`Therapeutic Class
`Formulation(s)
`Dosing Regimen
`
`
`
`
`
`Reference ID: 4117200
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`Table of Contents
`
`EXECUTIVE SUMMARY ......................................................................................................................................................... 3
`1
`Introduction ..................................................................................................................................................................... 3
`2 Background ...................................................................................................................................................................... 3
`2.1
`Product Information ........................................................................................................................................... 3
`2.2
`Regulatory History............................................................................................................................................... 4
`3
`Therapeutic Context and Treatment Options .................................................................................................... 4
`3.1
`Description of the Medical Condition .......................................................................................................... 4
`3.2
`Description of Current Treatment Options ............................................................................................... 5
`4 Benefit Assessment ....................................................................................................................................................... 4
`5 Risk Assessment & Safe-Use Conditions .............................................................................................................. 7
`Expected Postmarket Use ......................................................................................................................................... 10
`6
`7 Risk Management Activities Proposed by the Applicant ............................................................................. 10
`8 Discussion of Need for a REMS ............................................................................................................................... 10
`9
`Conclusion & Recommendations ........................................................................................................................... 11
`10 References ...................................................................................................................................................................... 11
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`Reference ID: 4117200
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`EXECUTIVE SUMMARY
`
`This review by the Division of Risk Management (DRISK) evaluates whether a risk evaluation and
`mitigation strategy (REMS) for the new molecular entity enasidenib (Idhifa) is necessary to ensure the
`benefits outweigh its risks. Celgene submitted a New Drug Application Application (NDA) 209606 for
`enasidenib with the proposed indication as treatment of patients with relapsed or refractory acute
`myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation. The applicant did not
`submit a REMS with this application but proposed Prescribing Information that includes Boxed Warning,
`Warnings and Precautions and a Medication Guide as part of labeling to inform patients regarding the
`potential risks of differentiation syndrome.
`
`
`DRISK and Division of Hematology Products (DHP) have determined that if approved, a REMS is not
`necessary to ensure the benefits of enasidenib outweigh its risks. The current standard treatment for
`AML is intensive chemotherapy potentially leading to an allogeneic stem cell transplant and is based
`mainly on the patient’s ability to tolerate intensive treatment. There are no FDA-approved drugs
`specifically for relapsed or refractory AML, and there is no standard of care treatment regimen for these
`patients. Therefore, there remains a clear medical need for new treatments for these patients. In the
`clinical trial, enasidenib appeared efficacious in both its primary and secondary outcomes. The most
`concerning adverse reaction associated with the use of enasidenib is differentiation syndrome; this risk,
`and recommendations for its management, will be communicated in the Boxed Warning and Warnings
`and Precautions section of the product label.
`
`
` 1
`
` Introduction
`
`
`This review by the Division of Risk Management (DRISK) evaluates whether a risk evaluation and
`mitigation strategy (REMS) for the new molecular entity (NME) enasidenib (Idhifa) is necessary to ensure
`its benefits outweigh its risks. Celgene submitted a New Drug Application Application (NDA) 209606 for
`enasidenib with the proposed indication as treatment of patients with relapsed or refractory acute
`myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation.1 This application is under
`review in the Division of Hematology Products (DHP). The applicant did not submit a REMS with this
`application but proposed Prescribing Information that includes Boxed Warning, Warnings and
`Precautions and a Medication Guide as part of labeling to inform patients regarding the potential risks of
`differentiation syndrome.
`
`
` 2
`
` Background
`2.1 PRODUCT INFORMATION
`
`Enasidenib is a NME NDA type 505(b)(1) pathway application.a It is an IDH2 inhibitor proposed for
`indication as treatment of patients with relapsed or refractory acute myeloid leukemia (AML) with an
`IDH2 mutation. Enasidenib inhibits certain mutant forms of IDH2 including R140Q, R172K, and R172S at
`approximately 40-fold lower concentrations than wild-type IDH2. The IDH enzymes catalyze the
`oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG), producing nicotinamide adenine
`dinucleotide phosphate (NADPH) in the process via the citric acid cycle. Enasidenib is prepared as 50 mg
`
`
`a Section 505-1 (a) of the FD&C Act: FDAAA factor (F): Whether the drug is a new molecular entity.
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`Reference ID: 4117200
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`and 100 mg tablets to be taken by the oral route.1,2 The proposed starting dose of enasidenib is 100 mg
`taken orally once daily until disease progression or unacceptable toxicity.b Enasidenib was granted an
`Orphan drug designation on June 12, 2014, and a fast track designation on July 31, 2014. Enasidenib is
`not currently approved in any jurisdiction.
`
`2.2 REGULATORY HISTORY
`
`The following is a summary of the regulatory history for enasidenib (NDA 209606) relevant to this
`review:
`• 07/18/2013: Investigation New Drug (IND) 117631 submission was received.
`• 06/12/2014: Orphan Drug designation granted.
`• 07/31/2014: Fast track designation granted.
`
`• 07/26/2016: Applicant informed at pre-NDA meeting that FDA has preliminary concerns about
`the risk of differentiation syndrome and appropriate management guidelines may need to be
`communicated effectively to physicians in some manner. The need for a REMS for enasidenib
`will be made upon reviewing the NDA.
`• 12/30/2016: NDA 209606 submission for enasidenib with the proposed indication for the
`treatment of patients with relapsed or refractory acute myeloid leukemia (AML) with an
`isocitrate dehydrogenase-2 (IDH2) mutation, received.
`• 04/28/2017: A Post Mid-cycle meeting was held between the Agency and the Applicant via
`teleconference. The Agency informed the Applicant that based on the currently available data,
`there were no safety issues that require a REMS for enasidenib.
`
`
`3 Therapeutic Context and Treatment Options
`3.1 DESCRIPTION OF THE MEDICAL CONDITION
`
`Acute myelogenous leukemia (AML) is a form of cancer that is characterized by infiltration of the bone
`marrow, blood, and other tissues by proliferative, clonal, abnormally differentiated, and occasionally
`poorly differentiated cells of the hematopoietic system.3 The pathophysiology in AML consists of a
`maturational arrest of bone marrow cells in the earliest stages of development. The mechanism of this
`arrest is under study, but in many cases, it involves the activation of abnormal genes through
`chromosomal translocations and other genetic abnormalities. This developmental arrest results in 2
`disease processes. First, the production of normal blood cells markedly decreases, which results in
`varying degrees of anemia, thrombocytopenia, and neutropenia. Second, the rapid proliferation of these
`cells, along with a reduction in their ability to undergo programmed cell death, results in their
`accumulation in the bone marrow, the blood, the spleen, and the liver.4 The American Cancer Society
`estimates that approximately about 21,380 new cases of AML will be diagnosed in United Statesc, and
`
`
`b Section 505-1 (a) of the FD&C Act: FDAAA factor (D): The expected or actual duration of treatment with the drug.
`
`c Section 505-1 (a) of the FD&C Act: FDAAA factor (A): The estimated size of the population likely to use the drug
`involved.
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`Reference ID: 4117200
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`about 10,590 deaths from AML in 2017.d Acute myeloid leukemia is generally a disease of older people
`and is uncommon before the age of 45. The average age of a patient with AML is 67 years.5
`
`3.2 DESCRIPTION OF CURRENT TREATMENT OPTIONS
`
`The general therapeutic strategy in patients with AML has not changed substantially in more than 30
`years. The standard treatment is intensive chemotherapy potentially leading to an allogeneic stem cell
`transplant and is based mainly on the patient’s ability to tolerate intensive treatment. Treatment of AML
`has been divided into induction chemotherapy and postremission (eg. consolidation) therapy.3 Although
`obtaining a remission is the first step in controlling the disease, it is also important for patients to
`emerge from the induction phase in a condition to tolerate subsequent more intensive treatments
`during consolidation to achieve durable disease control. Patients who do not receive postremission
`therapy may experience relapse, usually within 6 to 9 months.6 A complete response is achieved in 60 to
`85% of adults who are 60 years of age or younger. In patients who are older than 60 years of age,
`complete response rates are inferior (40 to 60%).3 Although advances in the treatment of AML have led
`to significant improvements in outcomes for younger patients, prognosis in the elderly, who account for
`the majority of new cases, remains poor.7 Therefore, treatment results are generally analyzed
`separately for younger (18-60 years) patients and for older patients (>60 years). In patients who can
`tolerate intensive therapy, which may be limited by factors such as age and comorbid conditions,
`cytarabine and daunorubicin induction followed by high-dose cytarabine consolidation is frequently
`used. Intensifying induction therapy with a high daily dose of anthracycline plus intensive consolidation
`therapy resulted in a high complete-remission rate and prolonged overall survival in patients with AML.
`This regimen typically results in CR rates of 60-70% and 2-year OS of approximately 50% in patients < 60
`years of age.8 Older patients fare less well, with CR rates of approximately 50% and 2-year overall
`survival of approximately 20%.9
`
`There are no FDA-approved drugs specifically for relapsed or refractory AML, and there is no standard of
`care treatment regimen for these patients. Patients who are fit for intensive therapy should receive a
`salvage chemotherapy regimen followed by HSCT. About half will achieve a second complete remission,
`and 5-year survival of patients who achieve a second remission is about 40%.10 In large, phase 3 studies
`of high-dose cytarabine or investigator’s choice (e.g., hypomethylating agents, multi-agent
`chemotherapy, cytarabine, hydroxyurea, or supportive care) in primary refractory AML or AML that has
`relapsed after 1 or more prior regimens, the rate of CR ranges from 12 to 16%, and median OS ranges
`from 3.3 to 6.3 months. There is a clear need for new treatments for patients with relapsed or refractory
`AML.11
`
` 4
`
` Benefit Assessment
`
`
`The efficacy of enasidenib was evaluated in an open-label, single-arm, multi-center, two-cohort clinical
`trial (Study AG-221-C-001, NCT01915498). The study population included 207 patients with relapsed or
`refractory AML (103 in Cohort I and 104 in Cohort II) who were assigned to receive 100 mg of enasidenib
`daily and who had IDH2 mutations identified by the Abbott RealTime TM IDH2 assay, which is the FDA-
`approved test for selection of patients with AML for treatment with enasidenib. The rationale for
`pooling from different cohorts was based on consistency of demographic and baseline disease
`
`d Section 505-1 (a) of the FD&C Act: FDAAA factor (B): The seriousness of the disease or condition that is to be
`treated with the drug.
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`Reference ID: 4117200
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`characteristics of the trial populations, same dose regimen between the 2 cohorts, and consistent
`improvements in investigator assessed complete response (CR) and durability of the response across the
`two cohorts. The CR is an accepted clinical meaningful endpoint beneficial in patients with AML.11,e Dose
`reductions were allowed for adverse events.
`
`At the time of this writing, labeling negotiations were still ongoing with the Applicant. The
`following section is a summary of relevant efficacy information to date for enasidenib. Efficacy
`was established on the basis of the rate of CR/complete response with partial hematologic recovery
`(CRh), the duration of CR/CRh, and the rate of conversion from transfusion dependence to transfusion
`independence.
`11,1 The median follow-up was
`
`
`
`
`Table 1: Efficacy results in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML)11,1
`
`
` months (range 0.4 – 27.7 months).
`
`
`In the population of relapsed or refractory (R/R) AML subjects who received 100 mg enasidenib daily
`and were IDH2 positive, there was a numerical difference for the sponsor assessed CR rates between
`Cohort I (16.5%) and Cohort II (12.5%). The median duration of CR for the combined Cohort I & Cohort II
`was 9.7 months with 95% CI of (5.5, NA) using Kaplan-Meier (KM) method. However, the estimated
`median durations of response were different between Cohort I (11.5 month) and Cohort II (6.5 month).
`The median follow-up times were different between Cohort I (8.3 month) study and Cohort II (5.5)
`study. The differences in response rates and durations of response indicate variations between the two
`trials. The statistical reviewer stated that caution should be exercised in the interpretation of the pooled
`results.11
`
`e Section 505-1 (a) of the FD&C Act: FDAAA factor (C): The expected benefit of the drug with respect to such disease
`or condition.
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`Reference ID: 4117200
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`The secondary end points included overall survival (OS), the median time to first response, the median
`time to best response, and the rate of conversion from transfusion dependence to transfusion
`independence. The estimated median OS in the Cohort II population of 6.6 months was shorter in
`comparison with the Cohort I population of 9.1 month. However, time to event endpoints such as OS is
`not interpretable in single arm studies as it includes the natural history of the disease.11,1
`
`For patients who achieved a CR or CRh, the median time to first response was 1.9 months (range, 0.5 to
`7.5 months) and the median time to best response of CR/CRh was 3.7 months (range,
` to
`11.2 months). By the end of Month 6,
`% (39 of
` patients) of patients achieved a best response of
`CR/CRh.
`
`
`11,1
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` 5
`
` Risk Assessment & Safe-Use Conditions
`
`
`At the time of this writing, labeling negotiations were still ongoing with the Applicant. The following
`section is a summary of relevant safety information to date for enasidenib. The safety analysis of
`enasidenib primarily focuses on 214 patients with relapsed or refractory AML treated in a phase 1/2
`trial. The median duration of exposure to enasidenib at the time of data analysis was 4.3 months (range
`0.3 to 23.6). The 30-day and 60-day mortality rates observed with enasidenib were 4.2% (9/214) and
`11.7% (25/214), respectively.1
`
`The most common adverse reactions (≥ 20%) of any grade were nausea, vomiting, diarrhea, bilirubin
`increased, and decreased appetite.
`
`Deaths
`
`There were a total of 127 (59%) on-treatment all cause deaths (i.e. death for any cause within 28 days of
`the last dose of AG-221). The cause of death in the majority of subjects was related to disease
`progression of AML or complications of their underlying AML disease, mainly within infection and
`respiratory failure, intracranial hemorrhage, and cardiac arrest. A total of 62 (29%) subjects had 1 or
`more treatment-emergent adverse events (TEAE) with an outcome of death (Grade 5 TEAE). There were
`15 deaths in on Phase I of AG-221-C-001 considered by the FDA to be at least possibly related to
`enasidenib. Infection with or without neutropenia was clearly the root cause of death in 4 cases. In all
`cases, the subject had prior prolonged periods of neutropenia or lymphopenia that may have potentially
`contributed to the infection. There were 11 deaths on Phase I not definitively caused by infection, in
`which six of the cases include manifestations of respiratory distress, pulmonary edema, and/or multi-
`organ dysfunction consistent with differentiation syndrome. The rest five of the cases have other
`possible causes of death (e.g. infection, underlying malignancy). Due to the overlap in clinical
`manifestations, it is difficult to distinguish between differentiation syndrome and sepsis in the absence
`of cultures.11 (See Section on differentiation on syndrome). While narratives are not available for
`patients enrolled on Phase II of the study, the all-cause mortality as calculated by the FDA for the 214
`subjects in the Primary Safety Pool was 4% (95% CI, 2-8%) at day 30 and 24% (95% CI, 19-31%) at day 90.
`The clinical reviewers stated that the all-cause mortality observed in patients treated with enasidenib
`compares favorably to the 10-20% seen in patients treated with chemotherapy.11
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`Reference ID: 4117200
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`(b)
`(4)
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`(b)
`(4)
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`(b) (4)
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`Serious Adverse Events (SAE)
`
`Serious adverse reactions (≥ Grade 3) were reported in 77.1% of patients. The most frequent serious
`adverse reactions (≥2%) were leukocytosis (10%),
`
`
`
`.1
`
`
`Overall, 114 of 214 (61%) of treated subjects had a dose interruption (n=114; 53%), dose reduction
`(n=21; 10%), or permanent discontinuation/withdrawal (n=24; 11%) due to an adverse event. The most
`common adverse reactions leading to dose interruption were febrile neutropenia (n=12; 6%), sepsis
`(n=9; 4%), hyperbilirubinemia (n=8; 4%), pneumonia (n=8; 4%), differentiation syndrome (n=8; 4%),
`dyspnea (n=8; 4%), pyrexia (n=7; 3%), leukocytosis (n=6; 3%), and fatigue (n=6; 3%).11
`
`Differentiation Syndrome
`
`In the clinical trial, 14% of patients treated with enasidenib experienced differentiation syndrome (DS),
`including 7% ≥Grade 3 events. DS is caused by rapid proliferation and differentiation of myeloid cells and
`can be fatal if untreated. While there is no diagnostic test for DS, symptoms in patients treated with
`enasidenib include acute respiratory distress represented by dyspnea and/or hypoxia (68%) and need
`for supplemental oxygen (76%); pulmonary infiltrates (73%) and pleural effusion (45%); renal
`impairment (70%); fever (36%); lymphadenopathy (33%); bone pain (27%); peripheral edema with rapid
`weight gain (21%); and pericardial effusion (18%). Hepatic, renal, and multi-organ dysfunction have also
`been observed. DS has been observed with and without concomitant hyperleukocytosis, and as early as
`10 days and at up to 5 months after enasidenib initiation.
`
`The 6 deaths in the Phase 1 of the study showed manifestations of respiratory distress, pulmonary
`edema, and/or multi-organ dysfunction consistent with differentiation syndrome. Death occurred in one
`patient, which was suspected as a treatment-related TEAE (cardiac tamponade). The subject
`experienced pericardial effusion, which was complicated by the cardiac tamponade leading to death.
`Retrospective analysis of this case suggests that pericardial effusion was a likely sign of differentiation
`syndrome. This patient was changed to “do-not-resuscitate”, and did not receive any treatment or
`intervention. Two of other deaths which represent DC as a possible alternative cause of death by FDA
`analysis have not appeared to have received steroids during the course of treatment. The fourth patient
`who showed multi-focal infection and mild pulmonary edema has received steroids, but subsequently
`died from respiratory failure. The fifth patient revealed pleural effusions in addition to the pneumonia.
`The patient was empirically treated with dexamethasone for differentiation syndrome, with no
`improvement in symptoms, and developed multi-organ failure and died. The sixth patient had
`developed pharyngeal mucositis and acute respiratory distress syndrome (ARDS). The subject later
`diagnosed with differentiation syndrome, although the basis of this is not reported. The patient was
`treated with dexamethasone, antibiotics and mechanical ventilation. The subject developed severe
`capillary leak syndrome, renal failure, bilateral pleural effusions and fever, and died with investigator-
`determined cause of death as sepsis. The FDA considers that differentiation syndrome remains a
`possible cause of this death.11
`
`Study treatment was temporarily interrupted during treatment for DS in 8 (4%) subjects. As per
`protocol guidelines for its management, subjects with diagnosed or suspected DS of any grade were
`treated with high doses of intravenous or oral steroids..
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`Reference ID: 4117200
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`(b) (4)
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`The risk of DS will be included in the label as a Boxed Warning. Management of DS, including
`recommendations for initiating oral or intravenous steroids and hemodynamic monitoring, will be
`included in the Warnings and Precautions section of the label to increase the prominence of this
`information and promote mitigation of DS. Monitoring and dosage modifications for toxicities to address
`the safety issues with enasidenib will be included in the Dosage and Administration section of the label.
`Additionally, the applicant will be required to conduct a post-marketing required (PMR) study to
`characterize enasidenib-related DS, looking at incidence, diagnostic criteria, and effective treatment
`based on data and pooled analysis from their trial in AML.12
`
`Embryo-Fetal Toxicity
`
`Based on animal embryo-fetal toxicity studies, enasidenib can cause embryo-fetal harm when
`administered to a pregnant woman. In animal embryo-fetal toxicity studies, enasidenib caused
`embryo-fetal toxicities starting at 0.1 times the steady state clinical exposure based on the area
`under the concentration-time curve (AUC) at the recommended human dose. The risk of embryo-
`fetal toxicity will be communicated in the Warnings and Precautions section of the label.
`
`Leukocytosis
`
`Enasidenib can induce myeloid proliferation resulting in a rapid increase in white blood cell (WBC)
`count. Leukocytosis was the most frequently reported adverse reaction in the clinical trial with an
`overall incidence of all grades of 12% (26 patients). In the clinical trial, leukocytosis without evidence of
`infection or disease progression occurred in 12% of patients. Grade ≥3 leukocytosis occurred in 6% (12
`patients) of enasidenib -treated patients. The risk of leukocytosis will likely be communicated in the
`Adverse Reactions section of the label.
`
`Tumor Lysis Syndrome
`
`In the clinical trial, tumor lysis syndrome (TLS) was reported in 6% (13) of patients treated with
`enasidenib. Grade ≥3 TLS occurred in 6% (12 patients) of enasidenib -treated patients. No events were
`considered as either life-threatening or fatal, and no patients required dose reduction or
`discontinuation. The risk of TLS will be communicated will likely be communicated in the Adverse
`Events section of the label.
`
`Elevated Bilirubin
`
`Enasidenib may interfere with bilirubin metabolism through inhibition of UGT1A1. Direct bilirubin
`elevations ≥ 2x ULN were observed in 38% of patients. Thirty three percent of patients with total
`bilirubin elevations (≥ 2x ULN) had no concomitant elevation of transaminases or other Grade ≥ 3
`adverse events related to liver disorders. Grade ≥3 were reported for 15% patients. Twenty-eight
`percent of Grade ≥ 2 bilirubin elevations were evident in the first month of treatment. No patients
`required a dose reduction for hyperbilirubinemia; treatment was interrupted in 3.7% of patients, for a
`median of 6 days. Three patients (1.4%) discontinued enasidenib permanently due to
`hyperbilirubinemia. The risk of hyperbilirubinemia will likely be communicated in the Adverse Reactions
`section of the label.
`
`
`Reference ID: 4117200
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`6 Expected Postmarket Use
`
`The proposed indication is for the treatment of patients with relapsed or refractory AML with an IDH2
`mutation. It is expected that oncologists/hematologists, who are familiar with the management of
`chemotherapeutic toxicities such as DS, embryo-fetal toxicity, leukocytosis and tumor lysis syndrome,
`will be the primary health care providers to prescribe enasidenib and the use will be in both inpatient
`and outpatient setting.
`
` 7
`
` Risk Management Activities Proposed by the Applicant
`
`
`The applicant did not propose any risk management activities for enasidenib beyond routine
`pharmacovigilance and labeling. The applicant proposes a Boxed Warning in the labeling and a
`Medication Guide as part of labeling to inform patients regarding the potential risks of differentiation
`syndrome.
`
` 8
`
` Discussion of Need for a REMS
`
`
`When evaluating factors of whether a REMS is necessary to ensure that the benefits outweigh the risks
`for enasidenib, DRISK considers patient population, seriousness of the disease, expected benefit of the
`drug, seriousness of known or potential adverse events, and the prescribing population.
`
`Enasidenib is an IDH2 inhibitor proposed for the treatment of patients with relapsed or refractory AML
`with an IDH2 mutation. Based on the efficacy and safety information currently available, the clinical
`reviewers stated that enasidenib shows clinical meaningful benefit to patients with AML, and
`recommends approval of enasidenib for the treatment of patients with relapsed or refractory AML with
`an IDH2 mutation.
`
`DRISK and DHP have determined that if approved, a REMS is not necessary to ensure the benefits of
`enasidenib outweigh its risks. Labeling, including a Boxed Warning, and Warnings and Precautions will
`be used to communicate the safety issues and management of toxicities associated with enasidenib. The
`most concerning adverse reactions observed with the use of enasidenib are DS, leukocytosis, tumor lysis
`syndrome and hyperbilirubinemia.The most commonly reported TEAEs were disorders characteristic for
`subjects with AML and other hematologic malignancies, such as anemia, febrile neutropenia and
`thrombocytopenia, pneumonia with dyspnea and cough, and general disorders, including fatigue and
`pyrexia. Enasidenib appeared efficacious in both its primary and secondary outcomes and its risks can
`be communicated and managed through labeling. The current standard treatment for AML is intensive
`chemotherapy potentially leading to an allogeneic stem cell transplant; treatment is based mainly on
`the patient’s ability to tolerate the intensive regimen. There are no FDA-approved drugs specifically for
`relapsed or refractory AML, and there is no standard of care treatment regimen for these patients.
`Therefore, there remains a clear medical need for new treatments for the patients with relapsed or
`refractory AML. The risk of DS will be included in the label as a Boxed Warning; recommendations for
`the management of DS will be included in the Warnings and Precautions section of the label to increase
`the prominence of this information and promote its mitigation. The adverse reactions of TLS,
`leukocytosis, and hyperbilirubinemia will likely be communicated in the Adverse Reactions section of the
`label. Monitoring and dosage modifications for toxicities will be included in the Dosage and
`Administration section of the label. To better characterize safety the Agency has issued five PMRs and
`one PMC.12
`
`Reference ID: 4117200
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` 9
`
` Conclusion & Recommendations
`
`
`If approved, DRISK has determined that a REMS is not necessary to ensure the benefits outweigh the
`risks of enasidenib. The management of the risks associated with enasidenib treatment can be
`communicated through labeling. Please notify DRISK if new safety information becomes available that
`changes the benefit-risk profile; this recommendation can be reevaluated specifically REMS.
`
`10 References
`
` 1
`
`
` Proposed Prescribing Information for enasidenib as currently edited by the FDA, last updated June 23, 2017.
`
`2 Celgene. Clinical Overview for Enasidenib, dated December 30, 2016.
`
`3 Doehner H, Weisdorf DJ, Bloomfield CD. Acute Myeloid Leukemia. N Engl J Med. 2015 Sep 17;373(12):1136-52.
`
`4 Acute myelogenous leukemia (AML): Pathophysiology. Medscape.
`http://emedicine.medscape.com/article/197802-overview#a3. Accessed May 5, 2017.
`
`5 What are the key statistics about acute myeloid leukemia? American Cancer Soceity.
`https://www.cancer.org/cancer/acute-myeloid-leukemia/about/key-statistics.html. Accessed May 5, 2017.
`
`6 Kumar CC. Genetic Abnormalities and Challenges in the Treatment of Acute Myeloid Leukemia. Genes & Cancer.
`2011;2(2):95-107.
`
`7 De Kouchkovsky I, Abdul-Hay M. 'Acute myeloid leukemia: a comprehensive review and 2016 update'. Blood
`Cancer J. 2016;6(7):e441.
`
`8 Fernandez HF, Sun Z, Yao X, et al. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med.
`2009;361(13):1249-1259.
`
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`11
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`TILL OLICKAL
`06/27/2017
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`CYNTHIA L LACIVITA
`06/27/2017
`Concur
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`Reference ID: 4117200
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