CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`211192Orig1s000
`
`RISK ASSESSMENT and RISK MITIGATION
`REVIEW(S)
`
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`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
`
`
`Application Type
`
`Application Number
`
`211192
`
`PDUFA Goal Date
`
`August 21, 2018
`
`OSE RCM #
`
`2017-2612; 2017-2614
`
`Reviewer Name(s)
`
`Till Olickal, Ph.D., Pharm.D.
`
`Team Leader
`
`Elizabeth Everhart, MSN, RN, ACNP
`
`Division Director
`
`Cynthia LaCivita, Pharm.D.
`
`Review Completion Date
`
`June 6, 2018
`
`Subject
`
`Review to determine if a REMS is necessary
`
`Established Name
`
`Trade Name
`
`Ivosidenib
`
`Tibsovo
`
`Name of Applicant
`
`Agios Pharmaceuticals, Inc.
`
`Therapeutic Class
`
`Isocitrate dehydrogenase-1 inhibitor
`
`Formulation(s)
`
`Dosing Regimen
`
`250 mg tablet
`
`500 mg orally once daily until disease progression or unacceptable
`
`toxicity.
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`Reference ID: 4273770
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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 ....................................................................................................................................................... 6
`
`5 Risk Assessment & Safe-Use Conditions .............................................................................................................. 7
`
`6
`
`Expected Postmarket Use ......................................................................................................................................... 10
`
`7 Risk Management Activities Proposed by the Applicant ............................................................................. 10
`
`8 Discussion of Need for a REMS ............................................................................................................................... 11
`
`9
`
`Conclusion & Recommendations ........................................................................................................................... 12
`
`10
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`References .................................................................................................................................................................. 12
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`Reference ID: 4273770
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`2
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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 ivosidenib (Tibsovo) is necessary to ensure the
`benefits outweigh its risks. Agios Pharmaceuticals, Inc. submitted a New Drug Application (NDA) 211192
`for ivosidenib with the proposed indication for the treatment of adult patients with relapsed or
`refractory acute myeloid leukemia (AML) with an isocitrate dehydrogenase-1 (IDH1) mutation as
`detected by an FDA-approved test. The serious risks associated with the use of ivosidenib are
`differentiation syndrome, QTc interval prolongation, Guillain-Barré syndrome, and embryo-fetal toxicity.
`The applicant did not submit a REMS with this application but proposed Prescribing Information that
`includes a Boxed Warning, Warnings and Precautions, and a Medication Guide as part of labeling to
`inform patients regarding the serious risk of differentiation syndrome.
`
`DRISK and the Division of Hematology Products (DHP) have determined that if approved, a REMS is not
`necessary to ensure the benefits of ivosidenib outweigh its risks. The current standard treatment for
`AML is intensive chemotherapy and an allogeneic stem cell transplant, which is based mainly on the
`patient’s ability to tolerate the intensive regimen. There are no FDA-approved drugs that are specifically
`targeted treatments for IDH1 mutation-positive R/R AML, and there is no standard of care treatment
`regimen for these patients. Therefore, there remains a clear medical need for new treatments for
`patients with relapsed or refractory AML. In the clinical trial, ivosidenib appeared efficacious in both its
`primary and secondary outcomes. The most concerning adverse reaction associated with the use of
`ivosidenib is differentiation syndrome (DS). Similar to another IDH inhibitor, enasidenib, labeling will
`include the risk of DS as a Boxed Warning, and recommendations for its management, will be
`communicated in the 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 ivosidenib (Tibsovo) is necessary to ensure the
`benefits outweigh its risks. Agios Pharmaceuticals, Inc. submitted a New Drug Application (NDA) 211192
`for ivosidenib with the proposed indication for the treatment of adult patients with relapsed or
`refractory acute myeloid leukemia (AML) with an isocitrate dehydrogenase-1 (IDH1) mutation as
`detected by an FDA-approved test.1 The applicant did not submit a REMS with this application but
`proposed Prescribing Information that includes a Boxed Warning, Warnings and Precautions, and a
`Medication Guide as part of labeling to inform patients regarding the serious risk of differentiation
`syndrome.
`
`
` 2
`
` Background
`
`2.1 PRODUCT INFORMATION
`
`Ivosidenib is a NME NDA type 505(b)(1) pathway application.a It is an IDH1 inhibitor proposed for
`indication as treatment of adult patients with relapsed or refractory AML with an IDH1 mutation as
`detected by an FDA-approved test. Isocitrate dehydrogenases (IDH) catalyze the oxidative
`
`
`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: 4273770
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`decarboxylation of isocitrate to α-ketoglutarate (α-KG) during cellular metabolism. Mutations of the
`IDH1 isoform are found in 6-16% of patients with AML.2 These mutations are typically heterozygous and
`confer a new ability of the enzyme to catalyze the production of 2-hydroxyglutarate (2-HG). Increased
`cellular 2-HG levels contribute to epigenetic mechanisms of pathogenesis by inhibiting α-KG-dependent
`enzymes important for normal DNA methylation. Ivosidenib was shown to inhibit a variety of IDH1 R132
`mutants at much lower concentrations than wild-type IDH1 in vitro. Inhibition of the mutant IDH1
`enzyme by ivosidenib led to decreased 2-hydroxyglutarate (2-HG) levels and induced myeloid
`differentiation in vitro and in vivo in mouse xenograft models of IDH1-mutated AML. Ivosidenib is
`prepared as 250 mg tablets to be taken by the oral route.1,3 The recommended dose of ivosidenib is 500
`mg taken orally once daily with or without food until disease progression or unacceptable toxicity.b
`Ivosidenib was granted fast track designation on May 13, 2015, and orphan drug designation on June 9,
`2015. Ivosidenib is not currently approved in any jurisdiction.
`
`
`2.2 REGULATORY HISTORY
`
`The following is a summary of the regulatory history for ivosidenib (NDA 211192) relevant to this review:
`
`
` 12/20/2013: Investigation New Drug (IND) 119341 submission was received.
`
` 05/13/2015: Fast track designation granted.
`
` 06/09/2015: Orphan Drug designation granted.
`
` 09/20/2017: Applicant informed at pre-NDA meeting that the need for a REMS for ivosidenib
`will be made upon reviewing the NDA.
`
` 12/21/2017: NDA 211192 submission for ivosidenib with the proposed indication for the
`treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an
`isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test, received.
`
` 04/12/2018: 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 ivosidenib.
`
` 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.4 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
`
`b Section 505-1 (a) of the FD&C Act: FDAAA factor (D): The expected or actual duration of treatment with the drug.
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`accumulation in the bone marrow, the blood, the spleen, and the liver.5,8 The American Cancer Society
`estimates that approximately 19,520 new cases of AML, mostly in adults, will be diagnosed in United
`Statesc, and there will be about 10,670 deaths from AML in 2018 with almost all in adults.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.6
`
`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 and an allogeneic stem cell transplant, which
`is based mainly on the patient’s ability to tolerate intensive treatment. Treatment of AML has been
`divided into induction chemotherapy and postremission (e.g. consolidation) therapy.4 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.7 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%).4 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.8 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.9
`Older patients fare less well, with CR rates of approximately 50% and 2-year overall survival of
`approximately 20%.10
`
`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%.11 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. In 2017 the following
`therapies were approved for AML: enasidenib (Idhifa) for the treatment of IDH2-mutated relapsed or
`refractory (R/R) AML12, midostaurin (Rydapt) for the treatment of patients with newly diagnosed AML
`with FLT3 mutations13; daunorubicin and cytarabine (Vyxeos) for the treatment of newly diagnosed
`therapy-related AML or AML with myelodysplasia-related changes14; and gemtuzumab ozogamicin
`(Mylotarg) for the treatment of adults with newly diagnosed CD33-positive AML, and for the treatment
`of patients aged ≥2 years with CD33-positive AML who have experienced a relapse or who have not
`
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`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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`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: 4273770
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`responded to initial treatment (refractory)15. Despite the availability of new therapies, the long-term
`prognosis for patients with R/R AML remains limited and there are no FDA-approved drugs that are
`specifically targeted treatments for IDH1 mutation-positive R/R AML. There is a clear need for new
`treatments for patients with relapsed or refractory AML.16
`
` 4
`
` Benefit Assessment
`
`
`The efficacy of ivosidenib was evaluated in an open-label, single-arm, multicenter clinical trial (Study
`AG120-C-001, NCT02074839). The study population included 173 adult patients with relapsed or
`refractory AML who were assigned to receive a 500 mg of ivosidenib daily and who had IDH1 mutations
`identified by the Abbott RealTime IDH1 assay, which is the FDA-approved test for selection of patients
`with AML for treatment with ivosidenib.
`
`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 ivosidenib. Efficacy was established on
`the basis of the rate of complete remission (CR) plus complete remission with partial hematologic
`recovery (CRh), the duration of CR+CRh, and the rate of conversion from transfusion dependence to
`
`transfusion independence.
` (range, 0.2 to 39.5 months) and median treatment
` The median follow-up was
`duration was 4.1 months (range, 0.1 to 39.5 months).
`
`Table 1: Efficacy Results in Patients with Relapsed or Refractory AML1,16
`
`
`Endpoint
`
`Ivosidenib (500 mg daily)
`N=
`43
`
`CR1 n (%)
`95% CI
`Median DOR2 (months)
`95% CI
`CRh3 n (%)
`95% CI
`Median DOR (months)
`95% CI
`CR+CRh4 n (%)
`95% CI
`Median DOR (months)
`95% CI
`CI: confidence interval
`1 CR (complete remission) was defined as <5% blasts in the bone marrow, no evidence of disease, and full
`recovery of peripheral blood counts (platelets >100,000/microliter and absolute neutrophil counts [ANC]
`>1,000/microliter).
`2 DOR (duration of response) was defined as time since first response of CR or CRh to relapse or death,
`whichever is earlier.
`3 CRh (complete remission with partial hematological recovery) was defined as <5% blasts in the bone
`marrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets
`>50,000/microliter and ANC >500/microliter).
`4 CR+CRh rate appeared to be consistent across all baseline demographic and baseline disease
`characteristics with the exception of number of prior regimens.
`
`10.1
`(6.5, 22.2)
`14
`(4.5,
`3.60
`(1, 5.5)
`57
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`8.2
`(5.6, 12)
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`Reference ID: 4273770
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`The secondary efficacy endpoints included CR rate, overall response rate (ORR), duration of CR+CRh,
`duration of CR (DOCR), duration of response (DOR), overall survival (OS), event-free survival (EFS), time
`to CR+CRh, time to CR, time to response, and transfusion independence. The clinical reviewer stated as
`the OS is not interpretable in single arm studies and EFS did not consider treatment failures, the
`duration of CR+CRh and DOCR should be more helpful to assess the length of meaningful responses in
`the patient population. An observed CR+CRh rate in R/R AML subjects with the lower bound of the exact
`binomial 95% CI greater than 10% was deemed as clinically meaningful. This was considered to be
`evidence of clinically significant activity from ivosidenib.16,17, e
`
`For patients who achieved a CR or CRh, the median time
` to CR or CRh was 2 months (range, 0.9 to 5.6 months). Of the 57
`patients who achieved a best response of CR or CRh, all achieved a first response of CR or CRh within 6
`months of initiating ivosidenib. Among the
` patients who were dependent on red blood cell (RBC)
`and/or platelet transfusions at baseline, 41
`%) became independent of RBC and platelet
`transfusions during any 56-day post-baseline period. Of the 64 patients who were independent of both
`RBC and platelet transfusions at baseline, 38 (59.4%) remained transfusion independent during any 56-
`day post-baseline period.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 ivosidenib. The safety analysis of
`ivosidenib primarily focuses on 179 adult patients with relapsed or refractory AML treated with 500 mg
`daily (R/R AML SAS). The median duration of exposure to ivosidenib was 3.9 months (range 0.1 to 39.5
`months). Sixty-five patients (36%) were exposed to ivosidenib for at least 6 months and 16 patients (9%)
`were exposed for at least 1 year.
`
`The most common adverse reactions (≥20%) of any grade were fatigue, leukocytosis, arthralgia,
`diarrhea, dyspnea, edema, nausea, electrocardiogram QT prolonged, rash, pyrexia, and constipation.
`
`Deaths
`
`There were a total of 129 (72%) all deaths and 50 on-treatment deaths (28% on or within 28 days after
`the last dose of ivosidenib) in the R/R AML SAS of 179 patient pool. The FDA determined that the
`majority (n=40, 80%) of the on-treatment deaths in R/R AML patients on Study AG120-C-001 were due
`to the primary malignancy. There were 10 deaths (5.6%) in R/R AML patients on AG120-C-001
`considered by the FDA to be at least possibly related to ivosidenib. Infection was clearly the cause of
`death in 3 cases. There were 7 deaths in R/R AML patients not definitively caused by infection that were
`considered by the FDA to be a direct toxicity of ivosidenib, in which 3 of the cases include manifestations
`of DS, although all the cases have other possible causes of death (e.g. infection, underlying malignancy).
`(See Section on differentiation on syndrome).16 Due to the overlap in clinical manifestations, it is difficult
`to distinguish between differentiation syndrome and infection. It is also difficult to determine
`conclusively whether DS contributed to progression of a pre-existing or developing infection. Four of the
`
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`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: 4273770
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`(b) (4)
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`cases have other possible causes of death (e.g. aspiration pneumonia, pericarditis/myocarditis,
`ventricular arrhythmia, Thrombotic stroke). FDA could not rule out the possibility that ivosidenib
`contributed to these deaths.16 The all-cause mortality as calculated by the FDA for the 179 subjects in
`the R/R AML SAS was 7% (95% CI, 4-11%) at day 30, 15% (95% CI 10-20%) at day 60, and 20% (95% CI,
`15-27%) at day 90.16 The clinical reviewers stated that the all-cause mortality observed in patients
`treated with ivosidenib compares favorably to the 10-20% seen in patients treated with
`chemotherapy.16
`
`Serious Adverse Events (SAE)
`
`Serious adverse reactions (≥ 5%) were differentiation syndrome (10%), leukocytosis (10%), and
`electrocardiogram QT prolonged (7%). The most common adverse reactions leading to dose interruption
`were electrocardiogram QT prolonged (7%), differentiation syndrome (3%), leukocytosis (3%) and
`dyspnea (3%). Three out of 179 patients (2%) required a dose reduction due to an adverse reaction.
`Adverse reactions leading to a dose reduction included electrocardiogram QT prolonged (1%), diarrhea
`(1%) nausea (1%) decreased hemoglobin (1%) and increased transaminases (1%). Adverse reactions
`leading to permanent discontinuation included Guillain-Barre syndrome (1%) and rash (1%), and
`increased creatinine (1%).
`
`If approved, labeling will include the following risks in the Warnings and Precautions section.
`
`5.1 DIFFERENTIATION SYNDROME:
`
`/179) patients with relapsed or refractory AML treated with ivosidenib
`In the clinical trial, % (
`experienced differentiation syndrome
`. Differentiation syndrome is associated with rapid
`proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated.
`Symptoms of differentiation syndrome in patients treated with ivosidenib included noninfectious
`leukocytosis
`, peripheral edema
`, pyrexia
`, dyspnea
`, pleural effusion
`,
`hypotension
`, hypoxia
`, pulmonary edema
` pneumonia
`, pericardial effusion
`, rash
` fluid overload
` tumor lysis syndrome
` and
` Of
`patients who experienced differentiation syndrome,
` recovered after treatment or
`the
`after dose interruption of ivosidenib. Differentiation syndrome occurred as early as days and up to
`months after ivosidenib initiation and has been observed with or without concomitant leukocytosis.1
`
`The 3 deaths showed manifestations of DS, although all the cases have other possible causes of death
`(e.g. infection, underlying malignancy). Death occurred in one patient, who was diagnosed with
`Aspergillosis and voriconazole was started. Five days after the final dose of ivosidenib, the patient died
`due to ARDS, assessed as due to the underlying malignancy. FDA assessed the cause of death to be due
`to the underlying malignancy and believes that DS may have contributed. The second patient was
`thought to have died from respiratory failure as a consequence of his AML. His WBC increased
`substantially around the time of his respiratory decompensation, renal failure, and hypotension.
`However, his peripheral blast count decreased steadily from a peak of 75% on day 18 to only 10% on day
`45, arguing somewhat against progression of disease. Infection is another possibility, but cultures were
`all negative. In the absence of a definitive alternative, DS as the cause of death could not be ruled out.
`The third patient was diagnosed with febrile bilateral pneumonia with chronic neutropenia and was
`treated with antibiotics. The final dose of study treatment was day 15 and 1 day later the patient died of
`sepsis including pulmonary infection, assessed as due to the underlying malignancy. Although the
`patient had a high burden of leukemia and possible pulmonary sepsis, no organism was identified. FDA
`
`8
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`Reference ID: 4273770
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`could not rule out that the pre-existing process in the lungs may have been exacerbated by DS
`(concomitant fever, polypnea, pleuropericardial effusions, and peripheral edema). (See clinical review
`for a detailed patient narratives).16
`
`Similar to another IDH inhibitor, enasidenib, labeling will include the risk of DS as a Boxed Warning.
`Management of DS, including recommendations for initiating oral or intravenous steroids and
`hemodynamic monitoring, will likely also be communicated in the Warnings and Precautions section of
`the label to increase the prominence of this information and promote mitigation of DS; a Medication
`Guide as part of labeling to inform patients regarding the potential risks of DS will also be included.
`Monitoring and dosage modifications for toxicities to address the safety issues with ivosidenib will likely
`be included in the Dosage and Administration section of the label.
`
`5.2 QTC INTERVAL PROLONGATION:
`
`QT (QTc) interval prolongation can develop in patients treated with ivosidenib. Of the 258 patients
`treated with ivosidenib in the clinical trial, 9% (n=17) were found to have a QTc interval greater than 500
`msec (Grade ≥3) and 14% (n=22) of patients had an increase from baseline QTc greater than 60 msec.
`Three patients (1%) developed ventricular arrhythmia, including ventricular fibrillation and ventricular
`tachycardia. Among the 179 subjects with R/R AML whose starting dose was 500 mg QD, results from
`the categorical analysis of the maximum post-baseline increase in QTcF from baseline showed that in
`the majority of subjects who had an increase in post-baseline QTcF, the increase was ≤60 msec. The
`change from baseline (ΔQTcF) reported in clinical trial for ≤ 30msec, >30 to ≤60 msec, and >60 msec
`were 45.3% (n=81), 42.5% (n=76), and 12.3% (n=22), respectively.18 The clinical trial excluded patients
`with baseline QTc of ≥450 msec (unless the QTc ≥ 450 msec was due to a pre-existing bundle branch
`block) or with a history of long QT syndrome or uncontrolled or significant cardiovascular disease.1
`Grade ≥3 AEs of electrocardiogram QT prolonged occurred in 18 subjects (10.1%); Grade ≥3 AEs were
`assessed as treatment-related in 14 subjects (7.8%). There were no Grade 4 AEs of electrocardiogram QT
`prolonged and no AEs with a fatal outcome. The incidence of dose reductions due to AEs of
`electrocardiogram QT prolonged was low (2 subjects, 1.1%); dose holds were reported in 13 subjects
`(7.3%). There were no AEs of electrocardiogram QT prolongation that led to study treatment
`discontinuation. Serious adverse events were reported in 12 subjects (6.7%); none of the SAEs were
`fatal. There were no reported cases of Torsade de Pointes or Sudden Death. The risk of QTc interval
`prolongation as well as monitoring will likely be communicated in the Warnings and Precautions section
`of the label. Monitoring and dosage modifications for toxicities to address the safety issues with
`ivosidenib will likely be included in the Dosage and Administration section of the label.
`
`5.3 GUILLAIN-BARRÉ SYNDROME:
`
`Guillain-Barré syndrome occurred in <1% (2/258) of patients treated with ivosidenib in the clinical
`study.1 The proposed label includes recommendation for the monitoring patients for onset of new signs
`symptoms of motor and/or sensory neuropathy such as unilateral or bilateral weakness, sensory
`alterations, or parasthesias. The risk of Guillain-Barré syndrome as well as monitoring for it will likely be
`communicated in the Warnings and Precautions and Dosage and Administration sections of the label.
`
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`Reference ID: 4273770
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`Other Serious Adverse Events (SAE)
`
`Leukocytosis
`
` A
`
` total of 65 (36.3%) of subjects with R/R AML whose starting dose was 500 mg QD experienced
`leukocytosis events. Grade ≥3 events were reported in 15 subjects (8.4%); most were assessed as
`unrelated to study treatment. These events were reported as SAEs in 18 subjects (10.1%); none were
`fatal. The risk of leukocytosis will likely be communicated in the Adverse Reactions section of the label.
`Management of leukocytosis, including recommendations for initiating hydroxyurea and hemodynamic
`monitoring, will likely be communicated in the Dosage and Administration section of the label to
`promote mitigation of leukocytosis.
`
`Tumor Lysis Syndrome
`
` A
`
` total of 12 (6.7%) of subjects with R/R AML whose starting dose was 500 mg QD had at least
`1 AE of tumor lysis syndrome (TLS); none of the events were assessed by the Investigator as treatment-
`related. Grade ≥3 events of TLS were reported in 10 subjects (5.6%). TLS was reported as an SAE in 6
`subjects (3.4%); none of the SAEs resulted in a fatal outcome. No subjects discontinued study treatment
`or required a dose reduction for management of this event; study treatment was held in 1 subject
`(0.6%). The risk of TLS will be communicated will likely be communicated in the Adverse Events section
`of the label.
`
` 6
`
` Expected Postmarket Use
`
`
`The proposed indication is for the treatment of adult patients with relapsed or refractory AML with an
`IDH1 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 likely health care providers to prescribe ivosidenib in both inpatient and outpatient setting.
`
` 7
`
` Risk Management Activities Proposed by the Applicant
`
`
`The applicant did not propose any risk management activities for ivosidenib beyond routine
`pharmacovigilance and labeling. The applicant proposed a Boxed Warning in the labeling and a
`Medication Guide as part of labeling to inform patients regarding the potential risks of differentiation
`syndrome.
`
`
`
`Reference ID: 4273770
`
`10
`
`(b) (4)
`
`

`

`
`
`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 ivosidenib, DRISK considers patient population, seriousness of the disease, expected benefit of the
`drug, seriousness of known or potential adverse events, and the prescribing population.
`
`Ivosidenib is an IDH1 inhibitor proposed for indication as treatment of adult patients with relapsed or
`refractory AML with an IDH1 mutation. Based on the efficacy and safety information currently available,
`the clinical reviewers stated that ivosidenib shows clinical meaningful benefit to patients with AML, and
`recommends approval of ivosidenib for the treatment of adult patients with relapsed or refractory AML
`with an IDH1 mutation.16
`
`DRISK and DHP have determined that if approved, a REMS is not necessary to ensure the benefits of
`ivosidenib 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 ivosidenib. The
`most concerning adverse reactions observed with the use of ivosidenib are DS, QTc interval
`prolongation, Guillain-Barré syndrome, and embryo-fetal toxicity. Ivosidenib 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 and 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 that are specifically targeted treatments for IDH1 mutation-positive R/R
`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.
`
`Similar to another IDH inhibitor, enasidenib, labeling will include the risk of DS as a Boxed Warning;
`recommendations for the management of DS will be included in the Warnings and Precautions sec