DailyMed Label: Tibsovo

DailyMed Label: TIBSOVO

2024

DailyMed Prescription

TIBSOVO

ivosidenib

Servier Pharmaceutical LLC

NDC: 72694-617

NDC: 72694-617

TIBSOVO (ivosidenib) is an inhibitor of isocitrate dehydrogenase 1 (IDH1) enzyme. The chemical name is (2 S )- N -{(1 S )-1-(2-chlorophenyl)-2-[(3,3-difluorocyclobutyl)-amino]-2-oxoethyl}-1-(4-cyanopyridin-2-yl)- N -(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide. The chemical structure is: The molecular formula is C 28 H 22 ClF 3 N 6 O 3 and the molecular weight is 583.0 g/mol. Ivosidenib is practically insoluble in aqueous solutions between pH 1.2 and 7.4. TIBSOVO (ivosidenib) is available as a film-coated 250 mg tablet for oral administration. Each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The tablet coating includes FD&C blue #2, hypromellose, lactose monohydrate, titanium dioxide, and triacetin. Chemical Structure

TIBSOVO is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for patients with a susceptible IDH1 mutation as detected by an FDA-approved test with: Newly Diagnosed Acute Myeloid Leukemia (AML) In combination with azacitidine or as monotherapy for the treatment of newly diagnosed AML in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy ( 1.1 ). Relapsed or refractory AML For the treatment of adult patients with relapsed or refractory AML ( 1.2 ). Relapsed or refractory Myelodysplastic Syndromes (MDS) For the treatment of adult patients with relapsed or refractory myelodysplastic syndromes ( 1.3 ). Locally Advanced or Metastatic Cholangiocarcinoma For the treatment of adult patients with locally advanced or metastatic cholangiocarcinoma who have been previously treated ( 1.4 ). TIBSOVO is indicated in combination with azacitidine or as monotherapy for the treatment of newly diagnosed acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy [see Dosage and Administration (2.1) , Clinical Pharmacology (12.1) and Clinical Studies (14.1) ]. TIBSOVO is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test [see Dosage and Administration (2.1) , Clinical Pharmacology (12.1) and Clinical Studies (14.2) ] . TIBSOVO is indicated for the treatment of adult patients with relapsed or refractory myelodysplastic syndromes (MDS) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test [see Dosage and Administration (2.1) , Clinical Pharmacology (12.1) and Clinical Studies (14.3) ] . TIBSOVO is indicated for the treatment of adult patients with previously treated, locally advanced or metastatic cholangiocarcinoma with an isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test [see Dosage and Administration (2.1) , Clinical Pharmacology (12.1) , and Clinical Studies (14.4) ] .

500 mg orally once daily with or without food until disease progression or unacceptable toxicity ( 2.2 ). Avoid a high-fat meal. Select patients for treatment with TIBSOVO based on the presence of IDH1 mutations [see Clinical Studies (14.1 , 14.2 , 14.3 , 14.4 )]. Information on FDA-approved tests for the detection of IDH1 mutations in AML, MDS, and cholangiocarcinoma is available at http://www.fda.gov/CompanionDiagnostics. The recommended dosage of TIBSOVO is 500 mg taken orally once daily until disease progression or unacceptable toxicity [see Clinical Studies (14.1 , 14.2 , 14.3 , 14.4 )] . For patients with AML or MDS without disease progression or unacceptable toxicity, continue TIBSOVO for a minimum of 6 months to allow time for clinical response. Administer TIBSOVO with or without food. Do not administer TIBSOVO with a high-fat meal [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ]. Do not split, crush, or chew TIBSOVO tablets. Administer TIBSOVO tablets orally about the same time each day. If a dose of TIBSOVO is vomited, do not administer a replacement dose; wait until the next scheduled dose is due. If a dose of TIBSOVO is missed or not taken at the usual time, administer the dose as soon as possible and at least 12 hours prior to the next scheduled dose. Return to the normal schedule the following day. Do not administer 2 doses within 12 hours. Newly Diagnosed AML (Combination Regimen) Start TIBSOVO administration on Cycle 1 Day 1 in combination with azacitidine 75 mg/m 2 subcutaneously or intravenously once daily on Days 1-7 (or Days 1-5 and 8-9) of each 28-day cycle [see Clinical Studies (14.1) ] . Refer to the Prescribing Information for azacitidine for additional dosing information. Obtain an electrocardiogram (ECG) prior to treatment initiation. Monitor ECGs at least once weekly for the first 3 weeks of therapy and then at least once monthly for the duration of therapy [see Warnings and Precautions (5.2) ] . Manage any abnormalities promptly . Interrupt dosing or reduce dose for toxicities. See Table 1 for dosage modification guidelines. Table 1: Recommended Dosage Modifications for TIBSOVO Adverse Reactions Recommended Action Differentiation syndrome [see Warnings and Precautions (5.1) ] If differentiation syndrome is suspected, administer systemic corticosteroids and initiate hemodynamic monitoring until symptom resolution and for a minimum of 3 days . Interrupt TIBSOVO if severe signs and/or symptoms persist for more than 48 hours after initiation of systemic corticosteroids . Resume TIBSOVO when signs and symptoms improve to Grade 2 or lower. Noninfectious leukocytosis (white blood cell [WBC] count greater than 25 × 10 9 /L or an absolute increase in total WBC of greater than 15 × 10 9 /L from baseline) Initiate treatment with hydroxyurea, as per standard institutional practices, and leukapheresis if clinically indicated. Taper hydroxyurea only after leukocytosis improves or resolves. Interrupt TIBSOVO if leukocytosis is not improved with hydroxyurea, and then resume TIBSOVO at 500 mg daily when leukocytosis has resolved. QTc interval greater than 480 msec to 500 msec [see Warnings and Precautions (5.2) and Drug Interactions (7.1) ] Monitor and supplement electrolyte levels as clinically indicated. Review and adjust concomitant medications with known QTc interval-prolonging effects. Interrupt TIBSOVO. Restart TIBSOVO at 500 mg once daily after the QTc interval returns to less than or equal to 480 msec. Monitor ECGs at least weekly for 2 weeks following resolution of QTc prolongation. QTc interval greater than 500 msec [see Warnings and Precautions (5.2) and Drug Interactions (7.1) ] Monitor and supplement electrolyte levels as clinically indicated. Review and adjust concomitant medications with known QTc interval-prolonging effects . Interrupt TIBSOVO. Resume TIBSOVO at a reduced dose of 250 mg once daily when QTc interval returns to within 30 msec of baseline or less than or equal to 480 msec. Monitor ECGs at least weekly for 2 weeks following resolution of QTc prolongation. Consider re-escalating the dose of TIBSOVO to 500 mg daily if an alternative etiology for QTc prolongation can be identified. QTc interval prolongation with signs/symptoms of life-threatening arrhythmia [see Warnings and Precautions (5.2) ] Discontinue TIBSOVO permanently. Guillain-Barré syndrome [see Warnings and Precautions (5.3) ] Discontinue TIBSOVO permanently. Other Grade 3 Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening; grading based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. adverse reactions As monotherapy in AML and MDS : Interrupt TIBSOVO until toxicity resolves to Grade 2 or lower. Resume TIBSOVO at 250 mg once daily; may increase to 500 mg once daily if toxicities resolve to Grade 1 or lower. If Grade 3 or higher toxicity recurs, discontinue TIBSOVO. In cholangiocarcinoma, or in AML in combination with azacitidine : Interrupt TIBSOVO until toxicity resolves to Grade 1 or lower, or baseline, then resume at 500 mg daily (Grade 3 toxicity) or 250 mg daily (Grade 4 toxicity). If Grade 3 toxicity recurs (a second time), reduce TIBSOVO dose to 250 mg daily until the toxicity resolves, then resume 500 mg daily. If Grade 3 toxicity recurs (a third time), or Grade 4 toxicity recurs, discontinue TIBSOVO. Patients with AML or MDS Assess blood counts and blood chemistries prior to the initiation of TIBSOVO, at least once weekly for the first month, once every other week for the second month, and once monthly for the duration of therapy. Monitor blood creatine phosphokinase weekly for the first month of therapy. If a strong CYP3A4 inhibitor must be coadministered, reduce the TIBSOVO dose to 250 mg once daily. If the strong inhibitor is discontinued, increase the TIBSOVO dose (after at least 5 half-lives of the strong CYP3A4 inhibitor) to the recommended dose of 500 mg once daily.

Tablets: 250 mg as a blue oval-shaped film-coated tablet debossed "IVO" on one side and "250" on the other side. Tablets: 250 mg ( 3 ).

None. None ( 4 ).

QTc Interval Prolongation : Monitor electrocardiograms and electrolytes. If QTc interval prolongation occurs, dose reduce or withhold, then resume dose or permanently discontinue TIBSOVO ( 2.3 , 5.2 ). Guillain-Barré Syndrome : Monitor patients for signs and symptoms of new motor and/or sensory findings. Permanently discontinue TIBSOVO in patients who are diagnosed with Guillain-Barré syndrome ( 2.3 , 5.3 ). Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal. Symptoms of differentiation syndrome in patients treated with TIBSOVO included noninfectious leukocytosis, peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome and creatinine increased. In the combination study AG120-C-009, 15% (11/71) patients with newly diagnosed AML treated with TIBSOVO plus azacitidine experienced differentiation syndrome [see Adverse Reactions (6.1) ] . Of the 11 patients with newly diagnosed AML who experienced differentiation syndrome with TIBSOVO plus azacitidine 8 (73%) recovered. Differentiation syndrome occurred as early as 3 days after start of therapy and during the first month on treatment. In the monotherapy clinical trial AG120-C-001, 25% (7/28) of patients with newly diagnosed AML and 19% (34/179) of patients with relapsed or refractory AML treated with TIBSOVO experienced differentiation syndrome [see Adverse Reactions (6.1) ] . Of the 7 patients with newly diagnosed AML who experienced differentiation syndrome, 6 (86%) patients recovered. Of the 34 patients with relapsed or refractory AML who experienced differentiation syndrome, 27 (79%) patients recovered after treatment or after dose interruption of TIBSOVO. Differentiation syndrome occurred as early as 1 day and up to 3 months after TIBSOVO initiation and has been observed with or without concomitant leukocytosis. In the monotherapy clinical trial AG120-C-001, 11% (2/19) of patients with relapsed or refractory MDS treated with TIBSOVO experienced differentiation syndrome [see Adverse Reactions (6.1) ] . Of the 2 patients who experienced differentiation syndrome, both recovered after treatment or after dose interruption of TIBSOVO. Differentiation syndrome occurred as early as 1 day and up to 3 months after TIBSOVO initiation and has been observed with or without concomitant leukocytosis. If differentiation syndrome is suspected, initiate dexamethasone 10 mg IV every 12 hours (or an equivalent dose of an alternative oral or IV corticosteroid) and hemodynamic monitoring until improvement [see Dosage and Administration (2.3) ] . If concomitant noninfectious leukocytosis is observed, initiate treatment with hydroxyurea or leukapheresis, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms and administer corticosteroids for a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid and/or hydroxyurea treatment. If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids, interrupt TIBSOVO until signs and symptoms are no longer severe [see Dosage and Administration (2.3) ]. Patients treated with TIBSOVO can develop QT (QTc) prolongation and ventricular arrhythmias [see Clinical Pharmacology (12.2) ]. Of the 71 patients with newly diagnosed AML treated with TIBSOVO in combination with azacitidine in the clinical trial (Study AG120-C-009), 10 (14%) were found to have a heart-rate corrected QT interval (using Fridericia's method) (QTcF) greater than 500 msec and 15 out of 69 (22%) had an increase from baseline QTcF greater than 60 msec [see Adverse Reactions (6.1) ] . The clinical trial excluded patients with a QTcF ≥ 470 msec or other factors that increased the risk of QT prolongation or arrhythmic events (e.g. NYHA Class III or IV congestive heart failure, hypokalemia, family history of long QT interval syndrome). Of the 265 patients with hematological malignancies, including patients with AML and MDS, treated with TIBSOVO monotherapy in the clinical trial (AG120-C-001), 9% were found to have a QTc interval greater than 500 msec and 14% of patients had an increase from baseline QTc greater than 60 msec [see Adverse Reactions (6.1) ] . One patient developed ventricular fibrillation attributed to TIBSOVO. 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. Of the 123 patients with cholangiocarcinoma treated with TIBSOVO in the clinical trial (Study AG120-C-005), 2% were found to have a QTc interval greater than 500 msec and 5% of patients had an increase from baseline QTc greater than 60 msec [see Adverse Reactions (6.1) ] . The clinical trial excluded patients with a heart-rate corrected QT interval (using Fridericia's formula) (QTcF) ≥ 450 msec or other factors that increased the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome). Concomitant use of TIBSOVO with drugs known to prolong the QTc interval (e.g., anti-arrhythmic medicines, fluoroquinolones, triazole anti-fungals, 5-HT 3 receptor antagonists) and CYP3A4 inhibitors may increase the risk of QTc interval prolongation [see Drug Interactions (7.1) , Clinical Pharmacology (12.2) ]. Conduct monitoring of electrocardiograms (ECGs) and electrolytes [see Dosage and Administration (2.3) ] . In patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval, more frequent monitoring may be necessary. Interrupt TIBSOVO if QTc increases to greater than 480 msec and less than 500 msec. Interrupt and reduce TIBSOVO if QTc increases to greater than 500 msec. Permanently discontinue TIBSOVO in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia [See Dosage and Administration (2.3) ] . Guillain-Barré syndrome can develop in patients treated with TIBSOVO. Guillain-Barré syndrome occurred in 0.8% (2/265) of patients treated with TIBSOVO in study AG120-C-001 [see Adverse Reactions (6.1) ] . Monitor patients taking TIBSOVO for onset of new signs or symptoms of motor and/or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing. Permanently discontinue TIBSOVO in patients who are diagnosed with Guillain-Barré syndrome [see Dosage and Administration (2.3) ].

The following clinically significant adverse reactions are described elsewhere in the labeling:

Strong or Moderate CYP3A4 Inhibitors: Reduce TIBSOVO dose with strong CYP3A4 inhibitors. Monitor patients for increased risk of QTc interval prolongation ( 2.4 , 5.2 , 7.1 , 12.3 ). Strong CYP3A4 Inducers: Avoid concomitant use with TIBSOVO ( 7.1 , 12.3 ). Sensitive CYP3A4 substrates: Avoid concomitant use with TIBSOVO ( 7.2 , 12.3 ). QTc Prolonging Drugs: Avoid concomitant use with TIBSOVO. If co-administration is unavoidable, monitor patients for increased risk of QTc interval prolongation ( 5.2 , 7.1 ). Strong or Moderate CYP3A4 Inhibitors Clinical Impact Co-administration of TIBSOVO with strong or moderate CYP3A4 inhibitors increased ivosidenib plasma concentrations [see Clinical Pharmacology (12.3) ]. Increased ivosidenib plasma concentrations may increase the risk of QTc interval prolongation [see Warnings and Precautions (5.2) ]. Prevention or Management Consider alternative therapies that are not strong or moderate CYP3A4 inhibitors during treatment with TIBSOVO. If co-administration of a strong CYP3A4 inhibitor is unavoidable, reduce TIBSOVO to 250 mg once daily [see Dosage and Administration (2.3) ]. Monitor patients for increased risk of QTc interval prolongation [see Warnings and Precautions (5.2) ] . Strong CYP3A4 Inducers Clinical Impact Co-administration of TIBSOVO with strong CYP3A4 inducers decreased ivosidenib plasma concentrations [see Clinical Pharmacology (12.3) ]. Prevention or Management Avoid co-administration of strong CYP3A4 inducers with TIBSOVO. QTc Prolonging Drugs Clinical Impact Co-administration of TIBSOVO with QTc prolonging drugs may increase the risk of QTc interval prolongation [see Warnings and Precautions (5.2) ]. Prevention or Management Avoid co-administration of QTc prolonging drugs with TIBSOVO or replace with alternative therapies. If co-administration of a QTc prolonging drug is unavoidable, monitor patients for increased risk of QTc interval prolongation [ see Warnings and Precautions (5.2) ]. Ivosidenib induces CYP3A4 and may induce CYP2C9. Co-administration will decrease concentrations of drugs that are sensitive CYP3A4 substrates and may decrease concentrations of drugs that are sensitive CYP2C9 substrates [see Clinical Pharmacology (12.3) ] . Use alternative therapies that are not sensitive substrates of CYP3A4 and CYP2C9 during TIBSOVO treatment. If co-administration of TIBSOVO with sensitive CYP3A4 substrates or CYP2C9 substrates is unavoidable, monitor patients for loss of therapeutic effect of these drugs. Do not administer TIBSOVO with anti-fungal agents that are substrates of CYP3A4 due to expected loss of antifungal efficacy. Co-administration of TIBSOVO may decrease the concentrations of hormonal contraceptives, consider alternative methods of contraception in patients receiving TIBSOVO.

Lactation: Advise women not to breastfeed ( 8.2) . Risk Summary Based on animal embryo-fetal toxicity studies, TIBSOVO may cause fetal harm when administered to a pregnant woman. There are no available data on TIBSOVO use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal embryo-fetal toxicity studies, oral administration of ivosidenib to pregnant rats and rabbits during organogenesis was associated with embryo-fetal mortality and alterations to growth starting at 2 times the steady state clinical exposure based on the AUC at the recommended human dose (see Data ). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. Data Animal Data Ivosidenib administered to pregnant rats at a dose of 500 mg/kg/day during organogenesis (gestation days 6-17) was associated with adverse embryo-fetal effects including lower fetal weights, and skeletal variations. These effects occurred in rats at approximately 2 times the human exposure at the recommended dose of 500 mg daily. In pregnant rabbits treated during organogenesis (gestation days 7-20), ivosidenib was maternally toxic at doses of 180 mg/kg/day (exposure approximately 3.9 times the human exposure at the recommended dose of 500 mg daily) and caused spontaneous abortions as well as decreased fetal weights, skeletal variations, and visceral variations. Risk Summary There are no data on the presence of ivosidenib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with TIBSOVO and for 1 month after the last dose. The safety and effectiveness of TIBSOVO in pediatric patients have not been established. Of the 304 patients who received TIBSOVO in the clinical studies for AML and MDS, 75% were 65 years of age or older and 35% were 75 years or older. Of the 124 patients with cholangiocarcinoma treated with TIBSOVO in Study AG120-C-005, 37% were 65 years of age or older and 11% were 75 years or older. No overall differences in effectiveness or safety were observed between patients who were 65 years and older compared to younger patients. No modification of the starting dose is recommended for patients with mild or moderate renal impairment (eGFR ≥ 30 mL/min/1.73m 2 , MDRD). The pharmacokinetics and safety of ivosidenib in patients with severe renal impairment (eGFR < 30 mL/min/1.73m 2 , MDRD) or renal impairment requiring dialysis are unknown [see Clinical Pharmacology (12.3) ] . For patients with pre-existing severe renal impairment or who are requiring dialysis, consider the risks and potential benefits before initiating treatment with TIBSOVO. No modification of the starting dose is recommended for patients with mild or moderate (Child-Pugh A or B) hepatic impairment [see Clinical Pharmacology (12.3) ] . The pharmacokinetics and safety of ivosidenib in patients with severe hepatic impairment (Child-Pugh C) are unknown. For patients with pre-existing severe hepatic impairment, consider the risks and potential benefits before initiating treatment with TIBSOVO.

How Supplied 250 mg tablet: Blue oval-shaped film-coated tablet debossed "IVO" on one side and "250" on the other side. 60-count bottles of 250 mg tablets with a desiccant canister (NDC 72694-617-60) Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Ivosidenib is a small molecule inhibitor that targets the mutant isocitrate dehydrogenase 1 (IDH1) enzyme. In patients with AML, susceptible IDH1 mutations are defined as those leading to increased levels of 2-hydroxyglutarate (2-HG) in the leukemia cells and where efficacy is predicted by 1) clinically meaningful remissions with the recommended dose of ivosidenib and/or 2) inhibition of mutant IDH1 enzymatic activity at concentrations of ivosidenib sustainable at the recommended dosage according to validated methods. The most common of such mutations in patients with AML are R132H and R132C substitutions. Ivosidenib was shown to inhibit selected 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-HG levels and induced myeloid differentiation in vitro and in vivo in mouse xenograft models of IDH1-mutated AML. In blood samples from patients with AML with mutated IDH1, ivosidenib decreased 2-HG levels ex-vivo, reduced blast counts, and increased percentages of mature myeloid cells. In a patient-derived xenograft intra-hepatic cholangiocarcinoma mouse model with IDH1 R132C, ivosidenib reduced 2-HG levels. Multiple doses of ivosidenib 500 mg daily were observed to decrease plasma 2-HG concentrations in patients with hematological malignancies and cholangiocarcinoma to levels similar to those observed at baseline in healthy subjects. In bone marrow of patients with hematological malignancies and in tumor biopsy of patients with cholangiocarcinoma, the mean [% coefficient of variation (%CV)] reduction in 2-HG concentrations were 93.1% (11.1%) and 82.2% (32.4%), respectively. Cardiac Electrophysiology The mean increase in QTc was 17 msec (UCI: 20 msec) following administration of TIBSOVO 500 mg in patients with newly diagnosed AML and patients with relapsed or refractory AML. The increase in QTc interval was concentration-dependent [see Warnings and Precautions (5.2) ] . A similar mean increase following administration of TIBSOVO 500 mg daily was observed in patients with relapsed or refractory MDS and in patients with solid tumors, including patients with cholangiocarcinoma. Co-administration with moderate or strong CYP3A inhibitors is expected to further increase QTc interval prolongation from baseline. The AUC and C max of ivosidenib increase in a less than dose-proportional manner from 200 mg to 1,200 mg daily (0.4 to 2.4 times the approved recommended dosage). The following ivosidenib pharmacokinetic parameters (Table 12) were observed following administration of ivosidenib 500 mg as a single dose or daily dose (for steady state), unless otherwise specified. The steady-state pharmacokinetics of ivosidenib 500 mg were comparable between patients with newly diagnosed AML, relapsed or refractory AML, and relapsed or refractory MDS, and were lower in patients with cholangiocarcinoma. Table 12: Pharmacokinetics of ivosidenib Newly diagnosed AML treated with a combination of TIBSOVO and azacitidine Relapsed or refractory AML treated with TIBSOVO Relapsed or refractory MDS treated with TIBSOVO Cholangiocarcinoma treated with TIBSOVO PK parameters Single dose C max (ng/mL) PK parameters expressed as mean (%CV). 4,820 (39%) 4,503 (38%) 4,020 (31%) 4,060 (45%) Steady state C max (ng/mL) 6,145 (34%) 6,551 (44%) 5,820 (37%) 4,799 (33%) Steady state AUC (ng∙hr/mL) 106,326 (41%) 117,348 (50%) 103,770 (40%) 86,382 (34%) Steady state PK Within 14 days    Accumulation     C max 1.2 1.5 1.4 1.2     AUC 1.6 1.9 2 1.5 Absorption   Median T max (hr) 2 3 3 2 Effect of Food Following administration of a single dose in healthy subjects, a high-fat meal (approximately 900 to 1,000 calories, 500 to 600 fat calories, 250 carbohydrate calories and 150 protein calories). C max 1.98-fold (90% CI: 1.79, 2.19) AUC 1.24-fold (90% CI: 1.16, 1.33) Distribution In vitro protein binding 92 to 96% Apparent volume of distribution at steady state (L) 504 (22%) 403 (35%) 552 (26%) 706 (45%) Elimination Apparent clearance at steady state (L/hr) 4.6 (35%) 5.6 (35%) 5.1 (35%) 6.1 (31%) Terminal half-life at steady state (hr) 98 (42%) 58 (42%) 96 (43%) 129 (102%)    Metabolism     Plasma Data from a single radiolabeled ivosidenib dose in healthy subjects. >92% of total radioactivity as ivosidenib    Metabolic pathways       Major CYP3A4       Minor N-dealkylation and hydrolytic pathways    Excretion     Urine 17% (10% as unchanged ivosidenib)     Feces 77% (67% as unchanged ivosidenib) Specific Populations No clinically significant effects on the pharmacokinetics of ivosidenib were observed based on age (18 years to 89 years), sex, race (White, Asian, Black or African American), body weight (38 to 150 kg), ECOG performance status, mild or moderate hepatic impairment (Child-Pugh A or B) or mild or moderate renal impairment (eGFR ≥30 mL/min/1.73m 2 , MDRD). The pharmacokinetics of ivosidenib in patients with severe renal impairment (eGFR <30 mL/min/1.73m 2 , MDRD) or renal impairment requiring dialysis or severe hepatic impairment (Child-Pugh C) is unknown. Drug Interaction Studies Clinical Studies and Model-Based Approaches Effect of Strong or Moderate CYP3A4 Inhibitors on Ivosidenib Co-administration of 250 mg ivosidenib with a strong CYP3A4 inhibitor (200 mg itraconazole once daily for 18 days) increased ivosidenib single-dose AUC by 269% (90% CI: 245%, 295%) with no change in C max in healthy subjects . Co-administration of 500 mg ivosidenib with the moderate CYP3A4 inhibitor fluconazole (dosed to steady-state) increases ivosidenib single-dose AUC by 173% with no change in C max . Co-administration of fluconazole following multiple daily ivosidenib doses is predicted to increase ivosidenib steady-state C max by 152% and AUC by 190% . Effect of Strong CYP3A4 Inducers on Ivosidenib Co-administration of ivosidenib with a strong CYP3A4 inducer (600 mg rifampin once daily for 15 days) is predicted to decrease ivosidenib steady-state AUC by 33% . Effect of Ivosidenib on CYP3A4 Substrates Ivosidenib induces CYP3A4, including its own metabolism. Co-administration of ivosidenib with CYP3A4 substrates, including certain azole anti-fungal agents, is expected to decrease CYP3A4 substrate steady-state AUC . Effect of Gastric Acid Reducing Agents on Ivosidenib No clinically significant ivosidenib pharmacokinetic differences were observed following co-administration with gastric acid reducing agents (e.g., proton pump inhibitors, H2-receptor antagonists, antacids). In vitro Studies Metabolic Pathways Ivosidenib may induce CYP2B6, CYP2C8, and CYP2C9 . Drug Transporter Systems Ivosidenib is a substrate for P-glycoprotein (P-gp). Ivosidenib is not a substrate for BCRP or hepatic transporters OATP1B1 and OATP1B3. Ivosidenib is an inhibitor of OAT3 and P-gp. Ivosidenib does not inhibit BCRP, OATP1B1, OATP1B3, OAT1, and OCT2.

Carcinogenicity studies have not been conducted with ivosidenib. Ivosidenib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Ivosidenib was not clastogenic in an in vitro human lymphocyte micronucleus assay, or in an in vivo rat bone marrow micronucleus assay. Fertility studies in animals have not been conducted with ivosidenib. In repeat-dose toxicity studies up to 90 days in duration with twice daily oral administration of ivosidenib in rats, uterine atrophy was reported in females at non-tolerated dose levels.

Newly Diagnosed AML in Combination with Azacitidine The efficacy of TIBSOVO was evaluated in a randomized (1:1), multicenter, double-blind, placebo-controlled clinical trial (Study AG120-C-009, NCT03173248) of 146 adult patients with newly-diagnosed AML with an IDH1 mutation who were 75 years or older, or had comorbidities that precluded the use of intensive induction chemotherapy based on at least one of the following criteria: baseline Eastern Cooperative Oncology Group (ECOG) performance status of 2, severe cardiac or pulmonary disease, hepatic impairment with bilirubin > 1.5 times the upper limit of normal, creatinine clearance < 45 mL/min, or other comorbidity. IDH1 mutations were confirmed centrally using the Abbott RealTi m e™ IDH1 Assay. Local diagnostic tests were permitted for screening and randomization provided a bone marrow or peripheral blood sample was sent for central confirmation. Gene mutation analysis to document IDH1 mutated disease from a bone marrow or peripheral blood sample was conducted for all patients. Patients were randomized to receive either TIBSOVO 500 mg or matched placebo orally once daily on Days 1-28 in combination with azacitidine 75 mg/m 2 /day either subcutaneously or intravenously on Days 1-7 or Days 1-5 and 8-9 of each 28-day cycle beginning on Cycle 1 Day 1. Patients were treated for a minimum of 6 cycles unless they experienced disease progression, unacceptable toxicity or undergoing hematopoietic stem cell transplantation. Baseline demographic and disease characteristics are shown in Table 13. Table 13: Baseline Demographic and Disease Characteristics in Patients with Newly Diagnosed AML (Study AG120-C-009) Demographic and Disease Characteristics TIBSOVO + azacitidine (500 mg daily) N=72 Placebo + azacitidine N=74 ECOG PS: Eastern Cooperative Oncology Group Performance Status; MPN = Myeloproliferative Neoplasm; MDS = Myelodysplastic syndrome Demographics Age (Years) Median (Min, Max) 76 (58, 84) 76 (45, 94) Age Categories, n (%) <65 years 4 (6) 4 (5) ≥65 years to <75 years 29 (40) 27 (36) ≥75 years 39 (54) 43 (58) Sex, n (%) Male 42 (58) 38 (51) Female 30 (42) 36 (49) Race, n (%) Asian 15 (21) 19 (26) White 12 (17) 12 (16) Black or African American 0 2 (3) Other 1 (1) 1 (1) Not provided 44 (61) 40 (54) Disease Characteristics ECOG PS, n (%) 0 14 (19) 10 (14) 1 32 (44) 40 (54) 2 26 (36) 24 (32) IDH1 Mutation, n (%) Using confirmatory Abbott RealTi m e IDH1 assay testing results. R132C 45 (63) 51 (69) R132H 14 (19) 12 (16) R132G 6 (8) 4 (5) R132L 3 (4) 0 R132S 2 (3) 6 (8) Wild type 1 (1) 0 Missing 1 (1) 1 (1) Cytogenetic risk status Cytogenetic risk status: National Comprehensive Cancer Network (NCCN) guidelines. n (%) Favorable 3 (4) 7 (9) Intermediate 48 (67) 44 (59) Poor 16 (22) 20 (27) Other 3 (4) 1 (1) Missing 2 (3) 2 (3) Transfusion Dependent at Baseline Patients were defined as transfusion dependent at baseline if they received any red blood cell or platelet transfusion within 56 days prior to the first dose of TIBSOVO. , n (%) 39 (54) 40 (54) Type of AML, n (%) De novo AML 54 (75) 53 (72) Secondary AML 18 (25) 21 (28)   Therapy-related AML 2 (3) 1 (1)   MDS related 10 (14) 12 (16)   MPN related 4 (6) 8 (11) Efficacy was established on the basis of event-free survival (EFS), overall survival (OS), and rate and duration of complete remission (CR). EFS was defined as the time from randomization until treatment failure, relapse from remission, or death from any cause, whichever occurred first. Treatment failure was defined as failure to achieve CR by 24 weeks. The efficacy results are shown in Table 14 and Figure 1. Table 14: Efficacy Results in Patients with Newly Diagnosed AML (Study AG120-C-009) Endpoint TIBSOVO (500 mg daily) + azacitidine N=72 Placebo + azacitidine N=74 Abbreviations: EFS = Event free survival; CI: confidence interval; OS = Overall survival; CR = Complete remission; CRh = Complete remission with partial hematologic recovery; NE = Not estimable. The 2-sided p-value boundaries for EFS, OS, CR, and CR+CRh are 0.0095, 0.0034, 0.0174, and 0.0174, respectively. EFS , events (%) 47 (65) 62 (84)   Treatment Failure 43 (60) 59 (80)   Relapse 3 (4) 2 (3)   Death 1 (1) 1 (1)   Hazard ratio Hazard ratio is estimated using a Cox's proportional hazards model stratified by the randomization stratification factors (AML status and geographic region) with Placebo+ azacitidine as the denominator. (95% CI) 0.35 (0.17, 0.72)   p-value Two-sided p-value is calculated from the log-rank test stratified by the randomization stratification factors (AML status and geographic region). 0.0038 OS events (%) 28 (39) 46 (62)   Median OS (95% CI) months 24.0 (11.3, 34.1) 7.9 (4.1, 11.3)   Hazard ratio (95% CI) 0.44 (0.27, 0.73)   p-value 0.0010 CR, n (%) 34 (47) 11 (15)   95% CI CI of percentage is calculated with the Clopper and Pearson (exact Binomial) method. (35, 59) (8, 25)   Risk difference Mantel-Haenszel estimate of risk difference in percentage between TIBSOVO + azacitidine and Placebo+ azacitidine is calculated. (95% CI), (%) 31 (17, 46)   p-value Two-sided p-value is calculated from the Cochran-Mantel-Haenszel test stratified by the randomization stratification factors (AML status and geographic region). <0.0001   Median duration of CR (95% CI), months NE (13.0, NE) 11.2 (3.2, NE) CR +CRh , n (%) 37 (51) 13 (18)   95% CI (39, 63) (10, 28)   Risk difference (95% CI), (%) 33 (18, 47)   p-value <0.0001   Median duration of CR + CRh (95% CI), months NE (13.0, NE) 9.2 (5.8, NE) Figure 1: Kaplan-Meier Curve for Overall Survival in AG120-C-009 The median time to first CR for TIBSOVO with azacitidine was 4 months (range, 1.7 to 11.9 months). The median time to first CR + CRh for TIBSOVO with azacitidine was 4 months (range, 1.7 to 11.9 months). Figure 1 Monotherapy in Newly Diagnosed AML The efficacy of TIBSOVO was evaluated in an open-label, single-arm, multicenter clinical trial (Study AG120-C-001, NCT02074839) that included 28 adult patients with newly diagnosed AML with an IDH1 mutation. IDH1 mutations were identified by a local or central diagnostic test and confirmed retrospectively using the Abbott RealTi m e™ IDH1 Assay. The cohort included patients who were age 75 years or older or who had comorbidities that precluded the use of intensive induction chemotherapy based on at least one of the following criteria: baseline ECOG performance status of ≥ 2, severe cardiac or pulmonary disease, hepatic impairment with bilirubin > 1.5 times the upper limit of normal, or creatinine clearance < 45 mL/min. TIBSOVO was given orally at a starting dose of 500 mg daily until disease progression, development of unacceptable toxicity, or undergoing hematopoietic stem cell transplantation. Two (7%) of the 28 patients went on to stem cell transplantation following TIBSOVO treatment. The baseline demographic and disease characteristics are shown in Table 15. Table 15: Baseline Demographic and Disease Characteristics in Patients with Newly Diagnosed AML (Study AG120-C-001) Demographic and Disease Characteristics TIBSOVO (500 mg daily) N=28 ECOG PS: Eastern Cooperative Oncology Group Performance Status. ELN: European Leukemia Net Demographics Age (Years) Median (Min, Max) 77 (64, 87) Age Categories, n (%) <65 years 1 (4) ≥65 years to <75 years 8 (29) ≥75 years 19 (68) Sex, n (%) Male 15 (54) Female 13 (46) Race, n (%) White 24 (86) Black or African American 2 (7) Asian 0 Native Hawaiian/Other Pacific Islander 0 Other/Not provided 2 (7) Disease Characteristics ECOG PS, n (%) 0 6 (21) 1 16 (57) 2 5 (18) 3 1 (4) IDH1 Mutation, n (%) Using confirmatory Abbott RealTi m e IDH1 assay testing results. R132C 24 (86) R132H 2 (7) R132G 1 (4) R132L 1 (4) R132S 0 ELN Risk Category, n (%) Favorable 0 Intermediate 9 (32) Adverse 19 (68) Transfusion Dependent at Baseline Patients were defined as transfusion dependent at baseline if they received any transfusion occurring within 56 days prior to the first dose of TIBSOVO. , n (%) 17 (61) Type of AML, n (%) De novo AML 6 (21) AML-MRC AML with myelodysplasia-related changes. 19 (68)   Therapy-related AML 3 (11) Prior Hypomethylating Agent for Antecedent Hematologic Disorder 13 (46) Efficacy was established on the basis of the rate of complete remission (CR) or complete remission with partial hematologic recovery (CRh), the duration of CR+CRh, and the rate of conversion from transfusion dependence to transfusion independence. The efficacy results are shown in Table 16. The median follow-up was 8.1 months (range, 0.6 to 40.9 months) and median treatment duration was 4.3 months (range, 0.3 to 40.9 months). Table 16: Efficacy Results in Patients with Newly Diagnosed AML (Study AG120-C-001) Endpoint TIBSOVO (500 mg daily) N=28 CI: confidence interval, NE: not estimable CR 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). n (%) 8 (28.6)    95% CI (13.2, 48.7)    Median DOCR DOCR (duration of CR), DOCRh (duration of CRh), and DOCR+CRh (duration of CR+CRh) was defined as time since first response of CR, CRh or CR/CRh, respectively, to relapse or death, whichever is earlier. + indicates censored observation. (months) NE The median durations of CR and CR+CRh were not estimable, with 5 patients (41.7%) who achieved CR or CRh remaining on TIBSOVO treatment (treatment duration range: 20.3 to 40.9 months).    95% CI (4.2, NE) CRh 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). n (%) 4 (14.3)    95% CI (4.0, 32.7)    Observed DOCRh (months) 2.8, 4.6, 8.3, 15.7+ CR+CRh n (%) 12 (42.9)    95% CI (24.5, 62.8)    Median DOCR+CRh (months) NE    95% CI (4.2, NE) For patients who achieved a CR or CRh, the median time to CR or CRh was 2.8 months (range, 1.9 to 12.9 months). Of the 12 patients who achieved a best response of CR or CRh, 11 (92%) achieved a first response of CR or CRh within 6 months of initiating TIBSOVO. Among the 17 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 7 (41.2%) became independent of RBC and platelet transfusions during any 56-day post-baseline period. Of the 11 patients who were independent of both RBC and platelet transfusions at baseline, 6 (54.5%) remained transfusion independent during any 56-day post-baseline period. The efficacy of TIBSOVO was evaluated in an open-label, single-arm, multicenter clinical trial (Study AG120-C-001, NCT02074839) of 174 adult patients with relapsed or refractory AML with an IDH1 mutation. IDH1 mutations were identified by a local or central diagnostic test and confirmed retrospectively using the Abbott RealTi m e™ IDH1 Assay. TIBSOVO was given orally at a starting dose of 500 mg daily until disease progression, development of unacceptable toxicity, or undergoing hematopoietic stem cell transplantation. Twenty-one (12%) of the 174 patients went on to stem cell transplantation following TIBSOVO treatment. The baseline demographic and disease characteristics are shown in Table 17. Table 17: Baseline Demographic and Disease Characteristics in Patients with Relapsed or Refractory AML (Study AG120-C-001) Demographic and Disease Characteristics TIBSOVO (500 mg daily) N=174 ECOG PS: Eastern Cooperative Oncology Group Performance Status. Demographics Age (Years) Median (Min, Max) 67 (18, 87) Age Categories, n (%) <65 years 63 (36) ≥65 years to <75 years 71 (41) ≥75 years 40 (23) Sex, n (%) Male 88 (51) Female 86 (49) Race, n (%) White 108 (62) Black or African American 10 (6) Asian 6 (3) Native Hawaiian/Other Pacific Islander 1 (1) Other/Not provided 49 (28) Disease Characteristics ECOG PS, n (%) 0 36 (21) 1 97 (56) 2 39 (22) 3 2 (1) IDH1 Mutation, n (%) Using confirmatory Abbott RealTi m e IDH1 assay testing results. R132C 102 (59) R132H 43 (25) R132G 12 (7) R132S 10 (6) R132L 7 (4) Cytogenetic Risk Status, n (%) Intermediate 104 (60) Poor 47 (27) Missing/Unknown 23 (13) Relapse Type Primary refractory 64 (37) Refractory relapse 45 (26) Untreated relapse 65 (37) Relapse Number 0 64 (37) 1 83 (48) 2 21 (12) ≥3 6 (3) Prior Stem Cell Transplantation for AML, n (%) 40 (23) Transfusion Dependent at Baseline Patients were defined as transfusion dependent at baseline if they received any transfusion occurring within 56 days prior to the first dose of TIBSOVO. , n (%) 110 (63) Median Number of Prior Therapies (Min, Max) 2 (1, 6) Type of AML, n (%) De novo AML 116 (67) Secondary AML 58 (33) 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. The efficacy results are shown in Table 18. The median follow-up was 8.3 months (range, 0.2 to 39.5 months) and median treatment duration was 4.1 months (range, 0.1 to 39.5 months). Table 18: Efficacy Results in Patients with Relapsed or Refractory AML (Study AG120-C-001) Endpoint TIBSOVO (500 mg daily) N=174 CI: confidence interval CR 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). n (%) 43 (24.7)    95% CI (18.5, 31.8)    Median DOCR DOCR (duration of CR), DOCRh (duration of CRh), and DOCR+CRh (duration of CR+CRh) was defined as time since first response of CR, CRh or CR/CRh, respectively, to relapse or death, whichever is earlier. (months) 10.1    95% CI (6.5, 22.2) CRh 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). n (%) 14 (8.0)    95% CI (4.5, 13.1)    Median DOCRh (months) 3.6    95% CI (1, 5.5) CR+CRh CR+CRh rate appeared to be consistent across all baseline demographic and baseline disease characteristics with the exception of number of prior regimens. n (%) 57 (32.8)    95% CI (25.8, 40.3)    Median DOCR+CRh (months) 8.2    95% CI (5.6, 12) 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 TIBSOVO. Among the 110 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 41 (37.3%) 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. The efficacy of TIBSOVO was evaluated in an open-label, single-arm, multicenter study (study AG120-C-001, NCT02074839) of 18 adult patients with relapsed or refractory MDS with an IDH1 mutation. IDH1 mutations were detected in peripheral blood or bone marrow by a local or central diagnostic test and confirmed retrospectively using the Abbott RealTi m e™ IDH1 Assay. TIBSOVO was given orally at a starting dose of 500 mg daily continuous for 28-day cycles until disease progression, development of unacceptable toxicity, or undergoing hematopoietic stem cell transplantation. One (6%) of the 18 patients went on to stem cell transplantation following TIBSOVO treatment. The baseline demographic and disease characteristics are shown in Table 19. Table 19: Baseline Demographic and Disease Characteristics in Patients with Relapsed or Refractory MDS (Study AG120-C-001) Demographic and Disease Characteristics TIBSOVO (500 mg daily) N=18 ECOG PS: Eastern Cooperative Oncology Group Performance Status. Demographics Age (Years) Median (Min, Max) 74 (61, 82) Age Categories, n (%) <65 years 3 (17) ≥65 years to <75 years 7 (39) ≥75 years 8 (44) Sex, n (%) Male 14 (78) Female 4 (22) Race, n (%) White 14 (78) Black or African American 1 (6) Not Reported 3 (17) Disease Characteristics ECOG PS, n (%) 0 5 (28) 1 10 (56) 2 3 (17) IDH1 Mutation, n (%) Using confirmatory Abbott RealTi m e IDH1 assay testing results. R132C 9 (50) R132H 5 (28) R132G 2 (11) R132L 1 (6) R132S 1 (6) Cytogenetic Risk Status, n (%) Good 4 (22) Intermediate 8 (44) Poor 5 (28) Missing 1 (6) Baseline Bone Marrow Blasts, n (%) < 5% 7 (39) ≥ 5% 11 (61) Prior Therapies Intensive chemotherapy 3 (17) Non-intensive chemotherapy 15 (83)   1 line of HMA-based therapy 14 (78)   2 lines of HMA-based therapy 1 (6) Efficacy was established on the basis of the rate of complete remission (CR) or partial remission (PR) as per the 2006 International Working Group response criteria for MDS, the duration of CR+PR, and the rate of conversion from transfusion dependence to transfusion independence. All observed responses were CRs. The efficacy results are shown in Table 20. The median follow-up was 27.1 months (range 3.7 to 88.7 months) and median duration of exposure to TIBSOVO was 8.3 months (range 3.3 to 78.8 months). Table 20: Efficacy Results in Patients with Relapsed or Refractory MDS (Study AG120-C-001) Endpoint TIBSOVO (500 mg daily) N=18 CI: confidence interval, CR: complete remission, NE: not estimable, derived based on Kaplan-Meier method. CR CR responders with baseline bone marrow blast < 5% was 43% (3/7). n (%) 7 (38.9)    95% CI (17.3, 64.3) DOCR Duration of CR (DOCR) = date of first documented CR (lasted at least 4 weeks) to date of first documented confirmed relapse or death, whichever is earlier. (months) median (range) NE (1.9, 80.8+ + indicates censored observation. ) For patients who achieved a CR, the median time to CR was 1.9 months (range, 1.0 to 5.6 months). Among the 9 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 6 (67%) became independent of RBC and platelet transfusions during any 56-day post-baseline period. Of the 9 patients who were independent of both RBC and platelet transfusions at baseline, 7 (78%) remained transfusion independent during any 56-day post-baseline period. The efficacy of TIBSOVO was evaluated in a randomized (2:1), multicenter, double-blind, placebo-controlled clinical trial (Study AG120-C-005, NCT02989857) of 185 adult patients with locally advanced or metastatic cholangiocarcinoma with an IDH1 mutation whose disease had progressed following at least 1 but not more than 2 prior regimens, including at least one gemcitabine- or 5-FU-containing regimen. Patients were randomized to receive either TIBSOVO 500 mg orally once daily or matched placebo until disease progression or unacceptable toxicity. Randomization was stratified by number of prior therapies (1 or 2). Eligible patients who were randomized to placebo were allowed to cross over to receive TIBSOVO after documented radiographic disease progression. Patients with IDH1 mutations were selected using a central diagnostic next generation sequencing assay. Tumor imaging assessments were performed every 6 weeks for the first 8 assessments and every 8 weeks thereafter. The major efficacy outcome measure was Progression Free Survival (PFS) as determined by independent review committee (IRC) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The median age was 62 years (range: 33 to 83); 63% were female; 57% were White, 12% Asian, 1.1% Black, 0.5% Native Hawaiian/Other Pacific Islander, 0.5% American Indian or Alaska Native, 28% race missing/not reported; and 37% had an ECOG performance status of 0 (37%) or 1 (62%). All patients received at least 1 prior line of systemic therapy and 47% received two prior lines. Most patients had intrahepatic cholangiocarcinoma (91%) at diagnosis and 92% had metastatic disease. Across both arms, 70% patients had an R132C mutation, 15% had an R132L mutation, 12% had an R132G mutation, 1.1% had an R132H mutation, and 1.6% had an R132S mutation. The efficacy results are shown in Table 21 and Figure 2. The study demonstrated a statistically significant improvement in PFS. Table 21: Efficacy Results in Patients with Locally Advanced or Metastatic Cholangiocarcinoma in AG120-C-005 Endpoint TIBSOVO (500 mg daily) Placebo IRC: Independent Review Committee; CI: Confidence Interval Progression-Free Survival by IRC Assessment N=124 N=61   Events, n (%) 76 (61) 50 (82)     Progressive Disease 64 (52) 44 (72)     Death 12 (10) 6 (10)   Hazard ratio (95% CI) Hazard ratio is calculated from stratified Cox regression model. Stratified by number of prior lines of therapy. 0.37 (0.25, 0.54)   p-value P-value is calculated from the one-sided stratified log-rank test. Stratified by number of prior lines of therapy. <0.0001 Objective Response Rate, n (%) 3 (2.4) 0 Overall Survival OS results are based on the final analysis of OS (based on 150 deaths) which occurred 16 months after the final analysis of PFS. The median OS (95% CI) for TIBSOVO was 10.3 (7.8, 12.4) months; and placebo was 7.5 (4.8, 11.1) months without adjusting for crossover. In the analysis of OS, 70% of the patients randomized to placebo had crossed over to receive TIBSOVO after radiographic disease progression. N=126 N=61   Deaths, n (%) 100 (79) 50 (82)   Hazard ratio (95% CI) 0.79 (0.56, 1.12)   p-value 0.093 Figure 2: Kaplan-Meier Plot of Progression-Free Survival per Independent Review Committee - Before Crossover (ITT) Figure 2

NDC 72694-617-60 TIBSOVO ® (ivosidenib tablets) 250 mg Dispense the enclosed Medication Guide to each patient Swallow tablets whole. Do not split, crush, or chew the tablet. 1 Bottle containing 60 tablets Rx only PRINCIPAL DISPLAY PANEL - 250 mg Tablet Bottle Carton