Komzifti

Description for Komzifti

KOMZIFTI contains ziftomenib, a menin inhibitor.

The chemical name is (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H- indole-2-carbonitrile.

The chemical structure is:

The molecular formula is C₃₃H₄₂F₃N₉O₂S₂ and the molecular weight is 717.88 g/mol.

Ziftomenib is a white to off-white powder and is highly soluble in aqueous solution at pH 1.2 and practically insoluble at pH ≥4.

KOMZIFTI (ziftomenib) is available as a 200 mg capsule for oral administration.

Each KOMZIFTI capsule contains 200 mg ziftomenib and the following inactive ingredients: croscarmellose sodium, magnesium stearate, mannitol, microcrystalline cellulose, and sodium lauryl sulfate. The capsule shells, imprinted with black ink, contain the following inactive ingredients: hypromellose and titanium dioxide.

INDICATIONS AND USAGE

KOMZIFTI is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible nucleophosmin 1 (NPM1) mutation who have no satisfactory alternative treatment options [see Dosage and Administration (2.1), Clinical Pharmacology (12.1), and Clinical Studies (14)].

Dosage for Komzifti

Patient Selection

Select patients for the treatment of relapsed or refractory AML with KOMZIFTI based on the presence of an NPM1 mutation [see Clinical Studies (14)].

An FDA-approved test for the detection of NPM1 mutations is not currently available.

Recommended Dosage

The recommended dosage of KOMZIFTI is 600 mg taken orally once daily until disease progression or unacceptable toxicity. Do not start KOMZIFTI until the white blood cell (WBC) count is reduced to less than 25 x 10⁹/L. For patients without confirmed disease progression or unacceptable toxicity, treatment for a minimum of 6 months is recommended to allow time for a clinical response.

Administration Instructions

• Administer KOMZIFTI once daily on an empty stomach (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3)].
• Administer KOMZIFTI orally at about the same time each day.
• Swallow capsules Do not open, break, or chew the capsules.
• If a dose of KOMZIFTI is missed or not taken at the usual time, administer the dose as soon as possible on the same day 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.

Dosage Modifications for Concomitant Use of Acid-Reducing Agents

Avoid concomitant use of proton pump inhibitors (PPIs) with KOMZIFTI.

Avoid concomitant use of a histamine-2 (H2) receptor antagonist or a locally acting antacid with KOMZIFTI [see Drug Interactions (7.1)]. If concomitant use cannot be avoided:

• Take KOMZIFTI 2 hours before or 10 hours after administration of an H2 receptor antagonist.
• Take KOMZIFTI 2 hours before or 2 hours after administration of a locally acting antacid.

Dosage Modifications for Adverse Reactions

Manage any abnormalities promptly [see Warnings and Precautions (5.1, 5.2) and Adverse Reactions (6.1)].

Interrupt or reduce dose for adverse reactions as per Table 1 and Table 2.

Table 1: Recommended Management and Dosage Modifications for KOMZIFTI for Adverse Reactions

Adverse Reactiona	Recommended Action
Differentiation syndrome [see Warnings and Precautions (5.1)]	If differentiation syndrome is suspected, interrupt KOMZIFTI. Administer systemic corticosteroids and initiate hemodynamic monitoring until symptom resolution and for a minimum of 3 days and provide supportive care. Resume KOMZIFTI at the same dose level when signs and symptoms improve and are Grade ≤ 2b.
Noninfectious leukocytosis (e.g., sudden or significant white blood cell (WBC) increase, including WBC doubling within the first 2 weeks of administration or an absolute increase of 10 x 109/L)	Evaluate for differentiation syndrome. Initiate treatment with hydroxyurea, as per standard institutional practices, and leukapheresis if clinically indicated. Taper hydroxyurea only after leukocytosis improves or resolves. Interrupt KOMZIFTI if leukocytosis is not controlled with hydroxyurea within 48 hours. If interrupted, resume KOMZIFTI at the same dose level once WBC counts are controlled.
Nonhematological adverse reactions Grade ≥ 3b [see Adverse Reactions (6.1)]	Interrupt KOMZIFTI until recovery to Grade ≤ 2b. Resume KOMZIFTI at the same dose level. If the same Grade ≥ 3 toxicity recurs, interrupt KOMZIFTI until recovery to Grade ≤ 2b. Restart KOMZIFTI at a reduced dosec.
a Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. b Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening. c See Table 2 for the reduced dose levels.

Table 2: Recommended Dosage Reductions for KOMZIFTI for Adverse Reactions

	Recommended Dosage
First dose reduction	400 mg orally once daily
Second dose reduction	200 mg orally once daily
* Permanently discontinue KOMZIFTI in patients unable to tolerate 200 mg orally once daily following second dose reduction.

HOW SUPPLIED

Dosage Forms And Strengths

Capsules of ziftomenib are available in 200 mg strength. The capsules are white and are imprinted with “ZIF 200” in black ink.

How supplied/Storage And Handling

How Supplied

KOMZIFTI 200 mg capsules are supplied as white capsules printed with “ZIF 200” in black ink.

KOMZIFTI capsules are available in white, induction-sealed, square, high-density polyethylene bottles of 90 capsules with child-resistant closure (NDC 84696-200-90).

Storage and Handling

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].

ADVERSE REACTIONS

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

• Differentiation Syndrome [see Warnings and Precautions (1)]
• QTc Interval Prolongation [see Warnings and Precautions (2)]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Relapsed or Refractory AML with an NPM1 Mutation

The safety of KOMZIFTI for the treatment of patients with relapsed or refractory AML with an NPM1 mutation was evaluated in KO-MEN-001 [see Clinical Studies (14)]. Patients received KOMZIFTI 600 mg once daily (n=112). The median duration of exposure to KOMZIFTI was 2.2 months (range 0.1 to 21.5 months).

Fatal adverse reactions occurred in 4 (4%) patients who received KOMZIFTI, including 2 with differentiation syndrome, 1 with infection, and 1 with sudden death. Serious adverse reactions were reported in 79% of patients who received KOMZIFTI. Serious adverse reactions occurring in ≥ 5% of patients included infection without an identified pathogen (29%), febrile neutropenia (18%), bacterial infection (16%), differentiation syndrome (16%), and dyspnea (6%).

Dosage interruption of KOMZIFTI due to an adverse reaction occurred in 54% of patients. Adverse reactions that required dose interruption in ≥ 2% of patients included infection without an identified pathogen (15%), differentiation syndrome (13%), febrile neutropenia (5%), pyrexia (4%), electrocardiogram QT prolonged (4%), leukocytosis (4%), bacterial infection (3%), cardiac failure (2%), cholecystitis (2%), diarrhea (2%), pruritus (2%), and thrombosis (2%). Dose reduction of KOMZIFTI due to an adverse reaction occurred in 4% of patients. Permanent discontinuation of KOMZIFTI due to an adverse reaction occurred in 21% of patients. Adverse reactions that required permanent discontinuation of KOMZIFTI in ≥ 2% of patients were infection without an identified pathogen (8%), bacterial infection (4%), cardiac arrest (2%), and differentiation syndrome (2%).

The most common (≥ 20%) adverse reactions, including laboratory abnormalities, were aspartate aminotransferase increased, infection without an identified pathogen, potassium decreased, albumin decreased, alanine aminotransferase increased, sodium decreased, creatinine increased, alkaline phosphatase increased, hemorrhage, diarrhea, nausea, fatigue, edema, bacterial infection, musculoskeletal pain, bilirubin increased, potassium increased, differentiation syndrome, pruritus, febrile neutropenia, and transaminases increased.

Table 3 summarizes the adverse reactions in KO-MEN-001.

Table 3: Adverse Reactions Reported in ≥20% (Any Grade) or ≥5% (Grade 3 or 4) of Patients with Relapsed or Refractory AML

Adverse Reaction	KOMZIFTI N=112
	All Grades† (%)	Grade 3 or 4 (%)
Infections and infestations
Infection without identified pathogena	52	38
Bacterial infectionb	28	17
Viral infectionc	16	5
Vascular disorders
Hemorrhaged	38	8
Hypertension	11	5
Gastrointestinal disorders
Diarrheae*	36	5
Nauseaf*	35	2
General disorders and administration site conditions
Fatigueg	34	8
Edemah*	30	3
Musculoskeletal and connective tissue disorders
Musculoskeletal paini	28	4
Neoplasms benign, malignant, and unspecified (incl cysts and polyps)
Differentiation syndrome	26	13
Skin and subcutaneous
Pruritusj*	23	0
Blood and lymphatic system disorder
Febrile neutropenia	22	22
Leukocytosisk*	16	5
Investigations
Transaminases increasedl	21	8
Electrocardiogram QT prolonged*	12	8
Renal and urinary disorders
Renal impairmentm	19	6
Respiratory, thoracic, and mediastinal disorders
Hypoxia	9	5
† Includes the following fatal adverse reactions: infection (n=1) and differentiation syndrome (n=2). * No Grade 4 events were reported for this adverse reaction. a Includes abdominal abscess, abscess limb, anal abscess, anorectal infection, bronchitis, conjunctivitis, device related infection, device related sepsis, diverticulitis, emphysematous cystitis, enterocolitis infectious, gingivitis, hordeolum, infection, large intestine infection, nail infection, necrotizing fasciitis, penile infection, periodontitis, perirectal abscess, peritonitis, pneumonia, postoperative abscess, respiratory tract infection, rhinitis, sepsis, septic shock, sinusitis, skin infection, soft tissue infection, tooth infection, upper respiratory tract infection, urosepsis, vaginal infection, vascular device infection, wound infection. b Includes bacteremia, bacterial infection, bacterial pyelonephritis, breast cellulitis, cellulitis, clostridial infection, clostridium difficile colitis, clostridium difficile infection, enterobacter sepsis, enterococcal bacteremia, erysipelas, escherichia bacteremia, escherichia infection, escherichia sepsis, escherichia urinary tract infection, klebsiella bacteremia, klebsiella infection, klebsiella urinary tract infection, paronychia, pneumonia bacterial, pneumonia klebsiella, pseudomonal bacteremia, staphylococcal bacteremia. c Includes adenovirus infection, COVID-19, genital herpes, herpes simplex reactivation, herpes virus infection, herpes zoster, nasal herpes, oral herpes, pneumonia influenzas, pneumonia parainfluenza viral, respiratory syncytial virus infection, rhinovirus infection. d Includes angina bullosa hemorrhagic, bladder tamponade, catheter site hematoma, conjunctival hemorrhage, contusion, disseminated intravascular coagulation, ecchymosis, epistaxis, gastric hemorrhage, gastrointestinal hemorrhage, gingival bleeding, hematemesis, hematochezia, hematoma, hematuria, hemoptysis, hemorrhage, hemorrhoidal hemorrhage, hyperfibrinolysis, injection site hematoma, injection site hemorrhage, lower gastrointestinal hemorrhage, melaena, mouth hemorrhage, oral blood blister, petechiae, purpura, rectal hemorrhage, retinal hemorrhage, shock hemorrhagic, skin hemorrhage, subdural hematoma, tongue hemorrhage, traumatic hematoma, upper gastrointestinal hemorrhage, vaginal hemorrhage, vitreous hemorrhage. e Includes diarrhea, colitis, colitis erosive. f Includes nausea, vomiting. g Includes fatigue, asthenia, malaise. h Includes edema, edema peripheral, generalized edema, localized edema, peripheral swelling. i Includes arthralgia, back pain, bone pain, flank pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, pain in extremity. j Includes pruritus, nasal pruritus. k Includes white blood cell count increased, leukocytosis, hyperleukocytosis. l Includes transaminases increased, alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyl transferase increased, hypertransaminasemia. m Includes renal impairment: acute kidney injury, azotemia, blood creatinine increased, blood urea increased, chronic kidney disease, postrenal failure, renal failure.

Table 4 summarizes the laboratory abnormalities in KO-MEN-001.

Table 4: Selected New or Worsening Laboratory Abnormalities in Patients with Relapsed or Refractory AML

Laboratory Abnormality	KOMZIFTI
	Grades 1-4* (%)	Grade 3-4* (%)
Aspartate aminotransferase increased	53	4
Potassium decreased	52	22
Albumin decreased	51	5
Alanine aminotransferase increased	50	6
Sodium decreased	49	3
Creatinine increased	45	4
Alkaline phosphatase increased	41	5
Bilirubin increased	27	6
Potassium increased	26	6
*The denominator used to calculate the rate varied from 108 to 110 based on the number of patients with a baseline value and at least one post-baseline value.

Drug Interactions for Komzifti

Effect of Other Drugs on KOMZIFTI

Strong or Moderate CYP3A4 Inhibitors

Monitor patients more frequently for KOMZIFTI-associated adverse reactions.

Ziftomenib is primarily metabolized by CYP3A. Concomitant use of KOMZIFTI with strong or moderate CYP3A4 inhibitors increases ziftomenib exposure [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions such as QT prolongation.

Strong or Moderate CYP3A4 Inducers

Avoid concomitant use of KOMZIFTI with strong or moderate CYP3A4 inducers.

Ziftomenib is primarily metabolized by CYP3A. Concomitant use of KOMZIFTI with strong or moderate CYP3A4 inducers may decrease ziftomenib exposure [see Clinical Pharmacology (12.3)], which may reduce the efficacy of KOMZIFTI.

Gastric Acid Reducing Agents

Concomitant administration of ziftomenib with proton pump inhibitors (PPIs) decreases ziftomenib exposure [see Clinical Pharmacology (12.3)], which may reduce the efficacy of KOMZIFTI.

Avoid concomitant use of KOMZIFTI with PPIs.

Avoid concomitant use of KOMZIFTI with H2 receptor antagonists (H2RAs) or locally acting antacids. If concomitant use cannot be avoided, modify KOMZIFTI administration time [see Dosage and Administration (2.4)].

Drugs that Prolong the QT Interval

Avoid concomitant use of KOMZIFTI with other product(s) with a known potential to prolong the QTc interval. If concomitant use cannot be avoided, obtain ECGs when initiating, during concomitant use, and as clinically indicated [see Warnings and Precautions (5.2)]. Interrupt KOMZIFTI if the QTc interval is > 500 ms or the change from baseline is > 60 ms [see Dosage and Administration (2.5)].

Ziftomenib causes QTc interval prolongation [see Clinical Pharmacology (12.2)]. Concomitant use of KOMZIFTI with other products that prolong the QTc interval may result in a greater increase in the QTc interval and adverse reactions associated with QTc interval prolongation, including Torsades de pointes, other serious arrhythmias, and sudden death [see Warnings and Precautions (5.2)].

Warnings for Komzifti

Included as part of the PRECAUTIONS section.

Precautions for Komzifti

Differentiation Syndrome

KOMZIFTI can cause fatal or life-threatening differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells. Symptoms of differentiation syndrome, including those seen in patients treated with KOMZIFTI, may include fever, hypoxia, joint pain, hypotension, dyspnea, rapid weight gain or peripheral edema, pleural or pericardial effusions, acute kidney injury, and rashes.

In the clinical trial, differentiation syndrome occurred in 29 (26%) of 112 patients with relapsed or refractory AML with an NPM1 mutation who were treated with KOMZIFTI at the recommended dosage. Differentiation syndrome was Grade 3 in 13% and fatal in two patients. In broader evaluation of all patients with any genetic form of AML treated with KOMZIFTI monotherapy in clinical trials, differentiation syndrome occurred in 25% of patients. Four fatal cases of differentiation syndrome occurred out of 39 patients with KMT2A-rearranged AML treated with KOMZIFTI. KOMZIFTI is not approved for use in patients with KMT2A-rearranged AML.

In the 112 patients with an NPM1 mutation, differentiation syndrome was observed with and without concomitant hyperleukocytosis, in as early as 3 days and up to 46 days after KOMZIFTI initiation. The median time to onset was 15 days. Two patients experienced more than one differentiation syndrome event. Treatment was interrupted and resumed in 15 (13%) patients, while it was permanently discontinued in 2 (2%) patients [see Adverse Reactions (6.1)].

Prior to starting treatment with KOMZIFTI, reduce the WBC counts to less than 25 x 10⁹/L. If differentiation syndrome is suspected, interrupt KOMZIFTI, initiate oral or intravenous corticosteroids (e.g., dexamethasone 10 mg every 12 hours) for a minimum of 3 days with hemodynamic and laboratory monitoring. Resume treatment with KOMZIFTI at the same dose level when signs and symptoms improve and are Grade 2 or lower. Taper corticosteroids over a minimum of 3 days after adequate control or resolution of symptoms [see Dosage and Administration (2.5)]. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid treatment.

QTc Interval Prolongation

KOMZIFTI can cause QT (QTc) interval prolongation [see Clinical Pharmacology (12.2)]. In the clinical trial, QTc interval prolongation was reported as an adverse reaction in 12% of 112 patients treated with KOMZIFTI at the recommended dosage for relapsed or refractory AML with an NPM1 mutation. QTc interval prolongation was Grade 3 in 8% of patients. The heart-rate corrected QT interval (using Fridericia’s method) (QTcF) was greater than 500 msec in 9% of patients, and the increase from baseline QTcF was greater than 60 msec in 12% of patients. KOMZIFTI dose reduction was required for 1% of patients due to QTc interval prolongation [see Adverse Reactions (6.1)]. QTc prolongation occurred in 14% of the 42 patients less than 65 years of age and in 10% of the 70 patients 65 years of age or older.

Correct electrolyte abnormalities, including hypokalemia and hypomagnesemia, prior to treatment with KOMZIFTI. Perform an ECG prior to initiation of treatment with KOMZIFTI, and do not initiate KOMZIFTI in patients with QTcF > 480 msec. Perform an ECG at least once weekly for the first four weeks on treatment, and at least monthly thereafter. Interrupt KOMZIFTI if the QTc interval is > 500 ms or the change from baseline is > 60 ms (Grade 3) [see Dosage and Administration (2.5)]. 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 ECG monitoring may be necessary.

Concomitant use of KOMZIFTI with drugs known to prolong the QTc interval may increase the risk of QTc interval prolongation [see Drug Interactions (7.1), Clinical Pharmacology (12.2)].

Embryo-Fetal Toxicity

Based on findings in animals and its mechanism of action, KOMZIFTI can cause embryo-fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of ziftomenib to pregnant mice during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality, structural abnormalities, and altered fetal growth at approximately 0.3 times the steady-state clinical exposure based on the area under the concentration-time curve (AUC) at the recommended human dose.

Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with KOMZIFTI and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with KOMZIFTI and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been conducted with ziftomenib. In a repeat dose toxicity study in mice treated with ziftomenib for 13 weeks, lymphoma was observed in multiple organs in one animal.

Ziftomenib was not mutagenic in an in vitro bacterial reverse mutation assay and was not genotoxic in an in vitro micronucleus assay or in an in vivo mouse bone marrow micronucleus assay.

Fertility studies in animals have not been conducted with ziftomenib. In a repeat dose, 13-week toxicity study in dogs treated with twice daily oral administration of ziftomenib at 6, 20, or 60 mg/kg/day, changes were reported in male and female reproductive organs, including decreased mean testis weight, increased vacuolation of the seminiferous tubular epithelial cells, marked decrease in sperm in the epididymal lumen at ≥ 20 mg/kg/day, and fewer developing follicles in the ovaries at ≥ 60 mg/kg/day. At the dose of 20 mg/kg/day in dogs, exposures (AUC) were as low as 0.3 times the human exposure (AUC) at the recommended dose. At the dose of 60 mg/kg/day, exposures were as low as 1.2 times the human exposure at the recommended dose. Reversibility was not assessed at 20 mg/kg/day and findings were not reversible at 60 mg/kg/day after the 4-week recovery period.

Patient Information for Komzifti

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Differentiation Syndrome

Advise patients of the risk of developing differentiation syndrome as early as 3 days after the start of therapy and during treatment. Instruct patients to immediately report any symptoms suggestive of differentiation syndrome, such as fever, joint or bone pain, dizziness, shortness of breath or difficulty breathing, cough, chest pain, rapid weight gain, rash, decreased urinary output, or swelling in the hands, feet, ankles, or legs, to their healthcare provider for further evaluation [see Boxed Warning and Warnings and Precautions (5.1)].

Prolonged QT Interval

Advise patients to consult their healthcare provider immediately if they feel faint, lose consciousness, or have signs or symptoms suggestive of arrhythmia. Advise patients with a history of hypokalemia or hypomagnesemia of the importance of monitoring their electrolytes [see Warnings and Precautions (5.2)].

Embryo-Fetal Toxicity

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to notify their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.3), Use in Specific Populations (8.1)].

Advise females of reproductive potential to use effective contraception during treatment with KOMZIFTI and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with KOMZIFTI and for 3 months after the last dose [see Use in Specific Populations (8.3)].

Lactation

Advise women not to breastfeed during treatment with KOMZIFTI and for 2 weeks after the last dose [see Use in Specific Populations (8.2)].

Drug Interactions

Advise patients to inform their healthcare providers of all concomitant medications, including over-the- counter medications and supplements [see Drug Interactions (7.1)].

Dosing Instructions

• Advise patients to take KOMZIFTI once daily, at around the same time each day, on an empty stomach, at least 1 hour before or 2 hours after a meal [see Dosage and Administration (3)].
• Advise patients to swallow KOMZIFTI capsules whole. Do not open, break, or chew the capsules [see Dosage and Administration (3)].
• Instruct patients, if they miss a dose of KOMZIFTI, to take the dose as soon as possible on the same day and at least 12 hours prior to the next scheduled dose and return to the normal schedule the following day. Advise patients not to take 2 doses within 12 hours to make up for the missed dose [see Dosage and Administration (3)].

Manufactured for:
Kura Oncology, Inc.,
San Diego, CA 92121

KOMZIFTI™ is a trademark of Kura Oncology, Inc.
© 2025 Kura Oncology, Inc.
US-KO539-2500154 11/25

OVERDOSES

No information provided.

Contraindications for Komzifti

No information provided.

Clinical Pharmacology for Komzifti

Mechanism Of Action

Ziftomenib is a menin inhibitor that blocks the interaction of menin and lysine [K]-specific methyltransferase 2A (KMT2A).

Acute leukemias can be driven by mutations in NPM1 that recruit the wild-type menin-KMT2A complex to promoters of leukemogenic genes. Susceptible NPM1 mutations are defined as those that result in loss of the nucleolar localization signal and the insertion of a new nuclear export signal leading to cytoplasmic accumulation of mutant NPM1 protein that disrupts normal cell function and drives leukemogenesis through altered gene expression.

Pharmacologic disruption of the menin-KMT2A protein-protein interaction by ziftomenib blocks oncogenic activity of mutant NPM1, which induces differentiation of leukemic cells as evidenced by increased expression of differentiation markers. In nonclinical studies, ziftomenib demonstrated in vitro and in vivo antitumor activity in models of NPM1-mutant leukemia.

Pharmacodynamics

Ziftomenib exposure-response relationships have not been fully characterized and the time course of pharmacodynamic response is unknown.

Cardiac Electrophysiology

The effect of KOMZIFTI on the QTc interval was evaluated at 600 mg (the approved recommended dosage) in patients with relapsed or refractory acute myeloid leukemia in KO-MEN-001 (n=133).

The increase in the QTc interval was concentration-dependent with the largest mean increase in QTc interval predicted to be 7.7 ms (upper confidence interval = 12.6 ms) after administration of ziftomenib 600 mg once daily. There were 9 subjects (7%) with QTcF > 500 ms and an increase in QTc > 60 ms over baseline [see Warnings and Precautions (5.2)].

Pharmacokinetics

Ziftomenib pharmacokinetics were characterized in patients with relapsed or refractory AML. Pharmacokinetic parameters are presented as mean (% CV), unless otherwise specified.

Table 5: Ziftomenib Pharmacokinetics in Patients with R/R AML

Parameter	Dosage
	600 mg once daily (with strong CYP3A4 inhibitors)	600 mg once daily (without CYP3A4 inhibitors)
General Information
Exposurea
Cmax (ng/mL)	617 (33)	288 (41)
AUC (ng•h/mL)	13,185 (36)	5,512 (48)
Dose Proportionality	Dose proportional over 200 mg to 600 mg once daily doses (0.33 to 1.0 times the recommended dose of 600 mg once daily)
Accumulation	~ 3-fold
Absorption
Tmax [Median (range)] (hours)	4.1 (0.5, 8.15)
Absolute Bioavailability	12.9%
Effect of Food
High-Fat Mealb	AUC and Cmax increased 4-fold
Distribution
Apparent Volume of Distribution (L)	30100 (98%)
Protein Binding	99% (albumin)
Elimination
Half-Life (hours)	189.8 (23)	93.6 (21)
Apparent Clearance (L/h)	41.5 (29)	101.2 (27)
Metabolism
Primary Pathway	CYP3A
Excretion
Feces	86% (73% as unchanged drug)
Urine	0.5% (0.03% as unchanged drug)
Abbreviations: Cmax = maximum plasma concentration; AUC = area under the time concentration curve; Tmax = time to peak concentration a Steady-state (Cycle 2 Day 1). b Approximately 1,000 calories, 60% fat, 25% carbohydrates, 15% protein.

Specific Populations

No clinically significant differences in the pharmacokinetics of ziftomenib were observed based on age (18 to 86 years), sex, race, ethnicity, mild (bilirubin less than or equal to ULN and AST greater than ULN or bilirubin less than or equal to 1.5 x ULN) or moderate (bilirubin 1.5 to 3 x ULN) hepatic impairment, or mild to moderate (CLCr 30 to 89 mL/min) renal impairment.

The effects of severe hepatic impairment (bilirubin greater than 3 x ULN) or severe renal impairment (CLCr less than 30 mL/min) on ziftomenib pharmacokinetics have not been studied.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

Gastric Acid Reducing Agents: Administration of PPIs reduced ziftomenib AUC0-inf by 53% and Cmax by 70%.

Strong, Moderate, or Weak CYP3A4 Inhibitors: Itraconazole, voriconazole, and posaconazole (strong CYP3A4 inhibitors) are estimated to increase ziftomenib AUC by up to 3-fold and Cmax by up to 2-fold.

Erythromycin, fluconazole, and isavuconazole (moderate CYP3A4 inhibitors) are estimated to increase ziftomenib AUC by up to 2-fold and Cmax by up to 2-fold.

Cimetidine (weak CYP3A inhibitor) is estimated to increase ziftomenib AUC and Cmax by up to 1.4-fold.

Strong, Moderate, or Weak CYP3A4 Inducers: Rifampin (strong CYP3A4 inducer) is estimated to decrease ziftomenib AUC by up to 80% and Cmax by up to 70%.

Efavirenz (moderate CYP3A4 inducer) is estimated to decrease ziftomenib AUC and Cmax by up to 70%.

Dexamethasone (weak CYP3A4 inducer) is estimated to decrease ziftomenib AUC and Cmax by up to

40%.

CYP3A4 Substrates: Ziftomenib is predicted to increase the AUC and Cmax of midazolam (CYP3A4 substrate) up to 1.9- and 1.4-fold, respectively, when ziftomenib is administered alone.

Other Drugs: Ziftomenib is not predicted to have clinically significant effects on the exposure of repaglinide (CYP2C8 substrate), (S)-warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), and raltegravir (UGT1A1 substrate).

In Vitro Studies

Cytochrome P450 (CYP450) Enzymes: Ziftomenib does not inhibit CYP1A2 or CYP2D6. Ziftomenib induces CYP1A2 but not CYP2B6 or CYP3A4.

UDP-Glucuronosyltransferase (UGT): Ziftomenib inhibits UGT1A9 and UGT2B17.

Transporter Systems: Ziftomenib is a substrate of P-gp and BCRP, but not BSEP or MRP. Ziftomenib does not inhibit P-gp, BCRP, OAT1, OAT3, OCT2, MATE1, MATE2-K, OATP1B1, OATP1B3, BSEP, or MRP2.

Animal Toxicology and/or Pharmacology

In 13-week repeat-dose toxicity studies in mice and dogs, incidences of hyperplasia in a variety of organs occurred in several animals from both species. The findings in the mouse study were observed at ≥ 12 mg/kg/day at exposures as low as 0.3 times the AUC at the recommended dose, and the findings in the dog study were observed at ≥ 6 mg/kg/day at exposures as low as 0.05 times the AUC at the recommended dose.

MEDICATION GUIDE

What is the most important information I should know about KOMZIFTI? KOMZIFTI can cause serious side effects including:

Differentiation Syndrome. Differentiation syndrome is a condition that affects your blood cells that is common during treatment with KOMZIFTI and can be life-threatening or lead to death if not treated. Differentiation syndrome can happen as early as 3 days after you start KOMZIFTI treatment and can also happen later during treatment with KOMZIFTI. Tell your healthcare provider or go to the nearest hospital emergency room right away if you develop any of the following signs or symptoms of differentiation syndrome during treatment with KOMZIFTI:

fever joint or bone pain dizziness shortness of breath or trouble breathing cough

chest pain rapid weight gain rash decreased urine output swelling of hands, feet, ankles, or legs

If you develop signs and symptoms of differentiation syndrome during treatment with KOMZIFTI, your healthcare provider may temporarily stop KOMZIFTI and give you a corticosteroid medicine. Your healthcare provider will monitor you until your signs and symptoms improve.

See “What are the possible side effects of KOMZIFTI?” for more information about side effects.

What is KOMZIFTI?

KOMZIFTI is a prescription medicine used to treat adults with acute myeloid leukemia (AML) with a nucleophosmin 1 (NPM1) mutation whose AML has come back or did not improve after previous treatment(s) and who have no other satisfactory treatment options.

Your healthcare provider will perform a test to make sure that KOMZIFTI is right for you. It is not known if KOMZIFTI is safe and effective in children.

Before taking KOMZIFTI, tell your healthcare provider about all of your medical conditions, including if you:

• have any heart problems, including a condition called long QT syndrome.
• have problems with abnormal levels of salts in your blood (electrolytes), such as potassium and magnesium levels.
• are pregnant or plan to become KOMZIFTI can harm your unborn baby.
• Females who are able to become pregnant:
  • Your healthcare provider will perform a pregnancy test before you start treatment with KOMZIFTI.
  • Use effective birth control (contraception) during treatment with KOMZIFTI and for 6 months after the last dose.
• Males who have female partners who are able to become pregnant:
  • Use effective birth control (contraception) during treatment with KOMZIFTI and for 3 months after the last dose.
  • Talk to your healthcare provider about birth control methods you can use during this time.
• are breastfeeding or plan to It is not known if KOMZIFTI passes into your breast milk. Do not breastfeed during your treatment with KOMZIFTI and for 2 weeks after your last dose.

Tell your healthcare provider about any other medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

KOMZIFTI and other medicines may affect each other causing side effects. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist.

How should I take KOMZIFTI?

• Take KOMZIFTI exactly as your healthcare provider tells you to.
• Do not change your dose or stop taking KOMZIFTI without talking to your healthcare provider.
• Take KOMZIFTI 1 time a day around the same time each day.
• Take KOMZIFTI on empty stomach, at least 1 hour before or 2 hours after a meal.
• Swallow KOMZIFTI capsules Do not open, break, or chew the capsules.
• If you take medicine to reduce stomach acid:
  • Avoid taking a proton pump inhibitor (PPI) medicine with KOMZIFTI.
  • Take KOMZIFTI either 2 hours before or 10 hours after taking an H2 receptor blocker medicine.
  • Take KOMZIFTI either 2 hours before or 2 hours after taking a locally acting antacid medicine (such as calcium carbonate).\
• If you miss a dose of KOMZIFTI or did not take it at the usual time, take your dose as soon as possible and at least 12 hours before your next scheduled dose. Return to your normal schedule the following day. Do not take 2 doses within 12 hours of each other to make up for the missed dose.

What are the possible side effects of KOMZIFTI? KOMZIFTI can cause serious side effects, including:

• See “What is the most important information I should know about KOMZIFTI?”
• Changes in electrical activity of your heart (QT prolongation). Changes in the electrical activity of your heart may lead to irregular heartbeats (rhythm) that can be life-threatening or lead to death. Your healthcare provider will check the electrical activity of your heart with a test called an electrocardiogram (ECG) and will also do blood tests to check your potassium and magnesium levels before and during treatment with KOMZIFTI. Tell your healthcare provider right away if you feel faint, lightheaded, or dizzy, or if you have shortness of breath, or if you feel your heart beating irregularly or fast during treatment with KOMZIFTI.

The most common side effects of KOMZIFTI include:

infections including bacterial infections bleeding diarrhea nausea feeling tired

swelling in the arms and legs muscle, bone, and joint pain itching fever with decreased white blood cell counts changes in liver function tests

Your healthcare provider may decrease your dose, temporarily stop, or completely stop your treatment with KOMZIFTI if you develop certain side effects during treatment with KOMZIFTI.

KOMZIFTI may cause fertility problems in females and males, which may affect your ability to have children. Talk to your healthcare provider if this is a concern for you.

These are not all of the possible side effects of KOMZIFTI.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store KOMZIFTI?

• Store KOMZIFTI at room temperature between 68°F to 77°F (20°C to 25°C).
• KOMZIFTI comes in a container with a child-resistant cap.

Keep KOMZIFTI and all medicines out of the reach of children.

General information about the safe and effective use of KOMZIFTI.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not take KOMZIFTI for conditions for which it was not prescribed. Do not give KOMZIFTI to other people, even if they have the

same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about KOMZIFTI that is written for health professionals.

What are the ingredients in KOMZIFTI?

Active ingredient: ziftomenib

Inactive ingredients: croscarmellose sodium, magnesium stearate, mannitol, microcrystalline cellulose, and sodium lauryl sulfate.

The capsule shells imprinted with black ink contain: hypromellose and titanium dioxide.

Manufactured for:
Kura Oncology, Inc.,
San Diego, CA 92121

KOMZIFTI^TM is a trademark of Kura Oncology, Inc.
Copyright © 2025 Kura Oncology, Inc.
For more information, go to www.komzifti.com or call Kura at 1-844-587-2662