Pivekimab Sunirine

1. INDICATIONS AND USAGE DECNUPAZ is indicated for the treatment of adult patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). DECNUPAZ is a CD123-directed antibody and alkylating agent conjugate indicated for the treatment of adult patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). ( 1 )

3. DOSAGE FORMS AND STRENGTHS For injection: 2 mg of pivekimab sunirine-pvzy as a white to off-white, lyophilized cake in a single-dose vial. For injection: 2 mg of pivekimab sunirine-pvzy as a lyophilized cake in a single-dose vial. ( 3 )

4. CONTRAINDICATIONS None. None. ( 4 )

5. WARNINGS AND PRECAUTIONS I nfusion -related reactions (IRR) : DECNUPAZ can cause serious, life-threatening IRR. Premedicate with a corticosteroid the day before infusion, and premedicate with a corticosteroid, antihistamine, and an antipyretic prior to DECNUPAZ infusion. Monitor patients for IRR. Interrupt, reduce the rate of infusion, or permanently discontinue DECNUPAZ based on the severity. ( 5.2 ) Edema : Monitor for the development of edema and fluid retention. Depending on severity, delay, consider resuming at a lower dose, or permanently discontinue DECNUPAZ. ( 5.3 ) Sulfite Allergic Reactions : DECNUPAZ contains sodium metabisulfite, which may cause allergic type reactions, including anaphylactic symptoms and asthmatic episodes in certain susceptible people. ( 5.4 ) Embryo-fetal toxicity : Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.5 )

5.1 Hepatotoxicity , Including Hepatic Veno-occlusive Disease (VOD) (also known as Sinusoidal Obstruction Syndrome) DECNUPAZ can cause hepatotoxicity, including VOD, a severe form of hepatotoxicity. In CADENZA, VOD occurred in 6% (7/116) of adult patients during treatment or following a subsequent hematopoietic stem cell transplantation (HSCT). Of the 7 total patients who developed VOD, 3 patients had treatment-naïve BPDCN and 4 patients had relapsed/refractory BPDCN. Among all 116 patients treated with DECNUPAZ at 0.045 mg/kg, VOD occurred in 2/116 (2%) during treatment, with onset up to 30 days after the last dose. Among 19 patients with BPDCN who proceeded to HSCT, VOD occurred in 5/19 patients (26%), including two fatal cases. The median time from subsequent HSCT to onset of VOD was 11 days (range: 7 – 25 days). After receiving DECNUPAZ, patients should be closely monitored for signs and symptoms of VOD including elevations in ALT, AST, total bilirubin, hepatomegaly (which may be painful), rapid weight gain, and ascites. Monitor liver tests, including ALT, AST, and total bilirubin, prior to each dose of DECNUPAZ. Based on elevations of liver tests, delay DECNUPAZ. In patients who experience VOD, discontinue DECNUPAZ and treat according to standard medical practice [see Dosage and Administration ( 2.4 )] .

5.2 Infusion-Related Reactions DECNUPAZ can cause serious, life-threatening infusion-related reactions (IRR); signs and symptoms of IRR include dyspnea, flushing, fever, chills, nausea, chest discomfort, hypotension, and vomiting. In CADENZA, IRRs occurred in 26% (30/116) of patients during treatment with DECNUPAZ at 0.045 mg/kg once every three weeks, including Grade 1 in 4.3% (5/116), Grade 2 in 16% (19/116), and Grade 3 in 5% (6/116) of patients. IRR occurred in Cycle 1 in 25% (29/116) of patients with decreasing frequency in subsequent cycles. IRR led to discontinuation in one patient. Premedicate with a corticosteroid the day before infusion, and premedicate with a corticosteroid, antihistamine, and antipyretic prior to dosing [ see Dosage and Administration ( 2.3 )] . Premedication the day before infusion and prior to dosing led to reduced frequency and severity of IRRs. Monitor patients closely for potential IRR during the infusion and for at least four hours, or longer as clinically indicated, after the first infusion and for at least 1 hour after subsequent infusions. Interrupt infusion of DECNUPAZ and institute appropriate medical management if an infusion-related reaction occurs. Depending on the severity of the infusion-related reaction, reduce infusion rate or permanently discontinue [see Dosage and Administration ( 2.4 )].

5.3 Edema DECNUPAZ can cause edema and fluid retention, including serious events. In CADENZA, Grade 3-4 edema occurred in 16% (18/116) of patients treated with DECNUPAZ, including Grade 3-4 generalized edema in 2.6% (3/116) of patients [see Adverse Reactions ( 6.1 )]. Monitor patients for new or worsening edema. For Grade 2 or Grade 3 edema, delay further dosing of DECNUPAZ until edema has returned to Grade 0-1 or baseline. For Grade 3 edema or Grade 2 edema with dose delay for more than 2 weeks, consider resuming at a lower dose. For Grade 4 edema, permanently discontinue. Institute appropriate medical management for edema [see Dosage and Administration ( 2.4 )] .

5.4 Sulfite Allergic Reactions DECNUPAZ contains sodium metabisulfite, a sulfite that may cause allergic type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people.

5.5 Embryo-Fetal Toxicity Based on its mechanism of action, DECNUPAZ can cause embryo-fetal harm when administered to a pregnant woman because it contains a genotoxic compound (FGN849) and affects actively dividing cells [see Clinical Pharmacology ( 12.1 ), Nonclinical Toxicology ( 13.1 )] . Advise patients of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with DECNUPAZ and for 7 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with DECNUPAZ, and for 4 months after the last dose [see Use in Specific Populations ( 8.1 , 8.3 )] .

6. ADVERSE REACTIONS The following clinically significant adverse reactions are discussed elsewhere in the labeling: Hepatotoxicity, Including Hepatic VOD (also known as Sinusoidal Obstruction Syndrome) [see Warnings and Precautions ( 5.1 )] Infusion-Related Reactions [see Warnings and Precautions ( 5.2 )] Edema [see Warnings and Precautions ( 5.3 )] The most common adverse reactions (≥20%) were edema, fatigue, musculoskeletal pain, hemorrhage, infusion-related reactions, nausea, and diarrhea. ( 6.1 ) The most common Grade 3 or 4 laboratory abnormalities (≥10%) were neutrophils decreased, platelets decreased, lymphocyte count decreased, white blood cells decreased, hemoglobin decreased, and glucose increased. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical T rials 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. The safety of DECNUPAZ was evaluated in CADENZA, a single-arm, open-label study that included 116 adults with newly diagnosed or relapsed/refractory myeloid malignancies, including 84 with BPDCN, treated with DECNUPAZ 0.045 mg/kg once every three weeks. The median number of cycles administered was 3 (range: 1 to 34) in the overall population, and 3.5 (range: 1 to 34) in patients with BPDCN. Serious adverse reactions occurred in 55% of patients treated with DECNUPAZ. The most common (≥2%) serious adverse reactions were febrile neutropenia, pneumonia, edema, sepsis, hemorrhage, thrombosis, infusion-related reactions, viral infection, pneumonitis, infections without specified pathogens, pyrexia, and musculoskeletal pain. Fatal adverse reactions occurred in 4.3% of patients who received DECNUPAZ, including cardiac arrest (0.9%), clostridium difficile infection (0.9%), failure to thrive (0.9%), depressed level of consciousness (0.9%), and respiratory failure (0.9%). Permanent discontinuation due to adverse reactions occurred in 10% of patients who received DECNUPAZ. Adverse reactions which resulted in permanent discontinuation of DECNUPAZ in ≥1% of patients included veno-occlusive disease and pneumonitis. Dosage interruptions of DECNUPAZ due to adverse reactions occurred in 37% of patients. Adverse reactions which resulted in dosage interruptions in ≥2% of patients included edema, pneumonia, infusion-related reaction, bacterial infections, fatigue, hemorrhage, neutropenia, pneumonitis, and pyrexia. Dose reductions of DECNUPAZ due to an adverse reaction occurred in 6% of patients. Adverse reactions which required dose reductions in ≥2% of patients included edema. The most common adverse reactions (≥20%) were edema, fatigue, musculoskeletal pain, hemorrhage, infusion-related reactions, nausea, and diarrhea. The most common Grade 3 to 4 laboratory abnormalities (≥10%) were neutrophils decreased, platelets decreased, lymphocyte count decreased, white blood cells decreased, hemoglobin decreased, and glucose increased. Table 3 summarizes the common adverse reactions (≥10%) in patients treated with DECNUPAZ in CADENZA. Table 3. Adverse Reactions (≥10%) in Patients Who Received DECNUPAZ in CADENZA DECNUPAZ (N=116) Adverse Reaction § All Grades (%) Grade 3 or 4 (%) General disorders and administration site conditions Edema a 52 16 Fatigue b 34 5 Pyrexia b 16

0.9 Chills 11 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain b 34 8 Vascular disorders Hemorrhage b 28 6 Thrombosis b 13 5 Injury, poisoning and procedural complications Infusion-related reactions 26 5 Fall 13

1.7 Gastrointestinal disorders Nausea b 24

0.9 Diarrhea b 21

0.9 Constipation 19 0 Abdominal pain b 14

0.9 Respiratory , thoracic and mediastinal disorders Dyspnea b 19

1.7 Cough b 15 0 Skin and subcutaneous tissue disorders Rash c 19 0 Nervous system disorder s Neuropathy peripheral d 18

1.7 Headache b 16

2.6 Dizziness b 10

0.9 Metabolism and nutrition disorders Decreased appetite b 16

0.9 Infections and i nfestations Infections without specified pathogens b 16 6 Viral infections e 13 6 Bacterial infections f 12 5 Pneumonia g 11 9 Psychiatric disorders Insomnia 15 0 Blood and lymphatic system disorders Febrile neutropenia 11 11 § Adverse reactions were graded based on CTCAE Version 4.03 a. Edema includes acute pulmonary edema, face edema, generalized edema, hypervolemia, edema, edema genital, edema peripheral, pericardial effusion, peripheral swelling, pleural effusion, pulmonary edema, swelling face, weight increased, ascites. b. Consists of multiple related terms. c. Rash includes erythema, erythema nodosum, guttate psoriasis, photosensitivity reaction, psoriasis, rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, skin lesion, skin lesion inflammation, stasis dermatitis. d. Neuropathy peripheral includes burning sensation, dysesthesia, facial nerve disorder, hypoesthesia, IIIrd nerve disorder, neuralgia, neuropathy peripheral, paresthesia, sciatica. e. Viral infections includes COVID-19, cytomegalovirus infection, HCoV-229E infection, herpes simplex, herpes zoster, herpes zoster disseminated, influenza, ophthalmic herpes simplex, oral herpes. f. Bacterial infections includes cellulitis, clostridium difficile infection, erysipelas, folliculitis, vulval abscess. g. Pneumonia includes pneumocystis jirovecii pneumonia, pneumonia, pneumonia viral. Clinically relevant adverse reactions occurring in <10% of patients who received DECNUPAZ in CADENZA included: Vascular disorders : capillary leak syndrome (9%) a , hypotension b (7%) Gastrointestinal disorders: stomatitis b (6%) Infections and infestations: sepsis c (7%), fungal infections d (5%) Respiratory, thoracic and mediastinal disorders: pneumonitis (5%) Cardiac disorders : arrhythmia e (6%) Renal and urinary disorders : acute kidney injury b (6%) Hepatobiliary disorders: veno-occlusive disease (1.7%) a. At least 2 of the following new onset signs and symptoms within 7 days of each other: hypoalbuminemia (including albumin <3.0 g/dL), edema (including weight increase >5 kg), hypotension (including systolic blood pressure <90 mmHg). b. Consists of multiple related terms. c. Includes bacteremia, klebsiella bacteremia, pulmonary sepsis, sepsis, and streptococcal bacteremia. d. Includes candida infection, fungal balanitis, fungal foot infection, fungal skin infection. e. Includes arrhythmia, atrial fibrillation, atrioventricular block, bradycardia, cardiac arrest, tachyarrhythmia. Table 4 summarizes laboratory abnormalities in CADENZA. Table 4. Select Laboratory Abnormalities (≥10%) That Worsened from Baseline in Patients Who Received DECNUPAZ in CADENZA Laboratory Abnormality* DECNUPAZ a All Grades (%) Grade 3 or 4 (%) Chemistry Creatinine increased 76 0 Glucose increased 53 10 Albumin decreased 50

1.8 Phosphate decreased 39 8 Calcium decreased 34

1.8 Alanine aminotransferase increased 32

4.4 Aspartate aminotransferase increased 29

0.9 Sodium decreased 28

1.8 Potassium decreased 26

3.5 Alkaline phosphatase increased 20

0.9 Magnesium decreased 18 0 Bilirubin increased 16

0.9 Hematology Platelets decreased 64 40 Neutrophils decreased 63 45 Lymphocyte count decreased 62 39 White blood cells decreased 55 34 Hemoglobin decreased 40 20 * Laboratory abnormalities were graded based on CTCAE Version 4.03. a The denominator used to calculate the rate varied from 78 to 114 based on the number of patients with at least one post-baseline value.

7. DRUG INTERACTIONS Strong and M oderate CYP3A Inhibitors : Closely monitor for DECNUPAZ adverse reactions ( 7.1 )

7.1 Effect of Other Drugs on DECNUPAZ Strong and moderate CYP3A inhibitors Closely monitor patients for adverse reactions with DECNUPAZ when used concomitantly with strong and moderate CYP3A inhibitors. FGN849 is a substrate of CYP3A [see Clinical Pharmacology ( 12.3 )] . Concomitant use of DECNUPAZ with strong and moderate CYP3A inhibitors may increase unconjugated FGN849 exposure, which may increase the risk of DECNUPAZ adverse reactions.

8. USE IN SPECIFIC POPULATIONS Lactation : Advise not to breastfeed ( 8.2 ) Infer tility : May impair fertility ( 8.3 ) Moderate to Severe Hepatic Impairment : Avoid use of DECNUPAZ ( 8.7 ) Moderate to Severe Renal Impairment : Avoid use of DECNUPAZ ( 8.6 )

8.1 Pregnancy Risk Summary Based on its mechanism of action, DECNUPAZ can cause embryo-fetal harm when administered to a pregnant woman because it contains a genotoxic compound (FGN849) and affects actively dividing cells [see Clinical Pharmacology ( 12.1 ), Nonclinical Toxicology ( 13.1 )] . There are no available data on the use of DECNUPAZ in pregnant women to inform a drug-associated risk. Advise patients of the potential risks to a fetus. 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 Animal reproductive or developmental toxicity studies were not conducted with pivekimab sunirine-pvzy. The cytotoxic component of DECNUPAZ, FGN849, is a DNA-alkylating agent that is toxic to rapidly dividing cells, indicating it has the potential to cause embryofetal lethality and teratogenicity.

8.2 Lactation Risk Summary There are no data on the presence of pivekimab sunirine-pvzy or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with DECNUPAZ and for 1 month after the last dose.

8.3 Females and Males of Reproductive Potential DECNUPAZ can cause fetal harm when administered to a pregnant patient [see Use in Specific Populations ( 8.1 )] . Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiation of DECNUPAZ. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with DECNUPAZ and for 7 months after the last dose. Males Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with DECNUPAZ and for 4 months after the last dose [see Nonclinical Toxicology ( 13.1 )] . Infertility Based on its mechanism of action, DECNUPAZ may impair male and female reproductive function and fertility.

8.4 Pediatric Use The safety and effectiveness of DECNUPAZ have not been established in pediatric patients.

8.5 Geriatric Use Of the 116 patients who were treated in CADENZA, 70% of patients were ≥65 years of age and 28% were ≥75 years of age. No overall differences in safety or effectiveness of DECNUPAZ have been observed between patients 65 years of age and older and younger adult patients. Age does not have a clinically meaningful effect on the pharmacokinetics of DECNUPAZ [see Clinical Pharmacology ( 12.3 )] .

8.6 Renal Impairment Avoid use of DECNUPAZ in patients with moderate to severe renal impairment (CLcr <60 mL/min, estimated by Cockcroft-Gault) or patients with end stage renal disease. A higher incidence of Grade ≥3 adverse events, serious adverse events, and dose delays was observed in patients with moderate renal impairment (CLcr 30 to <60 mL/min). DECNUPAZ has not been studied in patients with severe renal impairment (CLcr <30 mL/min) or end stage renal disease. No dosage adjustment of DECNUPAZ is recommended for patients with mild renal impairment (CLcr 60 to <90 mL/min, estimated by Cockcroft-Gault) [see Clinical Pharmacology ( 12.3 )] .

8.7 Hepatic Impairment Avoid use of DECNUPAZ in patients with moderate to severe hepatic impairment (total bilirubin >1.5 x ULN with any AST). Limited data are available in patients with moderate hepatic impairment (total bilirubin >1.5 to 3 times ULN and any AST). DECNUPAZ has not been studied in patients with severe hepatic impairment. No dosage adjustment of DECNUPAZ is recommended for patients with mild hepatic impairment (total bilirubin ≤ULN and AST >ULN or total bilirubin ≤1.5 times ULN and any AST) [see Clinical Pharmacology ( 12.3 )] .

Pivekimab sunirine-pvzy is a CD123 (alpha-subunit of the interleukin-3 receptor)-directed antibody-drug conjugate (ADC). The antibody is a humanized anti-CD123 IgG1. Pivekimab sunirine-pvzy binds to CD123 expressing cells and upon intracellular processing releases a cell membrane-permeable payload, FGN849, leading to DNA alkylation, single-strand DNA breaks, apoptosis, and cell death. The payload, FGN849, is a member of the indolinobenzodiazepine pseudodimer (IGN) class of cytotoxic molecules. Pivekimab sunirine-pvzy exhibited antitumor activity in in vitro and in vivo models of BPDCN.