Naxitamab

1 INDICATIONS AND USAGE DANYELZA is indicated, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), for the treatment of pediatric patients 1 year of age and older and adult patients with relapsed or refractory high-risk neuroblastoma in the bone or bone marrow who have demonstrated a partial response, minor response, or stable disease to prior therapy. This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). DANYELZA is a GD2-binding monoclonal antibody indicated, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), for the treatment of pediatric patients 1 year of age and older and adult patients with relapsed or refractory high-risk neuroblastoma in the bone or bone marrow who have demonstrated a partial response, minor response, or stable disease to prior therapy. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). ( 1 )

2 DOSAGE AND ADMINISTRATION The recommended dosage of DANYELZA is 3 mg/kg/day (up to 150 mg/day), administered as an intravenous infusion after dilution on Days 1, 3, and 5 of each treatment cycle. Treatment cycles are repeated every 4 weeks until complete response or partial response, followed by 5 additional cycles every 4 weeks. Subsequent cycles may be repeated every 8 weeks. Discontinue DANYELZA and GM-CSF for disease progression or unacceptable toxicity. Administer GM-CSF subcutaneously prior to and during each treatment cycle as recommended. ( 2.1 ) 2.1 Recommended Dosage The recommended dosage of DANYELZA is 3 mg/kg/day (up to 150 mg/day) on Days 1, 3, and 5 of each treatment cycle, administered as an intravenous infusion after dilution [see Dosage and Administration (2.4 and 2.5) ] in combination with GM-CSF subcutaneously as shown in Table 1. Refer to the GM-CSF Prescribing Information for recommended dosing information. Treatment cycles are repeated every 4 weeks until complete response or partial response, followed by 5 additional cycles every 4 weeks. Subsequent cycles may be repeated every 8 weeks. Discontinue DANYELZA and GM-CSF for disease progression or unacceptable toxicity. Administer pre-infusion medications and supportive treatment, as appropriate, during infusion. [see Dosage and Administration (2.2) ] The recommended dosage regimen for each treatment cycle is described below and in Table 1: Days -4 to 0: administer GM-CSF 250 µg/m 2 /day by subcutaneous injection, beginning 5 days prior to DANYELZA infusion. Days 1 to 5: administer GM-CSF 500 µg/m 2 /day by subcutaneous injection. Administer at least 1 hour prior to DANYELZA administration on Days 1, 3, and 5. Days, 1, 3, and 5: administer DANYELZA 3 mg/kg/day (up to 150 mg/day) by intravenous infusion. Table 1 Dose and Schedule of GM-CSF and DANYELZA Within One Treatment Cycle Day -4 -3 -2 -1 0 1 2 3 4 5 Subcutaneous GM-CSF 250 µg/m 2 /day 500 µg/m 2 /day Intravenous DANYELZA 3 mg/kg/day 3 mg/kg/day 3 mg/kg/day Missed Dose If a DANYELZA dose is missed, administer the missed dose the following week by Day 10. Administer GM-CSF 500 µg /m 2 /day on the first day of the DANYELZA infusion, and on the day before and on the day of the second and third infusion, respectively (i.e. a total of 5 days with 500 µg /m 2 /day). 2.2 Premedications and Supportive Medications Pain Management Prior to and During Infusion [see Warnings and Precautions (5.2) ]: Five days prior to the first infusion of DANYELZA in each cycle, initiate a 12-day course (Day -4 through Day 7) of prophylactic medication for neuropathic pain, such as gabapentin. Administer oral opioids 45-60 minutes prior to initiation of each DANYELZA infusion and additional intravenous opioids as needed for breakthrough pain during the infusion. Consider use of ketamine for pain that is not adequately controlled by opioids. Premedication: Reduce Risk of Infusion-Related Reactions and Nausea/Vomiting [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ] . Administer intravenous corticosteroids (e.g. methylprednisolone 2 mg/kg with maximum dose of 80 mg or equivalent corticosteroid dose) 30 minutes to 2 hours prior to the first infusion of DANYELZA. Administer corticosteroid premedication for subsequent infusions if a severe infusion reaction occurred with the previous infusion or during the previous cycle. Administer an antihistamine, an H2 antagonist, acetaminophen and an antiemetic 30 minutes prior to each infusion. 2.3 Dosage Modifications for Adverse Reactions The recommended dosage modifications for DANYELZA for adverse reactions are presented in Table 2. Table 2. Recommended DANYELZA Dosage Modifications for Adverse Reactions Adverse Reaction Severity Based on Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 Dosage Modifications Infusion-related reactions [see Warnings and Precautions (5.1) ] Grade 2 Defined as: Therapy or infusion interruption indicated but responds promptly to symptomatic treatment (e.g., antihistamines, NSAIDS, narcotics, IV fluids); prophylactic medications indicated for ≤24 hours Reduce DANYELZA infusion rate to 50% of previous rate and monitor closely until recovery to Grade ≤ 1. Increase infusion rate gradually to rate prior to the event as tolerated. Grade 3 Defined as: Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae Immediately interrupt DANYELZA infusion and monitor closely until recovery to Grade ≤ 2. Resume infusion at 50% of the rate prior to the event and increase infusion rate gradually to infusion rate prior to the event as tolerated. Permanently discontinue DANYELZA in patients not responding to medical intervention. Grade 4 infusion-related reactions Defined as: Life-threatening consequences: urgent intervention indicated or Grade 3 or 4 anaphylaxis Permanently discontinue DANYELZA. Pain [see Warnings and Precautions (5.2) ] Grade 3 unresponsive to maximum supportive measures Permanently discontinue DANYELZA. Reversible posterior leukoencephalopathy syndrome (RPLS) [see Warnings and Precautions (5.2) ] All Grades Permanently discontinue DANYELZA. Transverse myelitis [see Warnings and Precautions (5.2) ] All Grades Permanently discontinue DANYELZA. Peripheral neuropathy [see Warnings and Precautions (5.2) ] Motor neuropathy: Grade 2 or greater or Sensory neuropathy: Grade 3 or 4 Permanently discontinue DANYELZA. Neurological disorders of the eye [see Warnings and Precautions (5.2) ] Grade 2 to 4 resulting in decreased visual acuity or limiting activities of daily living Withhold DANYELZA until resolution. If resolved resume DANYELZA at 50% of the prior dose; if tolerated without recurrence of symptoms, gradually increase DANYELZA to dose prior to onset of symptoms. Permanently discontinue DANYELZA if not resolved within 2 weeks or upon recurrence. Subtotal or total vision loss Permanently discontinue DANYELZA. Prolonged urinary retention [see Warnings and Precautions (5.2) ] Persisting following discontinuation of opioids Permanently discontinue DANYELZA. Myocarditis [see Warnings and Precautions (5.3) ] Grade 2 or 3 Withhold, reduce dose, or permanently discontinue DANYELZA treatment based on severity and duration. Grade 4 Permanently discontinue DANYELZA. Hypertension [see Warnings and Precautions (5.4) ] Grade 3 Withhold DANYELZA or pause infusion until recovery to ≤ Grade 2. Resume infusion at 50% of prior rate; if tolerated without recurrence of symptoms, gradually increase DANYELZA to rate prior to onset of symptoms. Permanently discontinue DANYELZA in patients not responding to medical intervention. Grade 4 Permanently discontinue DANYELZA. Orthostatic hypotension [see Warnings and precautions (5.5) ] All grades Withhold DANYELZA until recovery to Grade ≤ 1. If resolved within 1 week, restart DANYELZA at 50% of the prior dose; if tolerated without recurrence of symptoms after completion of next cycle, resume to recommended dose for subsequent cycles. If not resolved within 1 week, permanently discontinue DANYELZA. Other Adverse Reactions [see Adverse Reactions (6.1) ] Grade 3 Withhold DANYELZA until recovery to Grade ≤ 2. If resolved to Grade ≤ 2 resume DANYELZA at same rate. Permanently discontinue DANYELZA if not resolved to Grade ≤2 within 2 weeks. Grade 4 Permanently discontinue DANYELZA. 2.4 Preparation Use appropriate aseptic technique. Visually inspect vial for particulate matter and discoloration prior to administration. Discard vial if solution is discolored, cloudy, or contains particulate matter. Add appropriate quantities of 5% Albumin (Human), USP and 0.9% Sodium Chloride Injection, USP to an empty, sterile intravenous infusion bag large enough to hold the volume needed for the relevant dose as indicated in Table 3. Allow for 5-10 minutes of passive mixing. Withdraw the required dose of DANYELZA and inject into the infusion bag containing the 5% Albumin (Human), USP and 0.9% Sodium Chloride Injection, USP. Discard any unused portion of DANYELZA left in the vial. Preparation instructions for DANYELZA are described in Table 3. Table 3. Preparation of DANYELZA, 4 mg/mL DANYELZA dose (mg) DANYELZA volume (mL) Volume of 5% Albumin (Human), USP (mL) Total infusion volume achieved by adding sufficient 0.9% Sodium Chloride Injection, USP (mL) Final concentration of prepared DANYELZA infusion (mg/mL) ≤ 80 ≤ 20 10 50 ≤ 1.6 81 to 120 > 20 to 30 15 75 1.1 to 1.6 121 to 150 > 30 to 37.5 20 100 1.2 to 1.5 If not used immediately, store the diluted DANYELZA infusion solution at room temperature (15°C to 25°C [59ºF to 77ºF]) for up to 8 hours or refrigerate (2°C to 8°C [36°F to 46°F]) for up to 24 hours. Once removed from refrigeration, initiate infusion within 8 hours. 2.5 Administration Administer DANYELZA as a diluted intravenous infusion as recommended. Do not administer DANYELZA as an intravenous push or bolus [see Dosage and Administration (2.4) ] . For the first infusion (Cycle 1, Day 1), administer DANYELZA intravenously over 60 minutes. For subsequent infusions, administer DANYELZA intravenously over 30 to 60 minutes, as tolerated. [see Dosage and Administration (2.1 , 2.3) ]. Observe patients for a minimum of 2 hours following each infusion.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are also described elsewhere in the labeling: Serious Infusion-Related Reactions [see Warnings and Precautions (5.1) ] Neurotoxicity [see Warnings and Precautions (5.2) ] Myocarditis [see Warnings and Precautions (5.3) ] Hypertension [see Warnings and Precautions (5.4) ] Orthostatic Hypotension [see Warnings and Precautions (5.5) ] The most common adverse reactions (≥25%) are infusion-related reaction, pain, tachycardia, vomiting, cough, nausea, diarrhea, decreased appetite, hypertension, fatigue, erythema multiforme, peripheral neuropathy, urticaria, pyrexia, headache, injection site reaction, edema, anxiety, localized edema, and irritability ( 6.1 ). The most common Grade 3 or 4 laboratory abnormalities (≥5%) are decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased platelet count, decreased potassium, increased alanine aminotransferase, decreased glucose, decreased calcium, decreased albumin, decreased sodium, and decreased phosphate ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Y-mAbs Therapeutics, Inc, at 1-833-339-6227 (1-833-33YMABS), or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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. The safety of DANYELZA in combination with GM-CSF was evaluated in patients with refractory or relapsed high-risk neuroblastoma in bone or bone marrow who had demonstrated a partial response, minor response, or stable disease following initial or subsequent therapy, and in patients who were in second complete remission, from two open-label, single arm studies, Study 201 (n=25) and Study 12-230 (n=72). Patients received DANYELZA 9 mg/kg/cycle administered as three separate intravenous infusions of 3 mg/kg (Day 1, 3 and 5) in the first week of each cycle. Patients also received GM-CSF 250 µg/m 2 /day subcutaneously on Days -4 to 0 and GM-CSF 500 µg/m 2 /day subcutaneously on Days 1 to 5 [see Clinical Studies (14) ]. The most common adverse reactions in Studies 201 and 12-230 (≥25% in either study) were infusion-related reaction, pain, tachycardia, vomiting, cough, nausea, diarrhea, decreased appetite, hypertension, fatigue, erythema multiforme, peripheral neuropathy, urticaria, pyrexia, headache, injection site reaction, edema, anxiety, localized edema and irritability. The most common Grade 3 or 4 laboratory abnormalities (≥5% in either study) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased platelet count, decreased potassium, increased alanine aminotransferase, decreased glucose, decreased calcium, decreased albumin, decreased sodium and decreased phosphate. Study 201 In Study 201, among 25 patients who received DANYELZA in combination with GM-CSF, 12% were exposed for 6 months or longer and none were exposed for greater than one year. Serious adverse reactions occurred in 32% of patients who received DANYELZA in combination with GM-CSF. Serious adverse reactions in more than one patient included anaphylactic reaction (12%) and pain (8%). Permanent discontinuation of DANYELZA due to an adverse reaction occurred in 12% of patients. Adverse reactions resulting in permanent discontinuation of DANYELZA included anaphylactic reaction (8%) and respiratory depression (4%). Dosage interruptions of DANYELZA due to an adverse reaction occurred in 84% of patients. Adverse reactions requiring dosage interruption in > 10% of patients included hypotension and bronchospasm. Table 4 summarizes adverse reactions in Study 201. Table 4. Adverse Reactions (>10%) in Patients with Refractory or Relapsed High-Risk Neuroblastoma in Bone or Bone Marrow Who Received DANYELZA with GM-CSF in Study 201 DANYELZA with GM-CSF Adverse reactions were graded using CTCAE version 4.0. (n=25) Adverse Reaction All Grades (%) Grade 3 or 4 (%) Body system General disorders and administration site conditions Pain Pain includes pain, abdominal pain, pain in extremity, bone pain, neck pain, back pain, and musculoskeletal pain. 100 72 Infusion-related reaction Infusion-related reaction includes hypotension, bronchospasm, flushing, wheezing, stridor, urticaria, dyspnea, pyrexia, infusion-related reaction, face edema, edema mouth, tongue edema, lip edema, respiratory tract edema, chills, hypoxia, pruritis and rash occurring on the day of infusion or the day following an infusion. 100 68 Edema 28 0 Fatigue Fatigue includes fatigue, asthenia. 28 0 Pyrexia Pyrexia not occurring on the day of infusion or the day following an infusion 28 0 Respiratory, thoracic and mediastinal disorders Cough 60 0 Rhinorrhea 24 0 Vascular disorders Hypertension 44 4 Gastrointestinal disorders Vomiting 60 4 Diarrhea 56 8 Nausea 56 0 Skin and subcutaneous tissue disorders Urticaria Urticaria, not occurring on the day of infusion or the day following an infusion 32 4 Cardiac disorders Tachycardia Tachycardia includes sinus tachycardia and tachycardia 84 4 Nervous system disorders Peripheral neuropathy Peripheral neuropathy includes peripheral sensory neuropathy, paresthesia, neuralgia. 32 0 Headache 28 8 Depressed level of consciousness 24 16 Eye disorders Neurological disorders of the eye Neurological disorders of the eye includes unequal pupils, blurred vision, and mydriasis. 24 0 Immune system disorders Anaphylactic reaction 12 12 Metabolism and nutrition disorders Decreased appetite 16 0 Infections and infestations Influenza 12 0 Rhinovirus infection 12 0 Upper respiratory tract infection 12 0 Investigations Weight decreased 12 0 Psychiatric disorders Anxiety 12 0 Clinically relevant adverse reactions occurring in ≤10% of patients who received DANYELZA with GM-CSF included peripheral edema (8%). Table 5 summarizes the laboratory abnormalities in Study 201. Table 5. Selected Laboratory Abnormalities (>20%) Worsening from Baseline in Patients with Refractory or Relapsed High-Risk Neuroblastoma in Bone or Bone Marrow Who Received DANYELZA with GM-CSF in Study 201 Laboratory Abnormality DANYELZA with GM-CSF The table presents laboratory parameters with available grading according to CTCAE version 4.0. Baseline evaluation was the last non-missing value prior to first DANYELZA dosing. Each test incidence is based on the number of patients who had both a baseline value and at least one on-study laboratory measurement (range: 23 to 24 patients). n=25 All Grades (%) Grade 3 or 4 (%) Chemistry Decreased potassium 63 8 Decreased albumin 50 0 Increased alanine aminotransferase 42 8 Decreased sodium 29 0 Hematology Decreased lymphocytes 74 30 Decreased platelet count 65 17 Decreased neutrophils 61 39 Decreased hemoglobin 48 4 Study 12-230 In Study 12-230, among 72 patients who received DANYELZA in combination with GM-CSF, 32% were exposed for 6 months or longer and 8% were exposed for greater than one year. Serious adverse reactions occurred in 40% of patients who received DANYELZA in combination with GM-CSF. Serious adverse reactions in > 5% of patients included hypertension (14%), hypotension (11%), and pyrexia (8%). Permanent discontinuation of DANYELZA due to an adverse reaction occurred in 8% of patients. Four (6%) patients permanently discontinued DANYELZA due to hypertension and one (1.4%) patient discontinued due to RPLS. Table 6 summarizes adverse reactions in Study 12-230. Table 6. Adverse Reactions (>10%) in Patients with Refractory or Relapsed High-Risk Neuroblastoma in Bone or Bone Marrow Who Received DANYELZA with GM-CSF in Study 12-230 DANYELZA with GM-CSF In Study 12-230, all adverse reactions occurring in Cycle 1 and 2, and adverse reactions of ≥ Grade 3 severity occurring in subsequent cycles were reported. In the dose finding phase, Grade 2 unexpected adverse reactions were also reported for Cycles 3 and later. , Adverse reactions were graded using CTCAE version 4.0. (n=72) Adverse Reaction All Grades (%) Grade 3 or 4 (%) Body system General disorders and administration site conditions Infusion-related reaction Infusion-related reaction includes hypotension, bronchospasm, flushing, wheezing, stridor, urticaria, dyspnea, pyrexia, face edema, periorbital edema, lip swelling, swollen tongue, chills, hypoxia, pruritis, rash maculopapular and rash erythematous occurring on the day of infusion or the day following an infusion. 94 32 Pain Pain includes pain, abdominal pain, pain in extremity, bone pain, neck pain, back pain, non-cardiac chest pain, flank pain, and musculoskeletal pain. 94 2.8 Fatigue Fatigue includes fatigue, asthenia. 44 0 Injection site reaction 28 0 Localized edema 25 0 Pyrexia Pyrexia not occurring on the day of infusion or the day following an infusion. 11 0 Vascular disorders Hypertension 28 7 Gastrointestinal disorders Vomiting 63 2.8 Nausea 57 1.4 Diarrhea 50 4.2 Constipation 15 0 Skin and subcutaneous tissue disorders Erythema multiforme 33 0 Hyperhidrosis 17 0 Erythema 11 0 Respiratory, thoracic and mediastinal disorders Cough 57 0 Oropharyngeal pain 15 0 Rhinorrhea 15 0 Nervous system disorders Peripheral neuropathy Peripheral neuropathy includes peripheral sensory neuropathy, peripheral motor neuropathy, paresthesia, neuralgia. 25 0 Headache 18 0 Lethargy 14 0 Metabolism and nutrition disorders Decreased appetite 53 4.2 Cardiac disorders Sinus tachycardia 44 1.4 Psychiatric disorders Anxiety 26 0 Irritability 25 0 Investigations Breath sounds abnormal 15 0 Injury and procedural complications Contusion 15 0 Infections and infestations Rhinovirus infection 14 0 Enterovirus infection 13 0 Eye Disorders Neurological disorders of the eye Neurological disorders of the eye includes unequal pupils, blurred vision, accommodation disorder, visual impairment and photophobia. 19 0 Clinically relevant adverse reactions in ≤10% of patients who received DANYELZA with GM-CSF included apnea (4.2%), hypopnea (2.8%), generalized edema (2.8%), peripheral edema (8.3%), and device related infection (4.2%). Table 7 summarizes the laboratory abnormalities in Study 12-230. Table 7. Selected Laboratory Abnormalities (>20%) Worsening from Baseline in Patients with Refractory or Relapsed High-Risk Neuroblastoma in Bone or Bone Marrow Who Received DANYELZA with GM-CSF in Study 12-230 Laboratory Abnormality DANYELZA with GM-CSF The table presents laboratory parameters with available grading according to CTCAE version 4.0. Baseline evaluation was the last non-missing value prior to first DANYELZA dosing. Each test incidence is based on the number of patients who had both a baseline value and at least one on-study laboratory measurement (range 19 to 72 patients). n=72 All Grades (%) Grade 3 or 4 (%) Chemistry Increased glucose 74 0 Decreased albumin 68 7 Decreased calcium 64 8 Increased alanine aminotransferase 55 9 Decreased magnesium 54 0 Increased aspartate aminotransferase 49 4 Decreased phosphate 47 5 Decreased potassium 47 32 Decreased sodium 38 6 Decreased glucose 29 8 Hematology Decreased lymphocytes 79 56 Decreased hemoglobin 76 42 Decreased neutrophils 72 46 Decreased platelets 71 40 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The detection of anti-drug antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of anti-drug antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies or to other naxitamab products may be misleading. In Study 201, 2 of 24 (8%) patients tested positive for anti-drug antibodies (ADA) after treatment with DANYELZA. In Study 12-230, 27 of 117 patients (23%) tested positive for ADA after treatment with DANYELZA by an assay that was not fully validated; therefore, the incidence of ADA may not be reliable. 6.3 Postmarketing Experience/Spontaneous Reports The following adverse reactions have been identified during expanded access and post-approval use of DANYELZA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Neurological: Orthostatic hypotension, Transverse myelitis Cardiac disorders: Myocarditis

12.3 Pharmacokinetics The geometric mean (CV%) maximum plasma concentration (C max ) of naxitamab-gqgk was 57.4 µg/mL (49%) following DANYELZA 3 mg/kg intravenous infusion over 30 minutes. Elimination The mean terminal half-life of naxitamab-gqgk was 8.2 days. Metabolism Naxitamab-gqgk is expected to be metabolized into small peptides by catabolic pathways. Specific Populations Population pharmacokinetic analyses suggest that age (range: 1 to 34 years), sex and race have no clinically important effect on the clearance (CL) of naxitamab-gqgk. The naxitamab-gqgk systemic exposure (AUC) at 150 mg/day (450 mg per cycle) for patients with body weight over 50 kg is not expected to differ clinically from that of the naxitamab-gqgk exposures at 3 mg/kg/day (9 mg/kg per cycle) for patients with body weight of 30 - 50 kg.