HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use DANYELZA safely and effectively. See full prescribing information for

DANYELZA.

DANYELZA® (naxitamab-gqgk) injection, for intravenous use Initial U.S. Approval: 2020

WARNING: SERIOUS INFUSION-RELATED REACTIONS and NEUROTOXICITY

See full prescribing information for complete boxed warning

·                    Serious Infusion-Related Reactions: DANYELZA can cause serious infusion reactions, including cardiac arrest, anaphylaxis, hypotension, bronchospasm, and stridor. Premedicate prior to each DANYELZA infusion as recommended. Reduce the rate, interrupt infusion, or permanently discontinue DANYELZA based on severity(2.2, 2.3, 4, 5.1).

·                    Neurotoxicity: DANYELZA can cause severe neurotoxicity, including severe neuropathic pain, transverse myelitis, and reversible posterior leukoencephalopathy syndrome (RPLS). Premedicate to treat neuropathic pain as recommended. Permanently discontinue DANYELZA based on the adverse reaction and severity (2.2, 2.3, 5.2).

----------------------------INDICATIONS AND USAGE---------------------------

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)

------------------------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)

----------------------DOSAGE FORMS AND STRENGTHS---------------------

Injection: 40 mg/10 mL (4 mg/mL) in a single-dose vial. (3)

-------------------------------CONTRAINDICATIONS------------------------------

History of severe hypersensitivity reaction to naxitamab-gqgk. (4)

------------------------WARNINGS AND PRECAUTIONS-----------------------

·      Neurotoxicity: Peripheral neuropathy, neurological disorders of the eye, and prolonged urinary retention have also occurred. Permanently discontinue as recommended (2.3, 5.2)

·      Hypertension: Monitor blood pressure during and after infusion as recommended. Withhold, reduce infusion rate, or discontinue based on severity. (5.3)

·      Embryo-FetalToxicity: May cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective

contraception (5.4)

-------------------------------ADVERSE      REACTIONS------------------------------

·      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.

----------------------------USE IN SPECIFIC POPULATIONS-------------------

Lactation: Advise not to breastfeed. (8.2)

See 17 for PATIENT COUNSELING INFORMATION

Revised: 11/2020

FULL PRESCRIBING INFORMATION: CONTENTS*

1          INDICATIONS AND USAGE

2          DOSAGE AND ADMINISTRATION

2.1   Recommended Dosage

2.2   Premedications and Supportive Medications

2.3   Dosage Modifications for Adverse Reactions

2.4   Preparation

2.5   Administration

3          DOSAGE FORMS AND STRENGTHS

4          CONTRAINDICATIONS

5          WARNINGS AND PRECAUTIONS

5.1   Serious Infusion-Related Reactions

5.2   Neurotoxicity

5.3   Hypertension

5.4   Embryo-Fetal Toxicity

6          ADVERSE REACTIONS

6.1   Clinical Trials Experience

6.2   Immunogenicity

6.3  Postmarketing Experience/Spontaneous Reports

8          USE IN SPECIFIC POPULATIONS

8.1   Pregnancy

8.2   Lactation

8.3   Females and Males of Reproductive Potential

8.4   Pediatric Use

8.5   Geriatric Use

11       DESCRIPTION

12       CLINICAL PHARMACOLOGY

12.1    Mechanism of Action

12.2    Pharmacodynamics

12.3    Pharmacokinetics

13       NONCLINICAL TOXICOLOGY

13.1    Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2    Animal Toxicology and/or Pharmacology

14       CLINICAL STUDIES

16       HOW SUPPLIED/STORAGE AND HANDLING

17       PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from the full prescribing information are not listed

WARNING: SERIOUS INFUSION-RELATED REACTIONS and NEUROTOXICITY

Serious Infusion-Related Reactions

·                   DANYELZA can cause serious infusion reactions, including cardiac arrest, anaphylaxis, hypotension, bronchospasm, and stridor. Infusion reactions of any Grade occurred in 94-100% of patients. Severe infusion reactions occurred in 32-68% and serious infusion reactions occurred in 4

- 18% of patients in DANYELZA clinical studies[see Warnings and Precautions (5.1)].

·                   Premedicate prior to each DANYELZA infusion as recommended and monitor patients for at least 2 hours following completion of each infusion. Reduce the rate, interrupt infusion, or permanently discontinue DANYELZA based on severity[see Dosage and Administration (2.2, 2.3), Contraindications (4), and Warnings and Precautions (5.1)].

·                   DANYELZA can cause severe neurotoxicity, including severe neuropathic pain, transverse myelitis and reversible posterior leukoencephalopathy syndrome (RPLS). Pain of any Grade occurred in 94-100% of patients of patients in DANYELZA clinical studies[see Warnings and Precautions (5.2)].

·                   Premedicate to treat neuropathic pain as recommended. Permanently discontinue DANYELZA based on the adverse reaction and severity[see Dosage and Administration (2.2, 2.3) and Warnings and Precautions (5.2)].

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).

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/m2/day by subcutaneous injection, beginning 5 days prior to DANYELZA infusion.

·                   Days 1 to 5: administer GM-CSF 500 µg/m2/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.

MissedDose

If a DANYELZA dose is missed, administer the missed dose the following week by Day 10. Administer GM-CSF 500 µg /m2/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 /m2/day).

PainManagementPriortoandDuringInfusion [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:ReduceRiskofInfusion-RelatedReactionsandNausea/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.

The recommended dosage modifications for DANYELZA for adverse reactions are presented in Table 2.

1Based on Common Terminology Criteria for Adverse Events (CTCAE) v 5.0

·                   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.

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.

·                   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.

Injection: 40 mg/10 mL (4 mg/mL) clear to slightly opalescent and colorless to slightly yellow solution in a single- dose vial.

DANYELZA is contraindicated in patients with a history of severe hypersensitivity reaction to naxitamab-gqgk. Reactions have included anaphylaxis[see Warnings and Precautions (5.1)].

5.1  erious Infusion-Related Reactions

DANYELZA can cause serious infusion reactions requiring urgent intervention including fluid resuscitation, administration of bronchodilators and corticosteroids, intensive care unit admission, infusion rate reduction or interruption of DANYELZA infusion. Infusion-related reactions included hypotension, bronchospasm, hypoxia, and

stridor[see Adverse Reactions (6.1)].

Serious infusion-related reactions occurred in 4% of patients in Study 201 and in 18% of patients in Study 12-230. Infusion-related reactions of any Grade occurred in 100% of patients in Study 201 and 94% of patients in Study 12-

230. Hypotension of any grade occurred in 100% of patients in Study 201 and 89% of patients in Study 12-230.

In Study 201, 68% of patients experienced Grade 3 or 4 infusion reactions; and in Study 12-230, 32% of patients experienced Grade 3 or 4 infusion reactions. Anaphylaxis occurred in 12% of patients and 2 patients (8%) permanently discontinued DANYELZA due to anaphylaxis in Study 201. One patient in Study 12-230 (1.4%) experienced a Grade 4 cardiac arrest 1.5 hours following completion of DANYELZA infusion.

In Study 201, infusion reactions generally occurred within 24 hours of completing a DANYELZA infusion, most often within 30 minutes of initiation. Infusion reactions were most frequent during the first infusion of DANYELZA in each cycle. Eighty percent of patients required reduction in infusion rate and 80% of patients had an infusion interrupted for at least one infusion-related reaction.

Premedicate with an antihistamine, acetaminophen, an H2 antagonist and corticosteroid as recommended [see Dosage and Administration (2.2)].Monitor patients closely for signs and symptoms of infusion reactions during and for at least 2 hours following completion of each DANYELZA infusion in a setting where cardiopulmonary resuscitation medication and equipment are available.

Reduce the rate, interrupt infusion, or permanently discontinue DANYELZA based on severity and institute appropriate medical management as needed[see Dosage and Administration (2.3) and Contraindications (4)].

DANYELZA can cause severe neurotoxicity, including severe neuropathic pain, transverse myelitis, and reversible posterior leukoencephalopathy syndrome.

Pain

Pain, including abdominal pain, bone pain, neck pain, and extremity pain, occurred in 100% of patients in Study 201 and 94% of patients in Study 12-230. Grade 3 pain occurred in 72% of patients in Study 201. One patient in Study 201 (4%) required interruption of an infusion due to pain. Pain typically began during the infusion of DANYELZA and lasted a median of less than one day in Study 201 (range less than one day and up to 62 days) [see Adverse Reactions (6.1)].

Premedicate with drugs that treat neuropathic pain (e.g., gabapentin) and oral opioids. Administer intravenous opioids as needed for breakthrough pain[see Dosage and Administration (2.2)].Permanently discontinue DANYELZA based on severity[see Dosage and Administration (2.3)].

TransverseMyelitis

Transverse myelitis has occurred with DANYELZA. Permanently discontinue DANYELZA in patients who develop transverse myelitis[see Dosage and Administration (2.3)].

ReversiblePosteriorLeukoencephalopathySyndrome(RPLS)

Reversible posterior leukoencephalopathy syndrome (RPLS) (also known as posterior reversible encephalopathy syndrome or PRES) occurred in 2 (2.8%) patients in Study 12-230. Events occurred 2 and 7 days following completion of the first cycle of DANYELZA. Monitor blood pressure during and following DANYELZA infusion and assess for neurologic symptoms [see Warnings and Precautions (5.3)]. Permanently discontinue DANYELZA in case of symptomatic RPLS [see Dosage and Administration (2.3) and Adverse Reactions (6.1)].

PeripheralNeuropathy

Peripheral neuropathy, including peripheral sensory neuropathy, peripheral motor neuropathy, paresthesia, and neuralgia, occurred in 32% of patients in Study 201 and in 25% of patients in Study 12-230. Most signs and symptoms of neuropathy began on the day of the infusion and neuropathy lasted a median of 5.5 days (range 0 to 22 days) in Study 201 and 0 days (range 0 to 22 days) in Study 12-230 [see Adverse Reactions (6.1)].

Permanently discontinue DANYELZA based on severity[see Dosage and Administration (2.3)]. NeurologicalDisordersoftheEye

Neurological disorders of the eye including unequal pupils, blurred vision, accommodation disorder, mydriasis, visual

impairment, and photophobia occurred in 24% of patients in Study 201 and 19% of patients in Study 12-230. Neurological disorders of the eye lasted a median of 17 days (range 0 to 84 days) in Study 201 with two patients (8%) experiencing an event that had not resolved at the time of data cutoff, and a median of 1 day (range less than one day to 21 days) in Study 12-230. Permanently discontinue DANYELZA based on severity [see Dosage and Administration (2.3) and Adverse Reactions (6.1)].

ProlongedUrinaryRetention

Urinary retention occurred in 1 (4%) patient in Study 201 and in 3 patients (4%) in Study 12-230. All events in both studies occurred on the day of an infusion of DANYELZA and lasted between 0 and 24 days. Permanently discontinue DANYELZA in patients with urinary retention that does not resolve following discontinuation of opioids [see Dosage

and Administration (2.3) and Adverse Reactions (6.1)].

Hypertension occurred in 44% of patients in Study 201 and 28% of patients in Study 12-230 who received DANYELZA. Grade 3 or 4 hypertension occurred in 4% of patients in Study 201 and 7% of patients in Study 12-

230. Four patients (6%) in Study 12-230 permanently discontinued DANYELZA due to hypertension. In both studies, most events occurred on the day of DANYELZA infusion and occurred up to 9 days following an infusion of DANYELZA.

Do not initiate DANYELZA in patients with uncontrolled hypertension. Monitor blood pressure during infusion, and at least daily on Days 1 to 8 of each cycle of DANYELZA and evaluate for complications of hypertension including RPLS[see Warnings and Precautions (5.2)]. Interrupt DANYELZA infusion and resume at a reduced rate, or permanently discontinue DANYELZA based on the severity[see Dosage and Administration (2.3) and Adverse Reactions (6.1)].

Based on its mechanism of action, DANYELZA may cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential, including pregnant women, of the potential risk to a fetus. Advise females of reproductive potential to use effective contraceptive during treatment with DANYELZA and for two months after

the final dose.[see Use in Specific Populations (8.1, 8.3)].

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)]

·                   Hypertension[see Warnings and Precautions (5.3)]

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/m2/day subcutaneously on Days -4 to 0 and GM-CSF

500 µg/m2/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.

Study201

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-GSF. 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.

1 Adverse reactions were graded using CTCAE version 4.0.

2Pain includes pain, abdominal pain, pain in extremity, bone pain, neck pain, back pain, and musculoskeletal pain.

3Infusion-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.

4Fatigue includes fatigue, asthenia.

5Pyrexia not occurring on the day of infusion or the day following an infusion

6Tachycardia includes sinus tachycardia and tachycardia

7Urticaria, not occurring on the day of infusion or the day following an infusion 8Peripheral neuropathy includes peripheral sensory neuropathy, paresthesia, neuralgia. 9Neurological disorders of the eye includes unequal pupils, blurred vision, and mydriasis.

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.

1The 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).

Study12-230

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-GSF. 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.

1In 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.

2Adverse reactions were graded using CTCAE version 4.0.

3Infusion-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.

4Pain includes pain, abdominal pain, pain in extremity, bone pain, neck pain, back pain, non-cardiac chest pain, flank pain, and musculoskeletal pain.

5Fatigue includes fatigue, asthenia.

6Pyrexia not occurring on the day of infusion or the day following an infusion.

7Peripheral neuropathy includes peripheral sensory neuropathy, peripheral motor neuropathy, paresthesia, neuralgia.

8Neurological disorders of the eye includes unequal pupils, blurred vision, accommodation disorder, visual impairment and photophobia.

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.

1The 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).

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.

The following adverse reactions have been identified from expanded access reports with 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:Transverse myelitis

8.1  regnancy

RiskSummary

Based on its mechanism of action, DANYELZA may cause fetal harm when administered to pregnant women [see Clinical Pharmacology (12.1)]. There are no available data on the use of DANYELZA in pregnant women and no animal reproduction studies have been conducted with DANYELZA. IgG1 monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. Advise pregnant women of potential risk 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% to 4% and 15% to 20%, respectively.

RiskSummary

There are no data on the presence of naxitamab-gqgk in human milk or its effects on the breastfed child, or on milk production, however, human IgG is present in human milk. Because of the potential for serious adverse reactions in a breastfed child from DANYELZA, advise women not to breastfeed during treatment and for 2 months after the final dose of DANYELZA.

DANYELZA may cause fetal harm when administered to a pregnant woman[see Use in Specific Populations (8.1)].

PregnancyTesting

Verify pregnancy status in females of reproductive potential prior to initiating DANYELZA.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment and for 2 months after the final dose of DANYELZA.

The safety and effectiveness of DANYELZA, in combination with GM-CSF for the treatment of relapsed or refractory high-risk neuroblastoma in the bone or bone marrow who have demonstrated a partial response, minor response or stable disease following prior therapy, have been established in pediatric patients 1 year of age and older.

Safety and effectiveness have not been established in pediatric patients younger than 1 year of age.

Neuroblastoma is largely a disease of pediatric and young adult patients. Clinical studies of DANYELZA in combination with GM-CSF did not include patients 65 years of age and older.

Naxitamab-gqgk  is  a  glycolipid  disialoganglioside  (GD2)-binding  recombinant  humanized  monoclonal  IgG1 antibody, that contains human framework regions and murine complementarity-determining regions. Naxitamab-gqgk

is produced in a Chinese hamster ovary cell line and has an approximate molecular weight of 144 kDa without glycosylation.

DANYELZA (naxitamab-gqgk) injection is a sterile, preservative-free, clear to slightly opalescent and colorless to slightly yellow solution for intravenous infusion. Each single-dose vial contains 40 mg of naxitamab-gqgk in 10 mL of solution. Each mL of solution contains 4 mg of naxitamab-gqgk, and citric acid anhydrous (0.71 mg), poloxamer 188 (1.5 mg), sodium chloride (7.01 mg), sodium citrate (6.3 mg), and Water for Injection, USP. The pH is approximately 5.7.

12.1  Mechanism of Action

Naxitamab-gqgk binds to the glycolipid GD2. GD2 is a disialoganglioside that is overexpressed on neuroblastoma cells and other cells of neuroectodermal origin, including the central nervous system and peripheral nerves. In vitro, naxitamab-gqgk was able to bind to cell surface GD2 and induce complement dependent cytotoxicity (CDC) and

antibody dependent cell-mediated cytotoxicity (ADCC).

The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of naxitamab-gqgk have not been fully characterized.

The geometric mean (CV%) maximum plasma concentration (Cmax) 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.

SpecificPopulations

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.

13.1  Carcinogenesis, Mutagenesis, Impairment of Fertility

No animal studies have been conducted to evaluate the carcinogenic or mutagenic potential of naxitamab-gqgk. Dedicated studies evaluating the effects of naxitamab-gqgk on fertility in animals have not been conducted.

Non-clinical studies suggest that naxitamab-gqgk-induced neuropathic pain is mediated by binding of the antibody to the GD2 antigen located on the surface of peripheral nerve fibers and myelin and subsequent induction of immune- mediated cytotoxic activity.

In a nude rat model, slight-moderate hyperplasia and erosion of the glandular mucosa of the stomach occurred, occasionally accompanied by diffuse inflammation. Complete recovery of all histopathological findings in the stomachs of male rats was observed; however, only partial recovery was observed in the stomachs of female rats during the four week off-drug period.

The efficacy of DANYELZA in combination with GM-CSF was evaluated in two open-label, single arm trials in patients with high-risk neuroblastoma with refractory or relapsed disease in the bone or bone marrow, Study 201 and Study 12-230.

Study201

The efficacy of DANYELZA in combination with GM-CSF was evaluated in Study 201 (NCT03363373), a multicenter open-label, single arm trial, in a subpopulation of patients who had refractory or relapsed high-risk neuroblastoma in the bone or bone marrow and demonstrated a partial response, minor response, or stable disease to prior therapy. Patients with progressive disease were excluded. All patients received at least one systemic therapy to treat disease outside of the bone or bone marrow prior to enrollment. Patients received DANYELZA 9 mg/kg/cycle administered as three separate intravenous infusions of 3 mg/kg on Days 1, 3 and 5 of each cycle. Patients received GM-CSF subcutaneously at 250 µg/m2/day on Days -4 to 0 and at 500 µg/m2/day on Days 1 to 5. Preplanned radiation to the primary site was allowed.

The major efficacy outcome measure was overall response rate (ORR) according to the revised International Neuroblastoma Response Criteria (INRC), as determined by independent pathology and imaging review and confirmed by at least one subsequent assessment. An additional efficacy outcome measure was duration of response (DOR).

Of the 22 patients included in the efficacy analysis, 64% had refractory disease and 36% had relapsed disease; the median age was 5 years (range 3 to 10 years), 59% were male; 45% were White, 50% were Asian and 5% were Black. MYCN amplification was present in 14% of patients and 86% of patients were International Neuroblastoma Staging System (INSS) stage 4 at time of diagnosis. Disease sites included 59% in the bone only, 9% in bone marrow only, and 32% in both. Prior therapies included surgery (91%), chemotherapy (95%), radiation (36%), autologous stem cell transplant (ASCT) (18%), and anti-GD2 antibody treatment (18%).

Efficacy results for Study 201 are described in Table 8.

CI = confidence interval NE: not estimable.

aOverall response rate is defined as a complete or partial response according to the revised INRC (2017) that was confirmed by at least one subsequent assessment. Responses were observed in the bone, bone marrow, or both bone and bone marrow.

In an exploratory analysis in the subset of patients previously treated with an anti-GD2 antibody (n=4), one patient demonstrated a confirmed complete response and no patients demonstrated a partial response.

Study12-230

The efficacy of DANYELZA in combination with GM-CSF was evaluated in Study 12-230 (NCT01757626), a single center, open-label, single arm trial, in a subpopulation of patients who had relapsed or refractory high-risk neuroblastoma in bone or bone marrow and demonstrated a partial response, minor response, or stable disease to prior

therapy. Patients with progressive disease were excluded. All patients received at least one systemic therapy to treat

disease outside of the bone or bone marrow prior to enrollment. Patients were required to have received at least one dose of DANYELZA at a dose of 3 mg/kg or greater per infusion and have evaluable disease at baseline according to independent review per the revised INRC.

Patients received DANYELZA 9 mg/kg/cycle administered as three separate intravenous infusions of 3 mg/kg (on Days 1, 3 and 5) in the first week of each cycle. Patients received GM-CSF subcutaneously at 250 µg/m2/day on Days

-4 to 0 and at 500 µg/m2/day on Days 1 to 5. Radiation to non-target bony lesions and soft tissue lesions was permitted at the investigator’s discretion; assessment of response excluded sites that received radiation. The major efficacy

outcome measures were overall response rate (ORR) and duration of response (DOR), as determined by independent pathology and imaging review according to the revised INRC and confirmed by at least one subsequent assessment.

Of the 38 patients included in the efficacy analysis, 55% had relapsed neuroblastoma and 45% had refractory disease; 50% were male, the median age was 5 years (range 2 to 23 years), 74% were White, 8% Asian and 5% were Black, 5% Native American/American Indian/Alaska Native, 3% other races and 5% was not available. MYCN-amplification was present in 16% of patients and most patients were International Neuroblastoma Staging System (INSS) stage 4 (95%). Fifty percent (50%) of patients had disease involvement in the bone only, 11% only in bone marrow, and 39% in both. Prior therapies included surgery (100%), chemotherapy (100%), radiation (47%), autologous stem cell transplant (ASCT) (42%), and anti-GD2 antibody treatment (58%).

Efficacy results are provided in Table 9.

CI = confidence interval

aOverall response rate is defined as a complete or partial response according to the revised INRC (2017) that was confirmed by at least one subsequent assessment. Responses were observed in the bone, bone marrow, or both bone and bone marrow.

In an exploratory analysis in the subset of patients previously treated with an anti-GD2 antibody (n=22), the ORR was 18% (95% CI 5%, 40%), with no patients having a documented response of 6 months or greater.

DANYELZA (naxitamab-gqgk) injection is a sterile, preservative-free, clear to slightly opalescent and colorless to slightly yellow solution for intravenous infusion supplied as a carton containing one 40mg/10 mL (4 mg/mL) single- dose vial.

NDC 73042-201-01

Store DANYELZA vial refrigerated at 2°C to 8°C (36°F to 46°F) in the outer carton to protect from light until time of use.

Advise the patient and caregiver to read the FDA-approved patient labeling (Patient Information). SeriousInfusion-RelatedReactions

Advise patients and caregivers that DANYELZA can cause serious infusion-related reactions and anaphylaxis and to immediately report any signs or symptoms, such as facial or lip swelling, urticaria, or difficulty breathing, that occur during or following the infusion [see Warnings and Precautions (5.1)].

Neurotoxicity

Advise patients and caregivers that DANYELZA can cause neurotoxicity, including severe pain, peripheral neuropathy, neurological disorders of the eye, prolonged urinary retention, transverse myelitis, and reverse posterior

leukoencephalopathy syndrome. Advise patients to contact their healthcare provider for any new or worsening

neurological symptoms.[see Warnings and Precautions (5.2)].

Hypertension

Advise patients and caregivers that DANYELZA can cause hypertension and to immediately report signs or symptoms of hypertension[see Warnings and Precautions (5.3)].

Embryo-FetalToxicity [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1, 8.3)]. Advise females of reproductive potential, including pregnant women, of the potential risk to the fetus.

Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy and to use effective contraception during treatment with and for 2 months after the final dose of DANYELZA

Lactation

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

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