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Safety - Danyelza
INDICATION 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 partiaI response, minor response, or stable disease to prior therapy.
This indication is approved under accelerated approval based on overalI 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).

Safety

Safety

Safety analysis of patients who received DANYELZA with GM-CSF

DANYELZA can cause serious infusion reactions, including hypotension, bronchospasm, hypoxia, and stridor, as well as severe neurotoxicity, including pain1:

Any-grade infusion-related reactions occurred in 94%−100% of patients

    . Any-grade hypotension occurred in               89%−100% of patients

Any-grade pain occurred in 94%−100% of patients

The most common ARs in Studies 12-230 and 201 (both analyses) (≥25% in either study)1,2

Infusion-related reaction

Erythema multiforme

Pain

Peripheral neuropathy

Tachycardia

Urticaria

Vomiting

Pyrexia

Cough

Headache

Pruritus

Injection site reaction

Nausea

Edema

Diarrhea

Anxiety

Decreased appetite

Localized edema

Hypertension

Irritability

Fatigue

Anemia

AR=adverse reaction.

Total DANYELZA exposure across
Studies 12-230 and 2011,2

Of the 72 patients in Study 12-230, 32% were exposed to DANYELZA with GM-CSF for ≥6 months and 8% for >1 year1

Of the 25 patients in Study 201 (initial analysis), an ongoing multicenter trial, 12% were exposed to DANYELZA with GM-CSF for ≥6 months and 0% for >1 year1

Of the 74 patients in the Study 201
pre-specified interim analysis, 18% were exposed to DANYELZA with GM-CSF for ≥6 months and 3% for ≥1 year2

AR=adverse reaction.

  • *Incidence of events related to DANYELZA or DANYELZA with GM-CSF occurring on day of infusion, after start of infusion.

    †Excludes procedural pain and vessel puncture site pain.

  • In the Study 201 initial analysis, dose interruptions due to an AR occurred in 84% of patients. ARs requiring dosage interruption in >10% of patients included hypotension and bronchospasm1

    In the Study 201 pre-specified interim analysis, dose interruptions due to an AR occurred in 69% of patients. ARs requiring dosage interruption in >10% of patients included hypotension, pain, and bronchospasm2

    *Serious ARs occurring in <5% of patients.

    †Serious ARs occurring in only 1 patient.

    ‡1% each: respiratory depression, myocarditis, hypotension, RPLS, and urticaria.

    RPLS=reversible posterior leukoencephalopathy syndrome.

  • Infusion-related reactions

    Grade 4, Grade 3 and not responding to medical intervention, or Grade 3-4 anaphylaxis
    Pain

    Grade 3 and unresponsive to maximum supportive measures

    Reversible posterior
    leukoencephalopathy
    syndrome (RPLS)

    All grades
    Transverse myelitis

    All grades
    Peripheral neuropathy

    Grade ≥2 motor neuropathy or Grade 3-4 sensory neuropathy

    Neurological disorders
    of the eye

    Grade 2-4 not resolving within 2 weeks or upon recurrence; any grade with subtotal or total vision loss

    Prolonged urinary retention

    Persisting following discontinuation of opioids

    Myocarditis

    Grade 4, Grade 2 or 3 based on severity and duration

    Hypertension

    Grade 4, or Grade 3 and not responding to medical intervention

    Orthostatic hypotension

    Any grade not resolved within 1 week

    Other ARs

    Grade 4, or Grade 3 not resolving to Grade ≤2 within 2 weeks

    *Based on Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

  • Table showing adverse reacNons in Study 12-230, the Study 201 IniNal Analysis, and the Study 201 Pre-specified Interim Analysis Table showing adverse reacNons in Study 12-230, the Study 201 IniNal Analysis, and the Study 201 Pre-specified Interim Analysis

    Adverse reactions were graded using CTCAE v4.0.

    *All adverse reactions occurring in Cycles 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.

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

    ‡Infusion-related reaction includes hypotension, bronchospasm, flushing, wheezing, stridor, urticaria, dyspnea, pyrexia, infusion-related reaction, face edema, edema mouth, periorbital edema, lip swelling, swollen tongue, tongue edema, lip edema, respiratory tract edema, chills, hypoxia, pruritus, rash, rash maculo-papular, and rash erythematous occurring on the day of infusion or the day following an infusion.

    §Fatigue includes fatigue and asthenia.

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

    IIUrticaria not occurring on the day of infusion or the day following an infusion.

    #Tachycardia includes sinus tachycardia and tachycardia

    **Peripheral neuropathy includes peripheral sensory neuropathy, peripheral motor neuropathy, paresthesia, and neuralgia.

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

  • Table showing treatment-emergent laboratory abnormaliNes in Study 12-230, the Study 201 IniNal Analysis, and the Study 201 Pre-specified Interim Analysis Table showing treatment-emergent laboratory abnormaliNes in Study 12-230, the Study 201 IniNal Analysis, and the Study 201 Pre-specified Interim Analysis

    The table presents laboratory parameters with available grading according to CTCAE v4.0 for studies 12-230 and 201, and v5.0 for the 201 pre-specified interim analysis. 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.
    †Range: 23 to 24 patients.

Efficacy: Study Result Mechanism Of Action
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CR=complete response; MIBG=meta-iodobenzylguanidine.

References: 1. Park JR, Bagatell R, Cohn SL, et al. J Clin Oncol. 2017;35(22):2580-2587. 2. DuBois SG, Kalika Y, Lukens JN, et al. J Pediatr Hematol Oncol. 1999;21(3):181-189.
3. Garaventa A, Poetschger U,Valteau-Couanet D, et al. J Clin Oncol. 2021;39(23):2552-2563. 4. Pinto N, Naranjo A, Hibbitts E, et al. Eur J Cancer. 2019;112:66-79. 5. Yanik GA, Parisi MT, Naranjo A, et al. J Nucl Med. 2018;59:502-508. 6. Yanik GA, Parisi MT, Shulkin BL, et al. J Nucl Med. 2013;54(4):541-548. 7. Streby KA, Parisi MT, Shulkin BL, et al. Pediatr Blood Cancer. 2023;70(8):e30418.

References: 1. DANYELZA® [package insert]. New York, NY: Y-mAbs Therapeutics, Inc.; 2024. 2. Data on file. Y-mAbs Therapeutics, Inc.

References: 1. Data on file. Y-mAbs Therapeutics, Inc. 2. DANYELZA® [package insert]. New York, NY: Y-mAbs Therapeutics, Inc.; 2024.

Reference: 1. Data on file. Y-mAbs Therapeutics, Inc.

References: 1. DANYELZA® [package insert]. New York, NY: Y-mAbs Therapeutics, Inc.; 2024. 2. Data on file. Y-mAbs Therapeutics, Inc. 3. NIH US National Library of Medicine. https://clinicaltrials.gov/ct2/ show/NCT01419834?term=NCT01419834&draw=2&rank=1. Accessed April 22, 2024.

References: 1. DANYELZA® [package insert]. New York, NY: Y-mAbs Therapeutics, Inc.; 2024. 2. Data on file. Y-mAbs Therapeutics, Inc.

References: 1. Yanik GA, Parisi MT, Shulkin BL, et al. J Nucl Med. 2013;54(4):541-548. 2. Yanik GA, Parisi MT, Naranjo A, et al. J Nucl Med. 2018;59:502-508. 3. Streby KA, Parisi MT, Shulkin BL, et al. Pediatr Blood Cancer. 2023;e30418. https://doi.org/10.1002/pbc.30418. 4. DANYELZA® [package insert]. New York, NY: Y-mAbs Therapeutics, Inc; 2024.

References: 1. DANYELZA® [package insert]. New York, NY: Y-mAbs Therapeutics, Inc.; 2024. 2. Lisby S, Liebenberg N, Bukrinski J, et al. Presented at the SIOP virtual congress. Abstract #945. October 16, 2020. 3. Cheung N-KV, Guo H, Hu J, et al. Oncoimmunology. 2012;1(4):477-486.

References: 1. Data on file. Y-mAbs Therapeutics, Inc. 2. DANYELZA® [package insert]. New York, NY: Y-mAbs Therapeutics, Inc.; 2024.

References: 1. DANYELZA® [package insert]. New York, NY: Y-mAbs Therapeutics, Inc.; 2024. 2. Data on file. Y-mAbs Therapeutics, Inc.

References: 1. DANYELZA® [package insert]. New York, NY: Y-mAbs Therapeutics, Inc.; 2024. 2. Data on file. Y-mAbs Therapeutics, Inc.

IMPORTANT SAFETY INFORMATION and INDICATION

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. lnfusion 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.
  • 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.

    • Neurotoxicity

  • 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 in DANYELZA clinical studies.
  • Premedicate to treat neuropathic pain as recommended. Permanently discontinue DANYELZA based on the adverse reaction and severity.
CONTRAINDICATION

DANYELZA is contraindicated in patients with a history of severe hypersensitivity reaction to naxitamab-gqgk. Reactions have included anaphylaxis.

WARNINGS AND PRECAUTIONS
Serious 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.

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 two 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.

Caution is advised in patients with pre-existing cardiac disease, as this may exacerbate the risk of severe hypotension.

Premedicate with an antihistamine, acetaminophen, an H2 antagonist and corticosteroid as recommended. 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.

Neurotoxicity

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).

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

Transverse Myelitis
Transverse myelitis has occurred with DANYELZA. Permanently discontinue DANYELZA in patients who develop transverse myelitis.

Reversible Posterior Leukoencephalopathy Syndrome (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. Permanently discontinue DANYELZA in case of symptomatic RPLS.

Peripheral Neuropathy
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.

Permanently discontinue DANYELZA based on severity.

Neurological Disorders of the Eye
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.

Prolonged Urinary Retention
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.

Myocarditis

Myocarditis has occurred in adolescent patients receiving DANYELZA in clinical trials and expanded access programs. Myocarditis occurred within days of receiving DANYELZA requiring drug interruption. Monitor for signs and symptoms of myocarditis during treatment with DANYELZA. Withhold, reduce the dose, or permanently discontinue DANYELZA based on severity.

Hypertension

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. Interrupt DANYELZA infusion and resume at a reduced rate, or permanently discontinue DANYELZA based on the severity.

Orthostatic Hypotension

Orthostatic hypotension has occurred in patients receiving DANYELZA in clinical trials and expanded access programs. Severe orthostatic hypotension, including cases requiring hospitalization, have occurred. Cases occurred within hours to 6 days of DANYELZA infusions in any cycle.

In patients with symptoms of orthostatic hypotension, monitor postural blood pressure prior to initiating treatment with DANYELZA and as clinically indicated with subsequent dosing. Withhold, reduce dose, or permanently discontinue DANYELZA based on severity.

Embryo-Fetal Toxicity

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 last dose.

ADVERSE REACTIONS

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.

INDICATION

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. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Please see full Prescribing Information and Patient Information for DANYELZA including Boxed Warning on serious infusion-related reactions and neurotoxicity.

References: 1. DANYELZA® [package insert]. New York, NY: Y-mAbs Therapeutics, Inc.; 2024.
2. Data on file. Y-mAbs Therapeutics, Inc.

References: 1. Data on file. Y-mAbs Therapeutics, Inc. 2. DANYELZA® [package insert]. New York, NY: Y-mAbs Therapeutics, Inc.; 2024. Available online at https://labeling.ymabs.com/danyelza. 3. Smith V, Foster J. High-risk neuroblastoma treatment review. Children (Basel). 2018;5(9):114. 4. Ahmed A, Zhang L, Reddivalla N, Hetherington M. Neuroblastoma in children: update on clinicopathologic and genetic prognostic factors. Pediatr Hematol Oncol. 2017;34(3):165-185. 5. London W, Castel V, Monclair T, et al. Clinical and biologic features predictive of survival after relapse of neuroblastoma: a report from International Neuroblastoma Risk Group project. J Clin Oncol. 2011;29(24):3286-3292.

References: 1. DANYELZA® [package insert]. New York, NY: Y-mAbs Therapeutics, Inc.; 2024. Available online at https://labeling.ymabs.com/danyelza. 2. National Cancer Institute. Published November 27, 2017. Accessed May 17, 2021. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf

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IMPORTANT SAFETY INFORMATION and INDICATION View less
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