Danyelza (naxitamab) is a new drug indicated to treat relapsed or refractory high-risk neuroblastoma with dissemination to bone or bone marrow in children (1 year of age and older) and adults who have demonstrated a partial response, minor response, or stable disease to prior therapy.

Danyelza is administered in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF).

Danyelza, developed by Y-mAbs Therapeutics, was approved by the U.S. Food and Drug Administration (FDA) in November 2020. The regulatory verdict is conditional, meaning Danyelza has yet to definitively confirm its own therapeutic efficacy.

For Danyelza sales in other markets, Y-mAb has already signed a number of agreements. Thus, Takeda Pharmaceutical will handle its sales in Israel, SciClone Pharmaceuticals International will be responsible for Danyelza sales in China, and Swixx BioPharma will sell the drug in Eastern Europe and Russia.

Danyelza (naxitamab).


What Is Neuroblastoma?

Neuroblastoma is a malignant tumor arising from primordial (primary) cells of the sympathetic nervous system. Neuroblastoma is the most common type of extracranial solid tumor in children. The adrenal medulla and paraspinal or periaortic region are most commonly affected. Neuroblastoma, being a clinically heterogeneous disease, is characterized by highly variable outcomes, from spontaneous tumor regression to aggressive therapy-resistant progression.

The treatment of neuroblastoma is carried out according to how the disease is classified according to the risk stratification system (based on the complex of histological features, grade of tumor differentiation, presence of chromosomal aberrations, gene amplifications and mutations, genomic alterations) that predicts clinical outcomes. Thus, if we are talking about high-risk neuroblastoma, an intensive multimodal approach is used, including three phases: induction (chemotherapy, surgical resection), consolidation (myeloablative chemotherapy with autologous hematopoietic stem cell transplant, radiotherapy), maintenance (differentiation therapy with isotretinoin, immunotherapy).

Among patients with high-risk neuroblastoma, 10% to 50% do not achieve remission after induction/consolidation therapy and are classified as refractory and 50% to 60% of those who complete the treatment will relapse. The two-year post-progression/relapse survival rates range from 8% to 29%, and 10-year overall survival rates are around 14%.

Before naxitamab, there was no approved pharmacotherapy for patients with high-risk neuroblastoma that is relapsed or refractory.


Danyelza: Efficacy of Neuroblastoma Treatment with Naxitamab

The regulator ruled in favor of naxitamab based on interim results gathered from two clinical trials that evaluated the safety and efficacy of Danyelza. Outpatient participants received naxitamab in combination with GM-CSF — 3 times a week, 1 month apart.

The ongoing NCT03363373 phase 2 clinical trial (non-randomized, open-label, multicenter, international) enrolled patients aged 1 year and older with high-risk neuroblastoma that is metastatically localized in bone and/or bone marrow and is characterized by either primary refractory to treatment or incomplete response to salvage therapy. In both cases, there had to be disease stabilization, minor response, or partial response. Patients with progressive disease were excluded.

Baseline data for the 22 subjects included in the treatment efficacy analysis:

  • refractory disease in 64% of patients, relapsing disease in 36%
  • median age 5 years (3–10)
  • 59% of men
  • MYCN amplification in 14%
  • stage 4 neuroblastoma in 86%
  • disease dissemination sites: bone only in 59%, bone marrow only in 9%, bone and bone marrow in 32%
  • prior therapy included: surgery (91% of participants), chemotherapy (95%), radiation (36%), autologous stem cell transplant (18%), and anti-GD2 antibody treatment (18%).

The primary endpoint, defined by overall response rate (ORR), was achieved by 45% (95% CI: 24–68; n=9/22) of subjects, with 36% having a complete response (CR) and the remaining 9% having a partial response (PR).

The median duration of response (DoR) was 6.2 months (95% CI: 4.9–NE), with 30% reporting response to treatment for 6 months or longer.

Updated data are as follows:

  • treatment of 24 patients with relapsed and/or refractory high-risk neuroblastoma with naxitamab resulted in an ORR of 79% (95% CI: 58–93; n=19/24), including a complete response in 71% (95% CI: 49–87)
  • 16 patients with primary refractory disease had an ORR of 88% (95% CI: 62–98; n=14/16), including a CR of 81% (95% CI: 54–96)
  • in 8 patients with incomplete response to salvage therapy, ORR and CR rates reached 63% (95% CI: 24–91) and 50% (95% CI: 16–84), respectively
  • almost all patients (n=13/14) who had neuroblastoma metastasized to bone marrow were completely free of metastases
  • the median progression-free survival (PFS) stopped at 42 weeks (95% CI: 26–NE).

The ongoing NCT01757626 phase 1/2 clinical trial (non-randomized, open-label) invited the aforesaid patient population.

Baseline data of the 38 subjects included in the treatment efficacy analysis:

  • refractory disease in 55% of patients, relapsing disease in 45%
  • median age 5 years (2–23)
  • 50% of men
  • MYCN amplification in 16%
  • stage 4 neuroblastoma in 95%
  • disease dissemination sites: bone only in 50%, bone marrow only in 11%, bone and bone marrow in 39%
  • prior therapy included: surgery (100% of participants), chemotherapy (100%), radiation (47%), autologous stem cell transplant (42%), and anti-GD2 antibody treatment (58%).

As can be seen, participants in NCT01757626 were characterized by a more advanced state of neuroblastoma compared to participants in NCT03363373.

ORR was recorded for 34% (95% CI: 20–51; n=13/38) of subjects, including CR 26% and PR 8%. The median DoR has not yet been established but a response to treatment of 6 months or more was noted in 23% of patients.

Updated data are as follows:

  • among 28 patients with primary refractory high-risk neuroblastoma: ORR 78%, PFS at 2 years in 50%
  • among 35 patients with relapsed neuroblastoma resistant to salvage therapy: ORR 37%, PFS at 2 years in 36%
  • among 44 patients with high-risk neuroblastoma showing second (or even later) complete remission and with no evidence of disease, naxitamab maintenance therapy together with GM-CSF provided a 2-year PFS rate of 52%.


Danyelza: Safety of Neuroblastoma Treatment with Naxitamab

The prescribing information of Danyelza has a black box warning, as the administration of naxitamab can lead to serious adverse events associated with its infusions, such as cardiac arrest, anaphylaxis, hypotension, bronchospasm, stridor.

These adverse reactions (of any severity) were experienced by 94–100% of patients, with severe reactions occurring in 32–68% and serious reactions in 4–18%.

This is why premedication is recommended before each infusion of naxitamab: intravenous corticosteroids before the first Danyelza infusion and for subsequent infusions if there are any issues. In addition, an antihistamine, an H2 antagonist, acetaminophen, and an antiemetic are administered before each infusion.

Danyelza administration can also cause severe neurotoxicity, including severe neuropathic pain, transverse myelitis, and reversible posterior leukoencephalopathy syndrome (RPLS).

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Neuropathic pain (of any severity) was found in 94–100% of patients: abdominal pain, bone pain, neck pain, extremity pain.

Premedication was recommended for neuropathic pain: with gabapentin followed by oral and intravenous opioids immediately before and during the infusion of naxitamab, respectively.


Danyelza: Mechanism of Action of Naxitamab

Naxitamab (Hu3F8) is a humanized IgG1 monoclonal antibody targeting the human tumor-associated antigen GD2. The latter, being a disialoganglioside, is limited in expression in normal cerebellar and peripheral nerve tissues and is highly expressed on tumors of neuroectodermal origin, such as neuroblastoma and melanoma. Naxitamab induces complement-dependent cytotoxicity (CDC) antibody-dependent cell-mediated cytotoxicity (ADCC) against GD2-expressing tumor cells.

Neuroblastoma is quite suitable for immunotherapy with different effectors. Neuroblastoma. Molecular Mechanisms and Therapeutic Interventions, 2019, pp. 147–173.

Naxitamab is said to be characterized by stronger GD2 binding than other anti-GD2 antibodies.

Thus, unlike the chimeric monoclonal antibody Unituxin/Qarziba (dinutuximab) by United Therapeutics, approved in 2015 by the FDA and the European Medicines Agency (EMA) for second-line therapy of high-risk neuroblastoma in children in the combination of GM-CSF, interleukin 2 (IL-2) and 13-cis-retinoic acid (isotretinoin), naxitamab has reduced immunogenicity (allowing for no problem with repeat treatment), enhanced ADCC effect, shorter infusion time (30 minutes instead of 10–20 hours), and a reduced burden of adverse reactions (such as strong neuropathic pain, anaphylaxis and anaphylactoid reactions, immunocomplex disease). As a result, naxitamab may well be used as an outpatient — the safety profile of dinutuximab requires an inpatient stay of at least four days each treatment cycle.

That’s how it is: outpatient administration of naxitamab for the 36 patients was achieved for 495/519 (95%) of infusions with similar rates across cycles and infusions, the median duration of all infusions was 37 minutes (17–97).


Danyelza: What’s Next for Naxitamab

Y-mAbs Therapeutics wants to bring naxitamab to the first-line treatment of high-risk pediatric neuroblastoma, and to do so is conducting the NCT03033303 phase 2 clinical trial in which it is testing the drug in combination with GM-CSF and isotretinoin among patients who have reached first remission status which is defined as complete response or very good partial response (VGPR). The hypothesis is that experimental therapy can permanently stop the growth of neuroblastoma.

Naxitamab is also being rolled out in the NCT03189706 phase 2 clinical trial in alternative treatment for relapsed and/or refractory high-risk neuroblastoma; the combination of Danyelza with GM-CSF and the chemotherapeutic irinotecan and temozolomide is being tested.

It is possible that naxitamab (with GM-CSF) will prove suitable as part of second-line therapy for recurrent osteosarcoma: the NCT02502786 phase 2 clinical trial among patients with second (or later) complete remission hopes to prolong it and/or prevent disease recurrence.

Danyelza (naxitamab).


Omburtamab: Healing Power of Radiation for Neuroblastoma

The Y-mAbs drug pipeline includes the radiopharmaceutical (therapeutic and diagnostic) experimental drug omburtamab (8H9), formerly burtomab. This is a murine monoclonal antibody targeting the surface glycoprotein B7-H3 and conjugated to a radioisotope element — iodine-131 (131I), iodine-124 (124I), or lutetium-177 (177Lu). Omburtamab reaches target cells by delivering a cytotoxic dose of beta particles to them. B7-H3 (CD276), which is an immune checkpoint and negative regulator of T-cell activation, is overexpressed on certain types of tumor cells and various immune cells and is responsible for immune surveillance evasion, tumor invasion, and metastasis.

Omburtamab is being clinically evaluated in the treatment of the following oncology diseases:

  • NCT03275402 phase 2/3: neuroblastoma with metastasis to the central nervous system or meninges (leptomeningeal)
  • NCT04022213 phase 2: desmoplastic small round cell tumor (DSRCT) and other peritoneal solid tumors
  • NCT04167618 phase 1/2: recurrent or refractory medulloblastoma
  • NCT04315246 phase 1/2: solid tumors (primary ductal or lobular breast cancer, non-small cell lung cancer, or malignant melanoma) with metastasis to the meninges
  • NCT01502917 phase 1: non-progressive diffuse intrinsic pontine glioma (DIPG) that has undergone radiation.

In 2021, Y-mAbs is going to send to the FDA and EMA the Biologics License Application (BLA) and Marketing Authorisation Application (MAA), respectively, for omburtamab for the treatment of pediatric patients with CNS/leptomeningeal metastasis from neuroblastoma.


Nivatrotamab: Dual Specificity for Neuroblastoma

Y-mAbs deals with nivatrotamab (Hu3F8-BsAb), a fully human bispecific antibody targeting GD2 and CD3 receptors for precision redirection of cytotoxic T cells (CTL) to GD2-expressing tumors. In preclinical trials, nivatrotamab has demonstrated efficacy greater than 1,000 times than conventional anti-GD2 antibodies, including naxitamab.

Nivatrotamab is the first T-cell-engaging antibody utilizing the BiClone format to enter clinical trials. The BiClone format utilizes an IgG-scFv format to maximize tumor binding and T-cell recruitment and minimize risk of non-specific T-cell engagement.

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Nivatrotamab is in the NCT03860207 phase 1/2 clinical trial in the therapy of relapsed and/or refractory neuroblastoma, high-grade osteosarcoma, and other GD2-expressing solid tumors.

The NCT04750239 phase 1/2 clinical trial, which will test therapy with nivatrotamab for metastatic small cell lung cancer (SCLC) that has relapsed or progressed after at least one line (no more than three) of platinum-containing chemotherapy with partial or complete response, is scheduled to start.


Cancer Vaccine for Neuroblastoma

Of particular interest to Y-mAbs is an experimental bivalent cancer vaccine designed to immunize patients with high-risk neuroblastoma who were previously treated with naxitamab and have gone into remission. The cancer vaccine, containing the GD2L and GD3L antigens, stimulates the immune system to produce antibodies against GD2 and GD3, which should prevent disease recurrence.

The cancer vaccine in the NCT00911560 phase 1/2 clinical trial has already demonstrated adequate efficacy, with two-year PFS and OS rates of 44%±5% and 88%±4% and five-year rates of 36%±7% and 70%±8%, respectively.


SADA: Liquid Radiation for Neuroblastoma

Y-mAbs prepares to launch first clinical trials of new SADA (Self-Assembly and DisAssembly) pre-targeted radioimmunotherapy technology for the treatment of GD2-positive solid tumors, colon cancer (GPA33), breast cancer (HER2), prostate cancer (B7-H3), and hematological cancers expressing CD33.

Traditional radioimmunotherapy delivers a radioactive payload to the right tumor cells but does not do so with acceptable efficacy and safety because the antibody motif of such drugs often cannot bind to the target antigen and continues to circulate aimlessly in the body, poisoning it.

The SADA approach refers to two stages of therapy. The antibody constructs, administered to the patient, assemble in tetramers and bind to the tumor target. Unbound constructs predictably disassemble into smaller antibody fragments and are excreted through the kidneys rapidly, within hours after administration. In a second infusion, a radioactive payload binds to the antibody constructs, that have already bound to their targets, to radiate the tumor.



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Y-mAbs Therapeutics. Company presentation. April 2021. [PDF]

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ESMO 2020. Efficacy and updated safety results from pivotal phase II trial 201 of naxitamab (Hu3F8), a humanized GD2 targeted immunotherapy for the treatment of refractory/relapsed (R/R) high-risk (HR) neuroblastoma (NB). [PDF]

ESMO 2020. Pivotal trial 201 data on outpatient administration of naxitamab (Hu3F8), a humanized GD2 targeted immunotherapy for the treatment of refractory/relapsed (R/R) high-risk (HR) neuroblastoma (NB). [PDF]

SIOP 2020. International, multicenter phase II trial with humanized anti-GD2 monoclonal antibody naxitamab for treatment of refractory/relapsed high-risk neuroblastoma: efficacy and safety. [PDF]

SIOP 2020. Naxitamab, an antibody with distinct complementary determining regions and high binding affinity to disialoganglioside GD2. [PDF]

Y-mAbs Therapeutics. SADA technology platform. Liquid radiation. December 16, 2020. [PDF]

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