Identification

Name

Tagraxofusp

Accession Number

DB14731

Description

Tagraxofusp is an IL-3 conjugated truncated diphtheria toxin.⁴ It is composed by the catalytic and translocation domains of diphtheria toxin fused via Met-His linker to a full-length human IL-3.^6,7 Tagraxofusp was developed by Stemline Therapeutics Inc and FDA approved on December 21, 2018, as the first therapy for blastic plasmacytoid dendritic cell neoplasm.³ This drug achieved approval after being designated with the title of breakthrough therapy, priority review, and orphan drug status.² Tagraxofusp has been designated as an orphan drug in the EU since November 2015.⁷

Type

Biotech

Groups

Approved, Investigational

Biologic Classification

Protein Based Therapies
Fusion proteins

Protein Structure

Protein Chemical Formula

C₂₅₅₃ H₄₀₂₆ N₆₉₂ O₇₉₈ S₁₆

Protein Average Weight

Not Available

Sequences

>>tagraxofusp<<<
MGADDVVDSSKSFVMENFSSYHGTKPGYVDSIQKGIQKPKSGTQGNYDDDWKGFYSTDNK
YDAAGYSVDNENPLSGKAGGVVKVTYPGLTKVLALKVDNAETIKKELGLSLTEPLMEQVG
TEEFIKRFGDGASRVVLSLPFAEGSSSVEYINNWEQAKALSVELEINFETRGKRGQDAMY
EYMAQACAGNRVRRSVGSSLSCINLDWDVIRDKTKTKIESLKEHGPIKNKMSESPNKTVS
EEKAKQYLEEFHQTALEHPELSELKTVTGTNPVFAGANYAAWAVNVAQVIDSETADNLEK
TTAALSILPGIGSVMGIADGAVHHNTEEIVAQSIALSSLMVAQAIPLVGELVDIGFAAYN
FVESIINLFQVVHNSYNRPAYSPGHKTRPHMAPMTQTTSLKTSWVNCSNMIDEIITHLKQ
PPLPLLDFNNLNGEDQDILMENNLRRPNLEAFNRAVKSLQNASAIESILKNLLPCLPLAT
AAPTRHPIHIKDGDWNEFRRKLTFYLKTLENAQAQQTTLSLAIF

References:

1. WHO reports [Link]

Download FASTA Format

Synonyms

• Diphtheria toxin-il-3 fusion protein targeting IL-3 receptor
• Tagraxofusp
• tagraxofusp-erzs

External IDs

• DT-3881L3
• DT388IL3
• Molecule 129
• Molecule-129
• SL-401

Pharmacology

Indication

Tagraxofusp is indicated for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in adults and pediatric patients over 2 years old. This treatment allows an alternative for the previous intense treatment which consisted of intensive chemotherapy followed by bone marrow transplantation.²

BPDCN is a rare hematologic malignancy derived from plasmacytoid dendritic cells. It is characterized by the significantly increased expression of cells expressing CD4/CD56/CD123 and other markers restricted to plasmacytoid dendritic cells and a lack of expression of lymphoid, natural killer or myeloid lineage-associated antigens.¹ A key feature of the malignant cells is the overexpression of CD123, also known as interleukin-3 receptor, and the constant requirement of IL-3 for survival.⁶

Associated Conditions

• Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)

Contraindications & Blackbox Warnings

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Pharmacodynamics

In vitro studies showed that BPDCN blasts are ultrasensitive to tagraxofusp by presenting IC50 values in the femtomolar scale.⁶ One of the main physiological changes of BPDCN is the presence of elevated interferon alpha and to produce an inflammatory response. In trials with tagraxofusp and following cell depletion, there was observed a significant reduction in the levels of interferon alpha and interleukin 6.⁵

In clinical trials, tagraxofusp reported complete remission and complete remission with a skin abnormality not indicative of active disease in 54% of the treated patients.²

Mechanism of action

Tagraxofusp binds to cells expressing the IL-3 receptor and delivers in them the diphtheria toxin after binding. This is very useful as the malignant cells in BPDCN present a particularly high expression of IL-3 receptor (CD123+ pDC).⁵ To be more specific, tagraxofusp gets internalized to the IL-3 receptor-expressing cell allowing for diphtheria toxin translocation to the cytosol and followed by the binding to ADP-ribosylation elongation factor 2 which is a key factor for protein translation. Once the protein synthesis is inhibited, the cell goes under a process of apoptosis.^4,6

As the apoptosis induction requires an active state of protein synthesis, tagraxofusp is not able to perform its apoptotic function in dormant cells.⁶

Target	Actions	Organism
AInterleukin-3 receptor subunit alpha	binder	Humans
AADP-ribosylation factor-like protein 2	binder	Humans

Absorption

The reported Cmax in clinical trials was of around 23 ng/ml.⁶ After a 15 min infusion of a dose of 12 mcg/kg the registered AUC and Cmax was 231 mcg.h/L and 162 mcg/L respectively.^Label

Volume of distribution

In BPDCN patients, the reported volume of distribution is of 5.1 L.^Label

Protein binding

Tagraxofusp is not a substrate of p-glycoprotein and other efflux pump proteins associated with multidrug resistance.⁶

Metabolism

For the metabolism, as tagraxofusp is a fusion protein, it is expected to get processed until small peptides and amino acids by the actions of proteases.

Route of elimination

Tagraxofusp is eliminated as small peptides and amino acids. More studies need to be performed to confirm the main elimination route.

Half-life

The reported half-life of tagraxofusp is of around 51 minutes.⁶

Clearance

The clearance of tagraxofusp was reported to fit a mono-exponential model.⁶ The reported clearance rate is reported to be of 7.1 L/h.^Label

Adverse Effects

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Toxicity

There haven't been analysis observing the carcinogenic, mutagenic potential nor the effect on fertility. However, in studies performed in cynomolgus monkeys at an overdose rate of 1.6 times the recommended dose, it was observed severe kidney tubular degeneration. Similar studies at the recommended dose reported the presence of degeneration and necrosis of choroid plexus in the brain were. This effect seems to be progressive even 3 weeks after therapy withdrawal.^Label

Affected organisms

• Humans and other mammals

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Darbepoetin alfa	The risk or severity of Thrombosis can be increased when Darbepoetin alfa is combined with Tagraxofusp.
Erythropoietin	The risk or severity of Thrombosis can be increased when Erythropoietin is combined with Tagraxofusp.
Methoxy polyethylene glycol-epoetin beta	The risk or severity of Thrombosis can be increased when Methoxy polyethylene glycol-epoetin beta is combined with Tagraxofusp.
Peginesatide	The risk or severity of Thrombosis can be increased when Peginesatide is combined with Tagraxofusp.

Additional Data Available

Extended Description
Extended Description
Extended description of the mechanism of action and particular properties of each drug interaction.
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Severity
Severity
A severity rating for each drug interaction, from minor to major.
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Evidence Level
Evidence Level
A rating for the strength of the evidence supporting each drug interaction.
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Action
Action
An effect category for each drug interaction. Know how this interaction affects the subject drug.
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Food Interactions

Not Available

Products

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Unlock Additional Data
Elzonris	Injection, solution	1000 ug/1mL	Intravenous	Stemline Therapeutics, Inc.	2019-01-18	Not applicable

Additional Data Available

Application Number
Application Number
A unique ID assigned by the FDA when a product is submitted for approval by the labeller.
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Product Code
Product Code
A governmentally-recognized ID which uniquely identifies the product within its regulatory market.
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Categories

ATC Codes

L01XX67 — Tagraxofusp

• L01XX — Other antineoplastic agents
• L01X — OTHER ANTINEOPLASTIC AGENTS
• L01 — ANTINEOPLASTIC AGENTS
• L — ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

Drug Categories

• Amino Acids, Peptides, and Proteins
• Antineoplastic Agents
• Antineoplastic and Immunomodulating Agents
• Narrow Therapeutic Index Drugs
• Proteins
• Recombinant Fusion Proteins
• Recombinant Proteins

Chemical TaxonomyProvided by Classyfire

Description

Not Available

Kingdom

Organic Compounds

Super Class

Organic Acids

Class

Carboxylic Acids and Derivatives

Sub Class

Amino Acids, Peptides, and Analogues

Direct Parent

Peptides

Alternative Parents

Not Available

Substituents

Not Available

Molecular Framework

Not Available

External Descriptors

Not Available

Chemical Identifiers

UNII

8ZHS5657EH

CAS number

2055491-00-2

References

General References

1. Kharfan-Dabaja MA, Lazarus HM, Nishihori T, Mahfouz RA, Hamadani M: Diagnostic and therapeutic advances in blastic plasmacytoid dendritic cell neoplasm: a focus on hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2013 Jul;19(7):1006-12. doi: 10.1016/j.bbmt.2013.01.027. Epub 2013 Feb 5. [PubMed:23396213]
2. FDA news [Link]
3. FDA Approved Drug Products: Apadaz (benzhydrocodone and acetaminophen) tablets [Link]
4. Oncology nursing news [Link]
5. Stemline therapeutics news [Link]
6. Blood journal [Link]
7. NHS reports [Link]

External Links

RxNav

2109054

Wikipedia

Tagraxofusp-erzs

FDA label

Download (455 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
2	Not Yet Recruiting	Treatment	Acute Myeloid Leukemia (AML)	1
2	Recruiting	Treatment	Agnogenic Myeloid Metaplasia / Chronic Myelomonocytic Leukemia	1
2	Recruiting	Treatment	Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)	2
1	Recruiting	Treatment	Acute Myeloid Leukemia (AML) / Myelodysplastic Syndrome	1
1, 2	Completed	Treatment	Acute Myeloid Leukemia (AML)	1
1, 2	Completed	Treatment	Acute Myeloid Leukemia (AML) / Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)	1
1, 2	Completed	Treatment	Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) / Leukemias / Myelodysplastic Syndromes (MDS)	1
1, 2	Completed	Treatment	Multiple Myeloma (MM)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection, solution	Intravenous	1000 ug/1mL

Prices

Not Available

Patents

Not Available

Properties

State

Solid

Experimental Properties

Not Available

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Drug created on December 21, 2018 11:08 / Updated on June 12, 2020 11:42