Tagraxofusp-erzs

Tagraxofusp-erzs Uses, Dosage, Side Effects, Food Interaction and all others data.

Tagraxofusp-erzs is an IL-3 conjugated truncated diphtheria toxin. It is composed by the catalytic and translocation domains of diphtheria toxin fused via Met-His linker to a full-length human IL-3. Tagraxofusp-erzs was developed by Stemline Therapeutics Inc and FDA approved on December 21, 2018, as the first therapy for blastic plasmacytoid dendritic cell neoplasm. This drug achieved approval after being designated with the title of breakthrough therapy, priority review, and orphan drug status. Tagraxofusp-erzs has been designated as an orphan drug in the EU since November 2015.

In vitro studies showed that BPDCN blasts are ultrasensitive to tagraxofusp by presenting IC50 values in the femtomolar scale. 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.

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.

Tagraxofusp-erzs
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	Tagraxofusp-erzs
Availability	Prescription only
Generic	Tagraxofusp
Tagraxofusp Other Names	Diphtheria toxin-il-3 fusion protein targeting IL-3 receptor, Tagraxofusp, tagraxofusp-erzs
Type	Intravenous
Formula	C₂₅₅₃ H₄₀₂₆ N₆₉₂ O₇₉₈ S₁₆
Protein binding	Tagraxofusp is not a substrate of p-glycoprotein and other efflux pump proteins associated with multidrug resistance.
Groups	Approved, Investigational
Therapeutic Class
Manufacturer
Available Country	United States
Last Updated:	September 19, 2023 at 7:00 am

Uses

Tagraxofusp-erzs is a CD123-directed cytotoxin used to treat plasmacytoid dendritic cell neoplasm.

Tagraxofusp-erzs 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.

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. 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.

Tagraxofusp-erzs is also used to associated treatment for these conditions: Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)

How Tagraxofusp-erzs works

Tagraxofusp-erzs 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). 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.

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

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.

Tagraxofusp-erzs Disease Interaction

Major: capillary leak syndromeModerate: hepatotoxicity, severe renal impairment

Volume of Distribution

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

Elimination Route

The reported Cmax in clinical trials was of around 23 ng/ml. 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.