5/18/2018 Axicabtagene ciloleucel - DrugBank

Axicabtagene ciloleucel

Targets (1)

IDENTIFICATION

Name Axicabtagene ciloleucel

Accession Number

DB13915

Type

Biotech

Groups

Approved

Biologic Classification Cell transplant therapies Autologous cell transplant

Description Axicabtagene ciloleucel is a chimeric antigen receptor (CAR) therapy for the treatment of Diffuse large B-cell (DLBCL), which is a type of a non-Hodgkin lymphoma (NHL). It is the second cell-based that is FDA-approved but the first in the treatment of large B- cell lymphoma in adult patients. Uniquely, axicabtagene ciloleucel utilizes each patient’s own immune system where each dose of the drug consists of the patient's genetically modified T-cells that were previously collected. The modified version of the T-cell expresses a new gene that targets and kills the lymphoma cells and is infused back into the patient.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of NHL in adults that mostly originates from the lymph nodes but can initiate outside of the lymphatic system. Lymphoma cells appear to be much larger in size than normal lymphocytes. In a multicenter clinical trial, the https://www.drugbank.ca/drugs/DB13915 1/9 5/18/2018 Axicabtagene ciloleucel - DrugBank patients who were treated with axicabtagene ciloleucel achieved the complete remission rate of 51%.

Developed by , Inc., it was approved on October 18th, 2017 by the FDA as an intravenously infused anticancer therapy and is marketed under the brand name Yescarta.

Synonyms

Autologous T cells transduced with retroviral vector encoding an anti-CD-19 CD28/CD3-zeta chimeric antigen rec eptor

External IDs

KTE-C19

Prescription Products

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MARKETING MARKETING NAME ↑↓ DOSAGE ↑↓ STRENGTH ↑↓ ROUTE ↑↓ LABELLER ↑↓ START ↑↓ END ↑↓ ↑↓ ↑↓

Yescarta Suspension 2000000 Intravenous Kite Pharma, 2017-10-18 Not applicable 1/68mL Inc.

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Categories Not Available

UNII U2I8T43Y7R

CAS number Not Available

PHARMACOLOGY

Indication

Indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma aer two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and https://www.drugbank.ca/drugs/DB13915 2/9 5/18/2018 Axicabtagene ciloleucel - DrugBank DLBCL arising from .

Structured Indications

Refractory Diffuse large B-cell lymphoma NOS

Refractory High grade B-cell lymphoma Burkitt-like lymphoma

Refractory Primary Mediastinal Large B-Cell Lymphoma

Relapsed Diffuse large B-cell lymphoma NOS

Relapsed High grade B-cell lymphoma Burkitt-like lymphoma

Relapsed Primary Mediastinal Large B-Cell Lymphoma

Pharmacodynamics

The levels of cytokines, chemokines and other blood molecules were measured over a 4-week interval aer the drug infusion. There were transient elevations of chemokines such as IL-6, IL-8, IL-10, IL-15, TNF-α, IFN-γ, and sIL2Rα where the peak elevation was reached within the first 14 days aer infusion, and the levels gradually returned to baseline within 28 days [FDA Label]. It is likely that axicabtagene ciloleucel may lead to aplasia, or low numbers of B cells or absent B cells, as expected by other chimeric anntigen receptor T-cell therapies.

Mechanism of action The CD 19 antigen is a 95 kDa integral membrane glycoprotein expressed on lymphocytes of the B-cell lineage but noton pluripotent stem cell. While this antigen is ubiquitously expressed on B lymphocyte lineage, the expression of this Ig protein is downregulated during terminal differentiation of premature and mature B cells into plasma cells [1]. In blood disorders, however, the expression CD19 is maintained in in B-lineage cells that has undergone neoplastic transformation [1]. Thus CD19 plays a critical role in clinical oncolgy as it aids in the diagnosis of blood cancers such as leukemias and and serves as a therapeutic target for immunotherapies.

Axicabtagene ciloleucel is a CD19-directed genetically modified autologous T cell immunotherapy that binds to CD19-expressing cancer cells and normal B cells. First, the patient's own peripheral blood mononuclear cells are obtained. The T cells are then harvested and genetically modified ex vivo by retroviral transduction to express a chimeric antigen receptor (CAR) comprising a murine anti-CD19 single chain variable fragment (scFv) linked to CD28 and CD3-zeta co-stimulatory domains [FDA Label]. These anti-CD19 CAR T cells are expanded and infused back into the patient.

Once the modified CAR T cells recognize the CD19-expressing target cells, the CD28 and CD3-zeta co-stimulatory domains activate downstream signaling cascades that lead to T-cell activation, proliferation, acquisition of effector functions and secretion of inflammatory cytokines and chemokines [FDA Label]. These events lead to elimination of the target cells.

https://www.drugbank.ca/drugs/DB13915 3/9 5/18/2018 Axicabtagene ciloleucel - DrugBank

A B-lymphocyte antigen CD19

antibody

Human

Absorption Following infusion of YESCARTA, anti-CD19 CAR T cells exhibited an initial rapid expansion followed by a decline to near baseline levels by 3 months. Peak levels of anti-CD19 CAR T cells occurred within the first 7-14 days aer YESCARTA infusion [FDA Label]. The mean AUC in Day 0-28 in responding patient was 557.1 days x cells/μL [FDA Label].

Volume of distribution

Not Available

Protein binding Not Available

Metabolism Not Available

Route of elimination

Not Available

Half life Not Available

Clearance Not Available

Toxicity Axicabatagene ciloleucel is reported to induce cytokine release syndrome (CRS) and neurotoxicity. No carcinogenicity or genotoxicity studies as well as reproductive toxicity studies have not been conducted with axicabatagene ciloleucel.

Affected organisms

Humans and other mammals

Pathways Not Available https://www.drugbank.ca/drugs/DB13915 4/9 5/18/2018 Axicabtagene ciloleucel - DrugBank Not Available

Pharmacogenomic Effects/ADRs

Not Available

INTERACTIONS

Drug Interactions

Not Available

Food Interactions

Not Available

REFERENCES

General References

1. Scheuermann RH, Racila E: CD19 antigen in leukemia and lymphoma diagnosis and immunotherapy. Leuk Lymphoma. 1995 Aug;18(5-6):385-97. [PubMed:8528044]

External Links PubChem Substance

347911476

Wikipedia Axicabtagene_ciloleucel

FDA label

Download (210 KB)

CLINICAL TRIALS

Clinical Trials

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PHASE ↑↓ STATUS ↑↓ PURPOSE ↑↓ CONDITIONS ↑↓ COUNT ↑↓ 1, 2 Recruiting Treatment Acute Lymphoblastic Leukaemias (ALL) 2 https://www.drugbank.ca/drugs/DB13915 5/9 5/18/2018 Axicabtagene ciloleucel - DrugBank

1, 2 Recruiting Treatment Refractory Diffuse Large B Cell Lymphoma 1

1, 2 Recruiting Treatment Refractory Diffuse Large B Cell Lymphoma / Refractory 1 Primary Mediastinal B Cell Lymphoma / Refractory Transformed Follicular Lymphoma / Relapsed/Refractory Large B Cell Lymphoma Including DLBCL, PMBCL, TFL and HGBCL Aer Two Systemic Lines of Therapy" in Phase 2 Expanded Cohorts / Relapsed/Refractory Transplant Ineligible Diffuse Large B Cell Lymphoma / Relapsed/Refractory Transplant Ineligible Primary Mediastinal B Cell Lymphoma / Relapsed/Refractory Transplant Ineligible Transformed Follicular Lymphoma

2 Recruiting Treatment Follicular Lymphoma (FL) / Indolent Non-Hodgkin's 1 Lymphomas / Marginal Zone Lymphoma

2 Recruiting Treatment Relapsed/Refractory Mantle Cell Lymphoma 1

3 Recruiting Treatment Relapsed/Refractory Diffuse Large B-Cell Lymphoma 1 (DLBCL)

Not Available Not Available Relapsed/Refractory Diffuse Large B Cell Lymphoma / 1 Available Relapsed/Refractory High-Grade B-Cell Lymphoma / Relapsed/Refractory Primary Mediastinal B Cell Lymphoma / Relapsed/Refractory Transformed Follicular Lymphoma / Relapsed/Refractory Transplant Ineligible Diffuse Large B Cell Lymphoma / Relapsed/Refractory Transplant Ineligible Primary Mediastinal B Cell Lymphoma / Relapsed/Refractory Transplant Ineligible Transformed Follicular Lymphoma

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PHARMACOECONOMICS

Manufacturers

Not Available

Packagers

Not Available

Dosage forms

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https://www.drugbank.ca/drugs/DB13915 6/9 5/18/2018 Axicabtagene ciloleucel - DrugBank

FORM ↑↓ ROUTE ↑↓ STRENGTH ↑↓ Suspension Intravenous 2000000 1/68mL

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Prices

Not Available

Patents

Not Available

PROPERTIES

State

Solid

Experimental Properties

Not Available

TAXONOMY

Classification

Not classified

TARGETS

1. B-lymphocyte antigen CD19

Kind

Protein

Organism

Human

Pharmacological action

Yes https://www.drugbank.ca/drugs/DB13915 7/9 5/18/2018 Axicabtagene ciloleucel - DrugBank

Actions

Antibody General Function

Receptor signaling protein activity

Specific Function

Assembles with the antigen receptor of B-lymphocytes in order to decrease the threshold for antigen receptor-dependent stimulation.

Gene Name

CD19

Uniprot ID

P15391

Uniprot Name

B-lymphocyte antigen CD19

Molecular Weight

61127.985 Da

Drug created on October 19, 2017 09:01 / Updated on May 02, 2018 00:40

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Data Licenses Support

This project is supported by the Canadian Institutes of Health Research (award #111062), Alberta Innovates - Health Solutions, and by The Metabolomics Innovation Centre (TMIC), a nationally-funded research and core facility that supports a wide range of cutting-edge metabolomic studies. TMIC is funded by Genome Alberta, Genome British Columbia, and Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with funding from the federal government. Maintenance, support, and commercial licensing is provided by OMx Personal Health Analytics, Inc. Designed by Educe Design & Innovation Inc.

https://www.drugbank.ca/drugs/DB13915 9/9