Brentuximab vedotin

Brentuximab vedotin

Monoclonal antibody
Type	Whole antibody
Source	Chimeric (mouse/human)
Target	CD30
Clinical data
Trade names	Adcetris
License data	US FDA: Brentuximab
Pregnancy category	US: D (Evidence of risk)
Routes of administration	Intravenous
ATC code	L01XC12 (WHO)
Legal status
Legal status	US: ℞-only
Identifiers
Synonyms	SGN-35, previously cAC10-vcMMAE
CAS Number	914088-09-8 N
ChemSpider	none
UNII	7XL5ISS668 N
Chemical and physical data
Formula	C6476H9930N1690O2030S40 (C68H105N11O15)3–5
Molar mass	149.2–151.8 kg/mol
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Brentuximab vedotin (INN, trade name Adcetris) is an antibody-drug conjugate (ADC) directed to the protein CD30, which is expressed in classical Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL).

On 28 February 2011 Seattle Genetics submitted a Biologics License Application or BLA to the U.S. Food and Drug Administration (FDA) for the use of brentuximab vedotin in relapsed or refractory Hodgkin's lymphoma and relapsed or refractory systemic anaplastic large cell lymphoma.^[1]

The drug was granted accelerated approval by the FDA^[2] on August 19, 2011 for relapsed HL and relapsed sALCL and conditional Marketing authorization from the European Medicines Agency in October 2012^[3] for relapsed or refractory HL and relapsed or refractory sALCL.^[4]

Design

Brentuximab vedotin ^[5] consists of the chimeric monoclonal antibody brentuximab (cAC10, which targets the cell-membrane protein CD30) linked to cathepsin cleavable linker (valine-citrulline), para-aminobenzylcarbamate spacer three to five units of the antimitotic agent monomethyl auristatin E (MMAE, reflected by the 'vedotin' in the drug's name).^[6] The peptide-based linker bonds the antibody to the cytotoxic compound in a stable manner so the drug is not easily released from the antibody under physiologic conditions to help prevent toxicity to healthy cells and ensure dosage efficiency. The peptide antibody-drug bond facilitates rapid and efficient drug cleavage inside target tumor cell. The antibody cAC10 part of the drug binds to CD30 which often occurs on diseased cells but rarely on normal tissues.The antibody portion of the drug attaches to CD30 on the surface of malignant cells, delivering MMAE which is responsible for the anti-tumour activity.^[7][8] Once bound brentuximab vedotin is internalised by endocytosis and thus selectively taken up by targeted cells. The vesicle containing the drug is fused with lysosomes and lysosomal cysteine proteases, particularly cathepsin B start to break down valine-citrulline linker and MMAE is no longer bound to the antibody and is released directly into the tumor environment. ^[9]

Skeletal formula of brentuximab vedotin. Three to five units of MMAE are attached to the monoclonal antibody (MAB) brentuximab via the spacer paraaminobenzoic acid (marked green), a cathepsin-cleavable linker (Cit=citrulline, Val=valine, marked blue), and an attachment group consisting of caproic acid and maleimide (marked brown).^[8][10]

Clinical trials

In a 2010 clinical trial,^[11] 34% of patients with refractory Hodgkin Lymphoma achieved complete remission and another 40% had partial remission.^[12] Tumor reductions were achieved in 94% of patients. In ALCL, 87% of patients had tumors shrink at least 50% and 97% of patients had some tumor shrinkage.^[13] Reports from the 55th Annual Meeting of the American Society of Hematology (2013) showed interim results^[14] from a Phase II, open-label, single-arm study designed to evaluate the antitumor activity of brentuximab vedotin in relapsed or refractory CD30-positive NHL, including B-cell neoplasms. These results demonstrated that single-agent brentuximab vedotin induced a 42% objective response rate and manageable safety profile among advanced diffuse large B-cell lymphoma patients.^[15][16] An ongoing phase III trial funded by Millennium Pharmaceuticals has the objective of comparing ABVD (a combination of chemotherapy drugs doxorubicin, bleomycin, vinblastine, and dacarbazine used for treatment of Hodgkin lymphoma) and brentuximab vedotin in combination with AVD (doxorubicin, vinblastine, and dacarbazine) for treatment of classical Hodgkin lymphoma. A phase I study shows that a high number of patients using combination of brentuximab vedotin and ABVD experienced pulmonary toxic effects, however 0 patients had pulmonary toxic effects when treated with brentuximab vedotin and AVD, proving that bleomycin- brentuximab vedotin interaction caused these effects. 24 out of 25 patients treated with brentuximab vedotin and AVD achieved complete remission but further studies are required to find progression-free survival time and measure the effectiveness of this new combination therapy.^[17] Brentuximab vedotin is also investigated as a substitute for vincristine (another mitotic inhibitor which prevents tubulin polymerization) which is used in non-Hodgkin lymphoma chemotherapy regimen CHOP (consisting of cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone or prednisolone). A phase III clinical trial is currently comparing the two combination therapies (CHOP and CHP- brentuximab vedotin) with estimated completion in December 2017.^[18]

Serious adverse events

Brentuximab vedotin was studied as monotherapy in 160 patients in two phase II trials. Across both trials, the most common adverse reactions (≥20%), regardless of causality, were chemotherapy-induced peripheral neuropathy (a progressive, enduring and often irreversible tingling numbness, intense pain, and hypersensitivity to cold, beginning in the hands and feet and sometimes involving the arms and legs), neutropenia (an immune system impairment), fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, fever, rash, thrombocytopenia, cough and vomiting.^[19]

Black box warning

On January 13, 2012, the FDA announced that because brentuximab vedotin had been linked with two cases of progressive multifocal leukoencephalopathy, they were requiring the addition of a black box warning to the drug regarding this potential risk.^[20]

Interactions

Patients who are receiving strong CYP3A4 inhibitors concomitantly with brentuximab vedotin should be closely monitored for serious adverse events.^[19]

Development and marketing collaboration

Brentuximab vedotin is marketed as Adcetris.^[21] Seattle Genetics and Millennium Pharmaceuticals/Takeda Oncology are jointly developing brentuximab vedotin. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and the Takeda Group has rights to commercialize in the rest of the world. Seattle Genetics and the Takeda Group are funding joint development costs for brentuximab vedotin on a 50:50 basis, except in Japan where the Takeda Group will be solely responsible for development costs.

Approval In Australia

The Australian PBAC (Pharmaceutical Benefits Advisory Committee) considered a March 2014 application by the manufacturer for inclusion of Brentuximab Vedotin under a Pharmaceutical Benefits Scheme Section 100 (Efficient Funding of Chemotherapy) arrangement. While this application was accepted, the committee noted that on the basis of inadequate cost-benefit, the medicine would not be made available more generally for the first-line treatment of relapsed or refractory systemic anaplastic large cell lymphoma (sALCL).^[22]

References