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The SARfaris: GPCR, Kinase, ADME

Saturday, 17 May 2014

New Drug Approvals 2014 - Pt. VII - Ramucirumab (Cyramza™)

ATC Code:

On April 21, 2014 the FDA approved Ramucirumab (Cyramza™) for the treatment of patients with advanced or metastatic, gastric or gastroesophageal junction (GEJ) adenocarcinoma with disease progression on or after prior treatment with fluoropyrimidine- or platinum-containing chemotherapy.

Gastric cancer has a very poor prognosis, with adenocarcinomas constituting ~95% of all gastric cancers (CRUK).

In a randomized, double-blind, multicenter study of ramucirumab plus best supportive care (BSC) compared with placebo plus BSC of 355 patients with locally advanced or metastatic gastric cancer (including adenocarcinoma of the gastro-esophageal junction [GEJ]), ramucirumab improved the overall survival to a median of 5.2 months, compared to 3.8 with the placebo arm. Progression-free survival (PFS) was improved from a median of 1.3 months in the placebo arm to 2.1 months in the ramucirumab arm.

Cyramza has been issued a boxed warning because of increases in the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events.

The structure of extracellular domains 2 and 3 of KDR (VEGFR2) in blue in complex with its ligand VEGFC in green. PDB=2x1x

The target of ramucirumab is the extracellular ligand-binding domain of the receptor tyrosine kinase, Vascular endothelial growth factor receptor 2 (KDR, also known as VEGFR2; Uniprot = P35968 ; ChEMBL = CHEMBL279 ;
canSAR = P35968). Ramucirumab specifically binds to KDR (VEGFR2) thus preventing the binding of its ligands VEGF-A, VEGF-C, and VEGF-D. This blockade inhibits ligand-stimulated activation of VEGF Receptor 2 and consequently, inhibits ligand-induced proliferation and migration of human endothelial cells. Elevated expression of the ligands has been shown to be clinically correlated with survival and with metastasis in gastric cancers.

Ramucirumab is administered intravenously 8 mg/kg every 2 weeks. The mean minimum concentrations (Cmin) were 50 μg/mL (6-228 μg/mL) after the third dose and 74 μg/mL (14-234 μg/mL) after the sixth dose.

Cyramza™ is a product of Eli Lilly & Co.

The full prescribing information can be found here

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