Brivanib alaninate (

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...

/USAN) also known as BMS-582664 is an investigational, anti-tumorigenic drug for oral administration. The drug is being developed by

Bristol-Myers Squibb The Bristol Myers Squibb Company (BMS) is an American multinational pharmaceutical company. Headquartered in New York City, BMS is one of the world's largest pharmaceutical companies and consistently ranks on the ''Fortune'' 500 list of the lar ...

for the treatment of hepatocellular carcinoma or HCC (also called ''malignant hepatoma''), the most common type of liver cancer. Brivanib is no longer in active development. Brivanib alaninate is a multitargeted

tyrosine kinase inhibitor A tyrosine kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a phosph ...

(as is sorafenib). Brivanib alaninate also inhibits VEGFR and

fibroblast growth factor Fibroblast growth factors (FGF) are a family of cell signalling proteins produced by macrophages; they are involved in a wide variety of processes, most notably as crucial elements for normal development in animal cells. Any irregularities in their ...

receptors (FGFR), which is known to play a major role in the etiopathogenesis of HCC. To date, brivanib alaninate has been investigated in 29 studies, including more than 4,000 patients around the world.

Hepatocellular carcinoma (summary)

Hepatocellular carcinoma is a primary cancer of the liver and is more common in men than in women. The disease occurs mostly in people who have scarring of the liver (

cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue rep ...

) or after infection with

hepatitis B Hepatitis B is an infectious disease caused by the '' Hepatitis B virus'' (HBV) that affects the liver; it is a type of viral hepatitis. It can cause both acute and chronic infection. Many people have no symptoms during an initial infection. ...

or hepatitis C. Symptoms include pain and swelling in the abdomen, weight loss, weakness, loss of appetite, and nausea. Hepatocellular carcinoma is a severe and life-threatening disease that is associated with poor overall survival. While the choice of treatment depends mainly on how advanced the disease is, the only proven therapies to cure the cancer are either surgical removal of the tumors or remove and replace the liver via transplantation, but these therapies can only be carried out in very few patients. Other treatments include

chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothe ...

and

immunotherapy Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as ''activation immunotherapies,'' while immunotherap ...

Radiofrequency ablation Radiofrequency ablation (RFA), also called fulguration, is a medical procedure in which part of the electrical conduction system of the heart, tumor or other dysfunctional tissue is ablated using the heat generated from medium frequency alternati ...

and ethanol injection are also used to remove small tumors. As a result of poor liver function,

metastases Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then ...

, or both, only 10% to 20% of patients undergo surgery. In patients having surgery, the 5-year survival rate is only 25% to 50%. Several

chemotherapeutic agents Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothera ...

have been evaluated for the treatment of hepatocellular carcinoma.

Doxorubicin Doxorubicin, sold under the brand name Adriamycin among others, is a chemotherapy medication used to treat cancer. This includes breast cancer, bladder cancer, Kaposi's sarcoma, lymphoma, and acute lymphocytic leukemia. It is often used toge ...

(trade name

Adriamycin Doxorubicin, sold under the brand name Adriamycin among others, is a chemotherapy medication used to treat cancer. This includes breast cancer, bladder cancer, Kaposi's sarcoma, lymphoma, and acute lymphocytic leukemia. It is often used toget ...

; also known as hydroxydaunorubicin), the most widely used agent in HCC, has shown a 4% to 10.5% response rate in patients with HCC. Studies have shown that the overall response (OR) rate, but not

overall survival Survival rate is a part of survival analysis. It is the proportion of people in a study or treatment group still alive at a given period of time after diagnosis. It is a method of describing prognosis in certain disease conditions, and can be use ...

(OS), doubles when doxorubicin was given in combination with

cisplatin Cisplatin is a chemotherapy medication used to treat a number of cancers. These include testicular cancer, ovarian cancer, cervical cancer, breast cancer, bladder cancer, head and neck cancer, esophageal cancer, lung cancer, mesothelioma, ...

IFN Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten the ...

, and

5-fluorouracil Fluorouracil (5-FU), sold under the brand name Adrucil among others, is a cytotoxic chemotherapy medication used to treat cancer. By intravenous injection it is used for treatment of colorectal cancer, oesophageal cancer, stomach cancer, pan ...

. The multi-targeted tyrosine kinase inhibitor

sorafenib Sorafenib, sold under the brand name Nexavar, is a kinase inhibitor drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma), advanced primary liver cancer ( hepatocellular carcinoma), FLT3-ITD positive AML and r ...

(trade name Nexavar), which inhibits

vascular endothelial growth factor receptor VEGF receptors are receptors for vascular endothelial growth factor (VEGF). There are three main subtypes of VEGFR, numbered 1, 2 and 3. Also, they may be membrane-bound (mbVEGFR) or soluble (sVEGFR), depending on alternative splicing. Inh ...

(VEGFR),

platelet-derived growth factor receptor Platelet-derived growth factor receptors (PDGF-R) are cell surface tyrosine kinase receptors for members of the platelet-derived growth factor (PDGF) family. PDGF subunits -A and -B are important factors regulating cell proliferation, cellu ...

, raf,

c-kit Proto-oncogene c-KIT is the gene encoding the receptor tyrosine kinase protein known as tyrosine-protein kinase KIT, CD117 (cluster of differentiation 117) or mast/stem cell growth factor receptor (SCFR). Multiple transcript variants encoding dif ...

, and flt-3, has been shown to inhibit HCC-induced proliferation and angiogenesis. Sorafenib has also been shown to provide a significant improvement in OS in patients with HCC. Based on these results, researchers concluded that this class of agents may be effective in the treatment of HCC.

Biological activity

Brivanib is the alanine ester of a VEGFR-2 inhibitor BMS-540215 and is hydrolyzed to the ''active moiety'' BMS-540215 ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

''. BMS-540215, a dual tyrosine kinase inhibitor, shows potent and selective inhibition of

VEGFR VEGF receptors are receptors for vascular endothelial growth factor (VEGF). There are three main subtypes of VEGFR, numbered 1, 2 and 3. Also, they may be membrane-bound (mbVEGFR) or soluble (sVEGFR), depending on alternative splicing. Inh ...

and fibroblast growth factor receptor ( FGFR)

tyrosine kinases A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases belong to a larger cla ...

. BMS-540215 is an ATP-competitive inhibitor of human

VEGFR-2 Kinase insert domain receptor (KDR, a type IV receptor tyrosine kinase) also known as vascular endothelial growth factor receptor 2 (VEGFR-2) is a VEGF receptor. ''KDR'' is the human gene encoding it. KDR has also been designated as CD309 (cluste ...

, with an IC₅₀ of 25 nmol/L and K_i of 26 nmol/L. In addition, it inhibits

VEGFR-1 Vascular endothelial growth factor receptor 1 is a protein that in humans is encoded by the ''FLT1'' gene. Function ''FLT1'' is a member of VEGF receptor gene family. It encodes a receptor tyrosine kinase which is activated by VEGF-A, VEGF-B, ...

(IC₅₀ = 380 nmol/L) and VEGFR-3 (IC₅₀ = 10 nmol/L). BMS-540215 also showed good selectivity for FGFR-1 (IC₅₀ = 148 nmol/L), FGFR-2 (IC₅₀ = 125 nmol/L), and FGFR-3 (IC₅₀ = 68 nmol/L). Furthermore, BMS-540215 has been shown to selectively inhibit the proliferation of

endothelial cells The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...

stimulated by

VEGF Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors ...

and FGF ''in vitro'' with IC₅₀ values of 40 and 276 nmol/L, respectively. It also shows broad-spectrum ''in vivo'' antitumor activity over multiple dose levels and induces stasis in large tumors, suggesting that it may have a role in the treatment of hepatocellular carcinoma (HCC).

Pharmacokinetic and pharmacodynamic profiles

Mechanisms of action

The exact mechanisms by which brivanib treatment induces growth inhibition are not well understood. Ongoing research has shown that brivanib affects the host endothelium based on both ''in vitro'' and ''in vivo'' effects). Brivanib may prevent the tumor mass from expanding by cutting off the supply of nutrients and growth factors to the tumor cells. A recent study showed that brivanib effectively inhibits tumor growth and that brivanib-induced

growth inhibition ''Growth inhibition'' (GI) is a medical term pertaining to cancer therapy and the specific reduction in growth of tumors and oncogene cells by a chemical compound, mechanical therapy (e.g. electroporation), radiation, gene therapy, protein therapy, ...

is associated with inactivation of VEGFR-2, increased apoptosis, a reduction in microvessel density, inhibition of cell proliferation, and

down-regulation In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary pr ...

of cell cycle regulators, including cyclin D1, Cdk-2, Cdk-4, cyclin B1, and phospho-c-Myc. Based on this study, researchers have concluded that cell cycle arrest due to a reduction in positive cell cycle regulators may be responsible for the observed growth inhibition. The same study showed that treatment with brivanib also led to a decrease in the number of proliferating cells compared with control.

Ongoing clinical development

While a phase II trial for hepatocellular carcinoma showed an acceptable safety profile and results indicating efficacy against HCC, four subsequent phase III trials found no increased survival and increased rates of adverse effects when compared with

or placebo.

Regulatory status

On 27 October 2011,

orphan designation An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases. The assignment of ...

(EU/3/11/918) was granted by the

European Commission The European Commission (EC) is the executive of the European Union (EU). It operates as a cabinet government, with 27 members of the Commission (informally known as "Commissioners") headed by a President. It includes an administrative body ...

to Bristol-Myers Squibb for brivanib alaninate for the treatment of hepatocellular carcinoma.orphan designation
/ref> At the time of the orphan designation, several medicines were authorized in the EU for the treatment of hepatocellular carcinoma.

References

External links

* * * * *{{ClinicalTrialsGov, NCT01253668, Brivanib Metastatic Renal Cell Carcinoma

Public summary of opinion on orphan designation. Brivanib alaninate for the treatment of hepatocellular carcinoma

New drug information/Abbreviate
Scientific Narrative
Bristol Myers Squibb Experimental cancer drugs Prodrugs Indole ethers at the benzene ring Amino acid derivatives Carboxylate esters