Brivanib Alaninate

Name: Brivanib Alaninate (also known as BMS-540215; BMS-582664; Brivanib and ZL-2301)

Current development status: In January 2017 Bristol-Myers Squibb discontinued a Phase-II clinical trial for Cervical cancer (Late-stage disease, Metastatic disease, Second-line therapy or greater) in the United States. In June 2018 Zai Lab planed a phase III registration trial in liver cancer for patients in Chin.

Summary of Scientific Narrative
The summary of Scientific Narrative is based on published medical literature, public information and information sources from US and European regulatory authorities. All recommendations must be considered in the light of the patients’ clinical condition. Before prescribing any medication always consult the complete prescribing information for your country or territory.

All brand names are trademarks or registered trademarks of their respective owners.

Pharmaco-therapeutic Group
Antineoplastic agents

Pharmacologic class
Dual tyrosine kinase inhibitor

Chemical Structure


Chemical designation (IUPAC)

CS)-(R)-1-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl)oxy)propan-2-yl 2-aminopropanoatehemical

Molecular formula

C22H24FN5O4

Appearance
Brivanib alaninate also known as BMS-582664 is an investigational, anti-tumorigenic drug for oral administration. The drug is being developed by Bristol-Myers Squibb for the treatment of hepatocellular carcinoma or HCC (also called malignant hepatoma), the most common type of liver cancer.

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) or after infection with hepatitis B 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 is surgery to remove the tumor and liver transplantation, but these therapies can only be carried out in very few patients. Other treatments include chemotherapy and immunotherapy . Radiofrequency ablation and ethanol injection are also used to remove small tumors.

As a result of poor liver function, metastases, 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 have been evaluated for the treatment of hepatocellular carcinoma. Doxorubicin, 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 (OS), doubles when doxorubicin was given in combination with cisplatin, IFN, and 5-fluorouracil. The multitargeted tyrosine kinase inhibitor sorafenib (Nexavar®, Bayer and Onyx Pharmaceuticals), which inhibits vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor, raf, c-kit, 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. Brivanib alaninate also inhibits vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor 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.

Biological Activity
Brivanib is the alaninate salt of a VEGFR-2 inhibitor BMS-540215 and is hydrolyzed to the active moiety BMS-540215 in vivo. BMS-540215, a dual tyrosine kinase inhibitor, shows potent and selective inhibition of [[VEGFR]] and fibroblast growth factor receptor (FGFR) tyrosine kinases.[1,2]

BMS-540215 is an ATP-competitive inhibitor of human VEGFR-2, with an IC50 of 25 nmol/L and Ki of 26 nmol/L. In addition, it inhibits VEGFR-1 (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 stimulated by VEGF and FGF in vitro with IC50 values of 40 and 276 nmol/L, respectively.[3,4] 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 & Pharmacodynamic Profiles
BMS-582664 was originally prepared in an effort to improve the aqueous solubility and oral bioavailability of the parent compound BMS-540215. Both BMS-540215 and its orally active ester prodrug BMS-582664 (brivanib alaninate), demonstrate broad-spectrum in vivo antitumor activity over multiple dose levels as well as being effective at inducing stasis in large tumors. Brivanib alaninate can also be safely dosed in combination with other targeted and cytotoxic drugs including paclitaxel (Taxol®, Bristol-Myers Squibb) resulting in enhanced antitumor activity as observed by a long period of tumor growth inhibition.

Mechanisms of action (MOA)
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 [1] showed that brivanib effectively inhibits tumor growth and that brivanib-induced [[growth inhibition]] is associated with inactivation of VEGFR-2, increased apoptosis, a reduction in microvessel density, inhibition of cell proliferation, and [[down-regulation]] 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.

Dosing
Doses required for achieving complete tumor stasis do not produce overt toxicity as defined by weight loss, mortality or unkempt appearance and behavior. The prodrug brivanib alaninate, which is completely hydrolyzed to BMS-540215 in vivo, has pharmacokinetic properties suitable for once a day or twice daily oral dosing.

Completed and ongoing clinical trials show that brivanib alaninate appears to be tolerable and may exhibits favorable pharmacokinetic and pharmacodynamic profiles with evidence of target inhibition in surrogate tissues. Clinical and pharmacodynamic data support an oral once daily administration at 800 mg. The investigational drug shows promising activity as single agent in HCC. Brivanib also shows promising activity in combination with cetuximab (Erbitux®, Bristol-Myers Squibb/Merck KGgA) in colorectal cancer.[5] Further evaluations are currently ongoing.

Regulatory Status
On 27 October 2011, [orphan designation] (EU/3/11/918) was granted by the European Commissionto Bristol-Myers Squibb Pharma EEIG, United Kingdom, for brivanib alaninate for the treatment of hepatocellular carcinoma. Designated orphan medicinal products are products that are still under investigation and are considered for orphan designation on the basis of potential activity. An orphan designation is not a marketing authorisation. As a consequence, demonstration of quality, safety and efficacy is necessary before a product can be granted a marketing authorisation. At the time of the orphan designation, several medicines were authorised in the EU for the treatment of hepatocellular carcinoma.

Submission and application
At the time of submission of the application for orphan designation, clinical trials with brivanib alaninate in patients with hepatocellular carcinoma were ongoing. As part of the submission process, Bristol-Myers Squibb has provided sufficient information to show that brivanib alaninate might be of significant benefit for patients with hepatocellular carcinoma because it could provide an alternative for patients who cannot take or for whom existing treatments do not work. Early studies show that it might improve the treatment of patients with this condition, particularly if used when existing treatment had
failed. However, this assumption needs to be confirmed at the time of EU marketing authorisation, in order to maintain the orphan status.

References
[1] Huynh H, Ngo VC, Fargnoli J, Ayers M, Soo KC, Koong HN, et al. Brivanib Alaninate, a Dual Inhibitor of Vascular Endothelial Growth Factor Receptor and Fibroblast Growth Factor Receptor Tyrosine Kinases, Induces Growth Inhibition in Mouse Models of Human Hepatocellular Carcinoma Clin Cancer Res. 2008 Oct 1;14(19):6146-53
[2] Cai ZW, Zhang Y, Borzilleri RM, Qian L, Barbosa S, Wei D, Zheng X, et al. Discovery of brivanib alaninate ((S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate), a novel prodrug of dual vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 kinase inhibitor (BMS-540215). J Med Chem. 2008 Mar 27;51(6):1976-80
[3] Ayers M, Fargnoli J, Lewin A, Wu Q, Platero JS. Discovery and Validation of Biomarkers that Respond to Treatment with Brivanib Alaninate, a Small-Molecule VEGFR-2/FGFR-1 Antagonist Cancer Res. 2007 Jul 15;67(14):6899-906
[4] Bhide RS, Cai ZW, Zhang YZ, Qian L, Wei D, Barbosa S, et al. Discovery and preclinical studies of (R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5- methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan- 2-ol (BMS-540215), an in vivo active potent VEGFR-2 inhibitor. J Med Chem. 2006 Apr 6;49(7):2143-6
[5] Cetuximab With or Without Brivanib in Treating Patients With K-Ras Wild Type Tumours and Metastatic Colorectal Cancer – ClinicalTrials.gov Identifier: NCT00640471

For more information

  • Brivanib (BMS-582664) in advanced solid tumors (AST): Results of a phase II randomized discontinuation trial(RDT).
  • Ascending Multiple-Dose Study of Brivanib Alaninate in Combination With Chemotherapeutic Agents in Subjects With Advanced Cancers – ClinicalTrials.gov Identifier: NCT00798252
  • A Phase I Study to Determine the Effect of Food on Brivanib (BMS-582664) – ClinicalTrials.gov Identifier: NCT00437437
  • Phase II Study of Brivanib (BMS-582664) to Treat Multiple Tumor Types – ClinicalTrials.gov Identifier: NCT00633789
  • Brivanib Alaninate in Treating Patients With Recurrent or Persistent Endotetrial Cancer – ClinicalTrials.gov Identifier: NCT00888173
  • Brivanib Metastatic Renal Cell Carcinoma. – ClinicalTrials.gov Identifier: NCT01253668
  • Public summary of opinion on orphan designation. Brivanib alaninate for the treatment of hepatocellular carcinoma

Page last update: September 19, 2018

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