Tivozanib (AV-951)

 

Click here for information on TIVO-1 Phase 3 trial in advanced renal cell carcinoma

 

Tivozanib, AVEO’s lead product candidate, is a highly potent and selective oral inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2 and 3 currently in Phase 3 development. VEGF is produced by the body and stimulates growth of new blood vessels, a process known as angiogenesis. Angiogenesis is required to support certain important natural processes such as embryonic development, reproduction and wound healing, but also plays an important role in cancer progression and the spread of tumors within the body, or metastasis. By blocking the VEGF pathway, VEGF inhibitors starve cancer cells of the blood and nutrients they need to survive and grow. This mechanism has shown to provide benefit to patients with a wide range of cancer types, including renal cell carcinoma (RCC), metastatic breast cancer, colorectal cancer, non-small cell lung cancer, liver cancer and brain cancer.

 

AVEO has completed a 272-patient Phase 2 clinical trial of tivozanib in advanced RCC. Data presented at the March 2010 Genitourinary Cancers Symposium (ASCO GU) showed the median progression-free survival (PFS) of patients with clear-cell RCC who had undergone nephrectomy (surgical removal of a kidney) was 14.8 months based on independent radiology assessments. More than 80% of patients who received tivozanib experienced some degree of tumor shrinkage while on therapy.

 

In addition, tivozanib was well-tolerated with a low rate of off-target toxicities commonly associated with other targeted therapies, such as mucositis, fatigue and hand-foot syndrome.  Hypertension (50%) and dysphonia (hoarseness of voice, 21.7%) were the most commonly reported treatment-related adverse events, mostly grades 1 and 2. Hypertension is believed to be directly related to the mechanisms of VEGF pathway inhibition and development of hypertension was associated with improved clinical outcomes among patients treated with tivozanib.

 

Following the successful completion of the Phase 2 trial, AVEO initiated patient enrollment in TIVO-1, a global Phase 3 clinical trial of tivozanib in patients with advanced RCC. TIVO-1 is evaluating the efficacy of tivozanib compared to sorafenib (Nexavar®), a product currently marketed in both the U.S. and Europe for the treatment of RCC. TIVO-1 is the first Phase 3 study designed to evaluate superiority in a head-to-head comparison against a widely prescribed anti-angiogenesis therapy in first-line RCC. The primary endpoint of the trial is to compare the PFS of tivozanib vs. sorafenib. Secondary endpoints include overall survival, objective response rate, safety and quality of life.  In February 2010, AVEO initiated enrollment in TIVO-1, and has successfully reached the target enrollment of 500 patients. TIVO-1 is being led by Robert Motzer, M.D. from the Memorial Sloan-Kettering Cancer Center.

 

In June 2010, AVEO received orphan medicinal product designation for tivozanib for the treatment of RCC by the European Medicines Agency (EMA). According to the EMA, tivozanib was awarded orphan medicinal product designation based on the prevalence of RCC among people in the European Union (EU); the life-threatening nature of the disease particularly for those with advanced or metastatic RCC; and the assumption that tivozanib may provide significant benefit for patients with RCC, and may be more potent and specific than existing treatments with similar mechanism of action as supported by preliminary clinical results. Companies that receive orphan medicinal product designation by the EMA receive, among other benefits, market exclusivity in the EU for ten years following market authorization, protocol assistance, reduced fees and the opportunity to receive grants from the EU and member states supporting research and development.

 

AVEO believes that tivozanib’s favorable efficacy and safety profile increases its potential to be combined with other anti-cancer agents in a manner that may produce better clinical outcomes. As a result, the company has initiated a series of clinical trials evaluating tivozanib in combination with other agents in multiple solid tumor settings, including an ongoing Phase 1b trial in combination with temsirolimus (Torisel®), an approved mTOR inhibitor, in patients with metastatic renal cell carcinoma (mRCC); a Phase 1b trial in combination with the FOLFOX6 chemotherapy regimen in patients with advanced colorectal cancer and other gastrointestinal cancers; and a Phase 1b trial in combination with paclitaxel (Taxol®) in patients with metastatic breast cancer. A Phase 1b trial evaluating tivozanib as monotherapy in patients with non-small cell lung cancer (NSCLC) is also being conducted.

 

AVEO is also utilizing its Human Response Platform™ (HRP) to help identify rational drug combinations and patient populations most likely to be responsive to these combination therapies.

 

AVEO licensed exclusive rights to develop and commercialize tivozanib (originally KRN951) in all territories outside of Asia from Kyowa-Kirin (formerly Kirin Brewery Co. Ltd.) in January 2007.

 

Patients are invited to visit www.clinicaltrials.gov for more information regarding tivozanib clinical trials, or contact AVEO’s clinical operations department at clinicaltrials@aveopharma.com.