Tivozanib is a small molecule VEGF receptor inhibitor in phase III development for renal cell carcinoma (RCC), developed by AVEO Pharmaceuticals and recently partnered with Astellas Pharma. It will not be the first VEGF pathway inhibitor to reach the market, having been preceded by Avastin, and three other small molecules - Nexavar, Sutent and Votrient. It will also not be the last as several other candidates are in development. AVEO hopes that tivozanib's unique product characteristics will lead to clinical superiority over other small molecules. Tivozanib performed well in an open label phase II study, but phase III represents a greater challenge. Here, we review the available clinical evidence for tivozanib, the odds for success in the pivotal phase III study, and tivozanib's long-term commercial potential as a member of a validated but increasingly crowded class of drugs.

Published: July 31st, 2011

Number of pages: 37

Authors: Dr. Drew Applefield and Dr. Ilana Fogelman


TABLE OF CONTENTS
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INTRODUCTION
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1. Cancer and the role of angiogenesis

2. Renal Cell Carcinoma – a validated target for anti-angiogenesis therapy
- Epidemiology
- Clinical picture
- Current treatments

AVEO PHARMACEUTICALS’ TIVOZANIB
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1. Phase I pilot study
- AVEO’s acquisition and final pilot study results

2. Clinical studies in advanced renal cell carcinoma (RCC)
- TIVO-1, a phase III study in RCC
- Tivosanib plus Torisel (temsirolimus) in advanced RCC
- Tivosanib biomarker study in advanced RCC

3. Clinical studies in other indications
- Tivozanib plus FOLFOX6 in advanced colorectal and other gastrointestinal cancers
- Tivozanib plus Taxol (paclitaxel) in advanced breast cancer
- Tivozanib monotherapy in advanced non-small cell lung cancer (NSCLC)
- Tivozanib plus Afinitor (everolimus) in advanced colorectal cancer
- Tivozanib plus Xeloda (capecitabine) in advanced solid tumors

CLINICAL AND REGULATORY DISCUSSION
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1. The VEGF pathway as a cancer target for RCC

2. Does tivozanib possess unique activity that is relevant to clinical outcomes?
- Potency
- Target specificity
- Which of the three VEGFR drives response?
- Pharmacokinetics

3. Activity and safety in phase II RCC study

4. Hypertension – is it good or bad?

5. What is the likelihood of tivozanib’s success in phase III?

6. Will AVEO’s tivozanib studies be sufficient to support approval?

MARKET ISSUES
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1. Market opportunity for tivozanib as a monotherapy in RCC

2. The impact of a restricted label – clear cell histology and prior nephrectomy

3. Pipeline competition

4. Can tivozanib be applied to other types of cancer besides RCC?
- Colorectal Cancer (CRC)
- Non-small cell lung cancer (NSCLC)
- Breast Cancer

5. Is tivozanib suitable for use in combination?

6. Royalty arrangements will impact net revenue on tivozanib sales

SUMMARY OPINION
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