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AVEO Pharmaceuticals (AVEO) was founded as Genpath Pharmaceuticals in 2001 in Cambridge, Massachusetts. The company engages in the discovery and development of targeted cancer therapies. AVEO's most advanced pipeline asset is tivozanib, a low-molecular-weight inhibitor of the VEGF receptor for which a marketing application for the treatment of metastatic renal cell carcinoma (RCC) was filed in September 2012.

The Phase-III results for tivozanib in RCC were reported in January 2012. The trial, known as TIVO-1, evaluated the comparative efficacy and safety of tivozanib relative to sorafenib in 517 patients with RCC. TIVO-1 was the first registrational study in 1st-line RCC to compare an investigational agent against an approved VEGF therapy. Based on independent radiological reviews, tivozanib demonstrated a statistically-significant improvement in progression-free survival (PFS) with a median PFS (primary endpoint) of 11.9 months compared to a median PFS of 9.1 months for sorafenib in the intent-to-treat population (HR=0.797, 95% CI 0.639-0.993; P=0.042). Tivozanib's investigators reported a median PFS of 12.7 months which is the longest ever reported for a Phase III trial in treatment-naïve RCC. The objective response rate (ORR) for tivozanib was 33% compared to 23% for sorafenib (P=0.014).

The efficacy advantage of tivozanib over sorafenib was consistent across subgroups in the study. In treatment-naïve patients advanced RCC (70% of total study population), tivozanib demonstrated a statistically-significant improvement in PFS with a median PFS of 12.7 months compared to a median PFS of 9.1 months for sorafenib (HR 0.756, 95% CI 0.580-0.985; P=0.037).

In the subpopulation of patients who were pretreated with systemic therapy including cytokines (30% of total study population), PFS for tivozanib and sorafenib were 11.9 months and 9.1 months, respectively. These results were not statistically significant.

With respect to overall survival (OS), there were a total of 219 deaths, 118 and 101 in the tivozanib and sorafenib arms, respectively. A trend toward longer OS was observed in the sorafenib arm compared with the tivozanib arm (median OS in the tivozanib arm was 28.8 months vs. 29.3 months in the sorafenib arm; HR=1.25, P=0.105).

The OS comparison between study arms was confounded by differential use of next-line cancer therapies. This was expected based on the study's one-way crossover to the experimental therapy after disease progression in the control arm. Significant enrollment in Central and Eastern Europe may have contributed to this result, as access to subsequent effective treatment options for RCC are limited in this region. In North America/Western Europe, a trend toward longer OS was observed with tivozanib compared to sorafenib (HR=0.503; P=0.195); median OS was not reached at the time of analysis in either arm. In the context of overall survival, it must be noted that of the pivotal trials with agents approved for the treatment of RCC since 2005, six of seven failed to show a survival benefit (Table).

Drugs Approved for the Treatment of Renal Cell Carcinoma

Drug

Brand Name

Approved

Indication

Study Design

Clinical Endpoint(s)

Sorafenib

Nexavar

2005

Advanced RCC

sorafenib vs. placebo in 2nd-line patients

PFS for full approval; no OS benefit

Sunitinib

Sutent

2006

First-line metastatic RCC

IFN vs. sunitinib

PFS for full approval; no OS benefit

Temsirolimus

Torisel

2007

First-line metastatic RCC

IFN vs. IFN ± temsirolimus

OS benefit for temsirolimus vs. IFN; No OS benefit for low-dose temsirolimus + IFN

Bevacizumab

Avastin

2009

First-line metastatic RCC

IFN ± bevacizumab

PFS for full approval; no OS benefit

Pazopanib

Votrient

2009

First-line metastatic RCC

pazopanib vs. placebo

PFS benefit for full approval; no OS benefit

Everolimus

Afinitor

2009

Metastatic RCC following failure with sunitinib or sorafenib

everolimus vs. placebo

PFS for full approval

Axitinib

Inlyta

2012

Metastatic RCC following failure with one systemic therapy

axitinib vs. sorafenib

PFS for full approval; no OS benefit

Tivozanib

First- & second- line metastatic RCC

tivozanib vs. sorafenib

PFS for full approval; no OS benefit

With respect to safety, the adverse event profile of tivozanib was superior to sorafenib. Dose reductions were needed in 11.6% of the tivozanib group versus 42.8% of the sorafenib group (P<.001); interruptions occurred in 17.8% of the tivozanib group versus 35.4% of the sorafenib group (P<.001); and discontinuations occurred in 4.2% of the tivozanib group versus 5.4% of the sorafenib group. Overall, there were fewer drug-related adverse events in the tivozanib arm: 67.6% versus 83.3%. Hypertension was the most frequent adverse event related to treatment with tivozanib (for grade 3 or higher, 23.6% in the tivozanib group vs. 15.2% in the sorafenib group). Hypertension is an established on-target effect of angiogenesis inhibitors; in this study it was easily managed with standard anti-hypertensives. As compared with the sorafenib arm, patients in the tivozanib arm also experienced more dysphonia, but less diarrhea, hand-foot syndrome, and alopecia.

Overall, and particularly in the context of the recent history of drugs approved for the treatment of advanced RCC, it is difficult to conceive of circumstances that would preclude the approval of tivozanib. An advisory committee of the FDA is scheduled to review the tivozanib data on May 2, 2013 and a final decision expected by/on July 28, 2013.

In addition to tivozanib, AVEO has a pipeline of monoclonal antibodies that includes ficlatuzumab, an antibody that inhibits hepatocyte growth factor and is currently in Phase II development for the treatment of non-small cell lung cancer, and AV-203, an antibody targeting the ErbB3 receptor that is currently being evaluated in a Phase I study.

AVEO has strategic partnerships with Merck, OSI Pharmaceuticals, Kyowa Hakko Kirin, Astellas, and Biogen Idec. With respect to tivozanib, Kyowa Hakko Kirin has marketing rights in Asia, Astellas has ex-U.S. rights excluding Asia, and AVEO has retained rights to North America.

As of December 31, 2012, the company had cash and short-term equivalents totaling $160 MM and an annual burn rate of ~$130 MM/year. The burn rate is anticipated to decrease now that TIVO-1 has been completed.

Source: Why AVEO Pharmaceuticals' Tivozanib Will Be Approved For The Treatment Of Advanced Renal Cell Carcinoma