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AVEO, Astellas Seek to Hang Tivozanib Hat on PFS Data

By Marie Powers

Staff Writer

AVEO Pharmaceuticals Inc. and partner Astellas Pharma Inc. reported top-line data from the global, randomized Phase III TIVO-1 trial indicating that lead compound tivozanib demonstrated superiority over Nexavar (sorafenib, Onyx) in advanced renal cell carcinoma (RCC), meeting the primary endpoint of progression-free survival (PFS).

TIVO-1 is the first registration study comparing an investigational agent – in this case, an oral, once-daily, investigational tyrosine kinase inhibitor – against an approved VEGF therapy in first-line RCC.

Cambridge, Mass.-based AVEO offered an upbeat assessment of the data. The 517 patients enrolled in TIVO-1 had clear cell RCC, had undergone a prior nephrectomy and had not previously been treated with either a VEGF or mTOR therapy. Based on the top-line analysis of events in TIVO-1 as determined by a blinded, independent review committee, tivozanib demonstrated a statistically significant improvement in PFS, with a median PFS of 11.9 months compared to a median PFS of 9.1 months for sorafenib in the overall study population, according to the company.

In treatment-naïve patients, who represented approximately 70 percent of the study population, the difference was more pronounced, with tivozanib demonstrating a median PFS of 12.7 months compared to a median PFS of 9.1 months for sorafenib.

In addition, AVEO said tivozanib was well tolerated, consistent with its Phase II experience, with hypertension the most commonly reported side effect. The company did not disclose details of the safety findings.

Based on the findings, AVEO and Astellas, of Tokyo, said they plan to submit a single core dossier for marketing approval of tivozanib in the U.S. and Europe this year, subject to final analysis of complete trial data.

The next step is a pre-new drug approval meeting with regulatory authorities to determine what data to include in the parallel submissions, according to Tuan Ha-Ngoc, AVEO's president and CEO. "At that time, we'll have a more definitive idea of when exactly in 2012 we'll be in a position to make the submissions on both sides of the ocean," he said.

"There can never be any better New Year's present," Ha-Ngoc told BioWorld Today.

Investors didn't share the company's optimism, however. AVEO shares (NASDAQ:AVEO) fell $3.37 Tuesday, or 19.6 percent, on 14 times average volume even as the broader market was posting hefty gains. The stock closed at $13.83, near the bottom of its 52-week range.

While declining to comment on the stock movement, Ha-Ngoc vigorously defended the study results, which were reported as the company nears its 10-year anniversary. In addition to showing statistically meaningful superiority to Nexavar and meeting endpoints that address unmet medical need, the compound also demonstrated a good safety profile, delivering "a solid foundation on which we can start delivering, first, tivozanib and then the rest of our pipeline," he said.

"Sometimes people focus only on efficacy, and of course for cancer that is foremost in the mind of patients and physicians," he added. "But the safety part is very important. If you cannot tolerate the drug, you have to get off the treatment. What good is a drug with nine, 10, 11 or 12 months of PFS if, by month six, you have to get out of treatment?"

On top of that, cancer patients are seeking drugs that allow them "to have as normal a life as possible" during treatment, Ha-Ngoc said, adding that many currently suffer as much from their therapy as from the disease itself. In both of those respects, tivozanib will prove superior in RCC, he maintained.

Although the FDA has keyed on overall survival data in recent years when reviewing cancer compounds, Ha-Ngoc said the company received assurances from regulatory agencies during its post-Phase II meetings that PFS will be accepted as the standard for approval in first-line RCC.

"Once the patient progresses on first-line, the patient will go on to additional second- or sometimes third- or fourth-line therapies, and the survival data will be so confounded that you cannot draw any conclusions," he explained.

In addition, last month FDA officials publicly stated at an ODAC meeting that they would accept PFS as the endpoint for RCC, "which gives us an additional level of timely assurance," Ha-Ngoc said.

Study participants continue to be observed to gather additional data for further analyses, with detailed findings from TIVO-1 scheduled for presentation at the American Society of Clinical Oncology's annual meeting in June.

Although AVEO raised more than $100 million last June in an underwritten public offering and has built an infrastructure to launch tivozanib, the drug must succeed commercially for AVEO to fully leverage its partnership with Astellas, which calls for up to $1.3 billion in milestones. (See BioWorld Today, Feb. 17, 2011, and June 16, 2011.)

The global agreement includes the application of tivozanib to a broad range of cancers, with AVEO leading commercialization in North America and Astellas leading commercialization in the European Union. AVEO and Astellas are evaluating the compound in colorectal cancer and plan to launch a study in breast cancer this year.

In a flash update, Canaccord Genuity analyst George Farmer suggested AVEO might have to rely on its partner's clout to propel the compound's commercial success.

"Along with safety data, we believe the Street will also be looking for tivozanib performance in cytokine-experienced patients, which constituted about 30 percent of the TIVO-1 treatment population," Farmer wrote. "While all data so far suggest that tivozanib is superior to standard-of-care Sutent [sunitinib, Pfizer Inc.] for treatment of RCC, we see a challenging marketing battle ahead with axitinib [Inlyta, Pfizer Inc.], which we expect will win approval as second-line treatment by the April 29 PDUFA date, but will be used off-label in front-line disease. Muscle from marketing partner Astellas will be essential for tivozanib market position, in our view."