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By Aafia Chaudhry, MD

On May 2, 2013, AVEO Oncology (AVEO) is set to face the FDA's Oncologic Drugs Advisory Committee (ODAC) for a review of the company's New Drug Application (NDA) for tivozanib, the proposed indication for treatment of patients with advanced renal cell carcinoma. The PDUFA goal date for the final decision is by July 28, 2013.

The vascular endothelial growth factor (VEGF) pathway plays a significant role in angiogenesis, which is critical in cancer. Angiogenesis, the formation of new blood vessels, is essential for endothelial cell proliferation, migration and survival. Tivozanib is a potent, selective, long half-life inhibitor of VEGF receptors 1,2 and 3 that is designed to optimize VEGF blockade while minimizing off-target toxicities. Several agents targeting VEGF are already approved for the treatment of advanced renal cell cancer (RCC), including Onyx's (ONXX) sorafenib, Pfizer's (PFE) sunitinib and axitinib, GlaxoSmithKline's (GSK) pazopanib, and Roche's (OTCQX:RHHBY) bevacizumab.

The NDA submission for Tivozanib is based on the TIVO-1 study, a global, randomized, open-label, phase 3 superiority clinical trial evaluating the efficacy and safety of tivozanib, 1.5mg p.o. daily, given in 3 weeks on/1 week off cycle, compared to sorafenib 400mg continuous daily dosing, in 517 patients with advanced RCC. Eighty-six centers participated in the TIVO-1 study, including centers in Europe (the majority) and North America. The primary efficacy endpoint of progression free survival (PFS) was ascertained for each subject by a central panel of blinded independent radiologists. Patients randomized to the sorafenib arm were eligible to cross over to tivozanib therapy under a separate protocol after radiographic confirmation of disease progression. No crossover protocol was available for patients randomized to the tivozanib arm. Importantly, the study was powered at 90% to detect a >45% improvement in median PFS from 6.7 months for sorafenib, to 9.7 months for tivozanib.

Results of TIVO-1 were first released in full at ASCO 2012. 70% of the patients enrolled in the study were treatment naive, and 30% had received prior systemic therapy with cytokines. As reported by the company, based on independent radiological reviews, 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 (Intent To Treat) study population (HR=0.797, 95% CI 0.639-0.993; P=0.042). This represents a 30% improvement in PFS. Objective response rate 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 patients who were treatment naïve for 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). This is the longest median PFS reported to date in treatment naïve advanced RCC patients in a pivotal study. This advantage was also consistently observed in the subpopulation of patients who were pretreated with systemic therapy (30% of total study population), tivozanib demonstrated an improvement in PFS with a median PFS of 11.9 months compared to a median PFS of 9.1 months for sorafenib.

Data for overall survival matured later and were presented in early 2013. The final OS analysis, as specified by the protocol, showed a median OS of 28.8 months (95% confidence interval [CI]: 22.5-NA) for tivozanib versus a median OS of 29.3 months (95% CI: 29.3-NA) for the comparator arm, sorafenib. No statistical difference between the two arms (HR=1.245, p=0.105) was observed.

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Of note, 70% of the patients randomized to the sorafenib arm went on to receive therapy with tivozanib following adjudicated progression. However, in the tivozanib arm, only 36% received subsequent therapy following progression. This likely accounts for the positive survival observed in the comparator arm.

These clinical data should be evaluated in the context of data from comparable oral tyrosine kinase inhibitors approved for RCC.

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Comparisons across studies are difficult to make as the study populations and comparator arms differ. However, we note the following:

The performance of the comparator arm in TIVO-1 far exceeded the projected PFS in this setting, or that observed in prior trials. Despite a vastly over-performing comparator arm, the tivozanib arm still demonstrated a 30% improvement in PFS vs. sorafenib in the primary end point, which was statistically significant. The median OS for the tivozanib arm is longer than that observed with sunitinib, which is considered the current standard of first-line care. The high rate of crossover from sorafenib to tivozanib, (which is highly active as a single agent) is likely to account for the improved OS observed in the comparator arm. Finally a nonsignificant OS is not a barrier to full approval in this setting.

Currently approved therapies for RCC are toxic. Tivozanib possesses a superior safety and tolerability profile compared with sorafenib. The dosing schedule of once a day, 3 weeks on and 1 week off provides patients with a "drug holiday" which helps improve quality of life. As observed in the clinical study, the rate of adverse events and treatment discontinuations was lower in the tivozanib treatment arm.

Unlike some currently approved therapies, there are no suggestions of significant hepatotoxicity or severe myelosuppression.

Additionally, treatment with tivozanib is associated with lower rates of diarrhea, hand-foot syndrome, and significantly less alopecia compared with sorafenib. All of these are highly meaningful to improving a patients' quality of life and will be important to oncologists.

In summary, with Robert Motzer, MD as principal investigator highly likely to be presenting on behalf of the sponsor (a veteran at RCC ODAC meetings), we see very little to suggest that a panel would vote against approval of this drug. While some may argue that the RCC market is crowded, we see tivozanib being used as an alternative to other oral therapies in the frontline setting. The agent's beneficial dosing cycle and superior tolerability profile make this an exciting addition to the current armamentarium. We believe oncologists would want to have this available in the clinic to offer patients. It also adds a useful alternative to more toxic agents used in sequencing for subsequent lines of therapy.

There are some potential issues which could hinder initial uptake. The trial was conducted head to head with sorafenib as a comparator and not versus sunitinib which is the preferred agent of choice in the first-line setting. Some oncologists may want to see comparative data vs. sunitinib before selecting this agent in their first-line patients. Another possible concern is that the study was conducted almost exclusively in eastern Europe. However, given that the events for the primary end point were all independently adjudicated by central radiographic review, and that all the sub-group analyses appear supportive, we do not see this as significant regulatory barrier to approval. Furthermore, we expect the sponsor to present sub-analyses from the US centers at ODAC which should help mitigate concerns.

In the near term, the RCC market is estimated to grow to $1.6Bn by 2016, 80% of which is occupied by angiogenesis inhibitors. Front-line treatment accounts for ~65% of this market, of which we see tivozanib playing a significant role. If 1 in 7 treatment naïve patients are receiving tivozanib as initial therapy by 2016, this would represent near term sales potential of:

$1.6 Bn x 0.8 x 0.65 x 0.14 = $116.5 in first-line sales. This does not represent peak sales potential and does not include further upside from use in the second-, third- and subsequent lines therapy where it will also play a role. Given that AVEO has a worldwide (ex-Asia) partnership with Astellas, the company could also be eligible to receive up to $90 MM in milestone payments in connection with regulatory approval as well as > $780MM in commercial milestones. Subject to regulatory approval, AVEO will lead commercialization of tivozanib in North America and Astellas will lead commercialization of tivozanib in the European Union (EU). The companies will share equally all North American and EU development and commercialization costs and profits for tivozanib. Outside of North America and EU, Astellas will be responsible for the development and commercialization costs of tivozanib and will be obligated to pay AVEO a tiered, double-digit royalty on sales in those territories. In the past 12 months, the stock has traded well above current levels, and we expect it to rise above $10 on a positive vote.

In summary, we expect a positive ODAC panel vote in favor of approval with a positive FDA decision by July 28, 2013.

Source: Aveo's Inflection Point: Tivozanib Likely To Receive Positive Advisory Vote, FDA Approval

Additional disclosure: PropThink is a team of editors, analysts and writers. This article was written by Aafia Chaudhry, MD. We did not receive compensation for this article, and we have no business relationship with any company whose stock is mentioned in this article. Use of PropThink’s research is at your own risk. You should do your own research and due diligence before making any investment decision with respect to securities covered herein. You should assume that as of the publication date of any report or letter, PropThink, LLC and persons or entities with whom it has relationships (collectively referred to as "PropThink") has a position in all stocks (and/or options of the stock) covered herein that is consistent with the position set forth in our research report. Following publication of any report or letter, PropThink intends to continue transacting in the securities covered herein, and we may be long, short, or neutral at any time hereafter regardless of our initial recommendation. To the best of our knowledge and belief, all information contained herein is accurate and reliable, and has been obtained from public sources we believe to be accurate and reliable, and not from company insiders or persons who have a relationship with company insiders. Our full disclaimer is available at www.propthink.com/disclaimer.