Update: On November 2, 2011, Aveo’s chief executive, Tuan Ha-Ngoc, revealed in the company’s third quarter results that headline data from Tivo-1 will not be available until the first quarter of 2012: “Importantly, based on the most recent review of the event data in our ongoing Phase 3 trial of tivozanib, TIVO-1, we believe we are on track to reach the necessary number of events in the fourth quarter, which means we now expect to announce top-line data in the first quarter of 2012."
News that Bayer’s Nexavar missed consensus estimates in the first quarter is not the news it or partner Onyx Pharmaceuticals needed, with use of the drug in kidney cancer under serious threat if Aveo Pharmaceuticals’ tivozanib wins a head-to-head trial.
Results from the Tivo-1 trial are expected within the next few months, and many analysts claim tivozanib has the potential to dramatically change current treatment practice for kidney cancer. A big win for tivozanib would be bad news for both Nexavar and the dominant therapy for kidney cancer, Pfizer’s Sutent, which generated nearly all its $1bn revenues last year in this tumour setting. The impact on Aveo would be equally dramatic – although its shares have made impressive progress since their public debut just over a year ago, positive data should spark significant share price gains.
|% of market cap||261%|
|Event type||Phase III (Tivo-1) trial results|
Kidney cancer, or renal cell carcinoma (RCC), is the third most common genitourinary cancer in the US. There are few warning signs, which means about a third of all patients already have advanced tumours at the time of diagnosis.
Around 300,000 people in the US are currently affected by kidney cancer, the annual incidence is 60,000 patients and five-year survival is estimated at 68%, according to the National Cancer Institute.
There are five major subtypes of kidney cancer, with clear-cell RCC being the most common at 75-85% of cases. Clear-cell RCC is the target patient population in the Tivo-1 trial, the specific setting in which tivozanib generated its most impressive phase II data.
There are six targeted therapies approved for kidney cancer, Sutent being the clear treatment of choice, accounting for half of the $2bn global kidney cancer market last year, according to EvaluatePharma.
Four of the six therapies target VEGF in some form: alongside Sutent and Nexavar are Roche’s Avastin and GlaxoSmithKline’s Votrient. The other two, Pfizer’s Torisel and Novartis' Afinitor, are mTOR inhibitors. Tivozanib is also a VEGF inhibitor, although phase II data suggest it could yet replace Sutent as the first choice therapy for kidney cancer, but the chances of doing so rest on the outcome of Tivo-1.
Enrolment of 500 patients in Tivo-1 was completed last August, five months ahead of schedule. The trial pits tivozanib against Nexavar (sorafenib) as a first-line treatment for patients with clear cell RCC who have undergone a prior nephrectomy, surgical removal of part or all of a kidney.
The primary endpoint is progression free survival (PFS), with secondary outcomes also looking at overall survival (OS), specific response rates and safety.
According to JP Morgan analysts, PFS of 12 months or more is the magic number for tivozanib, alongside a similarly favourable safety profile to that seen in phase II. A PFS of 12 months would be significant because the survival benefit for Sutent is around 11 months and physicians surveyed by JP Morgan stressed a need for PFS improvements from new kidney cancer therapies.
The phase II study generated PFS of 11.8 months across all 272 patients, which increased to 14.8 months in the specific population of patients with clear cell RCC. Aveo says the safety of tivozanib was notable for its minimal off-target toxicity which is often associated with VEGF and multi-kinase inhibitors.
Although Tivo-1 puts tivozanib directly against Nexavar, in reality the real target for Aveo’s drug is Sutent. Given the widespread preference for Sutent to treat kidney cancer, it may have been a cute decision by Aveo to pit tivozanib against the weaker drug in Nexavar, while still providing data which can be compared to Sutent’s performance.
Analysts estimate that a third of Nexavar’s $936m sales last year were derived from use in kidney cancer. Sales of the drug in kidney cancer are expected to decline over the next few years, in contrast to 10% annual growth in liver cancer and potential new uses in breast, thyroid and non-small cell lung cancers.
Meanwhile nearly all Sutent’s current and future sales will be from its use in kidney cancer, set to reach $1.49bn by 2016. A survival benefit for tivozanib with a better safety profile therefore poses a real threat to Sutent.
Current forecasts for tivozanib put US sales at $338m by 2016, which would be upgraded upon positive Tivo-1 data. Aveo will split profits 50/50 in the US and Europe with Astellas Pharma, having recently signed a global deal with the Japanese pharma giant to much fanfare (Astellas taps into tivozanib's potential with billion-dollar deal, February 17, 2011).
Analyst price targets for Aveo shares, which currently trade at $14.45, range from $20 to $23, with JP Morgan suggesting the stock could reach $32 should the Tivo-1 trial exceed all expectations.
Set against this optimism is the threat posed by Pfizer’s axitinib and the travails of Sanofi-Aventis and Regeneron Pharmaceuticals’ development of aflibercept for cancer; both are VEGF inhibitor drugs.
Pfizer reported positive headline PFS data six months ago for axitinib as a second-line treatment for kidney cancer, while another pivotal study is ongoing as a first-line therapy; full results are expected to be presented at Asco in June. Analysts currently forecast similar sales for axitinib to tivozanib, $383m by 2016.
As for aflibercept, the recently reported positive data in colorectal cancer followed three pivotal stage failures in other cancer types, a warning of how tough the development path for these drugs in these tumours can be (Regeneron, Sanofi finally get an aflibercept cancer win, April 27, 2011).
Nevertheless, all signs at this stage point to tivozanib becoming a significant new treatment for kidney cancer, good news for patients and Aveo’s shareholders alike.