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The renal cell carcinoma market: Votrient to challenge Sutent’s lead

Published on 25/11/10 at 09:04am
Lorena Tonarelli
renal clear cell carcinoma
Coloured urogram (X-ray) of the left kidney of a patient with renal clear cell carcinoma (blue). Credit: Sovereign, ISM/Science Photo Library

After decades of no new medicines emerging to treat renal cell carcinoma, no fewer than five new drugs were approved to treat the cancer in 2006 and 2007.

Pfizer’s Sutent (sunitinib) and Bayer’s Nexavar (sorafenib) arrived first, and brought important new treatment options to patients with advanced renal cell carcinoma (RCC).

Wyeth’s Torisel (temsirolimus) and Novartis’ Afinitor (everolimus) also gained their first approval in RCC, while Roche’s Avastin (bevacizumab) added RCC to its licenced indications in December that year.

Sutent was approved as a first line treatment for RCC from the outset, and it quickly established itself as the physicians’ favourite, and is now considered the new standard of care for treatment-naïve patients with advanced disease (it was simulateously approved to treat gastrointestinal stromal tumours). Sutent earned $964 million in worldwide sales in 2009, and is set to reach blockbuster status this year.

The progress in RCC doesn’t end there, however. The market will continue to evolve as new treatments continue to enter the market. Chief among the rivals to Sutent’s domination of the field will be GSK’s Votrient (pazopanib).

Analysts Decison Resources say the drug will in fact become the leading agent by 2019, overtaking Sutent and gaining a market share of 49 per cent. Decision Resources analyst Dr. Karen Pomeranz says Votrient will surpass Sutent in 2016 and, by 2019, Sutent’s market share will fall from 47 to 19 per cent.

Prolonging survival, reducing toxicity

The arrival of Sutent and other targeted drugs represents a major step forward compared to the previous standard treatment of interferon-alpha and interleukin-2.

Most of the new treatments target tyrosine kinase pathways and block angionesis, the formation of new blood vessels which help the tumour grow.

Sutent has been shown to prolong overall survival in patients with the advanced disease by nearly five months compared to interferon-alpha (26.4 months vs. 21.8 months). Pfizer says an exploratory analysis of patients who received only one line of treatment (i.e. no subsequent treatments after stopping their sunitinib or IFN-alpha therapies) showed that sunitinib almost doubles the time it keeps patients alive compared to IFN-alpha (28.1 months vs. 14.1). It says this is a reflection of clinical practice in the UK where generally patients are only funded for one line of treatment at most.

These results represent significant progress in treating RCC, but clearly there is room for further improvement. Numerous pharma companies are looking to produce a drug which will represent this next step forward. One of the most significant of these is GSK’s Votrient, which received conditional marketing authorisation from the European Commission earlier this year, and was launched in July. The conditional licensing status means GSK must provide post-marketing efficacy and safety data from ongoing trials. Regulators are expected to make a decision on these results by June 2012.

In the UK, NICE is currently assessing Votrient as a first line treatment, and final guidance is expected in early 2011. Sutent was given the green light from NICE in 2009, with all the other new RCC treatments being rejected.

Dr Minesh Jobanputra, a senior medical advisor at GlaxoSmithKline says indirect comparisons of efficacy data from phase III trials support the view that Votrient is a strong rival to Sutent. “Both drugs have shown about an 11-month improvement in progression-free survival, which is a clinically meaningful benefit. PFS is established as an appropriate surrogate for overall survival in RCC.

“Both drugs also have similar levels of activity at the receptors involved in angiogenesis and tumour growth,” says Jobanputra.

Very similar response rates are seen in patients between the two drugs in first line settings: 31% for Sutent and 32% for Votrient.

Highly selective

It looks like Votrient offers similar benefits to Sutent - so why should clinicians switch from an established medicine to a new product that has a conditional marketing authorisation?

GSK says Votrient’s differentiating factor is its very specific kinase affinity profile compared to Sutent. This means it more selectively targets the key receptors involved in angiogenesis and tumour growth: VEGFR 1, 2, and 3; PGFR alfa and beta; and stem cell factor receptor (c-kit) but with minimal activity at the Flt-3 receptor. As a result, treatment with the drug is associated with a lower risk of adverse events related to the unwanted inhibition of other kinases.

“Although the two drugs have similar activity, Sutent inhibits many more kinases than Votrient,” explains Jobanputra. “One example is the Flt-3 receptor, which is an important regulator of blood cell formation. Votrient has much lower affinity for this receptor than Sutent and the phase III study demonstrated that Votrient has fewer grade 3 and 4 haematological adverse events. There also appear to be less cardiotoxicity with Votrient than with Sutent, which can be explained, in part, by the activity that Sutent has at kinases such as RS6K and AMPK.”

So is Votrient safer than Sutent? “I wouldn’t use the word ‘safer’,” says Jobanputra, “as all of these drugs do have serious side effects. But it is apparent that Votrient has very little severe cardio and haematological toxicity”. This has important potential implications, given that adverse events are associated with increased costs, due to additional treatment and hospitalisation, and reduced patient quality of life.

Market penetration factors

There is, however, one crucial safety issue with Votrient. Treatment with this agent has been associated with severe hepatotoxicity. This appears to be rare, easily identifiable through liver function monitoring, and reversible. Nonetheless, it may discourage some clinicians from prescribing Votrient to their patients, and could hinder market penetration.

The results of two head-to-head phase III trials - COMPARZ and PISCES, due to be completed in August 2011 and April 2012, respectively - are currently comparing the efficacy and safety of Votrient and Sutent in treatment-naive patients with advanced RCC. The trials will help clarify the comparative effectiveness of the two agents as well as the hepatotoxicity issue, and will provide crucial information about the overall toxicity of the two drugs, as well as patient treatment preferences. Analysts expect Votrient to demonstrate comparable efficacy to Sutent, but to be better tolerated, making it the ideal choice.

Together with NICE’s decision, the results from COMPARZ and PISCES are considered the main drivers influencing Votrient’s market penetration in the UK, says Jobanputra. “The former trial, in particular, will ultimately help clinicians and commissioners decide what is the most appropriate treatment,” he adds. “If it is confirmed that Votrient and Sutent are similar in terms of efficacy, but that the safety data for Votrient is better, then that will be a key factor as to whether Votrient becomes the market leader or not.”

Another factor is the approval for use in other conditions. This could make it easier for Votrient to win market shares from Sutent. “Because Votrient is an anti-angiogenic drug, it has wide potential applicability, and there are a number of therapy areas where it may be active,” says Jobanputra. “Within the RCC space, we are currently undertaking a key study investigating Votrient’s efficacy in adjuvant disease. We are also looking at a number of other indications, including lung, breast, ovarian and sarcoma.”

In addition to looking for multiple indications, GSK is raising awareness about kidney cancer, in order to improve its detection. “Renal cell carcinoma has been, in the recent past, a condition with very limited treatment options and low index of suspicion. Most clinicians would give RCC patients no treatment other than palliative care,” says Jobanputra. “We have awareness campaigns in place to make sure that this condition is flagged early, so that treatment can start as soon as possible and patients have better chances of improved survival.”

Other factors are likely to influence Votrient’s penetration of the advanced RRC first line market. There are, of course, several other strong competitors - Bayer’s Nexavar, Roche’s Avastin, and Wyeth’s Torisel - all of these are European approved, but rejected by NICE to date.

Meanwhile, other new agents are in the late-stage pipeline. AVEO Pharmaceuticals’ tivozanib is expected to reach the market by 2013. Another anti-angiogenic tyrosine kinase inhibitor (TKI), phase II trial data show better median progression-free survival than both Votrient and Sutent (14.8 vs. 11 months). Analysts predict that, in 2019, tivozanib will generate annual sales of more than $200 million, similarly to Sutent, accounting for 18% of the market share.

Second and third line treatments

Competition will be fierce in the second and third line settings, for when patients see their disease progress on first line treatment. There are currently four major targeted agents for the second line treatment of advanced RCC. Nexavar was the leading therapy in 2009, with a 47% market share, followed by Torisel, Afinitor and Avastin, with market shares of 15, 14 and 11%, respectively.

Decision Resources analyst, Dr. Karen Pomeranz says the market is expected to reach $471 million in value by 2019 (currently $352 million) with Pfizer’s axitinib the leading agent, with a market share of 47%, followed by Afinitor and tivozanib.

In the second line setting, Pfizer’s axitinib is forecast to surpass Novartis’ Afinitor to become the leading agent, and Bayer’s Nexavar will plummet. In the third line setting, Afinitor will outperform Wyeth’s Torisel.

Two brand new targeted therapies, Pfizer’s axitinib and AVEO’s tivozanib, will play a major role. Axitinib is an anti-angiogenic TKI, set for launch by 2011, and for which there are only phase II data available from two trials of Nexavar-refractory and cytokine-refractory RCC patients.

“Afinitor is the only agent that has phase III data to support its use in this setting,” says Pomeranz. “In 2019, the third line market will total $53 million and Afinitor will be the leading agent with a market share of 59%,” followed by axitinib (17%), Avastin (10%), Torisel (6%), tivozanib (4%) and Nexavar (1 per cent).

RENAL CELL CARCINOMA

Renal cell carcinoma is the most common and aggressive form of any urologic cancer, and accounts for up to 85% of all malignant kidney tumours.

Carcinomas arise from the epithelial tissues of an organ, and risk factors include smoking, high blood pressure and long term dialysis. Because the early stages of RCC are generally asymptomatic, about 50% of cases are diagnosed incidentally, usually during imaging investigations conducted for other reasons, when the tumour is advanced.

Treatment is with surgical removal of the tumour or kidney. The cancer responds poorly to chemotherapy and radiotherapy. The prognosis for advanced RCC is very poor, with almost all of patients dying within five years of the diagnosis. It is estimated that, in the UK, the disease kills each year over 3,500 people, mostly men over 65 years old. Both incidence and mortality are increasing worldwide.

Lorena Tonarelli is an author, freelance healthcare journalist and medical writer and can be contacted at: lorenatonarelli@me.com

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