Brilinta advances, zibotentan steps back

The ‘two steps forward one step back’ nature of drug development has been neatly encapsulated by AstraZeneca’s pipeline announcements over the past few days.

First came news on Friday that Europe’s CHMP has recommended approval for new blood thinner Brilinta, to be sold as Brilique in Europe - Astra’s biggest growth driver, most valuable pipeline candidate and on whose shoulders rests Astra’s ability to negotiate its treacherous patent cliff. Today, however, comes news of yet another setback from its pipeline of cancer drugs, with zibotentan (ZD4054) failing to improve overall survival in men with metastatic prostate cancer. Although further trials of zibotentan are ongoing, the outlook is looking gloomy for a drug that could have been Astra’s fourth largest driver with sales exceeding $500m by 2016.

On its way

First, the good news - Europe’s expert panel have recommended that Brilique, known generically as ticagrelor, be approved for the prevention of atherothrombotic events in adult patients with acute coronary syndromes (ACS). Final approval from the European Commission should arrive by the end of the year.

While approval in Europe was largely expected, it will still come as a relief to the company and its shareholders given the concerns that remain over the FDA’s decision, which was recently delayed by three months until December 16 (Event - FDA all that stands in AstraZeneca's way on Brilinta, September 1, 2010).

Brilique will now go head-to-head against Sanofi-Aventis’ Plavix in Europe, and importantly also against generic versions of Plavix which have been launched in the past couple of years, which have significantly eroded Sanofi’s market share in the region.

As such, Astra’s launch in Europe could be a delicate balancing act between accentuating the positive clinical data which it will hope to support a superiority claim for Brilique over Plavix, while remaining competitive on price.

Data from the pivotal Plato trial of 18,624 patients showed that Brilique had a 16% relative risk reduction in death from cardiovascular causes, myocardial infarction (MI) or stroke and a 22% risk reduction of death from any cause compared to Plavix. Importantly, given the major drawback with Eli Lilly’s Effient, the trial also found no increase in major bleeding incidents.

Additionally, patients on Brilique can be ready for coronary artery bypass graft surgery in as little as 48 hours, compared to five to seven days for Plavix.

Heading for the R&D dustbin?

As for zibotentan, it seems any commercial planning can now be put on ice.

The drug belongs to a class of agents called endothelin A receptor antagonists, similar in mode of action to pulmonary hypertension drugs such as Gilead Sciences’ ambrisentan (Letairis/Volibris).

The theory is that as prostate cancer advances, the endothelin pathway becomes uncontrolled and helps drive the spread of cancer growth, so by blocking the endothelin A receptor zibotentan can slow tumour growth and the spread of cancer cells to other parts of the body.

Unfortunately, in the first of three phase III trials that read out today, that theory has not translated into practice.

Results from this first trial from the Enthuse clinical program, called Study 14 and which enrolled 594 patients with metastatic castration resistant prostate cancer (CRPC), showed that zibotentan failed to significantly improve overall survival (OS). This was disappointing given that phase II data had shown an encouraging benefit in OS.

Two further trials from the Enthuse program, called Study 15 and Study 33 which involve a further 3,000 patients, continue, with results from Study 33 in patients with metastatic hormone resistant prostate cancer due to be released in the middle of next year. Full results from the first trial, Study 14, will also be published next year.

For the time being, Astra has said the Anglo-Swedish company “plans no regulatory submissions for zibotentan at this time”, suggesting the writing could be on the wall for the drug’s future.

No news is bad news?

Perhaps the most intriguing aspect of zibotentan’s development so far has been the conspicuous lack of tangible newsflow or excitement coming out of Astra about the product, despite reaching such a late stage of development and potentially becoming a crucial new drug as it peers over the patent cliff abyss.

Consensus sales for 2016 currently sit at $416m, the highest of any clinical stage product in Astra’s pipeline, although analyst estimates range from Deutsche Bank with $245m to UBS at $620m.

Opinion as to the drug’s ultimate potential was clearly divided although either way zibotentan could have been an important success story from a cancer pipeline that continues to splutter – the setbacks to Recentin, Zactima and Iressa spring to mind here.

Perhaps Astra’s track record in the cancer space continues to temper its hopes and expectations.

Trial Name  ENTHUSE (Study 14; Study 33; Study 15)
Trial ID  NCT00554229 NCT00617669 NCT00626548
Product   ZD4054 (zibotentan)
Indication  Prostate Cancer
Phase  III 

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