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Brilinta, AstraZeneca’s (NYSE:AZN) blood-thinning agent on which huge expectations have been placed, duly delivered the goods with pivotal trial results presented over the weekend at the European Society of Cardiology (ESC) which demonstrated a clear efficacy advantage over current gold standard Plavix, whilst crucially also maintaining a comparable safety profile.

Despite these ‘best-case’ results according to some analysts, Astra’s shares gained just 1% to £28.76 ($46.65USD) in mid-day trading, a reflection of the fact that the stock is already trading close to a high for the year and that expectations were already sky-high following the release of top line data in May which helped spark a share price revival for the UK pharma giant in recent months (Brilinta data perks up Astra, May 11, 2009). Although some risks inevitably remain over Brilinta, it appears Astra has an approvable and massively commercially viable product on its hands, hugely important if the group is to successfully negotiate its precipitous patent cliff.

Superior and just as safe

Data from the Plato trial of 18,600 patients with acute coronary syndromes (ACS) demonstrated 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.

The extent of this mortality benefit in favour of Brilinta was at the top end of analyst expectations' and even outshone Effient in terms of efficacy, Eli Lilly’s (NYSE:LLY) antiplatelet agent which received regulatory approval this year (Event – Astra hoping to shine with full Brilinta data , August 19, 2009).

However, while Effient’s improved efficacy over Plavix comes at a significant cost of an increased risk of major bleeding, the Plato data showed no overall difference between Brilinta and Plavix in major bleeding rates.

All of which suggests that current consensus analyst forecasts for Brilinta sales of $686m by 2014 will be significantly upgraded in the coming months, especially considering that prior to the release of the full Plato data, some analysts at banks such as Bernstein and Morgan Stanley had not included any estimates for the drug in their forecast models for Astra.

Some nagging doubts

Whilst most analysts are in agreement that regulatory approval in both Europe and the US, possible by the end of 2010 if Astra makes its submissions in the fourth quarter, is now almost a formality, there were some concerning safety and efficacy signals from the Plato data.

Although Brilinta was comparable to Plavix with regard to the risk of major bleeding events, the Astra drug did cause significantly higher rates of minor bleeding, as well as showing a trend for increased intracranial bleeding and strokes, although these were not statistically significant.

In addition, Brilinta caused a higher rate of breathlessness (dyspnoea) and increased serum levels of uric acid and creatinine, side-effects that have not previously been observed with either Plavix or Effient.

However, most analysts and experts do not expect these more minor safety issues to be a barrier to approval, although clearly they will attract particular regulator scrutiny and will be part of any post-approval risk management programme.

What was attracting slightly more concern was sub-group analysis which revealed an anomaly in North America, the biggest commercial market for Brilinta. The Plato trial was divided into 66 sub-groups, 33 covering safety and 33 over efficacy. Of the 33 efficacy sub-groups, 30 were consistent with the overall trial results, however two groups in North America showed no benefit with Brilinta with a trend towards a worse outcome.

Trial investigators are so far at a loss to explain this anomaly, having already re-examined the data for clues. The duff result could be down to regional differences in patient populations or practice patterns, or just a “statistical fluke” as one expert suggested.

Whilst clearly a risk, and of specific concern for FDA approval, given the overwhelming nature of the overall data, the US regulator is still likely to approve the drug, but may well request an additional confirmatory trial in North America.

Bad news for Lilly and Daiichi

Although Astra tested Brilinta against Sanofi-Aventis (NYSE:SNY) and Bristol-Myers Squibb’s (NYSE:BMY) Plavix, given that the drug will not reach the market until early 2011, only just before Plavix loses patent protection in the same year in the US and is already suffering generic competition in some European countries, the tangible impact on Plavix is expected to be minimal.

Conversely the real impact of Brilinta should it receive approval, is most likely to be on Effient, given that Brilinta appears to outscore Lilly’s drug on both efficacy and safety measures.

Sales forecasts for Effient have been subject to consistent downgrades as regulatory delays and safety concerns have combined to seriously limit the drug’s commercial potential. Two years ago analysts were predicting global Effient sales of $1.43bn by 2012; today that estimate has almost halved to $755m.

The Brilinta data is therefore likely to cause further downgrades, eroding the sales potential of one of the most important growth drivers for both Lilly and its Japanese partner, Daiichi Sankyo (OTC:DSKYY).

Meanwhile, upgrades for Brilinta are expected and analysts are now estimating peak sales of $1.5bn to $3bn. Whilst these enhanced revenues and profits will be welcomed by Astra’s shareholders, the group faces one of the biggest patent cliffs amongst its peers - $23bn of sales are at risk from generic competition over the next five years according to EvaluatePharma – so even if Brilinta meets these lofty expectations, the group still needs more drugs like Brilinta to help flatten out these patent cliff concerns.

Source: Brilinta Data Should Soothe Some of AstraZeneca's Patent Cliff Woes