Event - Takeda's ARB may be approvable but commercial potential uncertain

Amazing as it might sound, the highly competitive and soon to be heavily genericised market of angiotensin II receptor blockers (ARB), widely prescribed to treat high blood pressure, could have a new entrant in Takeda’s TAK-491 (azilsartan).

The FDA is expected to issue its verdict later this month on azilsartan, a follow-on to Takeda’s hugely successful candesartan (Blopress/Atacand), global sales of which are forecast to peak this year at $3.25bn before generics appear in 2012. Novartis’ Diovan, the current ARB market leader, will also lose patent protection in 2012, creating a tough market for any new branded player (Therapeutic focus - angiotensin receptor blockers facing generic pain, July 22, 2009). As such, Takeda will be hoping its extensive phase III program that pitted azilsartan against the main incumbents in the hypertension space will be enough for the FDA. But even if the regulatory battle is won, a significant commercial fight awaits if azilsartan is to carve out a niche in the ARB market.

Things need only get better

To have any chance of success, azilsartan needs to show some important advantages over its marketed rivals.

As such, Takeda had to play the numbers game during azilsartan’s pivotal programme, conducting nine phase III trials involving 7,000 patients. The drug was tested in various trials alone or in combination with chlorthalidone, and compared to other ARBs such as Diovan and Daiichi Sankyo/Forest Laboratories’ Benicar, which will be the last of the current crop of ARBs to go off-patent in 2016. Additional studies were also conducted against alternate anti-hypertensives such as Pfizer’s Norvasc and King Pharmaceuticals’ Altace, both already off-patent.

In a head-to head trial against the highest dose of Novartis’ $6bn-seller Diovan, azilsartan was significantly better at reducing mean systolic blood pressure over 24 hours, by roughly 15mm Hg, compared with 11.3mm Hg in the Diovan-treated group.

Meanwhile a separate trial against Benicar, which sold nearly $3bn last year, revealed azilsartan decreased blood pressure by an average of 12mm Hg, compared with 11mm Hg for Benicar, also deemed a significant result.

Common adverse effects were reported in just 1% of patients taking azilsartan and were relatively mild – dizziness, increased blood creatine phosphokinase and diarrhoea.

In addition to the FDA verdict this month, European regulators are expected to make their decision on the drug by the middle of the year.

Forecasting doubt

Consensus sales estimates for azilsartan in 2014 currently stand at $426m, rising to $717m by 2016.

However, a high level of uncertainty hangs over azilsartan’s potential in such a competitive landscape, exemplified by the fact that consensus is a fraction of candesartan's peak sales levels and the widely differing analyst forecasts from late last year that comprise that figure.

Bullish Nomura and Credit Suisse see 2014 sales as high as $707m and $642m, respectively. Conversely, Bank of America-Merrill Lynch and JP Morgan estimate less than half these 2014 sales, with forecasts of $220m and $242m, respectively.

Pressures mount

Aside from the generic threat, the use of higher-priced branded ARBs is under pressure from a number of sides, with recent studies questioning the cost-effectiveness of the class.

A meta-analysis of hypertension and heart studies over the last decade was published recently in the International Journal of Clinical Practice. It compared the efficacy and cost-effectiveness of Blopress, versus Merck & Co's now-generic Cozaar (losartan), and recommended the UK’s National Health Service could save a minimum of £200m this year by buying generic ARBs, at no detriment to clinical performance.

Meanwhile the Canadian Medical Association Journal published a similarly restrictive analysis. It questioned why prescriptions for ARBs in Canada had increased by 4000% between 1996 and 2006, when their benefit over the older class of angiotensin-converting enzyme (ACE) inhibitors remains unproven. The article postulated that the Canadian healthcare system could have saved around $77m in 2006 if ARB use had been more restricted.

With some decent-looking data to back up the drug's effectiveness against the multi billion dollar incumbents, there certainly is a case for azilsartan’s approvability, although payers could well restriction use to patients that have failed on other therapies. The commercial landscape that lies before azilsartan is a harsh terrain.