AHA 2011 - Amarin's patent concerns set to prevail despite more strong data

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Further details from Amarin’s Anchor study released at the American Heart Association meeting yesterday, confirming AMR101 as potent triglyceride lowering agent, make for encouraging reading. However the days when data alone could propel this company’s shares are long gone (Amarin surges as hopes for heart drug soar, April 18, 2011).

Multiple concerns have been mounting in the last few months, erasing more than half of the company’s value since May, when top line data from its pivotal programme pushed its market cap over $2.5bn. Questions over the patent life of AMR101 – a pure form of omega-3 – its approvability and ultimate commercial potential have prompted much caution. It will take firm evidence of this drug’s potential to trigger a recovery.

Differentiating

The Anchor trial recruited 702 statin-treated patients with persistently high tryglycerides – judged to be between 200mg/dL and 500mg/dL. This is a distinct patient group from the company’s previous study, Marine, which included patients with very high triglycerides – above 500mg/dL – and in which the drug has already been filed for approval.

Presenting the data one of the co-authors of the study, Dr Christie Ballantyne of the Baylor College of Medicine in Texas described Anchor as essentially an obesity study; patients had very high BMIs and 73% were diabetic.

“This is reflective of a patient population that has emerged in the US, very overweight with very high triglycerides,” he said.

Adding AMR101 to statins significantly improved lipid profiles across a variety of markers over placebo; those on high dose statins saw the biggest reductions in triglycerides and significant reductions of high-sensitivity C-reactive protein, an inflammatory marker. Importantly the drug had no impact on LDL cholesterol; the high dose in fact prompted a significant reduction in patients on high dose statins.

This is the key differentiator between AMR101 and its main competitor, GlaxoSmithKline’s Lovaza. The hike in LDL cholesterol that Lovaza prompts, an unacceptable side effect for people at a lower overall cardiac risk, has blocked its use in the bigger population studied in the Anchor trial. As such it is only approved in those with very high triglycerides, essentially the Marine population.

Outcomes needed

AMR101 certainly appears to be a more potent and safer triglyceride lowering agent than Lovaza.

“Non-inferiority or even superiority on LDL lowering [compared to placebo] means this agent might be superior to other agents,” said Dr Amit Khera, Professor of Medicine at the University of Texas, who discussed the trial at the conference. “But we still need to see what this means clinically.”

This is a stance that the FDA agrees with. It has demanded an outcomes study be carried out in the Anchor population, to establish whether the drug has a mortality benefit, which must be substantially under way by the time of filing. The regulator agreed an SPA in August and Amarin reckons the 8,000 patient study will be half enrolled by the end of 2012, so a filing around this time should be feasible.

That the FDA wants hard proof of the drug’s worth before allowing many more patients to be exposed to it is not surprising. Incredibly mixed and sometimes unpredictable messages have emerged from trials of various cardiovascular agents over the last few years. These include the Illuminate trial of torcetrapib, niacin in AIM-High and the Accord study, which found that adding another widely used triglyceride lowering agent, Abbott’s fenofibrate Trilipix, to statins may not lower the risk of cardiovascular events in diabetics. This resulted in a safety update to doctors from the FDA earlier this month, and a demand for further studies to ascertain the agent's risks and benefits.

AMR101 might be very similar to other agents widely used for years throughout the world, but the FDA is not in the business of making assumptions. Neither are physicians, and persuading them to move this agent into patients with less immediate need of treatment would be a challenge without the evidence an outcome study could provide. Not to mention payers, who will need persuading that the drug is worth paying extra for.

Injection of realism

Throw into the mix an uncertain patent life, and it is no wonder that an element of realism has been injected into Amarin’s valuation. Shares in the company were trading at $6.86 this morning, giving a market cap of $920m.

While many analysts believe the company already has patents in place protecting the drug until 2024, it is struggling to win allowance of another patent, called ‘889, which seeks to extend exclusivity over AMR101 based on the data in the Marine study, until 2030. The USPTO has so far refused to grant this, on grounds of obviousness – essentially similarity of the use of AMR101 to Lovaza.

The company has 16 pending applications belonging to 11 US patent families so if the ‘889 patent is not granted all is not lost. Some analysts believe the company has a better chance of winning an extension based on the Anchor data anyway, considering existing omega-3 products are not approved to treat this lower-risk patient population.

What is more crucial however is whether the FDA will declare AMR101 a new chemical entity. This again is far from certain considering the existence of Lovaza and failing to win this classification would provide only three years of solid protection – a disastrous outcome for the company.

Fishy tale

The outcome of the NCE negotiations will emerge when the FDA rules on the drug’s approvability, due in the middle of next year. For Amarin, debates about the clinical utility of AMR101 are moot until the patent issue is resolved.

With $126m in cash at the end of September, enough to last another 12 months or so, and the outcomes trial estimated to cost $125m, further funds will be needed. Investors would like these funds to come from a partner but its hard to believe a third party will sign on the dotted line before at least the NCE status is confirmed.

AMR101 does appear to be a more effective and possibly safer version of Lovaza. But with patent concerns adding to questions over clinical and commercial potential, and as multiple drug launches disappoint and pricing pressure increases, Amarin will remain a fish story for many investors for now.

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