Published online 16 March 2009 | Nature | doi:10.1038/458269a

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Big interest in heavy drugs

The drug industry is seeking profits by modifying hydrogen in existing medications.

Substituting atoms in drugs could allow patenting opportunities and create better pharmaceuticals.Bloomberg News/Landov/Photoshot

Pharmaceutical companies are beginning to bet on the idea that simply switching a hydrogen atom with a heavier isotope in a currently approved drug could create a better drug. Encouraged by results from clinical trials, companies are snapping up intellectual-­property rights on many of the modified drugs.

On 16 March, for example, Concert Pharmaceuticals of Lexington, Massachusetts, reported results of a phase I clinical trial for a version of the antidepressant paroxetine, sold as Seroxat by GlaxoSmith­Kline and first marketed under that trade name in 1992. Concert's version swaps out one or more of the hydrogen atoms in the paroxetine structure (see 'Drug modifications') for deuterium, a heavier isotope of hydrogen that contains a proton and a neutron, rather than just a proton. The company was testing this deuterated version for treating hot flushes without the side effect of standard paroxetine in which the liver enzyme CYP2D6 is inactivated. Because this enzyme metabolizes many other drugs, inactivating it means it is hard to take other drugs along with paroxetine.

In Concert's trial, 94 women tested paroxetine — both standard and deuterated versions — along with the cough medicine dextromethorphan, which is metabolized by CYP2D6. Taken with standard paroxetine, metabolic uptake of the cough medicine is inhibited, says Roger Tung, chief executive at Concert. However, the deuterated version showed less metabolic inhibition — suggesting that the drug might be better to combine with others.

In theory, deuterated drugs can work differently in the body because deuterium can make stronger chemical bonds than hydrogen. This can affect how quickly a drug is broken down.

Another company working with deuteration is Auspex Pharmaceuticals, based in Vista, California. Last October, Auspex announced phase I clinical trial results with a deuterated version of venlafaxine. Venlafaxine was first produced by Wyeth, in 1993, as the antidepressant Effexor. The trial suggested that the deuterated version of the drug stayed in the bloodstream longer than the non-deuterated version and may even cause fewer side effects, says Mike Grey, chief executive of Auspex.

The company already has a patent on its deuterated version of venlafaxine, and has filed more than 150 other US patents on families of deuterated drugs. Concert has filed more than 100 US patent applications and has received two notices of allowance already, and is expecting to get its first patents this year.

Beyond the obvious

Kevin Mooney, a patent lawyer with Simmons & Simmons in London, says the strategy of piling up patent applications on deuterated versions of existing drugs is legitimate. "Every­one is entitled to research on other compounds," he says. Still, the onus will be on companies to demonstrate the usual criteria for patentability. "They would have to show that this deuterated form of paroxetine was new," he says, "then they would have to show that it wasn't an obvious thing to do." Patent applications — for example, those involving different salts of known compounds — often fail on this second requirement of non-obviousness.

Tung is confident that his company's tactics will work. "We treat this as an entirely new chemical entity," he says.

But in future, getting such patents will be harder, says Kirk Gallagher, a pharmaceutical patent lawyer at D Young and Co in London. "The obviousness bar will be raised as time goes by," he says, as the idea of deuterating a drug to get different pharmacokinetic properties becomes commonplace. Rather than the broad patents covering families of drugs being applied for now, companies will have to show improved action of specific molecules to convince a patent-giver that they have something new, Gallagher says. "They'll have to do more science before they file their patents."

Derek Lowe, a drug-discovery scientist and author of the In the Pipeline blog, says larger drug companies may take the same approach. "I think that every big pharma company is keeping this in mind," he says. "That's where the start-ups are going to have a problem."

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The approach with deuterated drugs is similar to that used by Sepracor, based in Marlborough, Massachusetts, in the 1980s. Until that point, patents didn't include specific information on isomeric forms of drugs. Sepracor made its business by filing patents on active isomers of known drugs. In response, pharmaceutical companies began to routinely specify chiral isomers on patents. "Pharma companies will now probably add deuterium analogues," says Gallagher.

Grey isn't worried. "There is still a vast landscape for us to explore," he says. Auspex hopes to partner with larger drug companies to continue developing its products.

Concert is similarly looking for ways forward. The company has raised US$96 million in start-up money so far, but has decided not to develop its deuterated paroxetine further for now — focusing instead on another deuterated drug, an HIV protease inhibitor, which it thinks will be a bigger seller. 

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