LEXINGTON, Mass. — It’s just a simple swap. Pop out a hydrogen atom, throw in a “heavy” counterpart, and you’ve got a new drug. But on the shoulders of those bulky hydrogen atoms rest lots of money and potential therapies — as well as some prickly questions.
The chemical tweak appears to improve some drugs, providing safer and easier-to-take treatments. But biopharma companies could also set high prices without competition for their fine-tuned therapies, even though the drugs are based on existing medicines for which cheap generics are often available.
The Food and Drug Administration recently completed its first review of such a drug, deutetrabenazine from Teva Pharmaceuticals. Teva announced on Tuesday that the FDA told the company it needed to see more lab data before it would approve the agent, but analysts say it’s only a matter of time before the first-ever drug containing heavy hydrogen hits the market.
Other companies are developing similar drugs for treating conditions from liver disease to narcolepsy to a form of baldness. Teva, meanwhile, said it would submit the data the FDA requested for deutetrabenazine later this year.
The idea of sprucing up older drugs with heavy hydrogen — a molecule formally called deuterium — has raised some eyebrows in the industry. Some have wondered, for example, if companies would be able to defend their patents on deuterium-modified versions of existing drugs as novel enough to deserve their own patent, though that hasn’t been a problem yet.
Experts say that incorporating deuterium into medicines is another case of companies reworking older drugs to improve them and, in some cases, gain new market exclusivity, without investing heavily in the roots of a new drug. Companies, for example, have long combined two existing drugs and taken the mashup to market.
“One could say that in some instances, a company may not have done all the research and development for a drug in question,” said Joshua Cohen of the Tufts Center for the Study of Drug Development. “But the company has done the bulk of the applied research and development to ensure that the drug” works in patients and gets approved.
The Teva drug was designed to treat the involuntary movements caused by the fatal neurodegenerative condition Huntington’s disease. It is a modified version of the generic tetrabenazine, which is not well-tolerated by some patients and has to be taken more frequently than deutetrabenazine, potentially hurting adherence. Studies have found that up to two-thirds of patients with certain neurodegenerative disorders fail to take their medicines regularly.
Teva took over deutetrabenazine, which is also in trials for Tourette syndrome and a movement condition called tardive dyskinesia, last year when it acquired its original developer, Auspex Pharmaceuticals, in a $3.5 billion deal. Teva would not comment on its pricing plans for deutetrabenazine, but according to forecasts from Sanford C. Bernstein & Co., worldwide sales of the drug could exceed $500 million by the end of the decade.
Federal regulators typically only look to see that deuterium-modified compounds fare better than placebos in clinical trials, meaning they do not necessarily have to be tested head-to-head against the original formulation or its generics. But executives at companies that specialize in deuterium-based drugs said the products do need to demonstrate improvements — payers, for example, won’t cover the updated drugs if they don’t provide benefits.
“You aren’t going to be able to advance it to the market if it’s not superior to the generic,” said Sheila DeWitt, chief executive of DeuteRx.
To understand how drugs with deuterium work, a quick flashback to high school chemistry class is needed. Standard hydrogen consists of one proton and one electron. Deuterium has an added neutron, doubling the atom’s mass — hence the name heavy hydrogen. (Electrons don’t have mass.)
In drugs like deutetrabenazine, deuterium is swapped for hydrogen at certain points where the hydrogen is bonded to carbon. The added mass strengthens the bond between the atoms, and the body in turn takes longer to dismantle that bond, like how doubling the size of the outmatched person would extend a tug-of-war match.
If a drug is metabolized more slowly, its effects last longer, meaning patients can take the drug less frequently. Deuterium modification also has the potential to reduce side effects by taming the cascade of reactions a drug can set off.
But the tweak won’t improve every drug compound, so companies have to weed through molecules before landing on candidates to develop. And the actual chemistry of swapping deuterium for hydrogen and finding the right places to do it can be complicated.
“It’s not a gimme,” said Roger Tung, chief executive of Concert Pharmaceuticals, a leading developer of deuterium-modified drugs. “You’ve still got to do a lot of work.”
At Concert’s headquarters here in this Boston suburb, stainless steel drums of water containing deuterium sit on hand in the lab’s fenced-in storage area. The company has several deuterium-modified drugs in its pipeline, some of which are aimed at treating conditions for which the original formulation was not developed. Its lead candidate, which is in Phase 3 trials to treat the agitation that people with Alzheimer’s experience, stems from a compound found in cough syrup.
Tung said that modifying existing drugs with deuterium could lead to better treatments while cutting the risk of crafting drugs from scratch because they are so similar to treatments already shown to be safe and effective. That in theory could lower the cost of getting a drug to market, but Tung said it was too early to discuss how Concert would price its drugs.
“The idea of the approach is one of being able to reduce the overall expense and uncertainty of the process,” he said. “If we’re correct and if we’re successful, then in principle, we should have a more efficient process.”
Since the emergence of specialty companies like Concert and Auspex in the 2000s, many mainstream drug developers have caught on to their chemical bag of tricks, incorporating versions of their compounds with deuterium when applying for initial patents.
Some large biopharma companies, including Vertex Pharmaceuticals, Bristol-Myers Squibb, and Pfizer, have already started testing drugs containing deuterium. Some researchers also think adding the heavy hydrogen to failed drug candidates could revive them by improving their tolerability.
Perhaps the most closely watched of these drug candidates is Concert’s version of Kalydeco, a cystic fibrosis treatment from Vertex. Tung, a former Vertex executive, said that Concert’s molecule could possibly be taken once daily (Kalydeco currently requires twice-per-day dosing) and that patients could take it with fewer restrictions on their diet.
But unlike with many other drugs with deuterium, no generic is on the market yet for Kalydeco — and none is expected for at least 10 years. Kalydeco, with its $300,000-a-year price tag, is forecasted to generate roughly $700 million in global revenue for Vertex in 2016, but Concert’s drug, if it is eventually approved, could undercut those sales in future years.
“I would imagine Vertex must be thinking about something,” said Graham Timmins, a biochemist at the University of New Mexico who has written about deuterium modification. He said people have wondered if Vertex might take Concert to court over its patent.
Vertex, for its part, declined to comment.