Deuterium switcheroo breathes life into old drugs | July 4, 2016 Issue - Vol. 94 Issue 27 | Chemical & Engineering News
Volume 94 Issue 27 | pp. 32-36
Issue Date: July 4, 2016

Cover Story

Deuterium switcheroo breathes life into old drugs

Drugmakers juggle isotopes in hopes of achieving novelty, stability, and success
Department: Science & Technology
News Channels: Biological SCENE, Organic SCENE
Keywords: drug development, deuterated drugs, deuterium, SD-809, AVP-786, CTP-656, VX-984, fludalanine, heavy water, Girdler sulfide process, ammonia-hydrogen, CANDU
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Credit: Richard C. Smith
Illustration of a scientist juggling hydrogen and deuterium atoms.
 
Credit: Richard C. Smith
In brief

The concept of swapping deuterium for hydrogen to increase the stability of drugs has fallen in and out of favor for decades. But with a handful of deuterated drug candidates nearing approval, the popularity of heavy drugs is again on the rise, despite some skepticism about the approach. Read on to learn how companies are using deuterium to revamp old drugs and create new ones.

Heavier than hydrogen by a single neutron, deuterium might not seem to have much chemical heft. But the small matter of that subatomic particle makes a massive difference in the reactivity of hydrogen versus its isotope deuterium.

In particular, deuterium can be far more difficult to pluck from a carbon atom than hydrogen. That property has long intrigued drugmakers: Metabolic enzymes often begin to break down drugs by stripping them of their hydrogen atoms. If pharma firms could strategically slow that denuding by replacing hydrogen with deuterium, they might be able to increase the lifetime of an active drug. The longer lifetime could translate to a lower dose. This is especially appealing because the hydrogen-deuterium switcheroo doesn’t change any of the drug’s other biological properties, such as its shape, size, or ability to bind its target.

Harold Urey, who won the 1934 Nobel Prize in Chemistry for discovering deuterium, had inklings that the isotope might act “as an indicator in the study of metabolic processes within living things” because it’s possible to feed an animal a deuterated compound and then follow its progress, he noted in the Encyclopaedia Britannica. And he was right. Deuterium has been used as a metabolic probe for decades. Even though pharmaceutical companies have seriously sought drug candidates that capitalize on the heavy-hydrogen phenomenon since Merck & Co. worked on the antibiotic fludalanine in the 1970s and 1980s, a deuterated drug has yet to receive approval from the Food & Drug Administration.

Critical mass for such compounds has been building over the past decade. Several biotechs devoted to developing deuterated drugs have sprung up. Hundreds of drug patents that feature deuterium have been issued. And several deuterated drug candidates are in clinical trials or under development for a wide variety of indications. But in the absence of an approved deuterated drug, many remain skeptical of the approach.

The most likely candidate to finally prove the theory that heavier drugs can make better drugs is Teva Pharmaceutical Industries’ SD-809, a deuterated version of Lundbeck’s Xenazine (tetrabenazine), a compound that was first identified more than 50 years ago. In 2008, FDA approved tetrabenazine to treat involuntary movements in patients with Huntington’s disease. But that drug must be given at least twice daily, and patients can experience daily withdrawal symptoms as its active metabolites wane in the body. By using deuterium to extend the lifetime of the compound and its active metabolites, it’s possible to prevent such withdrawal.

In SD-809, six deuteriums replace the hydrogens on tetrabenazine’s two methoxy substituents. Removing those methoxy groups is one of the key metabolic steps needed to break down the active form of the drug into an inactive metabolite. The heavy-hydrogen switch substantially slows that process, making it possible to give less of the deuterated version of the drug and give it less frequently than tetrabenazine.

SD-809 was originally developed at Auspex Pharmaceuticals, a deuterated-drug-focused firm that was acquired by Teva last year for $3.5 billion.

A few months after its purchase, Teva filed for FDA approval of SD-809, making it the first deuterated drug to come under regulatory review.

But at the end of May, FDA didn’t approve SD-809. The agency asked Teva to analyze the blood levels of certain metabolites of the drug candidate. The problem, explains Umer Raffat, a senior analyst specializing in pharmaceuticals at Evercore ISI, is that in its filing for SD-809, Teva referenced the safety data for tetrabenazine. Even though the metabolites are the same for both the deuterated and nondeuterated compounds, FDA wants quantitative data on SD-809’s metabolites, according to Raffat.

Raffat sees FDA’s response as only a minor setback, however. He says there’s little reason to question SD-809’s ultimate approvability or market profile.

Michael Hayden, Teva’s president of global R&D and chief scientific officer, said in a press release that “Teva will continue to work closely with FDA to bring SD-809 to the market as quickly as possible.” He anticipates that the company will respond to FDA’s request later this year.

After SD-809, another advanced deuterated drug candidate is Avanir Pharmaceuticals’ AVP-786, which contains a deuterium-substituted version of the cough suppressant dextromethorphan. Originally developed in the 1940s, dextromethorphan acts on numerous receptors in the brain. In 2010, Avanir gained FDA approval for Nuedexta—dextromethorphan in combination with quinidine—to treat pseudo­bulbar affect, an emotional condition that’s often associated with neurological conditions and brain injuries.

The problem is that most people metabolize dextromethorphan fairly quickly. The quinidine in Nuedexta slows down that metabolism, allowing the dextromethor­phan to circulate longer. The downside is that quinidine has some unwanted cardiac side effects. Scientists at Concert Pharmaceuticals, a company that develops deuterated drugs, created a version of dextromethorphan that has deuteriums instead of hydrogens on the molecule’s methoxy and methyl amine groups—key sites involved in metabolism. By making this switch, the amount of quinidine included in AVP-786 can be cut by more than half.

Concert partnered with Nuedexta developer Avanir on AVP-786 at the preclinical stage. In early 2015, Otsuka Pharmaceutical bought Avanir for $3.5 billion. AVP-786 is currently in Phase III clinical trials.

Dextromethorphan is a prime example of how deuterating can breathe new life into older drugs, says Roger Tung, Concert’s chief executive officer. The compound has been off patent for several decades, so it’s tough for pharmaceutical companies to develop the compound, as is, to treat a new disorder because it will be difficult for them to recoup their investment. But AVP-786, Tung points out, contains a patent-protected molecule that also offers an improvement over dextromethorphan.

Tung founded Concert in 2006 after spending decades in the pharmaceutical industry at Merck and then Vertex Pharmaceuticals. He says he had been consulting and spending some time as a stay-at-home dad while considering his next career move. “Being in the pharma industry, one recognizes how many ways there are to fail,” Tung says. “Many of those involve the poor translation between preclinical models and humans—difficulties of things like formulation, delivery, narrow therapeutic window. And the question I was asking myself was, ‘How do you reduce the likelihood of those bad things happening as you go along?’ ”

At this point in Concert’s origin story, Tung recalls how James W. Black, the physician, pharmacologist, and beta-blocker inventor who shared the 1988 Nobel Prize in Physiology or Medicine, once observed that the best way to find a new drug is to start with an old drug. Tung decided that Concert could accomplish this with deuterium. It wasn’t a new idea, he says, but so far big pharmaceutical companies had made only some isolated examples of deuterated drugs.

“It seemed like it was a plausible and a reasonable way of reducing the risks of drug discovery and development,” Tung says. Then two questions arose: Is there really going to be enough differentiation among the compounds to be clinically meaningful? And will people pay a premium for that difference?

“I think what we have is a model where incorporation of deuterium provides differentiated compounds that can be used both in similar and differentiated ways from preexisting compounds that will provide real clinical benefit over what’s currently available,” Tung says.

Although AVP-786 is Concert’s most advanced drug candidate, the firm has several others in its pipeline. For example, Concert has developed CTP-656, a deuterated version of Vertex’s cystic fibrosis drug Kalydeco (ivacaftor) that’s poised to enter Phase II clinical trials. The deuterated version of this compound has a 15-hour half-life as compared with ivacaftor’s 12-hour half-life, and studies have indicated that it doesn’t need to be taken with a fatty meal, as ivacaftor does for maximum efficacy.

But the company has also seen some promising deuterated drug candidates fall by the wayside. Concert partnered with Glaxo­Smith­Kline in 2009 to develop CTP-518, a deuterated version of the protease inhibitor Reyataz (atazanavir) for the treatment of HIV. GSK ultimately decided not to pursue protease inhibitors because of concerns about patients developing drug resistance to them.

Deuteration, Tung says, is one tool in the medicinal chemist’s toolbox. “It’s not going to be appropriate for all cases, but there will be situations where you can really improve the function of compounds, where you can enable new uses of existing agents, and where it will allow new medicines to be made.”

Not all of today’s deuterated drug candidates are heavy-hydrogen versions of existing drugs. At the American Chemical Society national meeting in San Diego this past spring, John Maxwell, director of medicinal chemistry at Vertex, unveiled the structure of VX-984, a deuterated molecule created to enhance the efficacy of certain cancer treatments.

Maxwell explained that Vertex scientists thought they had come up with a lead compound that was promising until they discovered it was being quickly metabolized at one of the molecule’s pyrimidine rings by the enzyme aldehyde oxidase. “We considered bulking up around the part of the molecule that was metabolized,” he said. “We considered trying to modify the electronics of the ring by pumping more electrons in. We considered getting rid of the protons there altogether.”

All of these strategies, Maxwell said, yielded compounds that aren’t metabolized by aldehyde oxidase. Unfortunately, their performance was not nearly as good as the lead compound.

“But we did have one thing left that we wanted to explore, and that was to deuterate,” Maxwell said. Putting the deuterium in place of hydrogen should slow aldehyde oxidase and hopefully slow metabolism to a reasonable degree, he adds. The compound is currently in a Phase I clinical trial.

Altering metabolism isn’t the only way to use deuterium in a drug candidate. Sheila DeWitt has built two companies—Deuteria Pharmaceuticals, which was sold in 2012, and DeuteRx—based on the concept that deuterium can prevent or slow epimerization, the interconversion of certain enantiomers.

Most chemists are familiar with the story of thalidomide: One enantiomer of the racemic drug can alleviate morning sickness in pregnant women, while the other enantiomer causes serious birth defects. But simply administering one enantiomer doesn’t fix the issue because the problematic chiral center is adjacent to a carbonyl and epimerizes inside the body. The harmful enantiomer gets made anyway.

By swapping deuterium for the hydrogen at that chiral center, it’s possible to slow down that epimerization and stabilize the desired enantiomer. Last year, DeuteRx used this strategy to make a stable, deuterated version of a thalidomide analog that is currently being developed as an anticancer agent.

The extent to which deuterium will stabilize a chiral center is unpredictable from molecule to molecule, DeWitt, currently CEO of DeuteRx, says. But DeuteRx has already used the strategy to stabilize the enantiomers for racemic active ingredients of more than a dozen marketed drugs or drug candidates. At the upcoming ACS national meeting in Philadelphia in August, the firm will disclose the structure of DRX-065, a deuterated version of the diabetes treatment Actos (pioglitazone). The company has been working on differentiating the enantiomers of pioglitazone for treating nonalcoholic steatohepatitis, a liver condition. DeuteRx scientists suspect that only one enantiomer causes unwanted side effects, such as weight gain, and they hope to eliminate those by using deuterium to stabilize the other enantiomer.

DeWitt confesses she was initially skeptical of the deuteration concept when chemist and entrepreneur Anthony Czarnik approached her about starting a company around the idea in 2009. Her initial response was, “Deuterium? Honestly, what difference does it make?” And she says she still finds it challenging to convince scientists and investors that deuteration provides a measurable benefit compared with existing drugs. An approved deuterated drug, she says, will help a lot.

Paul Reider, who spent decades working in the pharmaceutical industry before taking his current position on the faculty of Princeton University, says the deuterated drug concept is one that routinely moves in and out of fashion. “Every five years or so, someone calls me about a start-up company and they say, ‘We have this great new idea,’ ” he says. “I try not to laugh too hard, and I say, ‘Well, it’s a great idea. It’s not terribly new. It’s been done, and you just have to put the deuterium in the right place.’ ”

In the 1980s, Reider worked on the process chemistry for making Merck’s deuterated antibiotic fludalanine—the first deuterated drug candidate to make substantial strides in the clinic. The deuterium in fludalanine was put there to block formation of toxic metabolites. Ultimately, it didn’t work well enough. The fludalanine project was abandoned because those undesired metabolites appeared in the blood of bronchitis patients during Phase II clinical trials.

Reider thinks the deuterated drug concept has promise, but he’s skeptical about the current state of deuterated drug candidates. “I hope at some point that someone finds a novel molecule that puts deuterium in to solve a metabolite problem,” he says. “Unfortunately, I think people are using it as a trick. They’re using it as a way to create intellectual property through the back door.”

Even champions of deuterated drugs note there are plenty of pitfalls. Thomas Gant, scientific founder of the deuterated drug maker Auspex (he’s no longer with the company) and inventor of many deuterated drug candidates, including SD-809, says most synthetic chemists don’t have a good grasp of how chemical reactions operate in the presence of deuterated reagents or substrates.

“It is actually pretty surprising how many reactions that most chemists wouldn’t think would have an effect on the positions of hydrogens will actually cause quite a bit of randomization and dancing around of hydrogen radicals,” he says. “So you run these reactions expecting it to have no effect on your deuterated drug, and in fact, you can see a pretty dramatic effect in some instances. It’ll essentially spread the deuterium around the molecule” so you don’t have the original compound anymore.

Gant now heads Recondite Falls Discovery, a consulting company that specializes in pharmaceuticals and deuterium substitution. He says there are two areas people often perceive as being problematic with regard to deuterated drugs that aren’t: cost and intellectual property.

Counterintuitively, Gant says, adding deuterium to a molecule usually saves money. True, he says, deuterium is more expensive than hydrogen, but not that much more in the grand scheme of drug development. Deuterium’s ability to extend a drug’s half-life in the body can lead to a lower dose, which ultimately costs less.

As far as intellectual property is concerned, Gant says, it’s important to know the law. Deuterated compounds are considered new chemical entities and can be patented. But to get a patent, he explains, “you have to have actually done the chemistry, produced the deuterated compound, shown the spectra, shown deuterium incorporation rates, and shown biology to demonstrate a perceived benefit.”

It’s not unusual for pharmaceutical companies to include deuterated versions of original drugs in their boilerplate wording for patents. “This is something that companies routinely do to scare off people who don’t understand patents,” Gant says. “People think that the deuterated compounds have been covered. But they haven’t been covered because they haven’t been made and they haven’t been tested. So it might be written in the general description, but it doesn’t actually cover the application of deuterated compounds.”

Gant says he’s been thinking about deuterated drugs for more than 20 years, and although he’s excited to see one he invented come up for review at FDA, he thinks pharmaceutical companies have yet to tap into this area’s full potential. “People are really just getting the first generation of deuterated drugs across the goal line,” he says. “The prize in this field is going to be reducing toxicity and serious side effects of drugs. That’s really the limiting factor for most medicines on the market.”  


Sourcing deuterium for drugs
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Barrels of D2O in a Canadian government stockpile.
Credit: Isowater
Barrels of D2O on a forklift and in the background.
 
Barrels of D2O in a Canadian government stockpile.
Credit: Isowater

As a handful of deuterated drugs near approval, it raises the question, where does the deuterium come from? Ultimately, it originates with heavy water, or D2O. Deuterium, in the form of HDO and D2O, accounts for 0.0155% of the hydrogen nuclei in Earth’s ocean waters. The most popular process for extracting D2O from regular water is the Girdler sulfide process, which uses a temperature difference and hydrogen sulfide to enrich deuterium in water by up to 20%. That liquid is then distilled to create D2O that’s 99.8% pure.

The other popular process for making D2O relies on the exchange of deuterium in synthesis gas, which comes from a reaction of water and methane, with ammonia in the presence of a catalyst. The resulting deuterated ammonia then exchanges deuterium with protons in water to create water enriched with D2O.

Governments carry out these processes on a very large scale because heavy water is a critical component in Canada deuterium uranium (CANDU) nuclear reactors used to generate electricity. CANDU reactors are less expensive to operate than traditional nuclear reactors because of the type of uranium they use.

All nuclear power plants create electricity from the energy released when 235U is bombarded with neutrons and undergoes fission. In traditional nuclear power plants, water, which slows down neutrons, moderates this process. But water also absorbs plenty of the neutrons meant to bombard 235U, making it necessary to enrich natural uranium—which is more than 99% 238U—with 235U at great expense.

CANDU reactors can run on the small amounts of 235U found in natural uranium because they use heavy water to moderate the process. D2O is far less likely to absorb neutrons, so fewer bombarding neutrons are lost. The neutrons are instead able to find and split the smaller amount of 235U.

Some see trouble on the heavy-water horizon. The plants that make D2O are dwindling, and yet there’s growing demand for heavy water from both the nuclear industry and nonnuclear users, including chemical companies that make deuterated reagents. There is no production of D2O dedicated to the nonnuclear uses of life sciences and high technology, says Andrew Stuart, president and CEO of Isowater, a company that supplies D2O to such nonnuclear customers from a Canadian government stockpile. But Isowater is currently developing a new proprietary process for making D2O. “At some point, there is going to be a need for new supply,” Stuart says.

 
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Comments
Eszter Boros (Mon Jul 04 17:21:07 EDT 2016)
The naturally occurring isotope of hydrogen (1H), deuterium (2H), could have an important biological role. Deuterium depleted water delays tumor progression in mice, dogs, cats and humans...

More:
https://www.researchgate.net/publication/285579692_Submolecular_regulation_of_cell_transformation_by_deuterium_depleting_water_exchange_reactions_in_the_tricarboxylic_acid_substrate_cycle
Linh-Thao (Tue Jul 05 16:11:35 EDT 2016)
Wouldn't there be potential problems with deuterium being taken into the human biological processes as well? Since deuterium does have different kinetic properties compared to normal hydrogen, wouldn't deuterium be potentially toxic if it accumulates in chemicals involved in human metabolic processes?

Also, making drugs which are more difficult to break-down biologically (albeit being more effective) could also cause them be a potential environmental problem couldn't it? There's already a problem with drugs (particularly hormone control drugs) which accumulate in local bodies of water, which cause problems in marine ecosystems. Would making some of these drugs more difficult to degrade exacerbate this?
Bruce (Wed Jul 06 14:28:14 EDT 2016)
The deuterium released is not likely to pose a problem, although trials will bump into that contingency. The total amount of deuterium released into metabolism should be small. When D2O became widely available to researchers after WW II, they started feeding it to animals, etc. At very high levels, it is toxic, but I think that threshold is beyond 50%. Interestingly, I've heard tales that dogs being fed D2O could smell the difference from H2O.
Vladimir (Thu Jul 07 06:06:00 EDT 2016)
Firstly, you should keep in mind that D is a naturally existing isotope. Roughly, average human body contains 0.007% * 70 kg * 70% = 3.43 g of D. Let the average daily water intake is 1L (70 mg of D). Taking into account that,
- dosage of many modern drugs is often few orders below 1 g (let it be 100 mg);
- mass % of D in their D-analogues will hardly exceed 10-20%;
the amount of "exogenous" D (100 mg * 20% = 20 mg) will be negligible compared to its "natural" presence and daily intake.
Second, chemical properties of H and D are identical except for velocity of D-reactions are roughly two times slower. Considering ubiquity of reactions with hydrogen participation and fast water exchange of body with environment, it seems veeeery unlikely D to accumulate anywhere in organism, cause in that case concentration gradient will force its distribution and excretion.
Laszlo G. Boros (Thu Jul 07 14:09:02 EDT 2016)
Besides compromising proton tunneling in H-bridges of DNA, deuterons also disrupt proton transit by the FO nanomotor in ATP synthase. This protein sits in the inner mitochondrial matrix membrane and deuterons severely compromise proton on-off loading onto the Asp61 C protein residue, which is the heart of the biological nanomotor [Aksimentiev et al., (2004) Biophys. J. 86, 1332-1344]

This is because a deuteron has about one third (Delta_pKa_Asp61=0.35) of the acid dissociation constant in comparison with that of a proton from the Asp61 amino acid residue of the FO rapidly rotating inner mitochondrial membrane-bound subunit [Elston et al., (1998) Nature. 391, 510-513]. Therefore deuteronation slows down significantly the mitochondrial ATP synthase nanomotor, which causes metabolite crowding in the TCA cycle and glycolysis. Metabolite crowding inherently induces an uncoupling of ATP synthesis from the TCA cycle in the mitochondrial matrix, which consecutively contributes to the Warburg effect, as well as it diverts glycolysis towards serine oxidation and glycine cleavage in order to produce energy with reducing protons for macromolecule synthesis in tumor cells [https://goo.gl/4jUeD9].

Under optimum conditions the FOF1 subunit performs ~9,000 revolutions per minute with 1,500/second proton transfer velocity, where deuteronation rather than protonation may occur every 4.4 seconds in environmental water, where 1 deuteron is carried among ~6600 protons by oxygen. Deuteronation breaks the nanomotor as it is not a substrate of, or being transported by ATPase [Kotyk et al., (1990) FEBS. Lett. 264, 203-5].

Natural low deuterium ketogenic substrate oxidation decreases mitochondrial matrix water deuterium content metabolically [Mellanby (1942) Nature. 150, 21]. Therefore deuterium depleted water [Somlyai et al., (1993) FEBS Lett. 317(1-2), 1-4] and naturally occurring low deuterium substrate oxidation are essential to maintain the normal growth rate of cells by mitochondrial energy production and coupling.

Low deuterium matrix water and proton transfer maintain ATP synthase revolutions to preserve mitochondrial health via compartmentalized deuterium depletion as described elsewhere:

https://goo.gl/ykCEiG
https://youtu.be/GkYAjabGxJs

It seems that providing excess deuterium in the form of deuteronated drugs introduces this oncoisotope into human populations above its biological threshold [Perona et al., (1988) Nature. 334, 438-440] that can potentially trigger submolecular mechanisms with metabolic damages consistent with increased proliferation and/or malignant cell transformation.
David Wade, Ph.D. (Wed Jul 06 15:53:00 EDT 2016)
The article's statement, "...the hydrogen-deuterium switcheroo doesn’t change any of the drug’s other biological properties, such as its shape, size, or ability to bind its target." is incorrect. Deuteration of a molecule most definitely affects its noncovalent interactions with other molecules, such as target binding, as extensively reviewed in my article, "Deuterium isotope effects on noncovalent interactions between molecules." in Chemico-Biological Interactions (1999) 117: 191-217. This article has been cited more than 100 times by other authors in chemistry journals, indicating that the phenomenon described in my article is well known.
Reply »
Darell Engelhaupt (Wed Jul 06 19:07:52 EDT 2016)
Deuterium has different electrochemical properties than hydrogen. Therefor D2O Vs. H20 must be studied with respect to sensory responses in certain biological systems such as the heart, brain or nervous system. Has this been a topic studied to date? Thanks, Darell Engelhaupt
David Busath (Fri Jul 08 11:29:23 EDT 2016)
I am not aware of any behavioral studies, but the tendency of D2O to slow ion flow in gramicidin channels and influenza A M2 channels has been documented, and it might be reasonably expected in neuronal, heart and muscle ion channels as well. The effects are modest.
Gábor Somlyai (Fri Jul 08 03:45:55 EDT 2016)
We have been investigating the effect of deuterium depletion on biological system since 1990 and the first paper was published in 1993 (FEBS Lett. 317, 1-4) as Boros cited above. The focus was on the effect of D-depletion on cancer cells. We suggest that a submolecular regulatory system exsists in the cells (Boros et al. Medical Hypothesis 87, 2016, 69-74), which is able to modify the D/H ratio and the changing D/H ratio harmonized the genetic and biochemical processes in the living organism. Regarding your question, a paper was published in Neurosience Letters (583, 2014, 154-158) that the deuterium depleted water (DDW) stimulated the long term memory of rats.
Three international congress were hold to present the results of deuterium depletion, the presentations are available on www.deuteriumdepletion.com web site.
venkateswararao eeda (Wed Jul 13 19:48:43 EDT 2016)
So if we change H to D in a existing drug can i patent that molecule as a novel drug? with all biological data? please some one explain.
Trevor Rook (Sun Aug 21 23:32:23 EDT 2016)
Given the small amount of natural and introduced deuterium we are talking about here, shouldn't we be talking about HDO?

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