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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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June 2, 2009

A Deuterium Deal

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Posted by Derek

Well, there's someone who certainly believes in the deuterated-drug idea! GlaxoSmithKline has announced today that they've signed a deal with Concert Pharmaceuticals to develop these. There's a $35 million payment upfront, which I'm sure will be welcome in this climate, and various milestone and royalty arrangements from there on out. I know that the press story says that it's a "potential billion dollar deal", but you have to make a useless number of assumptions to arrive at that figure. Let's just say that the amount will be somewhere between that billion-dollar figure and. . .well, the $35 million that Glaxo's just put up.

Where things will eventually land inside that rather wide range is impossible to say. No one's taken such a compound all the way through development, and every one of them is going to be different. (Deuterium might be a good idea, but it ain't magic.) It looks like the first compound up for evaluation will be an HIV protease inhibitor, CTP-518, which is a deuterated version of someone's existing compound - Concert has filed paten applications on deuterated versions of both darunavir (WO2009055006) and atazanavir (WO2008156632). The hope is that CTP-518 will have an improved enough metabolic profile to eliminate the need to add ritonavir into the drug cocktail.

The company is also providing deuterated versions of three of GSK's own pipeline compounds for evaluation, which is interesting, since that's the sort of thing that Glaxo could do itself. In fact, that's one of the key points to the whole deuterated-compound idea: the window of opportunity. Deuteration isn't difficult chemistry, and the applications for it in improving PK and tox profiles are pretty obvious (see below). It's a good bet that drug company patent applications will hencrforth include claims (and exemplified compounds) to make sure that deuterated versions of drug candidates can't be poached away by someone else. This strategy has a limited shelf life, but it's long enough to be potentially very profitable indeed.

One more note about that word "obvious". Now that people are raising all kinds of money and interest with the idea, sure, it looks obvious. And I'm sure that it's a thought that many people have had before - and then said "Nah, that's too funny-sounding. Might not work. And besides, you might not be able to patent it. And besides, if it were that good an idea, someone else would have already done it. There must be a good reason why no one's done it, you know". Getting up the nerve to try these things, that's the hard part. Roger Tung and Concert (and the other players in this field) deserve congratulations for not being afraid of the obvious.

Comments (25) + TrackBacks (0) | Category: Business and Markets | Drug Development | Infectious Diseases | Pharmacokinetics | Who Discovers and Why


COMMENTS

1. Chemjobber on June 2, 2009 7:52 AM writes...

Is this the Roger Tung from "Billion Dollar Molecule"?

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2. Alig on June 2, 2009 8:09 AM writes...

"We believe Concert's approach to deuterium modification of medicines has broad potential to enhance certain drug properties and result in innovative new medicines," Patrick Vallance, Senior Vice-President Drug Discovery, GSK.

This is the same guy who said GSK will no longer develop drugs that only provide a small improvement to existing therapies, that GSK was only interested in developing truly transformational medicines. I guess he changed his mind.

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3. seethroughit on June 2, 2009 8:17 AM writes...

These compounds are nothing more than moronic attempts to circumvent IP. They are the lowest form of "me too" drugs.

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4. JT on June 2, 2009 8:21 AM writes...

About 15 years ago I made a D9 t-butyl group to improve PK...no change in half-life.

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5. outofthisworld on June 2, 2009 8:24 AM writes...

word is the next big thing is going to be drugs made from an extraterrestrial carbon source.

Let the PTO chew on that one for a while

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6. G2 on June 2, 2009 9:07 AM writes...

Why has Concert obtained 110 million dollars of financing for this stuff?

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7. DrSnowboard on June 2, 2009 9:53 AM writes...

OK, so we can all get on our intellectual high horses and say it's obvious, shallow, morally corrupt, intellectually debased to patent, or buy and sell, a deuterated analogue approach. I might even agree with you. But will the patient care, as long as they have to take one less pill? Will the investors care that they backed an outsider, as long as it got to the starting gate?

Let's face it, how many of us have been on projects with artificially high intellectual hurdles with lofty dreams of making the best compound out there, whilst the existing dirty compounds trundles along pleasing medics, patients and selling shedloads...
I'll get my coat.

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8. MolecularGeek on June 2, 2009 10:34 AM writes...

Chemjobber, I'm reasonably certain that he is the same Roger Tung.

I'm with Derek on this one. The crew at Concert were willing to take a chance and put their individual and collective posteriors on the line to try this. If it were truly obvious to the PHOSITA, there would be enough prior art out there to scare off their financiers.

MG

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9. Alf on June 2, 2009 11:27 AM writes...

In my experience, when people say a technology is obvious it is usually a sign of success. The best ideas are usually "obvious" in hindsight. In this case it is an investing success, hopefully improved drugs will follow.

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10. Kerry F on June 2, 2009 2:00 PM writes...

Since producing D2O also concentrates T2O, what are the consequences of partially tritiated (beta-emitting) drugs? Can I patent fully tritiated compounds? Perhaps they have some therapeutic or diagnostic use. You heard it here first and I donate my IP to the benefit of the world.

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11. CMCguy on June 2, 2009 2:40 PM writes...

#10 KF I think many places that generate T-labeled compounds for ADME studies sometimes prepare a D-analog first to verify chemistry. Believe there are radiolabeld drugs (antibodies) available that manufacturing is a logistical challenge due to handling and lifetime considerations.

I wonder about how FDA will view these derivatives. If D- is nonexchangeable would not expect D-leakage and if in a position that is metabolized then would have a D-delivery to cells/body. One concept is that such compounds who have different PK properties (presume target "better"). All these suggest submission will need a far amount of additional data to gain approval so unless a substantial advantage will likely be competing with a generic by time is marketed.

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12. You're Pfizered on June 2, 2009 3:09 PM writes...

You'd have to think that they'd have an array of pK/metabolism data to peddle showing that their specific deuterated compounds have an improved profile, otherwise, why would GSK buy into it?

I fully expect that all of our project heads will be asking "did you make the deuterated version of that compound?" at staff meetings around pharma soon enough...

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13. MolecularGeek on June 2, 2009 3:49 PM writes...

Without reading any of their papers, my guess is that they are deuterating their compounds at the sites where the cyps like to do their thing, in order to take advantage of the PKIE and reduce metabolic clearance. As far as this leading to appreciable accumulation of deuterium in vivo, I am not particularly worried. If they are only deuterating at the most commonly oxidized site to get the other cyps into the act, most of the clearance would then be via phase I action on a normal protonated position. Alternately, if the increased half-life means that clearance moves to the kidneys, you still aren't getting an increased HDO or deuterium oxide concentration in vivo. Even if the primary clearance mechanism is still deuteron abstraction, and 100% of the deuterium comes off into the bloodstream as deuterium oxide, that works out to about 2mg of deuterium oxide a day from metabolism. Assuming perfect distribution and isotopically pure 1H-water in the body, and neglecting to correct for water density at 37C, we get down into the range of 200 micromolar concentrations of D20. In a more familiar units, this works out to a blood concentration of 0.005%.

Finally, the human body completely turns over its water content in 12 days on average. Since this is mostly regulated by mass transport properties, rather than active chemical reactions, and we don't read horror stories of elderly patients poisoning themselves autologically by biological concentration of deuterated compounds, it seems likely that the proportion of deuterium oxide excreted is in direct proportion to its relative abundance in the body's water supply. Of course, there are metabolic processes using this water supply, but very few of the end products of using the water are going to be maintained in the body in that form in an adult. Again, no horror stories of sudden death by autologous deuterium poisoning on the front page of the National Star. So with long-term dosing, an increased steady state concentration of deuterons in the body will probably be reached. Whether it is toxic in the long term is a different question, which would require more rigor than I intend to apply to a blog comment.

Turning to the MSDS for deuterium oxide, no LC50 has been determined, and toxicology says "chemical presents no hazard unless large quantities are ingested". Considering that you get proportionately less deuterium in the blood from a days dose of these compounds than ethanol in the blood from a shot of Bushmill's, I don't know that 2mg qualifies as a large amount in anyone's book.

The FDA will want beaucoup studies on this before they consider approval, as they well should. But, based on these back of the envelope musings, I wouldn't expect toxicity to be the biggest problems these drugs have. Frankly, I'd be more afraid of the well-known dangers of PIs, and the consequences of being immunocompromised in general, but that's just me.

MG

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14. Chemjobber on June 2, 2009 4:08 PM writes...

I nominate #13 for best substantive comment of the week.

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15. Crop Rotator on June 2, 2009 10:58 PM writes...

OK chemists:

Deuteration of an existing drug is obvious and by itself not patentable. Now, if the deuterated drug improves the utility of an existing drug, and this
would not be expected by one skilled in the art then this may be patentable.

A similar example would be a company patents a drug with butyl, propyl, ethyl sidechains in a critical area. After the company receives a patent for their family of compounds a newcomer can't patent a drug with a methyl side chain unless it would be unobvious to try that and they have data to show the methyl compound improves utility.

You see, the methyl analog is new, but any chemist with a pulse would try that.

Obviously.

P.S- It's a reflection of the conformist culture of corporate chemistry that deuteration is considered state of the art. Too many Chinese and Indians who think alike and only follow orders.

Permalink to Comment

16. CMCguy on June 2, 2009 11:55 PM writes...

#15 Crop Rotator so how do you explain the U.S. Patent 4,331,803 for Clarithromycin which is only a Me-derivative of erythromycin? It certainly had some improved properties and utility but those are not in the claims as was seemingly obvious structure to any chemists. Lawyers are very good at exploiting such loop holes and I have to wonder about the PTO decisions at times (even more than the FDA).

#13 MolecularGeek you make very sound arguments however such science rationale often seems to have minimal impact on FDA perceptions so I fear there will be a few additional barriers created for Deuterated Drugs just because of uncertainties associated with such new analogs. The process is hard enough now and thus any requirement for extra studies makes it tougher.

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17. processchemist on June 3, 2009 2:06 AM writes...

Apart from strictly scientific considerations:
36 millions upfront... It recalls a bit the sirtrix deal...
Looking at the last published GSK pipeline, what you can see?
Elesclomol, still there
Tykerb, many extensions
an NK1 inhibitor, still there

I hope that this can be the solid beginning of a new flow of cash from big pharma to smaller companies and biotechs. It would be nice to see these guys with restored budgets not forced to go (far) east for the chemistry side of drug development.

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18. great Molecular Crapshoot on June 3, 2009 2:52 AM writes...

If you deuterate an existing drug, you'll still need to show the deuterated drug shows measurable clinical advantages over the undeuterated drug. One interesting safety issue that could arise from deuteration is that the predominant site of metabolism is likely to shift (assuming that improvements in PK have been observed) and this could lead to a potential reactive metabolite problem (somewhat unlikely but would need checking and the FDA will ask). I see deuteration and substituting silicon for carbon as Med Chem tactics that are certainly worth considering in drug discovery programs. However, the idea that you can deuterate a marketed drug and then sell it with minimal clinical evaluation is pushing it a bit.

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19. Porkpiehat on June 3, 2009 6:50 AM writes...

Sepracor --> Combinatorx --> CoNCErt. A common denominator between these companies (and others who imitate them) is the quest for leveraging known drugs, each in its own way (enantiomers of known drugs, pairwise combinations of known drugs, deutero derivatives of known drugs, etc), to de-risk the startup investment. So I ask you all: what is the next gen idea in this now established (chemistry specific) biotech tradition?

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20. Gambler on June 3, 2009 8:46 AM writes...

So far GSK has thrown a over a billion dollars at Phage Display (praecis), Grape juice (Sirtris), and now deuterated compounds.

Any one willing to bet they'll be laughed at in the future for making such gambles?

One things for sure, some investors and executives sure are feeding at the trough on these deals

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21. Fred Kahan on June 3, 2009 12:56 PM writes...

Fludalanine, a deuterated drug that almost succeeded.

Here's a story from the 70's of Merck's MK0641/MK0642, an antibacterial combination of 2-deutero-3-Fluoro-D-Alanine (MK0641) and pentizidone (MK0642), a prodrug adduct of D-cycloserine with acetylacetone. It made it all the way into Phase IIb before succumbing.
Fluoro-D-Alanine (3FDA) is metabolized by D-aminoacid oxidase (DAO) in kidney and liver to 3F-pyruvate which then undergoes oxidative defluorination. While the acute toxicity of this drug is very low and attributable to liberated fluoride, chronic studies in rats and monkeys revealed myelin vacuolation in the corpus callosum of the brain. The histopathology resembled that of “spongy brain" found in infants and burn patients exposed to topical hexachlorophene. The causative agent was determined to be 3F-lactate, which is in equilibrium with 3F-pyruvate during metabolism. Deuteration did reduce primary metabolism: a kinetic isotope effect of 2.8 was observed with DAO in vitro, however in the more relevant case of open system metabolism and elimination in vivo the reduction in 3F-lactate levels was a more modest two-fold relative to 3FDA. Our goal was to keep 3F-lactate during treatment in man to one-tenth of the levels inducing vacuolation during chronic exposure. Everything went well in Phase I with healthy volunteers, but the first trial with the intended beneficiaries, sick patients, provided our undoing. Bronchitis patients with COPD (MD's call them "pink puffers and blue bloaters" ) sustained double the levels of 3F-lactate we expected, presumably reflecting a more anaerobic status of their electron transport system.
This tale should not discourage deuteration where the objective is reducing primary metabolism alone, to produce for example greater half-life. However, where levels of a metabolic intermediate are involved, you have to worry about the impact of the diseased state on drug disposition.

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22. Paul on June 9, 2009 3:49 PM writes...

If we ever get around to having people live on Mars, the issue of the effect of deuterium on the body may become more important. The D:H ratio there is five times higher than on Earth. On Venus, it's 120 (!) times higher.

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23. DW on July 15, 2009 5:02 PM writes...

I want a piece of the Nobel Prize for this.
(doi:10.1016/S0009-2797(98)00097-0)

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24. jiajia on August 25, 2009 4:21 AM writes...

I did some work on this idea, and I think It's brilliant and useful! Simple and obvious,that's the power : )

"The water content in living organisms and the D2O concentration of natural water, which is 150 ppm (parts per million), the Deuterium (D) concentration in the living organisms is more than 10 mmol/L. Just to put this figure inperspective it should be noted that the Ca2+ (calcium) concentration in the body is approximately 2 mmol/L.This demonstrates that science has overlooked an element, which is present in the body at a five time's greater concentration than calcium. in fact, there is greater than 1 gram
of deuterium in the average human adult。。。。。。

and more:
1.Some deuterated drugs show different transport processes. include amphetamines, which are
more readily transported into the brain in the deuterated form (Wenzel, 1989 Most are more
resistant to metabolic changes, esp. those changes mediated by cytochrome P 450 systems.

2.Deuteration may also change the pathway of drug metab. (metabolic switching). Changed
metab.may lead to increased duration of action and lower toxicity. halogenated anaesthetics, such
as selvoflurane, which, when deuterated are no longer oxidized to toxic forms within the
body (Baker et al., 1993), It may also lead to lower activity, if the drug is normally changed to the
active form in vivo. Deuteration can also lower the genotoxicity of the anticancer drug tamoxifen and
other compds.

3. Deuteration increases effectiveness of certain antimicrobial compounds [long-chain fatty acids
(Abrahamson et al., 1982) and D-fluorophenylalanine (Merck and Co., 1977)] by preventing their
breakdown by target microorganisms.

It seems D drug can make significant improvement for some drugs.....

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25. Fred Kahan on September 12, 2009 4:43 PM writes...

Fludalanine comment (#21) has been published.
At the suggestion of a Merck colleague, the narrative in #21 was submitted as a letter to C&E News following their own feature article in June 22, p36 on Deuterated Drugs. This letter has now been published in C&EN 87:#36 09/07/09. I regret that the editors chose to delete my citation to the letter's original appearance in "The Pipeline".

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