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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: Twitter: Dereklowe

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November 18, 2010

Halaven: Holder of the Record

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Posted by Derek

The FDA has approved Eisai's Halaven (eribulin) for late-stage breast cancer. As far as I can tell, this is now the most synthetically complex non-peptide drug ever marketed. Some news stories on it are saying that it's from a marine sponge, but that was just the beginning. This structure has to be made from the ground up; there's no way you're going to get enough material from marine sponges to market a drug.
If anyone has another candidate, please note it in the comments - but I'll be surprised if there's anything that can surpass this one. There have been long syntheses in the industry before, of course, although we do everything we can to avoid them. Back when hydrocortisone was first marketed by Merck, it had a brutal synthetic path for its time. (That's where a famous story about Max Tishler came from - one of the intermediates was a brightly colored dinitrophenylhydrazone. Tishler, it's said, came into the labs one day, saw some of the red solution spilled on the floor, and growled "That better be blood") And Roche's Fuzeon is a very complicated synthesis indeed, but much of that is repetitive (and automated) peptide coupling. It took a lot of work to get right, but I'd still give the nod to eribulin. Can anyone beat it?

Comments (44) + TrackBacks (0) | Category: Cancer | Chemical News | Drug Industry History


1. anchor on November 18, 2010 8:45 AM writes...

Derek: I could hear clunking noise coming out of India and China where people are working 24X7, all year long to make the same. Perhaps, FDA knew that making synthetically complex molecule from Eisai was going to be bigger challenge and approving the same was very simple. They are simply throwing the gauntlet at Eisai to get it done, I suppose. Making and marketing Taxol derivative was an easy pie.

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2. milkshake on November 18, 2010 8:45 AM writes...

another approved marine monster is Yondelis, aka Trabectedin (Ecteinascidin 743). The nastiness of its structure clearly rivals halichondrines. But I think Yondelis is harvested from the natural source tunicates. There were fully-synthetic simplified analogs of ecteinascidin and saframycin that Corey and Mayers licensed out to PharmaMar and Celera respectively; these analogs are still lingering in the pipeline, after nearly a decade from their discovery

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3. Anonymous on November 18, 2010 9:00 AM writes...

There an epothilone analog, ixabepilone, that was approved back in 2007. as far as i know, it's synthetically produced as well.

eribulin is several orders of magnitude more complex than ixabepilone. developing a commercially viable sythesis must be exponentially more difficult.

i think it's quite an advance to go from the approval of ixavepilone to eribulin in only ~3 years. perhaps we are witnessing the dawn of a new age of synthetic med chem.

@anchor - I don't think Eisai would go through the trouble of getting FDA approval of the compound if they didn't have a economically sensible route to make it. FDA approval requires not only approval of the clinical utility of the api, but also approval of the specific route for the manufacture of the same.

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4. FMC on November 18, 2010 9:02 AM writes...

@ anchor: I think you are mistaken as you will find that the above molecule and the fact that it can be synthesized on an industrial scale can be traced back to Prof. Kishi. All I can say is hats of to him and to Eisai.

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5. processchemist on November 18, 2010 9:07 AM writes...

I remember something like 20 steps for fondaparinux and polysaccharide synthesis it's not like sequencing pepdtides...

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6. processchemist on November 18, 2010 9:20 AM writes...

Another historical industrial synthesis, 20 steps, was deserpidine. Anyway, the scale up of total syntheses of natural products it's one of the most fascinating chemistries I've worked on, also if it can be a real nightmare.

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7. quintus on November 18, 2010 9:21 AM writes...

@FMC, I totally agree with you, what an achievement.
Think of the GMP steps and the validation required.
This is great news for Organic chemistry.

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8. EZCorey on November 18, 2010 10:06 AM writes...

Actually its pretty easy - we had an undergraduate prepare it in our lab from basic starting materials in an overall yield of 83% (average yield per step of 99.8%).

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9. Old Timer on November 18, 2010 10:08 AM writes...

I heard a talk about this synthesis at a Gordon Conference this summer. Amazing work! I was especially pleased to see a former postdoc I worked with during grad school was responsible for a lot of the chemistry. He was an amazing Japanese chemist. It's great to see people "trained in the art" do so well in the workforce.

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10. Anonymous on November 18, 2010 10:27 AM writes...

Is the industrial synthesis or a process patent published?? I remember hearing a part of this story when I interviewed 5 years ago, and it used a Nozaki-Kishi chromium coupling at the time.

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11. Chemist with no lab on November 18, 2010 10:48 AM writes...

THIS is genius. Why take out a patent at all? Can you see the generics taking this on?

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12. Mike on November 18, 2010 10:58 AM writes...

I dunno how hard it is to make, but I recall being very much in awe of the structure of diprolene (betamethasone diproprionate), a topical anti-eczema drug. It's a freakin' monster.

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13. processchemist on November 18, 2010 11:05 AM writes...


Usuall processes are patented just before the expiration of the patent covering the product.
I should have a look at the patent covering eirbulin, probably I'll find a small scale synthesis and a "swiss claim".

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14. Kevin on November 18, 2010 11:12 AM writes...

No Spinal Tap joke yet?

"This synthesis goes all the way to Halaven..."

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15. processchemist on November 18, 2010 11:14 AM writes...

Just had a look at doi:10.1021/ja9058475
This is a NCE, so some time will pass before a patent will disclose a manufacturing process.

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16. nitrosonium on November 18, 2010 11:24 AM writes...

@#8: exactly what was "easy"?
and wrt "avg yield per step of 99.8%", see derek's post from earlier this week!

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17. Will on November 18, 2010 11:39 AM writes...

@ 11, there are several patents and published apps on the synthesis, see eg UE 20090198074 and 6,214,865

Depending on the expiration of the api patent(s) and when its fda's exclusivities expire, the process patents may be more useful

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18. Anonymous on November 18, 2010 12:15 PM writes...

For FDA approval, the company must show that it can produce the compound CONSISTENTLY (quantity and quality).

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19. anchor on November 18, 2010 12:20 PM writes...

# 3 and #4, I fully concur with your views. Also agree that the synthetic route to the piece herein including that of Yondelis, aka Trabectedin (as pointed out by milkshake) from the Harvard group is simply superb! To me the larger issue what use is approving this and other analogs (by FDA) and then later on to be denied coverage by the insurance companies (typically the yearly cost for these treatments starts at a minimum $ 100,000/annum). And, all these to draw out your life by another few weeks? I think not long back, Derck Lowe touched on these issues (merits vs. demerits). Anyway, lot more natural products are coming down the pike for cancer. Stay tuned

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20. KCNic on November 18, 2010 12:48 PM writes...

#8, 83% you say? I for one won't stand for such inefficiency.

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21. milkshake on November 18, 2010 12:59 PM writes...

if there is demonstrable advantage over older chemo drugs, the insurance companies in US have to cover it - or they will open themselves up to lawsuits.

In case of eribulin there appears to be improved safety profile over other tubulin-binding drugs, such as Taxol or epothilones. They have seen much less peripheral neuropathy with eribuling in clincial trials (few %) as opposed to >50% occurence with epothilone and Taxol. Since a preferred tubulin binding site of eribulin is distinct from the other two drugs (it is localized at one terminus of growing microtubuli) there is reason to speculate that eribulin may cause less axonal damage because of its mechanism of action

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22. anchor on November 18, 2010 1:01 PM writes...

#8, read, 99% Yield? That, Friends, Is Deception-by Derek Lowe and recent publication by Prof. Hudlicky.

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23. JAB on November 18, 2010 1:44 PM writes...

Ixabepilone is a semisynthetic epothilone - the lactam is made from natural epo B. You're thinking of Berlex/Bayer/Schering's sagopilone, which is in phase II trials. As far as I can tell, all of the other epothilones have washed out, except for Dansihevsky's isofludelone, which has just been licensed by BMS.

@19 here come a lot of NPs indeed!

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24. Pig Farmer on November 18, 2010 2:05 PM writes...

I calculate that your synthesis must be 93 steps long, if your average yield is 99.8% per step and the overall yield is 83%. What did you start from? Hydrogen?
Never did believe anything that came out of the Corey lab!

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25. alig on November 18, 2010 2:57 PM writes...

The other thing that makes the process difficult is the potency of the material. Your exposure limits are basically zero for the last few steps.

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26. flavor on November 18, 2010 3:32 PM writes...

with regard to #8, I see that sarcasm/irony identification is still in project definition phase in the US.

How long would it take to make this in a factory and what scale we talking about? Are they actually able to do it in a factory, or did they use steps which are very hard to do on larger scale.

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27. CMCguy on November 18, 2010 3:34 PM writes...

#18 "For FDA approval, the company must show that it can produce the compound CONSISTENTLY (quantity and quality)."

While true these are required by FDA the agency is silent (at least directly) on economic viability and market supply capability of new drugs. Whether a particular compound can even be produced to meet a projected patient demand (Marketing WAG) coupled with in ROI constraints (Process "educated" estimates vs Business mandates) is very tough evaluation (and getting harder). I would venture that these type considerations, which are subject to wide variation and error, probably have halted as many if not more compounds coming out of drug discovery then tox/efficacy issues. The back story on development of this molecule is probably very interesting as they likely ignored predominate mentality and advise at many points along the way.

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28. Anonymous on November 18, 2010 4:16 PM writes...

#26: From speaking with an Eisai chemist, it sounds like they have been making about 200-300g per batch. With sub nM activity (~0.5 nM from the paper I saw), that might be enough material to get them started, although I have no clue what the national/global demand will be.

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29. InfMP on November 18, 2010 4:37 PM writes...

I think I had talked about this before on here but it was a triple JACS full article by Kishi:


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30. Nick K on November 18, 2010 5:26 PM writes...

@28: Making 200-300g per batch of this compound is an astonishing accomplishment. A real landmark in process chemistry.

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31. Anonymous on November 18, 2010 9:09 PM writes...

Can we estimate how much chromium and nickel is required to produce 1 g of the final product?

I am sure the NHK is still a key step in the synthesis.

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32. Processing on November 18, 2010 10:30 PM writes...

regarding Et-743 (Trabectedin, Yondelisâ„¢), I believe the commercial route is a semisynthesis from cyanosafracin B, obtained from the fermentation of the bacteria "Pseudomonas fluorescens" (ref. Eur. J. Org. Chem. 2006, 8, 1926-1933 and references therein). So even though Et-743 was originally found in small quanities in sea tunicates, it's part of family of bisisoquinoline alkaloids that are more accessible through non-total synthesis routes.

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33. Pallas Renatus on November 19, 2010 1:28 AM writes...

Christ, that's impressive indeed. And to think the hardest total synthesis I ever had to work through was for Ibogaine... and that was only in research amounts. I can't imagine the work involved that went into eribulin.

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34. petros on November 19, 2010 3:36 AM writes...

Another impressive synthesis of a complex natural product was that of disocdermolide, another marine sponge anticancer.

A lot of Chemistry was done at Cambridge at Ian paterson's group before Novartis address process development but the development seemed to stall in phase II.

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35. Paul Hurley on November 19, 2010 5:01 AM writes...

It's impressive indeed. Does it win the crown of Largest "small molecule" Drug to make it to market, or is there something else with a higher mol weight (excluding bio's and polymers) ??

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36. quintus on November 19, 2010 6:20 AM writes...

@Petros, discodermolide died in phase 1 due to tox problems

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37. anchor on November 19, 2010 8:49 AM writes...

Unrelated to this posting (Halaven) is Pfizer, Bristol-Myers blood thinner clinical trial was halted on Bleeding. This is a big setback for both hoping to make big on the blood thinner market to be valued at $ 14-15 billion in 2015.

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38. S on November 19, 2010 11:48 AM writes...

Eisai was here at our school for recruitment a month ago and a very smart process chemist gave us the run-down on the process chem. aspects of synthesizing this beast. They were practically running crystallizations at every stage and were able to eliminate all but one maybe two chromatographic purifications. The key step still involves Ni/Cr early on enough, which they said was being brought down to acceptable levels after subsequent filtration sequences.

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39. CMCguy on November 19, 2010 3:37 PM writes...

#35 Answer may depend on how erythromycin analogs are classified (with slightly higher MWs) since are semi-synthnetic molecules based on fermentation. I see these as falling into biologic although term has morphed to more cover peptides, proteins, DNA and similar materials.

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40. David Young MD on November 21, 2010 11:51 PM writes...

Yes, Eribulin is a derivative of Halichondrin. Halichondrin looks like Eribulin with a long arm attached. I recall hearing an hour lecture by someone at Eisai describe the effort that went into determining which parts of the Halichodrin molecule were necessary for the anticancer effects. Halichondrin was an impractical anti-neoplastic, but the derivative was reasonable. Kudos to the team that took this project from conception to fruition. I am hoping that Eribulin will prove to be a useful drug.... and not just for Breast Cancer.

Now, when I meet the rep from Eisai, I'll drawl "Hey dude, what's Havalen?" (followed by loud groans...)


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41. barry on November 23, 2010 12:06 AM writes...

and for all that, it's yet another modulator of tubulin polymerization. I.e. it's going to whack any cell that tries to divide, rather than targetting a defect in cancer cells.

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42. Anonymous on November 30, 2010 4:42 PM writes...

The synthesis to make API is 48 steps long and the halichondrin B link is not tenuous. Kishi had alot to do with the discovery of this one.

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43. sponge on December 6, 2010 2:37 PM writes...

#42 The link between erubilin and halichondrin B is indeed very strong. Erubilin (originally known as E7389) was one of many halichondrin analogs produced in a synthetic program run by Kishi and Eisai. Eisai were on the verge of dropping the project in the mid 1990s when they became aware of some studies at the NCI which showed that naturally occurring halichondrin B from a New Zealand sponge Lissodendoryx sp was very effective in a late stage xenograft experiment. Eisai/Kishi then supplied a sample of E7389 and its diol precursor to the NCI for side by side experiments with the halichondrin B in the late stage xenograft model. E7389 proved to be much superior to the halichondrin B, thus prompting Eisai to continue with the development of erubilin, in collaboration with the NCI in establishing Phase I clinical trials.

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44. Sideline Chemist on October 24, 2013 10:00 AM writes...

Sadly, the reward for the process chemists at Eisai Andover who were responsible for this achievement was a pink slip. The company just laid off the entire process & pilot plant groups this week.

Thanks for the amazing hard work...don't forget to pick up your severance on the way out the door.

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