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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 15, 2013

Zafgen's Epoxide Clears A Hurdle

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Posted by Derek

I wrote here about Zafgen and their covalent Met-Ap2 inhibitor beloranib. Word is out today that the compound has passed its first Phase II trial handily, so score one for covalent epoxides as drug candidates.

Zafgen has followed up promising results from early-stage work on its weight drug beloranib with a stellar Phase II study that tracked rapid weight loss among the severely obese, with one group shedding an average of 22 pounds in 12 weeks. CEO Tom Hughes says the mid-stage success clears a path to a Phase IIb trial that can fine tune the dose while taking more time to gauge the longterm impact of its treatment on weight. And the data harvest sets the right tone for ongoing talks with investors about a new financing round for the biotech.

Efficacy, though, doesn't seem to have been in much doubt with this compound. Phase III will be the big one, because the worry here will be some sort of funny longer-term toxicity. No one's quite sure what inhibiting that enzyme will do (other than this pretty impressive weight loss), and a covalent drug (even a relatively benign and selective one like an epoxide) is always going to have questions around it until it's proven itself in human tox. But so far, so good.

One thing that beloranib has going for it is that patients would presumably take for a relatively limited course of therapy and then try to keep the weight off on their own. That's a big distinction, toxicologically. On one end of the spectrum, you've got your one-time-use drugs, like an anesthetic, and then there are the anti-infectives that you might take for two weeks or (at most) a few months. But at the other end, you have the cardiovascular and diabetes drugs that your patient population is going to be taking every morning for the rest of their lives, and the safety profile is clearly going to have to clearer in those cases.

Critics of the industry never fail to mention that we, supposedly, are not looking for cures, but rather for drugs in that latter category so we can reap the big, big profits. They haven't thought this through well enough: for one thing, a cure is worth more money up front. And there is that tiny little factor of patent lifetime. To hear some people talk, you'd think that a drug's discoverers continue to reap the gains forever, but it ain't so. Ask Eli Lilly right now how that's going - most of their revenue is in the process of packing up and leaving for the generics companies. It doesn't matter if a company finds a drug that people need to take for fifty years; they're not going to be selling it that long.

Back to Zafgen, though. They've got an interesting program going here, and I'm very curious to see how it works out. Going after obesity from the metabolic end is something that a lot of people have tried, through various mechanisms, but it's still probably a better bet than trying to affect appetite. And I'll be glad to see an epoxide-based drug prove itself in the clinic, because I think that evidence suggests that they're better drug candidates than we give them credit for (see the link in the first line of this post for more on that). We medicinal chemists need all the options we can get. From the way things look, I'd bet on beloranib going fine through the rest of Phase II - and then begins the finger-crossing and rabbit's-footing.

Comments (16) + TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity


1. lynn on November 15, 2013 9:37 AM writes...

Could be impressive. Will keep watching for more data/IPO.

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2. The Fat Layer on November 15, 2013 9:53 AM writes...

From a medchem perspective this is an eye opener.

Talk about a compound that is an ester, a Micheal acceptor, and with 2 epoxide groups being selected for development AND passing Phase 2 trials.

If today had been April first I would've thought this was a joke.

If this compound passes Phase 3 and it's approved, it'll give us medchemists tons to think about about our rules for compound selection and development.

Something to mull over...

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3. Stu West on November 15, 2013 10:07 AM writes...

I'm not sure I follow the argument in paragraph 4 of the post. Is a new antibiotic really worth more up-front than a new asthma maintenance therapy? I also don't see how it's relevant that patients will only be using your company's asthma inhaler for 20 years rather than 50. That's still a lot more than a two-week anti-infective course!

I was at a conference last month where one of the speakers on antibiotic resistance made the comment that drug companies were perhaps not particularly interested in developing anti-infectives for this reason. Then he added "But perhaps that's just me being cynical." As if you have to be a conspiracy nut to believe corporations are trying to maximise their profits...

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4. Morten G on November 15, 2013 10:16 AM writes...

Cue "These people just need to eat less and move more".

Seriously though, if this is just short treatment shouldn't they just have to beat the 0.5% mortality rate on gastric by-pass? "Our treatment kills fewer than one out of two hundred patients." And by-pass only has a ~75% success rate anyway.

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5. PPedroso on November 15, 2013 11:23 AM writes...


What about the cost of a bypass surgery?

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6. Anonymous on November 15, 2013 11:33 AM writes...

I'm sure if people eat the drug *instead* of food it will be quite effective.

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7. Unchimiste on November 15, 2013 1:39 PM writes...

I just want to point out that it is a derivative from natural products (fumagilin/ovalicin). As we know these secondary metabolites have been selected throughout millions years of evolution. In this case those epoxides are maybe exceptions and are less reactive than what chemistry teaches us (at least the one on the side chain, for the spiro one it's a different story as it reacts with a cysteine residue within the Met-AP2 catalytic site)

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8. noname on November 15, 2013 2:02 PM writes...

#7: Yes, fumagillin is the product of millions of years of evolution. But the selective pressure was not oral availability and non-toxicity in humans, nor was it making humans skinny. Using it in that capacity is the product of non-natural (i.e. human) ingenuity, not evolution.

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9. lynn on November 15, 2013 2:26 PM writes...

#8 noname - Beloranib is administeed subQ; so probably not orally bioavailable. Fumagillin is indeed an inhibitor of MA-AP2 as well. So it is likely that evolution played a large hand here. Speculation follows: It has always interested me that many of the target-specific antibacterials and antifungals made by bacteria and fungi respectively are also non-toxic [or have limited toxicity] to humans. Maybe evolution toward target-specificity gets rid of the non-target-based toxicities. On the other hand, fumagillin appears to be somewhat RBC lytic - so maybe shortening the polyene gets rid of that problem. And I'd speculate that beloranib has less antifungal activity, possibly due to lowered cell entry.

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10. milkshake on November 15, 2013 2:54 PM writes...

#2: cinnamates eseters are really poor Michael acceptors, especially when decorated with electron donating para alkoxy group. My bigger worry, looking at a greasy molecule decorated with amine sidechain, would be CYPs metabolism and QT prolongation.

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11. Reactivechem on November 15, 2013 9:44 PM writes...

The whole reactivity-toxicity is over played. Allyl isothiocyanate is horseradish. Most veggies have high levels of other electrophiles (yum!). Makes the taste linger and activates NRF2 through kEAP.

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12. iwasachocolateseller on November 16, 2013 2:57 AM writes...

A lifelong "maintenance" drug will be more profitable than a "cure" drug, limited patent-protection period notwithstanding. Let's look at a hypothetical and simplistic example:
Say there are 2 diseases (or conditions), one having a cure and another needing lifelong maintenance. Say that there are 100 patients in each category, with 20 being added each year. The “cure” will have 100 patients in the first year, who are all cured after being administered a few weeks’ treatment once the “cure” hits the market. So this drug has a market of 100 patients in the first year followed by 20 in each subsequent year, till its patent protection expires. Compare this with the “maintenance” drug : it has 100 patients in the first year, but 120 in the second (original 100 + 20 new patients), 140 in the third and so on till the patent protection expires.
Although the “cure” will be administered only for a few weeks, let us say that one patient treated by the cure is equivalent to one patient-year (as he is given one course per year and does not need again as he is treated). Now let’s say that each drug is in market for 12 years (actually might be more – depends on time-to-market for the drug) before the patent protection expires. The “cure” has a market for 320 patient-years (100 in first year + 20 in each of subsequent 11 years). The “maintenance” drug has a market for 2520 patient-years (100 + 120 + 140 etc). That is almost 8 times the market for the “cure”.
So the “cure” would have to be priced about 8 times for a few weeks treatment compared to the yearly cost of the “maintenance” drug to have the same top-line (and by assuming similar profit margins, the same bottom-line).
Of course the assumptions above are simplistic, but you can play around with the numbers and still get similar results. You could do time-adjusted discounting and the results are similar (discounting at 5% per year will give a market for the “maintenance” drug 7 times that of the “cure”)
I say it again, limited patent protection period notwithstanding, a “maintenance” drug will be more lucrative. That said, I do not agree with industry critics when they claim drug cos are not looking for “cures”.

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13. Anonymous on November 16, 2013 9:47 AM writes...

@12: You're forgetting the fact the small issue of price: people would pay much, much more for a cure, than to just control the disease over many years. Also, with a cure you make all your money at once, without the risk that a competitor will step in and take your future profits by launching a cure (or even just a better treatment) himself. It's common sense, but unfortunately you can't buy that.

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14. a-non on November 17, 2013 1:27 PM writes...

Even if this works & is miraculously tox free...... when was it discovered? 99 problem, but patent life is #1

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15. Anonymous on November 18, 2013 10:32 AM writes...

@iwasachocolateseller: Your argument only holds true when the available patient populations are equivalent. A maintenance drug for a tiny patient population vs. a 'cure' for a huge number of people are not equivalent. As I recall, when GW and SKB merged, SKB's biggest drug was augmentin, an antibiotic. One of the reasons that big pharma is now targeting orphan drugs is because they can charge exorbitant amounts. You can't charge $250,000/year for a new asthma drug especially when there are so many already out there that actually work. But you might be able to charge that for a short course of a drug that actually cured your asthma so that you never had to hack and cough again. The other reason that they're now targeting orphan indications is lack of competition in those therapeutic areas. The huge patient population therapies, by and large, have numerous drugs already on the market and often generic. Obesity is an area where there are only a couple drugs and they don't work very well. The other issue is that it's hard to come up with a drug that is safer than diet and exercise which, believe it or not, has actually shown clinical efficacy.

As for epoxides, try to open one up with an amide anion. I've had the hardest time in the past opening them up even when I was cooking the nucleophile and the epoxide together for many hours. They're surprisingly unreactive and always when you actually don't want them to be and usually many steps into your synthesis. (Murphy's law I guess.) So I'm not too surprised that they're not seeing toxicity.........(yet).

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16. iwasachocolateseller on November 19, 2013 7:04 AM writes...

@13 & @15 : Thank you for reading my comment, I was not really sure if anyone will actually read it.

My primary point is that limited patent period does not make a difference in the calculation of profitability of cure vs maintenance drug, as implied by in the 4th paragraph of Derek's post.

A relevant data point on this discussion will be how many of the top 10 drugs (by value) fall in either category. Anybody got data on this?

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