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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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May 28, 2014

Would You Have Advanced BBI608?

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Posted by Derek

Over the weekend, Dainippon Sumitomo got some very bad news about a compound they were developing against cancer stem cells. It's BBI608, which they picked up by buying Boston Biomedical a couple of years ago, for pretty substantial money. The compound was in a colorectal cancer trial, but the first interim analysis of the treatment group was so bad that enrollment was stopped entirely.
Cancer stem cells - now that's a field with a lot of promise and a lot of risk. No one, it's safe to say, really understands what's going on there. And you can find some people who doubt the whole concept. Are there really pluripotent cells (a small population) driving some kinds of tumors? Evidence points that way, but getting a handle on them and figuring out their role has been hard. These latest results are not going to clear things up much, either.

I have to say, though, I would have been wary about shelling out $200 million up front for a compound that looks like this. That's BBI608 to the left, and yep, it's a big ol' quinone. I will freely admit my own biases here: I strike quinones (and their hydroquinone partners) off any list of screening hits I get. Life's too short. There are just too many things that can go wrong with dosing such an obvious, screaming, reactive redox compound in a living system. People who've worked with me can corroborate my statements; I've drawn red X marks through compounds that look a lot like this one and never looked back. Note that I am not saying that no quinones can ever be drugs. I'm just saying that the odds are stacked against them.

It's not like the activity you get is spurious - quite the contrary. Quinones can do a lot of things inside cells, which make them over-represented in cellular and phenotypic assays (assuming you let them into your compound collection in the first place). But those activities can change, depending on what sort of oxidative or metabolic stress the cells are under (and many other factors besides). BBI608 must have had some pretty compelling early-stage data to make Dainippon Sumitomo jump at the chance to buy it (and its company), but look at it now.

I wouldn't have even trusted this one as a tool compound, given the number of possible activities (even Boston Biotech kept taking about "inhibiting multiple pathways"). What kind of tool compound is it, given these clinical data? It's true that by tossing this structure into the trash that I wouldn't have had a company that got bought out for $2.6 billion dollars. And I wouldn't have had the satisfaction of taking a compound into the clinic with hopes of success, misguided or not (I haven't had that satisfaction too often, come to think of it). So there's that. But on the other hand, I've been working on things during that time that at least haven't failed yet, and the next molecule I do help push into the clinic will not, I assure you, look like this one, because I want to give it every chance I can to have it actually work.

Comments (25) + TrackBacks (0) | Category: Cancer | Clinical Trials


1. anon on May 28, 2014 8:12 AM writes...

no pic of structure seen on my computer.


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2. Justin on May 28, 2014 8:32 AM writes...

It's amazing to me that BBI608 made it that far. You'd think someone along the way would have looked at it and had the gut reaction of "that doesn't look like a drug."

High risk, high reward makes people do strange things. Hopefully they've got a plan B .... Naphthoquinone-free.

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3. DSPAnon on May 28, 2014 8:35 AM writes...

Excellent scientific appraisal as usual. If only this were the point. The only reason that DSP bought BBI was to say that they have an oncology company in "the hot hot Boston area". DSP succeeded in fooling investors just long enough to tread water for a few more years. The emperor has no clothes and never did, but who cares, right? Time and time and time again, somebody gets rich by selling the wanton a bill of goods at the expense our collective reputations. Science is purely secondary or teriary... quaternary at best?

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4. SP on May 28, 2014 8:35 AM writes...

"that doesn't look like a drug."
Dangerous thing to say, you just lost the market for a lot of things e.g. metformin. Much prefer someone to say, "That doesn't look like a drug, show me the data that makes you argue that it will be safe and effective."

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5. Mike Parker on May 28, 2014 8:36 AM writes...

It is similar in structure to the anthraquinone core of the anthracycline drugs used in oncology, so maybe that similarity was used to defend the viability of BBI608.

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6. JD on May 28, 2014 8:48 AM writes...

@4: Exactly.

And I say that as a chemist who used to love sanctimonious chemdraw-based assertions about 'drug-likeness'

Now, I push ugly covalent inhibitors with excellent toxicity and efficacy profiles forward and still get reactionary bs from colleagues who cannot get over their pre-conceived notions of what works.

I'm beginning to think that the #1 reason people should drop unusual looking compounds in not because of their lower probability of success (scientifically), but because the battle against ignorant prejudices is almost always a losing one.

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7. Anonymous on May 28, 2014 8:51 AM writes...

dimethyl fumarate did not look any better

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8. a. nonymaus on May 28, 2014 8:52 AM writes...

Since the structure isn't showing up, a quick google search suggests that it's naphtho[1,2-b](2'acetylfuran)-4,9-dione. Image here:

Looking at the structure, I'd call it as drug-like as anthraquinone. On the other hand, there are a slew of pharmacologically active anthraquinones. On the grasping hand, they are mostly laxatives that are also suspected carcinogens.

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9. Hap on May 28, 2014 9:01 AM writes...

If one were going to push a quinone through to try to make a drug, cancer would seem to be the place. There are enough quinone antitumor agents to have precedent, and for recalcitrant tumors, you don't seem to have much to lose, other than $200M, I guess.

I wonder if the furoquinone has unusual behavior for quinones.

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10. A Nonny Mouse on May 28, 2014 9:30 AM writes...

Interesting; I made some related compounds for a small company, but I don't think that they were aware of this molecule (or they never mentioned it to me).

Unfortunately, they didn't get $200m as they did some metabolic studies first and found that the molecules were rapidly metabolised in whole blood......

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11. anon on May 28, 2014 10:31 AM writes...

The real shame about this (and other) late-stage failures is not knowing what the preceding clinical and nonclinical data actually looked like. Would the data have convinced an independent review committee to advance the drug? More than likely, this is the first true independent, or more importantly unbiased, review that this molecule has had (FDA reviews for safety aside).

But I suppose for $200m upfront I wouldn't want to risk failing early either...

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12. Lyle Langley on May 28, 2014 10:44 AM writes...

"What kind of tool compound is it, given these clinical data? It's true that by tossing this structure into the trash that I wouldn't have had a company that got bought out for $2.6 billion dollars."
I don't think they got bought out for $2.6 billion. The $2.6 billion figure was total amount, if they met the sales goals, etc. The buyout number, as was mentioned earlier, was ~$200 million. Depending on the development goals, they may have received more than the upfront $200 million, but I'm sure it's quite a bit less than $2.6 billion.

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13. Hap on May 28, 2014 10:55 AM writes...

I imagine that with a structure like this, the cosst of failure are greater for the people who push it through; as said before (here) , dirty compounds are great when they work, and career-limiting when they don't, while clean failures are not necessarily career-limiting events. That may not matter much, though, considering for many pharmas both successes and failures are career-limiting.

It may be either a feature or a bug considering how many compounds fail because of toxicology, but with an obvious reactive moiety, you always have to keep looking for toxicity and cross-reactivity, because everyone will nail you if you find something in trials that you should have caught earlier. If you know you're walking though a minefield, you're likely to be pretty careful. It's still a minefield though, and if it's possible to avoid it (big if), you'd rather do so.

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14. Lyle Langley on May 28, 2014 11:25 AM writes...

@#13, Hap et al.,
I know what you are saying; however, the Fierce Biotech story simply said it was due to the fact that the compound did not clear an efficacy hurdle, not due to toxicity. Yes, if someone took a compound with known toxicity into the clinic and it failed then they should have "career-limiting" issues. However, at first pass, this does not appear to be toxicity related, so it's just another compound, no matter how much we chemists don't like it.

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15. Anonymous on May 28, 2014 11:32 AM writes...

Why is this is getting such an easy ride in the comments? If it was academic group I imagine they would be somewhat different in tone.

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16. Ann O'Nymous on May 28, 2014 12:31 PM writes...

The problem isn't the quinone so much as the suspicion that due diligence was not done by the acquirer. If I am about to plop down $200m on an acquisition I am going to have my accountants all over the target's books and my scientific advisers asking hard, hard questions to their R&D people. So either the diligence was terrible, or there actually was enough in the compound to convince the advisers that acquiring the target on the strength of this compound alone was worthwhile. Or maybe, there were other compounds/IP in the mix that made the efficacy of this compound moot. Say, they have the next Viagra up their sleeve.

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17. milkshake on May 28, 2014 1:09 PM writes...

this molecule is not too crazy, look at mitoxanthrone. One fairly important thing about quinone-based leads is that you want to have lots of electron donating groups on it, like hydroxy and amino, to make the quinone a weaker oxidant .

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18. Sideline Chemist on May 28, 2014 3:56 PM writes...

As much as most chemists (myself included) don't like quinones for all of the obvious reasons stated above, this particular quinone is well-tolerated in humans at the doses studied. It failed for lack of efficacy in advanced colorectal cancer patients, plain and simple.

The big question is what pre-clinical efficacy data was available to warrant moving into clinical trial and whether the PhII clinical trial was sufficiently powered to give an efficacy signal that warranted advancement into PhIII. Could the lack of efficacy have been caught sooner with enough due diligence or did hand-waving & poor trial design lead to a major financial spend that could have been avoided?

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19. Anonymous on May 28, 2014 6:47 PM writes...

@#3 it really is amazing how little people understand about what makes this industry tick.

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20. anonymous on May 28, 2014 8:03 PM writes...

@#18 I wonder if they've done any patient-derived xenografts (PDX) animal studies before moving into clinical trials. The PDX thing is getting prevailing in oncology drug development. It is much cheaper and safer to try the drug on mice than on humans.

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21. i'm no professional on May 28, 2014 11:51 PM writes...

But I've learned that people in biotech/pharma put millions down on some really ugly looking compounds. Much like people in tech put down millions on some really awful business ideas. If I had millions, I know I would not be blowing money like this, but I wasn't born rich. Geez.

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22. anony-mous(e) on May 29, 2014 6:01 AM writes...

To Derek's point:
it is my understanding that the shortest lived compound in our (very large) Safety department's history of evaluating "advanced" preclinical candidate was a quinone.....Just saying !

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23. Oldwellcie on May 29, 2014 9:46 AM writes...

Agree with @17 Milkshake. The anti-malarial Atovaquone is a hydroxy-naphthoquinone with a good efficacy and toxicity profile. It acts by inhibiting co-enzyme Q electron transport in the parasite.

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24. jad on June 24, 2014 10:45 AM writes...

My brother may be taking part in the Mayo trial of this drug combined with Folfox. Yes? No? Thanks-

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25. Anonymous on January 12, 2015 3:12 PM writes...

As someone who is close to a person taking this and who is having extreme stomach pains - can you shed some light on how this is effective or if he should stop the treatment?

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