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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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September 10, 2012

Geron, And The Risk of Cancer Therapies

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Posted by Derek

Geron's telomerase inhibitor compound, imetalstat, showed a lot of interesting results in vitro, and has been in Phase II trials all this year. Until now. The company announced this morning that the interim results of their breast-cancer trial are so unpromising that it's been halted, and that lung cancer data aren't looking good, either. The company's stock has been cratering in premarket trading, and this stock analyst will now have some thinking to do, as will the people who followed his advice last week.

I'm sorry to see the first telomerase inhibitor perform so poorly; we need all the mechanisms we can get in oncology. And this is terrible news for Geron, since they'd put all their money down on this therapeutic area. But this is drug discovery; this is research: a lot of good, sensible, promising ideas just don't work.

That phrase comes to mind after reading this article from the Telegraph about some Swedish research into cancer therapy. It's written in a breathless style - here, see for yourself:

Yet as things stand, Ad5[CgA-E1A-miR122]PTD – to give it the full gush of its most up-to-date scientific name – is never going to be tested to see if it might also save humans. Since 2010 it has been kept in a bedsit-sized mini freezer in a busy lobby outside Prof Essand's office, gathering frost. ('Would you like to see?' He raises his laptop computer and turns, so its camera picks out a table-top Electrolux next to the lab's main corridor.)
Two hundred metres away is the Uppsala University Hospital, a European Centre of Excellence in Neuroendocrine Tumours. Patients fly in from all over the world to be seen here, especially from America, where treatment for certain types of cancer lags five years behind Europe. Yet even when these sufferers have nothing else to hope for, have only months left to live, wave platinum credit cards and are prepared to sign papers agreeing to try anything, to hell with the side-effects, the oncologists are not permitted – would find themselves behind bars if they tried – to race down the corridors and snatch the solution out of Prof Essand's freezer.

(By the way, does anyone have anything to substantiate that "five years behind Europe" claim? I don't.) To be sure, Prof. Essand tries to make plain to the reporter (Alexander Masters) that this viral therapy has only been tried in animals, that a lot of things work in animals that don't work in man, and so on. But given Masters' attitude towards medical research, there's only so much that you can do:

. . .Quacks provide a very useful service to medical tyros such as myself, because they read all the best journals the day they appear and by the end of the week have turned the results into potions and tinctures. It's like Tommy Lee Jones in Men in Black reading the National Enquirer to find out what aliens are up to, because that's the only paper trashy enough to print the truth. Keep an eye on what the quacks are saying, and you have an idea of what might be promising at the Wild West frontier of medicine. . .

I have to say, in my experience, that this is completely wrong. Keep an eye on what the quacks are saying, and you have an idea of what might have been popular in 1932. Or 1954. Quacks seize onto an idea and never, ever, let it go, despite any and all evidence, so quackery is an interminable museum of ancient junk. New junk is added all the time, though, one has to admit. You might get some cutting-edge science, if your idea of cutting-edge is an advertisement in one of those SkyMall catalogs you get on airplanes. A string of trendy buzzwords super-glued together does not tell you where science is heading.

But Masters means well with this piece. He wants to see Essend's therapy tried out in the clinic, and he wants to help raise money to do that (see the end of the article, which shows how to donate to a fund at Uppsala). I'm fine with that - as far as I can tell, longer shots than this one get into the clinic, so why not? But I'd warn people that their money, as with the rest of the money we put into this business, is very much at risk. If crowdsourcing can get some ideas a toehold in the clinical world, I'm all for it, but it would be a good thing in general if people realized the odds. It would also be a good idea if more people realized how much money would be needed later on, if things start to look promising. No one's going to crowdsource a Phase III trial, I think. . . .

Comments (12) + TrackBacks (0) | Category: Cancer | Clinical Trials | Drug Development


1. RB Woodweird on September 10, 2012 9:27 AM writes...

The only thinking that stock analyst is doing is deciding whether to buy the Ferrari or the Lamborghini, because he shorted the hell out of the stock before pumping it up in his report.

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2. processchemist on September 10, 2012 9:35 AM writes...

It's not exactly my field, but I would say that this is more another failure of small nucleotides as drugs than a tombstone on the inhibition of telomerase...

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3. Chemist turned Hedgie on September 10, 2012 9:58 AM writes...

#1- Lovely as it would be to say that your conspiracy theory is true, the real world doesn't work like that (I have yet to meet an analyst, even in botech, who has strayed that far into the illegal shadows), so safer to put this on down to cockup. That happens MUCH more often;)

Derek- as a reader of the Telegraph for decades, I hang my head in shame when I see tripe like this published under its name, however well-meaning (and don't get me started on the fruticakes that have commented on it!). Bill Deedes must be spinning in his grave...

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4. Anatoly on September 10, 2012 10:16 AM writes...


If I remember correctly, Imetelstat worked on models faster than telomerase inhibitor should have worked, killing cells before generations where lethal shortening of telomerase should kick in. This means in probably worked by different mechanism.

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5. Singaporean on September 10, 2012 12:26 PM writes...

I don't get it. Why didn't it work? Only about 10-15% percent of cancers use alternative lengthening of telomeres (ALT), while the rest should be highly susceptible to telomerase inhibition. Could it be possible, that the inhibition was screwed or is the whole approach useless now?

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6. barry on September 10, 2012 12:45 PM writes...

By the time a cell line has ticked off all the "hallmarks of cancer", it's too late to treat with a teleomerase inhibitor. It might have added years worth of teleomer already. If this cmpd is to have worth, it is in preventing a precancerous tissue ("nevus", "benign tumor" "mole") from crossing that threshold. but that of course would require getting that pre-cancerous condition defined as a "disease" so that treatments could be reimbursed by insurers, and so that the FDA would deign to license such a drug.

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7. Target Engagement? on September 10, 2012 1:45 PM writes...

Did it hit the target? I always wonder if results like this are due to a flawed molecule or idea. Any info appreciated.

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8. David Formerly Known as a Chemist on September 10, 2012 3:28 PM writes...

This is really unfortunate. Geron has always been a very innovative company, pursuing very risky research on unvalidated targets (telomerase) and forging forward with very high risk products (stem cells). The complete opposite of today's highly risk-averse big pharma industry. I wouldn't be surprised if this is the beginning of the end for them.

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9. Hugo on September 10, 2012 5:18 PM writes...

The reality is that Imetelstat was always a bit of a long shot for solid tumors. It failed in hER2 Breast Cancer because of toxicity when combined with Paclitaxol. The lung cancer study was a real long shot and did have minor positive results. Imetelstat is still in 4 other clinical trials and may yet be proven to be effective against cancer stem cells. While today's results are very disappointing - the fat lady has yet to sing.

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10. Andy on September 10, 2012 9:28 PM writes...

The toxicity tells you it's active off-target. They should try again with a real SM telomerase inhibitor.

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11. LJStewartTweet on September 12, 2012 12:54 PM writes...

@5 I have followed Geron for many years now, going all the way back to McMaster U where as an undergraduate taking classes from Harley and Bacchetti.

Telomerase always struck me as a double-edge sword type of target. Inhibit telomerase and you age faster (possibly), so if you cure cancer with a telomerase inhibitor, you may take years off your life in other ways. Mechanistic interwine presents a huge challenge.

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12. VASANTHA on September 13, 2012 2:11 PM writes...

@11 I thought adult cells (except some like bone-marrow cells) do not exhibit telomerase activity. Isn't that the reason why telomerase inhibitor was such a big deal--that it does not affect healthy adult cells?

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