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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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February 15, 2013

ABT-199 Clinical Trial Suspended (Updated)

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Posted by Derek

Abbott - whoops, pardon me, I mean AbbVie, damn that name - has been developing ABT-199, a selective Bcl-2-targeted oncology compound for CLL. Unlike some earlier shots in this area (ABT-263, navitoclax), it appeared to spare platelet function, and was considered a promising drug candidate in the mid-stage clinical pipeline.

Not any more, perhaps. Clinical work has been suspended after a patient death due to tumor lysis syndrome. This is a group of effects caused by sudden breakdown of the excess cells associated with leukemia. You get too much potassium, too much calcium, too much uric acid, all sorts of things at once, which lead to many nasty downstream events, among them irreversible kidney damage and death. So yes, this can be caused by a drug candidate working too well and too suddenly.

The problem is, as the Biotech Strategy Blog says in that link above, that this would be more understandable in some sort of acute leukemia, as opposed to CLL, which is the form that ABT-199 is being tested against. So there's going to be some difficulty figuring out how to proceed. My guess is that they'll be able to restart testing, but that they'll be creeping up on the dosages, with a lot of blood monitoring along the way, until they get a better handle on this problem - if a better handle is available, that is. ABT-199 looks too promising to abandon, and after all, we're talking about a fatal disease. But this is going to slow things down, for sure.

Update: I've had email from the company, clarifying things a bit: "While AbbVie has voluntarily suspended enrollment in Phase 1 trials evaluating ABT-199 as a single agent and in combination with other agents such as rituximab, dosing of active patients in ABT-199 trials is continuing. Previous and current trials have shown that dose escalation methods can control tumor lysis syndrome and we have every expectation that the trials will come off of clinical hold and that we will be able to initiate Phase 3 trials in 2013, as planned."

Comments (18) + TrackBacks (0) | Category: Cancer | Clinical Trials | Toxicology


COMMENTS

1. nitrosonium on February 15, 2013 10:57 AM writes...

i thought aromatic nitro groups were a big No No in drug design??

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2. Anonymous on February 15, 2013 12:05 PM writes...

#1 Generally so. But the odd exception makes it through, e.g. nitrazepam.

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3. anon on February 15, 2013 12:55 PM writes...

It's a shame because if the drug is kicking but that's exactly what you would expect to happen. Namely all of the tumor cells are wiped out. So the molecule is really active and worth pursuing.

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4. ScientistSailor on February 15, 2013 1:17 PM writes...

A similar thing happened with Avastin in early trials, they got around that, they'll get around this, limit tumor size or something like that...

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5. Anonymous on February 15, 2013 2:20 PM writes...

So was this first announced through a blog? Am I reading that correctly? If so - what does that say about the power of blogging and the future of 'confidential' clinical disclosure?

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6. sgcox on February 15, 2013 5:40 PM writes...

I really hope they'll get it work. This is such a novel approach to cancer treatment that if succeed, it may open a whole new field, just like what imatinib did for TKI.

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7. David Young, MD on February 16, 2013 12:21 AM writes...

The same thing happened with Flavopiridol. And it still is not on the market. The drug floundered in early clinical trials and then, about 7 years ago there was news of a patient who had trouble with tumor lysis syndrome, and studies were put on hold. Studies resumed, but now, 7 years later there is no news of Flavopiridol seeing the light of day.

I hope that ABT199 has some better luck.

I suspect that developing tumor lysis syndrome is only partly due to a rapid tumor lysis..... I suspect that there are other metabolic factors, some perhaps genetic, that make certain individuals susceptible to high uric acid levels and acute renal failure. And if you have someone with these metabolic features (genetic) that even moderate amounts of tumor killing will result in tumor lysis. This could explain why a drug, such as flavopiridol, that may have only modest anti-CLL effects can result in what appears to be a tremendously good anti-CLL effect when in fact it does not. Just a theory.

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8. petros on February 16, 2013 3:23 AM writes...

re #1

Quite a few in the cardiovascular field. Nifedipine is perhaps the most succesful

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9. DRMMD on February 16, 2013 8:40 AM writes...

Tumor lysis syndrome is preventable if patients are given prophylactic measures before initiation ot therapy for acute or chronic lymphblastic leukemia or for non Hodgkin lymphoma. In fact the standard of care rquires prophylaxis in these patients to prevent TLS Curious to know if the treating physicians protected their patients before initiating ABT-199. Had they done so and the patients developed TLS, that would have been unfortunate. Had they not used prophylactic measures, that would be a deviation from an accepted standard of care and might have saved this promising new agent. Most protocols today include a section of required supportive care measures in these patients to prevent TLS.

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10. anonymous on February 16, 2013 9:59 AM writes...

@7 -
Flavopiridol is as dirty as the day is long...so few surprises there (to my mind, at least)

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11. David Young MD on February 16, 2013 6:18 PM writes...

#9 A physician would never anticipate tumor lysis syndrome in a patient with Chronic Lymphocytic Leukemia (there is no such disease as chronic lymphoblastic leukemia). So, if your patients eligible for the clinical trial are low grade lymphomas or CLL then one would never have to worry about Tumor Lysis Syndrome. Now, obviously, what I said is false, because tumor lysis syndrome has been reported in this trial. But the standard of care would tell us not to worry about tumor lysis syndrome in CLL. These research oncologist would not be expected to prevent tumor lysis syndrome by putting the patients on Allopurinol or elitek (well, elitek-raspuricase at 4 thousand dollars a dose... maybe not). Something else is going on here. Is ABT-199 so good in just a few patients that there is a huge sudden tumor lysis in a disease where tumor lysis is not normally described? Well, it happened to a few patients with "dirty" Flavopiridol (what makes it "dirty" #10?) so I guess it could happen with another drug. Did these patients have creatinines of 1.5 and uric acids of 9 to start out with? Generally patients are excluded from studies if their creatinine is above 1.5. And perhaps the uric acid was not checked.

I suspect that there is something else going on here making a few patients especially susceptable to the consequences of modest tumor lysis that medical science does not know about. Maybe these same patients would had tumor lysis syndrome with Treanda or Fludarabine or any number of other investigational agents.

Few oncologists recall the letter to the editor, published about 20 years ago in the Journal of Clincal Oncology.... where a woman allegedly had tumor lysis syndrome from Tamoxifen in a metastatic breast cancer setting. And the tumor lysis syndrom played out over several weeks. Doesn't make sense and I don't know that I believe it..... but the letter was published.

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12. Greg Zevin on February 18, 2013 12:12 AM writes...

Guys, I am the guinea pig that is waiting for the ABT199 trial's lift. Also I had experienced Flavopirodol (with TLS) and I had a low dose abdo irradiation which resulted with a TLS that almost killed me - just because no one anticipated a TLS in CLL!!!!

Flavopirodol is not simply dirty. It's an absolute crap! and I hope it will never see the light of day, as I read. I am not sure how the cooked the statistics, but it did just bad things to me. Rasburicse did not help much. I had a VazCath put in me and we had been located in the dialysis room during the treatment. The rest of the treatments they were feeding me with Resonium that is CRAP CRAP CRAP. try drink 90 grams of it.

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13. Greg Zevin on February 18, 2013 12:15 AM writes...

Guys, I am the guinea pig that is waiting for the ABT199 trial's lift. Also I had experienced Flavopirodol (with TLS) and I had a low dose abdo irradiation which resulted with a TLS that almost killed me - just because no one anticipated a TLS in CLL!!!!

Flavopirodol is not simply dirty. It's an absolute crap! and I hope it will never see the light of day, as I read. I am not sure how the cooked the statistics, but it did just bad things to me. Rasburicse did not help much. I had a VazCath put in me and we had been located in the dialysis room during the treatment. The rest of the treatments they were feeding me with Resonium that is CRAP CRAP CRAP. try drink 90 grams of it.

After I had the abdo radiation I had a bout of TLS that indeed required renal catheters, ICU, and 2 emergency dialysis sessions.

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14. Morten G on February 18, 2013 6:53 AM writes...

ABT-199 has a secondary amine ortho to the nitro which then forms a five-membered ring - you can't exactly think of it as a nitro. I hate that chemists write their structures mostly uncharged.
I am aware that nifedipine and nitrazepam don't have that.

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15. London Chemist on February 18, 2013 8:53 AM writes...

"i thought aromatic nitro groups were a big No No in drug design??"

Does look like a molecule that was designed by somebody saying "Hey, what are all the groups those Pfizer guys in Sandwich won't use?" and then bolting them all together

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16. Stacy Feinstein on February 18, 2013 2:46 PM writes...

The find is pretty astounding just in the leaps and bounds scientists have taken in recent years. Take this article for instance, how has there not been more surrounding regenerative tissue for cancer treatment? http://bit.ly/11vw6Y5

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17. argo on February 18, 2013 4:05 PM writes...

Thanks for contacting the company. Not sure that we've actually heard confirmation of TLS from AbbVie themselves? Started with a blog, and picked up by two additional blogs. Anyway, are there other BCL-X(L)-sparing molecules in development? TIA.

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18. argo on February 18, 2013 5:19 PM writes...

And a related question, are there any platelet sparing or platelet replacement methods that could be used in combination with pan-reactive inhibitors? Does 199 hit mcl-1? Guess that's two questions, and no contributions. ;-)

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