The New York Times is starting a series of articles on the clinical trials of a recent B-Raf inhibitor (from Plexxikon and Roche, PLX4032). The first installment is an excellent look at what early-stage clinical research is like in this field. For example:
Typically, Phase 1 trials are limited to a few dozen patients and end when the dose reaches the point where side effects like rashes and diarrhea make patients too uncomfortable.
Dr. Flaherty and Dr. Chapman started the first three patients on 200 milligrams per day. After two months with no side effects — and no response — they doubled it.
Two more months passed, still nothing. They gave three more patients 800 milligrams, the equivalent of the dose that made tumors stop growing in mice. Even shrinking tumors, the doctors knew, would not mean the cancer had been cured but might at least offer a reprieve.
Dr. Flaherty pounced on the scans when they arrived. In some patients, tumors had remained the same size. “Maybe we’re starting to see something,” he could not help thinking. But at the next set of scans, the disease had progressed. On conference calls, Dr. Nolop sometimes referred to those patients as “responders.”
“They’re not responders,” Dr. Flaherty gently corrected him: under the accepted definition, tumors had to shrink to qualify patients as responders.
By the time they had doubled the dose four times, Dr. Flaherty could not help wondering if the targeted therapy skeptics were right. Dr. Chapman, crisp and businesslike on the weekly calls, supplied no comfort. He pointed out new research that B-RAF was mutated even in benign moles, and therefore could not be the key driver in melanoma. . .
What everyone involved in this work has to deal with is living between two very different mental states: you have to see people who are dying, and who you will probably not be able to help, even with your best efforts. But it's also possible that the next new thing you try might be the thing that keeps some of them alive. It's a hard place to work.
Back here in early research we don't see the patients, of course (which is good, since I'm pretty sure I couldn't take it). But we also have the same narrow path to walk: most of the compounds we make aren't drug candidates. Most of the drug candidates we send on for development fail. But the answer to that is not to stop making drug candidates, because every so often, something works.
1. azetidine on February 22, 2010 9:35 AM writes...
Just another illustration of the worst thing you can do in medicinal chemistry: to think you know what is going on.
Permalink to Comment2. milkshake on February 22, 2010 11:06 AM writes...
single-kinase selective drug is likely to fail in cancer treatment, especially if the oncogene target has high spontaneous mutation rate in tumors. When I was at SUGEN we discovered single-digit nanomolar low-MW compounds for c-Met kinase. We were shut down by Pfizer soon after that but almost every other major company took our series and advanced them for this target. They ended up running into the same problem - superactive compounds with atypical binding mode that is very specific to human c-Met, but not to common c-Met mutated versions known to occur in cancer. We had another, far dirtier c-Met series that were also active in c-Met mutants, and I think it was this other series that ended up advanced by Pfizer in the end
Permalink to Comment3. okemist on February 22, 2010 11:20 AM writes...
Derek you always acknowledge the extreme deadline pressure later in development. A year ago I had a client yelling at me that people in the trials were dying while waiting for the drug we were trying to make. Well fortunately that 50+ patient trial was very successful; so I am stuck with the pride of helping very sick people and an order of magnitude more pressure to now guarantee successful synthesis for Phase III.
Permalink to Comment4. barry on February 22, 2010 11:46 AM writes...
single-kinase inhibitors might be terrific drugs for early cancers. Unfortunately, the clinical population in which we try new potential drugs are old cancers (patients that have failed existing treatments). It is therefore likely that compounds that would have been efficacious in an other clinical population have already been discarded because of this bias.
Permalink to Comment5. HFM on February 22, 2010 12:31 PM writes...
@milkshake:
Depends on the kinase. Something like BRAF gives you a clean activating mutation - pretty much all BRAF-dependent melanomas have the same one (V600E). This makes it possible to aim your compounds directly at the mutant, and maybe even get some selectivity vs. wild type. This has been done before successfully, e.g. imatinib against BCR-ABL.
Something like c-Met, which (iirc) gets a generic up-regulation - that's much harder. Lots of mutations, lots of pathways, harder to whack any one of them in a useful manner (and fragments your market, and makes it harder to screen your patients).
I do believe that we're moving towards a targeted-therapy model. We have to. Not all cancers from the same cell line are the same disease - for instance, only something like 50% of melanomas are BRAF-dependent. (And if you whack a non-BRAF tumor with a BRAF inhibitor, it grows *faster*.) If you can't screen your patients to pick out the potential responders, you're stuck in the land of straight-up chemo (unless you get very lucky, e.g. imatinib again). Academic centers are already doing targeted sequencing on tumors, and I'm fairly sure this will be routine by the end of the decade.
* Disclaimer: yes I'm in the field, but not in the research groups mentioned.
Permalink to Comment6. Ed on February 22, 2010 12:54 PM writes...
HFM,
Those V600E mutants might look tempting targets at the moment, but I think its a fairly safe bet that a new set of treatment-conditioned mutants resistant to your beautifully designed drug will emerge fairly rapidly (e.g. imatinib again, T351I this time).
Permalink to Comment7. Fries With That? on February 22, 2010 1:06 PM writes...
Folks working in targeted cancer treatment should spend some time in a virology laboratory to get a first hand look at resistance.
Permalink to Comment8. RKN on February 22, 2010 1:24 PM writes...
On the evidence of the outcomes of this drug in mutated vs. non-mutated B-RAF tumors, I really have to wonder if these targeted therapies are like shooting in the dark.
Don't get me wrong, I'm not the least bit cynical about the intentions of researchers, doctors or drug makers, I think they're all doing the best they can. But can we rule out, for instance, that these mutations may be the result of the cancer, rather than (one of) the key drivers of it?
Years down the road we may finally understand why these drugs simply didn't work in a large number of patients, but for now, they may work in some, even if we don't understand why.
Permalink to Comment9. alig on February 22, 2010 1:52 PM writes...
These BRAF inhibitors do seem to be working in patients with the V600E mutation. There are currently no good treatments for melanoma, so patients typically have no or only 1 previous therapy when they start these trials. However, it is yet to be seen how long these responses will last. It may be similar to glivec, the earlier you can get the patient on the drug, the longer the response. It'll also be interesting to see how the GSK & AZ drugs perform. They may not need the special formulation to get to relevant doses, and may end up allowing for more comlete knockdown. I wonder if the NYT article will talk about the newer drugs.
Permalink to Comment10. FormerGSK on February 22, 2010 2:44 PM writes...
Hope it works. PLX4032 is a 7-azaindole hinge binder. Nothing amazing there. Also contains o,o-difluorophenyl sulfonaminde. The NH of the sulfonamide appears to make a H-bond with the E600 in the mutant, which is presumably absent in the V600 wild-type. Would be curious to know if it would work in a V600Q mutant.
Now they seemed to indicate in the NYT article that it was really safe, given that there were no adverse events at huge doses, but isn't that most likely due to the poor oral bioavailability? Wonder what the reformulation was...some kind of sustained release?
Permalink to Comment11. In Vivo Veritas on February 22, 2010 3:59 PM writes...
Has anyone looked at the Comment section of that NYT article? If that's a barometer of how people feel about Big Pharma - we have an even bigger image problem than I thought. I guess the Avandia thing ain't helping either.
Permalink to Comment12. David, Health Blogger on February 22, 2010 8:43 PM writes...
I found this to be very informative and useful in better understanding the process of drug development for cancer - it's an area which has prompted some real innovation and new pharmacological models, but still is far from where it should be.
Permalink to Comment13. researchfella on February 23, 2010 12:19 AM writes...
Did anyone notice the little bit at the bottom of page two of this article, where there's an error perpetuating the myth that drugs are developed by academics? Talking about sorafenib (but not mentioned by name), the article reads: "Dr. Flaherty enrolled several hundred patients in trials of the drug, developed by an academic pioneer in targeted therapy and now owned by Bayer." What a load of crap. Just check the inventor names on the Bayer patents and the authors on the drug discovery journal publications to get educated as to who discovered and developed that drug.
Permalink to Comment14. alig on February 23, 2010 8:03 AM writes...
2nd article in the series:
Permalink to Commenthttp://www.nytimes.com/2010/02/23/health/research/23trial.html?pagewanted=1&hp
15. retread on February 23, 2010 8:57 AM writes...
"you have to see people who are dying, and who you will probably not be able to help, even with your best efforts. But it's also possible that the next new thing you try might be the thing that keeps some of them alive. It's a hard place to work.
Back here in early research we don't see the patients, of course (which is good, since I'm pretty sure I couldn't take it)."
Exactly -- that's why it's good to be retired from medicine (after 38 years in the trenches). You never really get used to it.
Such articles are good for you guys (the few remaining after all the cuts), because it shows just how very important your work is. The drugs you really need will not have been developed the day you die.
Permalink to Comment16. MedChem on February 23, 2010 11:39 AM writes...
No 15
"Such articles are good for you guys (the few remaining after all the cuts), because it shows just how very important your work is. "
It still amazes me how low on the respectability scale we're ranked as an industry in the US. Don't know about Europe. But pharmaceutical science is considered noble in most parts of the world.
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