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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 1, 2011

Exelixis Fights City Hall, and City Hall Looks Like Winning

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Posted by Derek

So what happens when you and the FDA disagree on the clinical trials needed to show efficacy for your new drug? Well, this happens: your stock opens down 40%. That's what's going on with Exelixis today - here are the details. Basically, the company had a fast clinical path in mind, taking their prostate cancer candidate cabozantinib into late-stage patients and using pain reduction as an endpoint. But the FDA wasn't (and isn't) buying that as a marker.

I see their point. Survival is really what you're looking for, and there doesn't seem to be enough evidence that pain reduction is going to translate to that. As that Adam Feuerstein piece notes, all the other prostate drugs have had to show survival benefits. EXEL was planning to follow up with a second trial to show that, but hoped to jump-start things by getting approval just on the pain data. It appears that they're going to stick with their strategy and hope that the numbers are so dramatic that the agency will reverse course. But is that realistic - both for the chances of getting great data and the chances of persuading the FDA? The market doesn't think so. Neither do I.

Comments (17) + TrackBacks (0) | Category: Business and Markets | Cancer | Clinical Trials


1. johnnyboy on November 1, 2011 9:46 AM writes...

I'm starting to think cancer patients need an organization like 'ACT UP'.
Look, this was for advanced, non-responsive prostate cancer with bone metastases. No miracles possible for that indication. Instead of going for a something puny like a 1-month survival benefit, the exel drug might actually improve quality of life for the remaining time the patient has. The FDA is stuck in a rigid way of thinking, which is failing its mission to protect the public. Survival benefit should not be the only criteria for new cancer drugs. Provenge had a "big" (ie 4 months) survival benefit - a lot of good that's done...

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2. Jonny on November 1, 2011 10:01 AM writes...

johnnyboy--what do you mean in relation to your Provenge comment? Also, if pain relief were to be the only labeled benefit, couldn't patients achieve similar results using a variety of existing analgesics?

I think FDA is (rightly) concerned that if they aren't careful, every cancer developer is going to seek approval on the (easier) surrogate endpoints, and we'll end up with an industry that does nothing to stop cancer patients dying (statistically speaking).

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3. bbooooooya on November 1, 2011 10:17 AM writes...

EXEL is a great example of an arrogant management team destroying shareholder value. The company knew what the FDA wanted, and should give it to them.

No clue what these morons are thinking (note, CEO is a chemistry Ph.D.), but this dogged pursuit of a pain endpoint will cause a lot of pain for shareholders and EXEL employees.

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4. CMCguy on November 1, 2011 10:32 AM writes...

#2 jonny this really is the main point and I disagree (with you and Derek) that this is the right approach by FDA. The FDA regulations do allow grant of approval based on surrogates as fast track mode (believe that is how Avastin gained for MBC) in order to get a critical unmet/undeserved need addressed. Yes overall survival is an ultimate target in all cancer drugs but is much harder and longer to actually prove so takes longer and more extensive trials, and even then the statistical requirements are difficult in separating response from noise.

For Prostate cancer as #1 states bone metastases with pain have significant impacts and yes it does largely entail QOL issues because increasing survival dramatically is tough battle. Most existing analgesics that are required are opioids so yes pain might be less but the patient is drugged up and can't function. It would be nice to have all those great breakthroughs that directly increase survival, and that is how most programs start, but if in the end result is only incremental improvements those can be very worthwhile to the patients and families. The R&D discovery and FDA ideals need to be balanced against practical value that can be achieved in clinic.

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5. biotechbaumer on November 1, 2011 10:54 AM writes...

They have TWO independent, complementary trials in the prostate cancer indication. One for pain (306) and one for OS (307). If they are both positive, the company can put on the label that the drug extends both survival and reduces pain. NO OTHER competitor in the PC market can say that. It comes down to positioning the drug. I think it's quite savvy. As they said on the conference call, EXEL has the potential to show that the drug increases both 'the quality and quantity of life'...pretty profound. PS. I'm long if you couldn't tell!!

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6. Hap on November 1, 2011 12:04 PM writes...

The last time a prostate cancer drug was approved based on pain only was in 1996 (from article) - given the presence of drugs that prolong life for the same indication, I'm not sure why they'd be surprised that the FDA didn't allow approval based on pain relief only.

In addition, pain is a major factor in quality of life but it doesn't guarantee function - side effects determine that. If the side effects are significantly less (or less severe) than opioids, the quality of life argument makes sense, but it might not. Cancer drugs are not known for pleasant side effect profiles, after all.

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7. simpl on November 1, 2011 2:54 PM writes...

Will they do pain pill pricing?
They could submit in a country where the HA is more sympathetic, though (Netherlands?).

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8. Jones on November 1, 2011 3:10 PM writes...

biotech- hope you weren't long prior to the announcement.
Crappy management + BOD. Same old rushing preclin/trials. Fail.
Nobody seems to remember XL784,999,647,019,281, and many more. Only EXEL has luxury of so many failures

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9. Jones on November 1, 2011 3:12 PM writes...

biotech- hope you weren't long prior to the announcement.
Crappy management + BOD. Same old rushing preclin/trials. Fail.
Nobody seems to remember XL784,999,647,019,281, and many more. Only EXEL has luxury of so many failures

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10. David Young MD on November 1, 2011 4:00 PM writes...

The quality of pain relief obtained from making a cancer regress is so much superior to masking the pain with narcotics in someone whose cancer is progressing. If Cabo is really that good, the FDA should approve it on quality of life issues. And if they don't.... well, if the data is there and there are patients sufferisng from pain, the FDA will be sure to hear of it.

Sounds like a good study.... our research associates will be contacting Exilixis very soon.

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11. MLBpitcher_and_MedicinalChemist on November 1, 2011 4:15 PM writes...

Hi, Derek, Looks like you have to move to Cleveland now since you were trade to the Indians.

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12. confused chemist on November 1, 2011 4:41 PM writes...

I'm a little confused as to why with all of this coverage there is not one mention that Cabozantinib met it's Phase 3 progression free survival endpoint for MTC? I realize that it's not an apples to apples comparison but from my admittedly naive perspective it seems that a successful Phase 3 trial for survival in MTC plus a pain endpoint for CRPC should allow for some flexibility (like a conditional approval, for instance) while the CRPC survival study is ongoing.

I'm of the opinion that the worst reason for doing something is because that's the way it's always been done. That's no justification...just lazy thinking.

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13. somebody on November 1, 2011 8:04 PM writes...

The FDA's job should be to make sure the drug does what it the company claims it does (efficacy) and that it does so with acceptable or known side-effects (safety). It should not act as a 'moral compass' dictating what form a treatment may take. Which, as it appears in this case, is exactly what they are doing - subjectively denying a drug in spite of what appear to be legitimate, therapeutic benefits to a subsection of patients.

Even if there is no survivability improvement, isn't a straight QOL improvement worthy?

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14. Anonymouse on November 1, 2011 8:25 PM writes...

"Even if there is no survivability improvement, isn't a straight QOL improvement worthy?"

Where has the FDA stated that QOL improvement is not worthy? All that they have stated is that unnatural unblinding due to the tox profile of the TKI as well as the placebo effect can markedly bias the results of the study. Thus, they are not comfortable granting a SPA and be held to their word once the trial results are out. Once the company has generated the data the FDA will likely have ODAC opine and then take a decision on the basis of the relative merits / demerits of the data.

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15. Just sayin' on November 1, 2011 9:17 PM writes...

I have friends from grad school who work at Exelixis. They survived the last mass-layoff. I hope they will emerge from this latest challenge unscathed and successful

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16. mr. fixit on November 2, 2011 7:13 AM writes...

How many over these comments came from exelixs IP addresses?


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17. Big Freddie on November 19, 2011 5:03 PM writes...

Hmm. If ever a company was on a "random walk through science" EXEL would be it...remember ActTag for biofuels, "Drosophila Mutations for a Better Tomorrow", and XL--^infinity "sure thing" compounds? fun, fun, fun...except for shareholders.

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