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Yes, the email did flow after Monday's

Medarex

(MEDX)

column. Most of it came from Medarex fans disputing my bearish stance on the company's melanoma drug, MDX-010.

Many of the letters were quite long, and some were nearly identical in parts, which probably indicates a group effort coordinated on the Yahoo! message boards. No matter. Some good points were raised, so let's get to them:

James K. says I cherry-picked negative data on MDX-010 to support my thesis. Among his many complaints, James calls me out for highlighting lackluster efficacy results from studies that used a low dose of MDX-010. The current phase III study uses a higher dose of 10 mg/kg, which he reasons, will yield far better results.

"In one

phase II trial using the high dose, the

response rate was 9%, as you correctly state, but the disease control rate (DCR) was a robust 39%, with duration of response exceeding six months for 89% of the patients in the DCR category," writes James.

I didn't cherry pick anything. I went back to look at all the published MDX-010 clinical data. Much of that work was done at a lower dose. It's hardly my fault that Medarex hasn't done much work at higher doses of MDX-010. In fact, the relative paucity of high-dose MDX-010 data is just another reason to be worried about results from the upcoming phase III trials.

James' second point is important, and one that I addressed in my original column, but maybe I wasn't clear enough. I agree with James that MDX-010 data suggests the drug is more cytostatic (stops tumors from growing) than cytotoxic (kills or shrinks tumors.) There's nothing wrong with a cytostatic drug, in fact, they can provide real benefits to patients, as long as you measure that benefit correctly.

The problem for Medarex, in my opinion, is that its current phase III studies aren't really set up to capture the right kind of efficacy data for a cytostatic drug like MDX-010.

Let me give an example:

Onyx Pharmaceutical's

(ONXX)

TST Recommends

kidney cancer drug Nexavar is also cytostatic. The successful phase III study that got the drug approved reported a very low, single-digit response rate, meaning Nexavar didn't really shrink tumors very much. But there was a high rate of stable disease reported in patients, which means the drug stopped tumors from growing.

In order to prove that a cytostatic drug like Nexavar could help kidney cancer patients, however, Onyx needed to show that Nexavar, by halting tumor growth, could also prolong survival. For this reason, the endpoint of Onyx's pivotal trial for Nexavar measured survival (progression-free survival, to be exact).

If Onyx had used response rate (tumor shrinkage) as the endpoint for its phase III Nexavar study, the drug would not have been approved.

So here comes Medarex with a drug, MDX-010, that seems cytostatic, too. Yet, its phase III studies are measuring tumor shrinkage. The studies don't have a real control arm, so evaluating disease-control rates and duration of response as a proxy for survival becomes very difficult, since there's nothing to which you can compare these effects.

If I'm right, why didn't Medarex design MDX-010 studies to measure survival or progression-free survival? I don't know, but perhaps because the current studies were started before the company had a good idea of how its drug might be working.

This brings up another criticism of my column from several readers, including Stan S., who points to the Special Protocol Assessment, or SPA, between Medarex and the FDA as evidence that these current phase III studies are the right ones to get MDX-010 approved. Furthermore, Stan says, "there is not significant wiggle room for the FDA on how the data will be assessed as you erroneously state..."

I discussed the SPA between Medarex and the FDA in my column, and I'll stand by what I said. Such agreements are not ironclad; there is plenty of wiggle room for the FDA to change its mind. Nor does an SPA dictate to the FDA how to assess clinical data.

I don't like it when companies talk incessantly about SPAs because the conversation is one-sided. The actual wording of the SPA is never made public, and the FDA doesn't comment. That leaves investors trusting the word of the drug company -- a scary proposition if I've ever heard one. Biotech companies rarely, if ever, tell investors everything they need to know. That should be Rule No. 1 in any biotech investor's handbook.

Stan and others with comfort over Medarex's SPA should look at what happened with GPC Biotech and its prostate cancer drug satraplatin. For months, GPC executives assured investors that its SPA was the real deal. Well, when satraplatin was reviewed by an FDA advisory panel in July, it was disclosed that the FDA, in fact, never agreed to the endpoint used in the satraplatin study.

So much for the sanctity of the SPA.

Several readers were irked by my discussion of the different ways to measure tumor shrinkage. In the phase III MDX-010 studies, Medarex is using the WHO criteria instead of the more commonly used RECIST criteria.

I wasn't insinuating that Medarex was trying to flim-flam results by changing the way tumors are measured. I was merely pointing out that, in general, WHO criteria will give you a higher response rate than RECIST, so that needs to be taken into account when comparing the phase III data to previous study results (which used RECIST.)

Lastly, almost every reader who chimed in with an email absolutely hated the column's headline, "Medarex Misses the Mark."

Joe M. writes, "I have read your article ... twice ... but am still wondering what mark Medarex has missed. Your article appears to be your personal projection of future clinical-trial results. Nowhere do I see any facts that substantiate Medarex missing some critical mark. Based on my interpretation of your article, it may have been better titled "I think Medarex will miss the mark," or "Medarex may likely miss the mark."

Joe has a good point, but alas, his suggestions for headlines aren't very attention grabbing. This may sound like I'm passing the buck, but I don't write the headlines on my columns. My editor who does, however, will be happy to know that most of you hated it.

Adam Feuerstein writes regularly for RealMoney.com. In keeping with TSC's editorial policy, he doesn't own or short individual stocks, although he owns stock in TheStreet.com. He also doesn't invest in hedge funds or other private investment partnerships. Feuerstein appreciates your feedback;

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