Elan Corp., plc
Bapineuzumab Trial Thoughts

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By TMFBreakerTinker
August 20, 2008

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Been pondering the Bap trial some and would like to get some responses.

As we know, phase II did not have the pre-specified end point that distinguished between APo - and Apo + gene carriers.

Had such a pre-specified end point been in place, taken the population as a whole, the phase 2 trial for ApoE4 non-carriers, with n=46 for treatment arm and 31 for SoC placebo arm would have been a roaring success it seems. As 3 of the 4 measures used, utilizing all dosages (and not just the .5 dosage) was very statistically significant. Which given the small numbers, is somewhat extraordinary. One would normally think that not enough number of patients exist to make this so.

The adverse events would have been very benign in this grouping, and the only real questions would be what happened with the 1.0 dosing, why did it take so long for the curves to diverge, and was the SoC group simply a fluke. A very lucky draw in that they were extremely sick in comparison to the treatment group so that for example the Adas.c0g .026 p value is really meaningless that the SoC group is that 1 random selection our of the 2.6 out of 100 that may be just by chance, or the 1 in 6000 trials randomized in this way this placebo SoC group was by chance?

That is why they run bigger Phase IIIs. However, had this been pre-specified, there would be little doubt that the drug easily exceeds the efficacy of the SoC.

The data with the completer ApoE4 - population is even more compelling. I note that only 6 of the ApoE4 patients in the MITT population did not complete. The n in this section is 36, ten less than the entire population. The SoC group is 21. Approximately the same amount of non-completers from each grouping for whatever reason.

But going through this, and again this is a phase II and limited its numbers as such. But going through this, had ELN and Wyeth pre-specified these endpoints, is there any reason to think that these results would not be considered to be highly interesting and even exciting?

Yes, the numbers are small. Yes, the numbers are not so exciting for ApoE4 + patients. (although Phase III might better treat these patients). But even the delay in divergence of the treatment curves is understandable given that it takes time to clear out the plaque. It does not happy overnight.

I just do not see an excess of data wringing here.

Please others comment in this context. Were this the pre-specified endpoint, do you really think Wall Street would have acted so disappointed in the data after the initial presentation?

In regard to Tysabri. Reading through many MS boards and such, I think there was much less apprehension and more excitement when Tysabri returned in 2006 to the market. What I am reading now is a lot more apprehension in the small numbers of people with MS who do post. I would say from my feel that the majority say Tysabri is indeed worthwhile, probably 60-75%, but there is clearly a lot of angst. I only read of one MS patient who said she would discontinue use of Tysabri (she had been on it for 6 months, she cried when she heard of PML (and perhaps her doctor will give her some more sober thoughts on the subject before she discontinues), but had not gotten great results in her mind as of yet. Most already on it sound like they are going to stay on it. I do not expect a lot of attrition. There will be some, but there is simply nothing else out there for these people for the most part.

Where the angst is really, really, coming from is new patients. I think it is clear that Tysabri was moving more into the mainstream of MS treatment. It was starting to be more routinely prescribed. I think now it is going to be truly a second line, perhaps third line medication after Avonex and Copaxone. Reading the blogs, most patients who switched to Tysabri started out with avonex and then switched to copaxone before going on Tysabri anyways.

Long and short, expect some material decline in new prescriptions. There will be new prescriptions however, and they should at least be enough to cover existing patients who decide to drop out. All in, either much slower growth for awhile or at least probably no loss. This would leave Tysabri still on the path to $1 billion in sales for the next 4 months.

However, the big money is growing beyond this, and that is the big question. Will prescriptions again accelerate?

This might give us some answers. Just the top search I did on drug induced PML and its prognosis:

It is alarming how PML is always cited, practically 100% as a fatal condition with no known treatment. Now I expected that with AIDS patients who are the predominant victims of PML, however, read down to the bottom of the linked article. Even with AIDS induced PML, some patients continue to live for years. With drug induced PML then it appears very likely that the immune system, once the drug is removed, can remove the virus. Or at least that is what looks like is happening.

I remember all the angst that surrounded owning Elan stock and the frustration that every Tysabri story basically started with how it was a killer drug, Tysabri caused PML, etc. Well, you know what happened over 6-12 months, word started getting out, and suddenly the efficacy of Tysabri became the lead, that it was in combination that PML was more of an issue, not in mono, and geez, Tysabri took off to get on a $1 billion a year run rate in just its third year back on the market. Something I believe I predicted way back when.

If PML actually is not almost always fatal and untreatable (even in the AIDS setting , much less the drug induced setting) then I think the news articles about Tysabri and PML will also change in the future.

One thing we do know about the two patients with PML, is that they have had it for at least 2 months already. Popular press has usually stated that PML is almost always fatal in the first 1 to 4 months.

What we are going to find is that Tysabri is associated with a PML risk, but out of x number of patients on the drug, each person who developed PML, and who were caught early due to the TOUCH program, also largely recovered.

Well, we have to wait and see for sure on these current two patients in Europe, but I believe this not to be unlikely given what we are learning about drug induced PML and the little we do know about the conditions of the two new PML patients.

This does not meant that another PML patient might not pop up tomorrow.

Presently, if I recall correctly, there are 14,400 patients on Tysabri for more than 12 months, and 6,600 for more than 18 months. None of those 6,600 patients have reported any PML after 18 months. Of the remaining 7,800, 2 have reported PML. Just in this smaller category of 12-18 months the PML rate is presently 1 in 4,000. 1 in 7,000 for the entire group, and of course 1 in 16,000 or so for the entire population. But there could be 2 more reported here, another there, don't know.

Point being, we are not out of the PML woods yet. I do think another 1 or 2 PML reports in the next few months could again be very deleterious to the stock price. We are still at risk here stock price wise.

This said, if in 6 months from now, these PML patients turn out to actually be treatable, then a very strong reversal in Tysabri's fortunes will probably begin.

But just wanted to share some of my own stock owning angst with you, as well as some longer term comments. And appreciate anyone's comments and follow-ups.