Elan, Wyeth Play by Own Rules in Alzheimer's Trial

Elan ( ELN) and Wyeth ( WYE) are using a new and unproven endpoint to measure the memory and mental status of patients in phase III trials of their experimental Alzheimer's drug bapineuzumab, say sources familiar with the studies' protocols.

By creating their own test to measure bapineuzumab's efficacy, Elan and Wyeth are seeking an alternative to the so-called ADAS-cog, despite that test's imprimatur as the gold standard measure of cognitive function. The ADAS-cog has been used as the basis for approval for all Alzheimer's disease drugs to date.

Elan has devised a new clinical endpoint, which it calls the Neuropsychological Test Battery, or NTB. The Irish drugmaker has used the NTB in previous studies of its Alzheimer's drugs to demonstrate improvements in the mental status of patients when similar measurements using ADAS-cog showed no benefit.

This is the first time, however, that Elan and partner Wyeth will attempt to convince regulatory authorities in the U.S. and Europe that the NTB should be considered as the basis to approve a new Alzheimer's drug.

The companies are pushing the test even though the NTB has not yet been independently validated by anyone outside the two companies, nor has it ever been used as a primary endpoint in any pivotal trial for Alzheimer's.

The ADAS-cog test, by comparison, is the most widely recognized and utilized measure of cognition in Alzheimer's drug trials.

All four Alzheimer's drugs currently on the market used the ADAS-cog test as the endpoint of their phase III trials. As well, the only other two drug companies with experimental Alzheimer's drugs in phase III studies right now -- Myriad Genetics ( MYGN) and Medivation ( MDVN) -- are using the measure as their primary endpoint in their respective studies.

Dr. Peter Davies, an Alzheimer's researcher at New York's Albert Einstein College of Medicine, questions why any company would seek to develop an alternative cognitive test when the standard and well-understood ADAS-cog test has proven time and time again to be entirely adequate.

"What we need are better Alzheimer's disease drugs, not better tests," says Davies. "If a drug cannot show improvement in cognitive function using the ADAS-cog test, then the drug is not worth bothering with."

Unusual Step

There is intense interest in bapineuzumab, both from the Alzheimer's research community and Wall Street, because it is the first antibody drug in Alzheimer's to reach phase III studies. Bapineuzumab is so closely tracked because it has been designed to actually improve a patient's memory and mental status instead of merely temporarily treating the symptoms of Alzheimer's.

Any drug that can modify or reverse the course of Alzheimer's will generate billions of dollars in sales. The potential for blockbuster profits from bapineuzumab has pushed Elan's stock price higher. Shares hit $26 earlier this month, a level they hadn't seen since 2005.

Elan and Wyeth have announced plans to conduct four bapineuzumab phase III trials, which will track approximately 4,000 patients with mild to moderate forms of Alzheimer's. Two of those studies began enrolling North American patients in December; the remaining two studies, to be conducted in Europe and the rest of the world, are expected to begin soon.

To date, neither Elan nor Wyeth has announced publicly the primary efficacy endpoints of these studies. The companies have stated only that the efficacy of bapineuzumab will be measured using one cognitive and one functional endpoint.

Two Alzheimer's researchers familiar with the study protocols for the bapineuzumab phase III studies have confirmed that NTB was chosen as the primary endpoint, with the ADAS-cog test listed as a secondary endpoint.

Elan spokesman Jonathan Birt would only acknowledge that the primary cognitive endpoint of the phase III studies will be either the NTB or the ADAS-cog test. The companies will be measuring both and will choose one as the primary endpoint sometime during the course of the trials, he says.

"This is all being done in close cooperation with the FDA and other regulators who are fine with the approach," Birt adds.

This approach, however, is far from typical. In nearly all clinical studies, primary endpoints are chosen well before the first patient is ever enrolled.

Birt did confirm that Elan and Wyeth have met with FDA officials to discuss use of the NTB as the primary endpoint of the bapineuzumab studies. Birt would not comment, however, when asked if Elan and Wyeth had reached agreement with the FDA on a Special Protocol Assessment, or SPA, for the bapineuzumab phase III studies.

An SPA is a written agreement between a drug sponsor and the FDA that says the agency has signed off on an acceptable study design, including the clinical endpoints that could lead to a drug's approval.

Typically, drug companies will negotiate an SPA with the FDA for drug trials involving unusual or little-used clinical endpoints, or in situations where the requirements for approval are not entirely clear. An SPA doesn't guarantee a drug's eventual approval, but it does provide some assurance that the drug company and the FDA are on the same page when it comes to a clinical trial design.

In the case of bapineuzumab, an SPA between Elan, Wyeth and the FDA would specify that the NTB could be used as the primary measure of cognition in the phase III studies, and that data collected using the NTB, if positive, could form the basis of the drug's approval.

Yet Elan and Wyeth declined to comment on whether they sought an SPA from the FDA. The FDA's own rules require SPAs to be in place before clinical trials begin enrolling patients.

Mixed Results

If the ADAS-cog is a perfectly acceptable way to assess the effect of an Alzheimer's drug, why are Elan and Wyeth going to great lengths to devise their own test?

The answer, says Elan's Birt, is that the companies believe the NTB may be more sensitive than the ADAS-cog in measuring cognitive function in patients with milder forms of Alzheimer's.

But it should be noted that none of the drugs in Elan's highly touted Alzheimer's drug development program have demonstrated an improvement in memory or mental status when measured using traditional tests, including the ADAS-cog.

That's likely one of the issues prompting Elan to come up with new ways of showing the benefit of its Alzheimer's drugs, including coming up with its own cognitive test.

Elan researchers created the NTB by combining six older tests of memory and cognitive function to record nine measures of patient performance.

While the individual components of the NTB are in wide use (mainly as standard memory tests for all types of patients), they have never before been used to assess the mental status or memory of patients in a phase III Alzheimer's disease clinical trial meant to lead to a drug's approval.

Elan admits as much in a paper published in the Archives of Neurology in September. This paper describes the use of the NTB to measure the mental status and memory of patients in a study of AN-1792, an older Alzheimer's drug and predecessor to bapineuzumab that Elan was forced to shelve in 2002 due to toxicity.

The paper used a complicated statistical analysis to demonstrate that an alternative cognitive test like the NTB could be just as reliable, perhaps more so, than traditional measures like ADAS-cog.

The paper concludes that the "NTB may represent a useful cognitive measure for clinical trials to assess cognitive change in patients with mild to moderate Alzheimer's ... and may be more effective than traditional measures in detecting cognitive changes in the clinical assessment of a therapy designed to reverse or halt disease pathological features."

But the same paper states, "This is the first study to formally evaluate the NTB as a composite measure for Alzheimer's clinical trials. Performance on the NTB from other Alzheimer's patient samples would provide additional support for the NTB as an alternative cognitive tool."

Five of the six authors of the paper published in the Archives of Neurology are employed by Elan or Wyeth, which paid for the study to be conducted. The sixth author is an outside consultant who works for the companies.

In the phase II study of Elan's AN-1792, patients taking the drug scored worse on the ADAS-cog test than those administered a placebo. It was only using the NTB test that any cognitive benefit was demonstrated with AN-1792, and even then, the improvement was limited.

Whether bapineuzumab can improve the cognitive function of Alzheimer's patients remains an unanswered question. A phase II study of the drug is nearing completion. Analysis of the data from this randomized and controlled study, which enrolled approximately 240 patients with mild to moderate Alzheimer's disease, is expected to begin in April, with results made public in the middle of the year.

It's unusual for drug companies to start pivotal phase III studies without first getting complete data from a phase II study. Elan investors have brushed this anomaly aside and, in some cases, embraced it as a bullish indicator.

That sentiment follows this logic: If bapineuzumab weren't showing a remarkable effect on Alzheimer's patients in the phase II study, Elan and Wyeth would not have taken the risk -- and committed tens of millions of dollars -- to start an ambitious phase III program with 4,000 patients enrolled worldwide.

Most investors expect bapineuzumab to demonstrate any profound effect on cognitive function via an improvement in ADAS-cog scores. But if bapineuzumab follows the path of Elan's past Alzheimer's drug candidates, it may be the NTB, and not ADAS-cog, that picks up any improvement in mental status.

Given the unproven and uncertain nature of the NTB, investors may be in for an unpleasant surprise.
Adam Feuerstein writes regularly for TheStreet.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; click here to send him an email.

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