By Clifton Leaf
July 30, 2018

One headline wondered breathlessly if the new experimental drug was “the most promising development on Alzheimer’s in recent history.” Another said the same experimental medicine showed “little efficacy in trial.”

ABC News gushed: “New Alzheimer drug shows big promise.” CBS News said flatly: “Alzheimer’s drug results disappoint.”

When Biogen, the Boston biotech, and Eisai, a Japanese pharmaceutical company, announced the results of their 18-month Phase II clinical trial of an antibody called BAN2401 last week, the responses were like the reflections in a funhouse mirror: wildly out of proportion, depending on where you stood.

The London–based news service, “The Pharma Letter,” summed it up well: “Biogen and Eisai suffer amid Alzheimer’s data confusion.”

Why the confusion, you ask? Lots of reasons. But here are three to start with:

1. Measures of early cognitive decline are surprisingly squishy.

In the great mass of Alzheimer’s trials that have been done over the years, drugmakers have largely tested their experimental agents on patients with full-on disease. Biogen and Eisai, by contrast, set out to evaluate BAN2401 in patients in the early or “prodromal” stage, who typically have only mild cognitive impairment. The thinking here was (and is) smart: In decades’ worth of attempts, no drug has been able to reverse, stop, or even slow this pathological terror; perhaps attacking it earlier in its progression—a strategy that has proven effective in everything from heart disease to hypertension to cancer—can yield a better result.

(For some truly surprising insight on this subject—and a heckuva good read at that—I highly recommend you dig into Erika Fry’s 2015 feature in FORTUNE, “Can Biogen Beat The Memory Thief?”)

While attacking the disease earlier is a step forward, certainly, there’s one key snag: There aren’t great tests yet for measuring change in cognitive ability and mental function at early stages of this disease (see here and here).

So the team at Eisai developed their own—called ADCOMS, for Alzheimer’s Disease Composite Score. And indeed, patients receiving the highest dosage of BAN2401 during the study seemed to do pretty well, according to this bespoke model: showing 30% less cognitive decline over the 18-month stretch than those in the placebo arm. In another, more traditional measure—ADAS-cog (or Alzheimer’s Disease Assessment Scale-cognitive subscale)—high-dose patients seemed to fare even better.

But in a third measure—the awkwardly named Clinical Dementia Rating Sum of Boxes—BAN2401 failed to demonstrate, to the point of statistical significance at least, that it was more effective than the placebo. While CDR-SB is a fairly insensitive measure for mild cognitive impairment, the FDA has long recognized it as an appropriate “clinical endpoint” for Alzheimer’s drug studies; and ADCOMS, of course—despite the far superior acronym—is the new kid on the block.

Biogen and Eisai may have also shot themselves in the foot by announcing early in July that they had “positive” results—allowing their stocks to soar—while leaving the not-so-clear details to be sorted out later.

2. This trial had its share of Mulligans.

Here’s the thing about clinical science. It mostly isn’t one—a pure science, that is. Rather, it’s a form of artisanship mixed with a little partisanship. I’ll dwell on this more another time (and, well, I did write a book chapter on this, for those inclined). But for now, consider two somewhat classic oddities of the BAN2401 study.

First, is that the research team began with one statistical analysis— then seemed to change their mind when it didn’t deliver the goods. That’s how an investigative agent could appear ineffective after a year, but curiously effective just six months later.

In late December last year, at the one-year mark of the study, Biogen and Eisai announced that an Independent Data Monitoring Committee had determined that the drug “did not meet the criteria for success” in their primary endpoint, the ADCOMS measure noted above. (Studies like this one are designed to allow such interim analyses so that they can be halted for safety or other reasons.) The companies blamed the failure on a statistical technique…and said they’d keep going anyway.

Second, is that the trial may have been off-balance from the get-go—which is to say the experimental and control groups may not have been so evenly matched. As several analysts and veteran biotech watchers have pointed out, the share of people with a major risk factor for Alzheimer’s was much smaller in the pivotal drug arm than it was in the group getting placebo. That decision was due to European regulators, not to the companies, who were concerned that patients with this particular genetic susceptibility would also be at greater risk of brain injury if they received the drug. But it also may have inadvertently skewed the results: It’s not unreasonable to think that carriers of this telltale gene (APOe4) could have declined more precipitously during the 18 months of the study, making the response of those in the experimental arm look comparatively better.

That may seem like an incidental thing, but in a medical crusade that has long been measured in inches, such asterisks matter immensely.

Which brings us to the main reason for confusion…

3. We may still be chasing the wrong damn target.

In Alzheimer’s, neurons are seemingly choked to death by two types of normal central nervous system proteins that, for some reason, begin to accumulate in large quantities in the cerebral cortex. The first are beta-amyloid peptides that, when not cleared from the brain, begin to encircle neurons en masse, clogging their synapses, inflaming surrounding tissue (perhaps as the result of an associated immune response), and ultimately kill off critical brain cells. The second are twisted protein fibers or “tangles” called tau, which aggregate within the neurons themselves and cause degeneration.

The beta-amyloid plaques and the tau tangles are the twin hallmarks of Alzheimer’s disease—a conclusion first drawn by Alois Alzheimer more than a century ago—but most efforts at stopping or reversing the disease have focused only on the former phenomenon: the mysterious amyloid deposits.

BAN2401 follows the same worn track. And in this latest trial, what no one doubts is that the targeted antibody does a bang-up job of clearing beta-amyloid plaques from the brain. The higher the dose, in fact, the more it wipes it clean. But as one expert put it, that hasn’t exactly resulted in “shock and awe” in terms of a real-world clinical effect.

Dozens of drugs before BAN2401 have likewise targeted—and, in many cases, sharply reduced—this glomming protein from the human brain, and from an untold number of mouse models too. But this approach doesn’t seem to flip the Alzheimer’s switch, causing many in the field to doubt whether the ancient and vaunted “amyloid hypothesis” is the right one.

Which brings me to the real “confusion” of this well publicized Phase II trial: What do Biogen and Eisai hope to discover in Phase III that’s different from what we see now? The two companies have announced full steam ahead for the next study phase—which will involve hundreds more volunteers and take even longer to complete. That one will be done alongside Biogen’s ongoing trial of another high-profile anti-amyloid agent, aducanumab, which the biotech has licensed from Neurimmune—which will be done alongside dozens of others. As of the start of the year, there were no less than 32 investigative agents targeting amyloid in mid- to late-stage clinical trials, according to Jeffrey Cummings and colleagues at the Cleveland Clinic Lou Ruvo Center for Brain Health.

So far the failure rate for Alzheimer’s drugs is 99.6%. That’s right: Virtually every time we’ve tried this strategy, it has failed.

Maybe that’s why so many caregivers, Alzheimer’s advocates, research scientists—and perhaps even a few biotech investors—seem so befuddled about this latest well-hyped drug study. Maybe they’re wondering why we’re not trying something else.

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