Drug Development

Merck can’t prove its Alzheimer’s drug works, yet, but it did just explain why it’s spending a fortune on PhIII

Investigators for Merck $MRK have very carefully outlined all the early-stage human and animal data they can muster for their Alzheimer’s drug verubecestat. Now in an ambitious Phase III due to read out in mid-2017, tests proved that the BACE drug can successfully target one of the key biomarkers for the disease.

They just don’t have any convincing data to show whether it will actually make a difference in patients’ cognitive abilities, or improve their ability to function in their daily lives.

In many ways, Merck’s case echoes all the upbeat data we’ve heard about Alzheimer’s drugs in recent years, and also helps explain why this field has been so frustrating.

First, the data. The key takeaway from the article in Science Translational Medicine is that Merck’s drug significantly reduced levels of amyloid beta in the fluid surrounding the brain among the actual patients taking the drug. Dosing was short, with only 32 patients getting the drug daily for a week.

That’s not nearly enough time to detect any reduction in these toxic clusters by way of a brain scan. And it’s far short of any kind of evidence that the therapy can actually have an impact on a disease that damages the brain, perhaps irrevocably.

But it does explain why Merck and others are spending a fortune on late-stage studies on these BACE drugs.

The mechanism of action for this drug lies upstream of amyloid beta. It’s designed to interfere with the production of amyloid beta, cutting the supply of a protein that has become one of the chief culprits in the disease. Ratchet down the flow of amyloid beta, the theory goes, and you can prevent the cognitive and physical eruptions that eventually wipe out a person’s memory and requires careful supervision.

The problem with these studies is that companies like Merck — and this includes companies like Eli Lilly, Biogen, J&J and many others — often jump from a Phase I biomarker study into broad Phase III studies, looking for evidence that they can bend a remorseless disease curve.

Merck also included data from its studies involving animals and healthy subjects. But aside from providing important insights on safety, such results rarely mean much of anything when it comes to predicting efficacy. But big companies are willing to overlook big issues as they hustle into late-stage Alzheimer’s trials.

Lilly was so committed to solanezumab — which also targets amyloid beta — that it mounted a new Phase III program after the last one failed. It also recently relegated one key measure on function to a secondary endpoint, flagging its lack of confidence on that score.

And most investigators in the field are moving upstream in the disease pathology, hoping to check the disease before it causes serious damage.

Despite billions spent on new trials over the past decade, though, the field has been afflicted by one setback after the next. Now Merck will take the most advanced study on BACE and help set the stage for a new field in which rivals are hustling along competing therapies, hoping to cash in on one of the biggest unmet medical needs in the business.

Lilly will be first up with new Phase III data on solanezumab in a matter of weeks. Merck will follow in July. Sometime over the next year, we’ll be able to understand much better just what role amyloid beta plays in Alzheimer’s. And if anyone scores pay dirt data, the payoff will potentially be worth billions a year from a new drug franchise. Losers will be relegated to a growing cemetery of failed programs.


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