The Alzheimer's R&D Odyssey Comes to An­oth­er Fork in the Road

With Phase III fail­ures start­ing to of­fer hard lessons, the R&D field starts to re­fo­cus on ever-ear­li­er stages of the dis­ease. And the FDA is help­ing.

From a dis­tance, the fail­ure of Mer­ck’s BACE drug verube­ce­s­tat in back-to-back Phase III stud­ies may have looked like just an­oth­er set­back in a 15-year blur of clin­i­cal dead ends, mis­steps and blun­ders.

Get up close, though, by mix­ing among the re­searchers who did the work, and you’ll get a much dif­fer­ent per­spec­tive — a view that re­flects the lat­est dis­tinct shift in the grad­ual evo­lu­tion of Alzheimer’s re­search.

Matt Kennedy

I talked with Matt Kennedy, Mer­ck’s head of ear­ly dis­cov­ery for neu­ro­sciences, who has been work­ing on Mer­ck’s BACE ef­forts since short­ly af­ter he joined the com­pa­ny 19 years ago. By the time the Mer­ck group was ready to start two Phase III stud­ies with verube­ce­s­tat, he says, they felt they not on­ly had the right drug, but al­so the right tech­nol­o­gy for se­lect­ing the right tri­al pa­tients and track­ing their re­spons­es.

They al­so be­lieved they were us­ing the right ap­proach. Their phi­los­o­phy: “If we in­vest in the right clin­i­cal tri­al — which we feel we con­duct­ed — it would pro­vide un­equiv­o­cal ev­i­dence of whether the drug would work,” Kennedy says.

With­out doubt, he says, the drug worked as planned in pa­tients with mild to mod­er­ate Alzheimer’s, as shown in the first of verube­ce­s­tat’s Phase III tri­als. By mov­ing up­stream of the tox­ic clus­ters of amy­loid be­ta that clog the brains of many — though not all — pa­tients with more ad­vanced dis­ease, the re­searchers were able to throw a mon­key wrench in­to the me­chan­ics of its pathol­o­gy.

As one re­searcher in the field told me, it was a way of turn­ing off the faucet steadi­ly drib­bling in­to a tub.

The drug in­hib­it­ed the de­vel­op­ment of plaques in the brains of pa­tients. But it did not in any sig­nif­i­cant way stop the tra­jec­to­ry of the dis­ease. Per­haps be­cause the tub was al­ready full.

If that sounds like just an­oth­er fail­ure, how­ev­er, you’re not pay­ing close enough at­ten­tion. The verube­ce­s­tat tri­al helped chart a new course for Alzheimer’s re­searchers.

“It pro­vides very clear da­ta so that we can now move and evolve our clin­i­cal strat­e­gy,” Kennedy says, “and oth­ers can as well.”

About five years ago we saw the first dis­tinct shift of Alzheimer’s re­search pro­grams in­to ear­li­er di­ag­noses for the dis­ease. If drugs had lit­tle chance of treat­ing a dis­ease once it had start­ed caus­ing ob­vi­ous signs of brain dam­age, maybe they’d have a shot if ther­a­py be­gan ear­ly on, when pa­tients could still be eval­u­at­ed us­ing stan­dard tests for cog­ni­tion and dai­ly func­tion. Turns out — as Mer­ck dis­cov­ered — re­search may need to move even fur­ther up­stream.

Some are do­ing just that. The drum­beat of neg­a­tive clin­i­cal da­ta that con­tin­ued with Mer­ck’s first verube­ce­s­tat tri­al is push­ing every­one in the field to­ward com­bi­na­tion ap­proach­es and pre-symp­to­matic Alzheimer’s dis­ease. And it’s not just re­searchers. The FDA it­self is grad­u­al­ly de­vel­op­ing new stan­dards for late-stage tri­als that will as­sist the on­go­ing sea change in re­search.

Not on­ly are most ma­jor drug de­vel­op­ment play­ers still re­fus­ing to quit, but at least one big out­fit is mak­ing a cal­cu­lat­ed leap in­to the game. And the ar­rival of an up­start biotech com­pa­ny has grabbed the spot­light as it takes ad­van­tage of the shift to bet­ter tech­nolo­gies in clin­i­cal re­search.

Here’s why.

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