Alzheimer’s: Learn­ing From a Lega­cy of Bit­ter Set­backs


In bio­phar­ma R&D, the biggest and best drug tar­gets al­ways in­volve un­met med­ical need—and Alzheimer’s fits that de­f­i­n­i­tion bet­ter than any oth­er ma­jor dis­ease.

There’s good rea­son for that, and it’s in­side our heads. The cir­cuit­ry of the hu­man brain is in­cred­i­bly com­plex, with some 100 tril­lion synaps­es fer­ry­ing elec­tri­cal mes­sages be­tween neu­rons in a con­stant fren­zy. In the brains of Alzheimer’s pa­tients, those bi­o­log­ic process­es break down. Mes­sages go awry, of­ten to cat­a­stroph­ic re­sults.In­ves­ti­ga­tors have been fo­cus­ing on tox­ic con­cen­tra­tions of amy­loid be­ta that clog up those synaps­es and on a sub­stance called tau that’s found in­side neu­rons. While some big play­ers like Glax­o­SmithK­line and As­traZeneca have stepped back in re­cent years, pre­fer­ring to fo­cus their re­sources in dis­eases where they’re like­ly to make a big­ger im­pact, and more quick­ly, a group of big and small drug de­vel­op­ers re­main stub­born­ly com­mit­ted to the field.

To un­der­stand why they’ve dou­bled down, you need to un­der­stand the num­bers. And they all point to a crush­ing cost from a dead­ly se­ri­ous ag­ing dis­ease.

Of the 5.5 mil­lion Amer­i­cans with Alzheimer’s, 4% are un­der 65, ac­cord­ing to a new re­port from the Alzheimer’s As­so­ci­a­tion. That  num­ber swells to 16% among se­niors be­tween 65 and 74, then 44% for the next decade and 38% in the 85-and-old­er group. That’s a lot of peo­ple, and in an ag­ing pop­u­la­tion, the num­bers are about to grow.

It’s not just pa­tients, ei­ther. There are close to three un­paid care­givers for each of the Amer­i­cans with Alzheimer’s, and they’re de­vot­ing in­creas­ing amounts of time to their af­flict­ed fam­i­ly mem­bers.

The cost of Alzheimer’s care will hit $259 bil­lion this year. And that pales in com­par­i­son to what’s com­ing.

By 2050, the cost of care is ex­pect­ed to quadru­ple, to more than a tril­lion dol­lars. Medicare can’t han­dle that kind of math. Nor can the health­care sys­tems in oth­er coun­tries that will have to ad­just to even big­ger pa­tient pools as pop­u­la­tion de­mo­graph­ics go in­creas­ing­ly gray.

Num­bers like that are scary for so­ci­ety, but they spell a big op­por­tu­ni­ty for drug­mak­ers. If any­one cre­ates a treat­ment that mod­i­fies the pro­gres­sion of the dis­ease—or even de­liv­ers gains on the symp­to­matic side—that’s a gold­en tick­et. The po­ten­tial pay­off could dri­ve bil­lions in an­nu­al prof­it.

As a re­sult, com­pa­nies like Eli Lil­ly, Roche and Mer­ck & Co. have been pump­ing bil­lions of dol­lars in­to late-stage re­search projects. The pay­off over the past 14 years: $0.

As a re­sult, com­pa­nies like Eli Lil­ly, Roche and Mer­ck & Co. have been pump­ing bil­lions of dol­lars in­to late-stage re­search projects.

The pay­off over the past 14 years: $0

Alzheimer’s brain. Com­put­er graph­ic of a ver­ti­cal (coro­nal) slice through the brain of an Alzheimer pa­tient (at left) com­pared with a nor­mal brain (at right). The Alzheimer’s dis­ease brain (red) is con­sid­er­ably shrunk­en, due to the de­gen­er­a­tion and death of nerve cells. Apart from a de­crease in brain vol­ume, the sur­face of the brain is of­ten more deeply fold­ed. Tan­gled pro­tein fil­a­ments (neu­rofib­ril­lary tan­gles) oc­cur with­in nerve cells and pa­tients al­so de­vel­op brain le­sions of be­ta- amy­loid pro­tein. Alzheimer’s dis­ease ac­counts for most cas­es of se­nile de­men­tia. Symp­toms in­clude mem­o­ry loss, dis­ori­en­ta­tion, per­son­al­i­ty change and delu­sion. It ul­ti­mate­ly leads to death.

Phar­ma com­pa­nies have an­nounced one failed study af­ter an­oth­er. The grow­ing litany in­cludes every sin­gle Phase III read­out. Alzheimer’s R&D hasn’t even pro­duced new ad­di­tions to the short list of mod­est­ly ef­fec­tive symp­tom-fo­cused drugs on the mar­ket.

That’s the bad news. The good news is that each fail­ure has of­fered at least mar­gin­al in­sight in­to what went wrong be­fore. Deep­en­ing ex­pe­ri­ence and im­prove­ments in tech­nol­o­gy il­lu­mi­nate which paths re­searchers should con­tin­ue to fol­low, and where new paths should be blazed.

Large con­cen­tra­tions of non-Alzheimer’s pa­tients were ac­ci­den­tal­ly scooped up in­to ear­li­er stud­ies; now, di­ag­no­sis is more pre­cise and pa­tient re­cruit­ment more dis­crim­i­nat­ing. Tri­als are bet­ter run, thanks to the emer­gence of a glob­al net­work of sites. They’re sharp­en­ing stan­dards as in­ves­ti­ga­tors track the cog­ni­tive and func­tion­al abil­i­ties of tri­al par­tic­i­pants.

Mean­while, re­searchers’ think­ing has evolved, push­ing steadi­ly up­stream to ear­li­er and ear­li­er stages of the dis­ease.

Old con­flicts be­tween dis­ease trig­gers have be­gun to re­solve in­to a bet­ter ap­pre­ci­a­tion of the kind of drug cock­tails nec­es­sary to change the cur­rent Alzheimer’s prog­no­sis—de­men­tia and death—to a man­age­able, chron­ic dis­ease that no longer wipes out mem­o­ries and per­son­al­i­ties.

Still, ex­perts in the field agree that some­thing con­crete needs to hap­pen in drug de­vel­op­ment. Some­thing that will ac­tu­al­ly ben­e­fit pa­tients. And the soon­er the bet­ter.

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