Hunt­ing for an Alzheimer’s cure, re­searchers fi­nally look past amy­loid

Drug de­vel­op­ment has fo­cused on one facet of the dis­ease, marginal­iz­ing other ap­proaches “The amy­loid peo­ple are still fight­ing. They’re not will­ing to see the facts in front of them”

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Eli Lilly has spent al­most three decades work­ing on drugs for Alzheimer’s dis­ease with not much to show for it yet. This year the com­pany be­gan hu­man tests us­ing a to­tally new ap­proach. Its lat­est drug tar­gets an aber­rant pro­tein called tau that spreads through the brain as Alzheimer’s pro­gresses, ac­cu­mu­lat­ing in tell­tale tan­gles that strangle brain cells.

Lilly’s tau drug marks a shift in Alzheimer’s re­search. Drug com­pa­nies have long fo­cused on a dif­fer­ent pro­tein called amy­loid that clumps in the brains of Alzheimer’s pa­tients and is thought to trig­ger the dis­ease. Com­pa­nies have poured bil­lions into amy­loid-block­ing drugs with lit­tle suc­cess. In 2010, Eli Lilly halted tri­als of sema­gace­s­tat af­ter pa­tients on the drug de­te­ri­o­rated more quickly than those on a placebo. In 2012, Pfizer and John­son & John­son re­leased re­sults of large tri­als that showed their amy­loid treat­ment didn’t slow pro­gres­sion of the dis­ease. All told, at least 190 Alzheimer’s drugs have failed in hu­man tri­als, ac­cord­ing to Bernard Munos, a se­nior fel­low at Faster­Cures, a health non­profit.

Big Pharma might have thrown in the towel if Alzheimer’s weren’t one of the in­dus­try’s last big un­tapped mar­kets. More than 5 mil­lion Amer­i­cans have the dis­ease, and that num­ber may rise to 13.8 mil­lion by 2050, ac­cord­ing to the Alzheimer’s As­so­ci­a­tion. Ex­ist­ing medicines, which mostly treat symp­toms, have com­bined sales of about $3 bil­lion to­day. “If any of these drugs ac­tu­ally man­age to slow the progress of the dis­ease, their sales po­ten­tial would be or­ders of mag­ni­tude higher,” says Sam Fazeli, se­nior phar­ma­ceu­ti­cals an­a­lyst for Bloomberg In­tel­li­gence.

The dis­ease got its name from Ger­man psy­chi­a­trist Alois Alzheimer, who in 1906 re­ported that an au­topsy of a woman with se­vere de­men­tia had re­vealed clumps and tan­gles in the brain. More than a cen­tury later, no­body knows for sure whether amy­loid is the main cause of Alzheimer’s or a mi­nor contributor.

The in­dus­try has fo­cused on amy­loid be­cause the ge­netic ev­i­dence “has been so com­pelling,” says Roger Perl­mut­ter, head of re­search at Merck. In 2012, re­searchers in Ice­land dis­cov­ered a rare gene mu­ta­tion that ap­pears to pro­tect against Alzheimer’s by low­er­ing amy­loid pro­duc­tion. Merck ex­pects to com­plete its first fi­nal-stage trial next year of a pill called verube­ce­s­tat that blocks amy­loid pro­duc­tion.

As nu­mer­ous amy­loid drugs have fiz­zled, how­ever, Big Pharma’s in­ter­est in al­ter­na­tives has grown. The in­dus­try “is real­iz­ing you may need more than get­ting rid of amy­loid to cure the dis­ease,” says Vir­ginia Man-Yee Lee, a pro­fes­sor at the Univer­sity of Penn­syl­va­nia. Since 2014, ven­ture cap­i­tal­ists and other in­vestors have put at least $350 mil­lion into star­tups pur­su­ing novel ap­proaches. Most drugs tar­get­ing tau are years—or even a decade— be­hind amy­loid ther­a­pies in terms of clin­i­cal tri­als. Bio­gen has two drugs tar­get­ing tau near­ing hu­man tri­als. For now, its fo­cus is on an amy­loidremov­ing medicine called ad­u­canumab. But in a pre­lim­i­nary trial last year, only some of the doses tested slowed cog­ni­tion loss, rais­ing ques­tions about the drug’s ef­fec­tive­ness.

Driv­ing some of the in­ter­est in tau is re­search pub­lished in 2012 and 2013 show­ing that the pro­tein can spread be­tween brain cells, which makes it eas­ier for drug com­pa­nies to de­velop medicines to com­bat it. “The amy­loid peo­ple are still fight­ing. They are not will­ing to see the facts in front of

them,” says Har­vard Med­i­cal School pro­fes­sor Jie Shen, whose work sug­gests that amy­loid plays only a mod­est role in the dis­ease. Sa­man­tha Budd Hae­ber­lein, vice pres­i­dent of clin­i­cal de­vel­op­ment at Bio­gen, has a dif­fer­ent per­spec­tive. She says that while tau is “pos­si­bly the ex­e­cu­tioner” of brain cells, amy­loid is “the gun.”

Ab­b­Vie, which has a tau drug in early hu­man tri­als, says tar­get­ing tau could have cer­tain ad­van­tages over hit­ting amy­loid. Tau’s buildup is slower than amy­loid’s and con­tin­ues as symp­toms de­velop, mean­ing it might be pos­si­ble to treat pa­tients with more ad­vanced stages of the dis­ease and still get “a very valu­able ther­a­peu­tic ben­e­fit,” Eric Kar­ran, vice pres­i­dent of Ab­b­Vie’s Foun­da­tional Neu­ro­science Cen­ter, told an­a­lysts in June.

TauRx Phar­ma­ceu­ti­cals plans to present re­sults from a fi­nal stage trial of its tau drug at a big Alzheimer’s con­fer­ence in late July. A suc­cess­ful re­sult would have “huge im­pli­ca­tions” for the en­tire tau field, says Claude Wis­chik, the com­pany’s co-founder.

In the mean­time, the amy­loid drugs will con­tinue mov­ing through the pipe­line. Merck, Bio­gen, and Roche Hold­ing all have treat­ments in lat­estage tri­als, while Eli Lilly is retest­ing solanezumab, which didn’t suc­ceed in ear­lier tri­als. Steven Paul, a for­mer head of re­search for Eli Lilly who’s now the chief ex­ec­u­tive of­fi­cer of Voy­ager Ther­a­peu­tics, is bullish on the cur­rent crop of drugs be­cause they’re more po­tent and are be­ing tested at ear­lier stages of the dis­ease, when they’re more likely to work. “We have a much greater pos­si­bil­ity of suc­cess than we did three or four or five years ago,” he says.

De­spite the cau­tious op­ti­mism, Michael Hut­ton, a dis­tin­guished med­i­cal fel­low at Eli Lilly, con­jures a “night­mare sce­nario” in which money for re­search and de­vel­op­ment on Alzheimer’s dries up if the lat­est amy­loid drug tri­als re­port lack­lus­ter re­sults next year. If that hap­pens, “I do sus­pect we’ll see pull­back from some phar­ma­ceu­ti­cal com­pa­nies,” he says.

Robert Lan­greth and Cyn­thia Koons, with Caro­line Chen

The bot­tom line Most Alzheimer’s drugs tar­get­ing brain-cell-killing tau are as much as a decade be­hind amy­loid ther­a­pies.

Amy­loid and tau buildup

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