Dis­eases’ dif­fi­cul­ties stump drug com­pa­nies

The Washington Post - - ECONOMY & BUSINESS - BY CAR­OLYN Y. JOHN­SON car­olyn.john­son@wash­post.com More at wash­ing­ton­post.com/ wonkblog

The first days of 2018 have been a bleak re­minder of how tough it is to de­velop drugs for some of the world’s most fright­en­ing dis­eases, which rob peo­ple of their mem­o­ries, abil­i­ties and per­son­al­i­ties.

In the span of one week, pharma gi­ant Pfizer an­nounced that it was end­ing its in­ter­nal ef­forts to de­velop new drugs for Alzheimer’s and Parkin­son’s dis­eases. Ax­o­vant Sciences an­nounced that its ex­per­i­men­tal drug, which late last year failed an Alzheimer’s trial, had also failed to treat a dif­fer­ent form of de­men­tia. A day later, a lead­ing med­i­cal jour­nal pub­lished an ac­count of yet an­other ex­per­i­men­tal drug that failed to pre­vent cog­ni­tive de­cline in peo­ple with mild-to-mod­er­ate Alzheimer’s dis­ease.

Th­ese set­backs pile on to an al­ready de­press­ing sit­u­a­tion: More than 400 failed clin­i­cal tri­als since the last Alzheimer’s drug — which treats only the symp­toms of the dis­ease, tem­po­rar­ily — was ap­proved more than a decade ago.

“If you think it’s been a bad week, it’s been a bad 14 years. It’s 14 years since the last new drug was ap­proved by the FDA, and the string of fail­ures this week is noth­ing new, and not un­ex­pected,” said David Ben­nett, di­rec­tor of the Rush Alzheimer’s Dis­ease Cen­ter in Chicago. “I view Pfizer get­ting out of the Alzheimer’s busi­ness as not a good thing for the field, but that doesn’t mean that I have a strong rec­om­men­da­tion for what Pfizer should do in its next trial.”

Alzheimer’s is a for­mi­da­ble foe for a num­ber of rea­sons. The brain isn’t easy to ac­cess, and much about how it works re­mains mys­te­ri­ous, even as sci­en­tific knowl­edge has moved for­ward. Doc­tors can’t take easy, re­peat biop­sies to see whether a drug is work­ing.

Tri­als are long and ex­pen­sive. It has be­come in­creas­ingly clear that it is nec­es­sary to treat pa­tients early, then wait to see if the dis­ease is pre­vented or slowed.

Pa­tients, though they are af­fected in heart­break­ing ways, typ­i­cally are un­able to act as ad­vo­cates for more fund­ing or re­search when they are in the throes of the dis­ease — un­like can­cer or AIDS pa­tients.

That doesn’t mean phar­ma­ceu­ti­cal com­pa­nies and re­searchers are giv­ing up. Den­nis Selkoe, a pro­fes­sor of neu­rol­ogy at Brigham and Women’s Hospi­tal in Bos­ton, who has served as the head of the ex­ter­nal neu­ro­science ad­vi­sory board for Pfizer, said that part of the rea­son for the long string of fail­ures is that in their des­per­a­tion to find a drug, com­pa­nies con­ducted tri­als that weren’t op­ti­mal — not tar­get­ing peo­ple early enough in the dis­ease, or not us­ing the best pos­si­ble drugs.

“When the world says, ‘Man, it’s ter­ri­ble — Alzheimer’s has got­ten nowhere,’ I don’t think it’s a lack of knowl­edge about the dis­ease mech­a­nism. It’s be­cause we’ve cho­sen weak drugs that don’t do much. And we’ve tried them when peo­ple al­ready have sig­nif­i­cant im­pair­ment,” Selkoe said.

The fail­ures have helped in­form re­search. Tri­als in­creas­ingly test drugs ear­lier, when they are more likely to have an ef­fect. Im­proved imag­ing tech­nol­ogy has helped re­searchers to peer into the brain. Grow­ing knowl­edge of the dis­ease, which is char­ac­ter­ized by the buildup of amy­loid beta pro­tein, as well as tan­gles of tau pro­tein, has helped guide the de­vel­op­ment of smarter drugs.

An ex­per­i­men­tal drug called ad­u­canumab, from the Mas­sachusetts-based biotech com­pany Bio­gen, is be­ing tested in lat­estage tri­als af­ter show­ing suc­cess in re­duc­ing amy­loid plaque in early tri­als. Selkoe said that he en­rolls his own pa­tients in this trial and is hope­ful that, if it shows good re­sults, it could spur more com­pa­nies to de­velop drugs in this space. Selkoe has no fi­nan­cial re­la­tion­ship with Bio­gen.

But the long list of fail­ures may make com­pa­nies hes­i­tant to fund re­search when they have limited re­sources and more promis­ing drug de­vel­op­ment pro­grams in other dis­ease ar­eas.

Pfizer will main­tain a ven­ture fund of undis­closed size to in­vest in neu­ro­science re­search.

“Af­ter years of re­search and in­vest­ment and putting our strong and fo­cused ef­forts into ad­vanc­ing neu­ro­science ther­a­pies, we rec­og­nized our on­go­ing ef­forts were not go­ing to de­liver the im­pact­ful med­i­cal ad­vances for pa­tients that we had as­pired to achieve,” Pfizer spokes­woman Neha Wad­hwa said in a state­ment. “This was a dif­fi­cult de­ci­sion and it is not lost on us that there is a tremen­dous need for new ther­a­pies in this ther­a­peu­tic area.”

Part of the dif­fi­culty is that peo­ple with Alzheimer’s dis­ease of­ten suf­fer from other brain patholo­gies that also make ma­jor con­tri­bu­tions to their cog­ni­tive de­cline. That is yet an­other com­plex­ity of the ag­ing brain that could make it harder to know if a po­ten­tial Alzheimer’s drug is work­ing. It also raises the prospect that frag­ile, elderly pa­tients might one day have to take cock­tails of drugs to pre­serve their cog­ni­tion.

One so­lu­tion is to try to iso­late peo­ple with the purest form of the dis­ease, us­ing imag­ing scans or other tools to find peo­ple with Alzheimer’s who are lack­ing other signs of pathol­ogy.

But Ben­nett is try­ing to get com­pa­nies in­ter­ested in de­vel­op­ing drugs that bol­ster cog­ni­tive re­serves gen­er­ally, rather than treat a spe­cific dis­ease. The idea is that there could be pro­teins that serve a pro­tec­tive ef­fect or neg­a­tive ones that could be sup­pressed.

Selkoe pointed out that, de­spite the fail­ures, the ur­gency of the dis­ease keeps com­pa­nies push­ing for­ward.

“I’m op­ti­mistic,” Selkoe said. “Even though they keep on fail­ing, there are lots of other shots on goal.”

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