Can the controversial FDA approval of Aduhelm backfire and delay the discovery of actual Alzheimer’s treatments? (Yes, it can)

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The U.S. Food and Drug Admin­is­tra­tion (FDA) recent­ly approved adu­canum­ab, the first treat­ment that aims to slow the pro­gres­sion of Alzheimer’s dis­ease. But approval of the drug has pro­voked mixed reac­tions from the sci­en­tif­ic community.

Alzheimer’s dis­ease is char­ac­ter­ized by pro­gres­sive mem­o­ry loss, spa­tial dis­ori­en­ta­tion and many oth­er cog­ni­tive and behav­iour­al dis­or­ders that ulti­mate­ly lead to a state of total dependence.

As researchers who study Alzheimer’s bio­mark­ers — objec­tive bio­log­i­cal mea­sures used to iden­ti­fy the dis­ease, mea­sure its pro­gres­sion and deter­mine the effec­tive­ness of treat­ments — we’re very inter­est­ed in the dis­cov­ery of new treat­ments for this disease.

Adu­canum­ab, which will be mar­ket­ed under the name Aduhelm, was joint­ly devel­oped by Bio­gen and Eisai. It is a mon­o­clon­al anti­body admin­is­tered by injec­tion that binds to brain aggre­gates of amy­loid and allows our bod­ies to dis­pose of them. The treat­ment is based on the idea that amy­loid, a small pro­tein that accu­mu­lates in the brains of peo­ple with Alzheimer’s dis­ease, is at the ori­gin of a cas­cade of events that leads to the disease.

Questionable results

The FDA approval is based on two 18-month clin­i­cal tri­als that were con­duct­ed with adu­canum­ab. One showed a slow­ing of the pro­gres­sion of cog­ni­tive impair­ment by about 22 per cent in peo­ple who received the high-dose treat­ment. The oth­er showed no dif­fer­ence between those who were giv­en adu­canum­ab and those giv­en the placebo.

Typ­i­cal­ly, reg­u­la­to­ry author­i­ties require two Phase 3 tri­als with pos­i­tive results to approve a drug. Bio­gen and Eisai ter­mi­nat­ed both tri­als after an inde­pen­dent pan­el of experts con­clud­ed that based on pre­lim­i­nary results, adu­canum­ab was unlike­ly to be effec­tive in slow­ing the cog­ni­tive decline of the dis­ease despite show­ing some effec­tive­ness in reduc­ing brain amy­loid levels.

In addi­tion, adu­canum­ab has been asso­ci­at­ed with cere­bral ede­ma in 40 per cent of those treat­ed. Ede­ma is a flu­id mass that pro­duces pres­sure in the skull and requires med­ical mon­i­tor­ing or surgery.

After fur­ther review of the results from the two clin­i­cal tri­als, Bio­gen and Eisai announced in Octo­ber 2019 that adu­canum­ab admin­is­tered in high dos­es showed effi­ca­cy on cog­ni­tive symp­toms in patients with ear­ly Alzheimer’s. This way of ana­lyz­ing the results was strong­ly crit­i­cized by the sci­en­tif­ic com­mu­ni­ty, includ­ing some of the inves­ti­ga­tors who had par­tic­i­pat­ed in the clin­i­cal trials.

Amyloid may have little influence

The amy­loid cas­cade, the idea behind how adu­canum­ab works, is the sub­ject of great con­tro­ver­sy in the sci­en­tif­ic com­mu­ni­ty. This hypoth­e­sis has dom­i­nat­ed for near­ly 30 years and guid­ed the search for treat­ments that aim to remove amy­loid from the brain. Yet every clin­i­cal tri­al using this approach has failed, rep­re­sent­ing dozens of prod­ucts and hun­dreds of bil­lions of dol­lars in investment.

More and more, we are real­iz­ing that the prob­lems with Alzheimer’s may not involve amy­loid either direct­ly or sole­ly. For exam­ple, a per­son who is genet­i­cal­ly pre­dis­posed to accu­mu­late amy­loid may devel­op Alzheimer’s ear­li­er, but may not progress more rapid­ly than a per­son who is not pre­dis­posed. This means that amy­loid may have lit­tle influ­ence on dis­ease progression.

Even advo­cates of the amy­loid hypoth­e­sis have become more mea­sured about its pos­si­ble influ­ence, propos­ing that it may only have an indi­rect impact on brain dys­func­tion in Alzheimer’s dis­ease. This would occur through a process of brain inflam­ma­tion, which is one of the pos­si­ble caus­es of neu­ronal death in this disease.

In short, while the amy­loid hypoth­e­sis has fal­tered, the approval of adu­canum­ab, which is based pri­mar­i­ly on this the­o­ry, sug­gests that the the­o­ry may once again dom­i­nate research, and could reduce the chances of find­ing more promis­ing treat­ments. For exam­ple, tau pro­tein, which also accu­mu­lates in the brains of Alzheimer’s patients — long before the amy­loid pro­tein does — has been shown to be close­ly asso­ci­at­ed with the cog­ni­tive impair­ment result­ing from the disease.

A risky precedent

So how can one explain the FDA’s deci­sion, which runs con­trary to the rec­om­men­da­tion of its own expert pan­el and is based on evi­dence that shows that amy­loid only makes a small con­tri­bu­tion to the pro­gres­sion of the disease?

Adu­canum­ab reduced the amount of amy­loid accu­mu­lat­ed in the brain by near­ly two-thirds in treat­ed indi­vid­u­als. While this is a dra­mat­ic result, their symp­toms per­sist­ed, mean­ing that amy­loid is not a good bio­mark­er of the disease.

The dis­cov­ery and val­i­da­tion of reli­able bio­mark­ers to detect dis­eases and assess the effi­ca­cy of treat­ments only comes about after a long and rig­or­ous process. The use of amy­loid has nev­er real­ly gone through this process, yet the FDA approved a treat­ment based on this. Bypass­ing this process sets a risky precedent.

No cura­tive treat­ment tar­get­ing Alzheimer’s symp­toms has emerged since the first treat­ments came to mar­ket in 1997. Adu­canum­ab is the first approved treat­ment aimed at slow­ing the pro­gres­sion of the dis­ease. The sur­prise and excite­ment gen­er­at­ed by the first suc­cess in a jour­ney that has includ­ed hun­dreds of failed clin­i­cal tri­als may explain why the FDA grant­ed the drug con­di­tion­al approval.

The approval also sat­is­fies the finan­cial inter­ests of Bio­gen, Eisai and its investors. The most mod­est esti­mates put annu­al rev­enues from the sale of adu­canum­ab at more than US$50 bil­lion. Expec­ta­tion of new rev­enue for Eisai and Bio­gen pushed the stock val­ues of these com­pa­nies up by 75 per cent and 40 per cent respec­tive­ly the day the announce­ment was made.

New evi­dence col­lect­ed after the launch of adu­canum­ab will be crit­i­cal to the future of the amy­loid hypoth­e­sis and our under­stand­ing of Alzheimer’s dis­ease. With such a com­plex dis­ease, it is like­ly that we will need to devel­op mul­ti­ple approach­es to stop its pro­gres­sion, much like triple ther­a­py for HIV/AIDS. That’s why we must not inter­rupt research on bio­mark­ers and new ther­a­peu­tic approaches.

– Éti­enne Aumont is PhD stu­dent in Psy­chol­o­gy and Marc-André Bédard is Pro­fes­sor of cog­ni­tive phar­ma­col­o­gy at Uni­ver­sité du Québec à Mon­tréal (UQAM). This arti­cle was orig­i­nal­ly pub­lished on The Con­ver­sa­tion.

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