Lon Schneider (Keck School of Medicine of USC)

'About as true as say­ing the earth is flat': Alzheimer's ex­pert picks apart Bio­gen's Aduhelm man­u­script

Lon Schnei­der, the Uni­ver­si­ty of South Cal­i­for­nia pro­fes­sor who di­rects the Cal­i­for­nia Alzheimer’s Dis­ease Cen­ter, has been one of the most vo­cal crit­ics of Bio­gen’s de­vel­op­ment pro­gram for ad­u­canum­ab. Wary from the be­gin­ning, he picked apart the da­ta that Bio­gen pre­sent­ed along the way and, when the FDA stamped its ap­proval on Aduhelm, was among a group of ex­perts to call for its “ac­cel­er­at­ed with­draw­al” and ap­plaud­ed the CMS’ de­ci­sion to re­strict cov­er­age.

So when Bio­gen fi­nal­ly pub­lished its Phase III re­sults in a jour­nal, you could be sure Schnei­der would be on it. And he didn’t mince words.

Writ­ing in the Jour­nal of Pre­ven­tion of Alzheimer’s Dis­ease — the same place where Bio­gen pub­lished the Aduhelm man­u­script — Schnei­der dis­sect­ed the pa­per and blast­ed the cen­tral mes­sage as “so wrong on many lev­els.”

The bot­tom line:

Bio­gen and the FDA dropped an un­fin­ished, un­der­test­ed, po­ten­tial­ly un­safe prod­uct, with­out ev­i­dence of ben­e­fit, on a vul­ner­a­ble Amer­i­can pub­lic, as if to say, “We’re done here, you deal with it”.

He is not alone. A host of crit­ics had roast­ed Bio­gen’s lengthy de­lay in pub­lish­ing its re­sults, its choice of a low-rank­ing pub­li­ca­tion the lack of rig­or­ous peer re­view that should be re­served for da­ta as im­por­tant and an­tic­i­pat­ed as these. That’s not to men­tion the is­sues with the con­tent of the pa­per, which some re­searchers found want­i­ng as it didn’t re­al­ly grap­ple with the big ques­tions many had.

Schnei­der’s ed­i­to­r­i­al — ti­tled “Ad­u­canum­ab Tri­als EMERGE But Don’t EN­GAGE” in a tongue-in-cheek ref­er­ence to the names of the Phase III tri­als — al­so took time to re­flect on just how long it took for Bio­gen to pub­lish the tri­al re­sults at all.

“The Emerge (302) and En­gage (301) man­u­script ap­pears to have been with­held over two years be­cause the Bio­gen and aca­d­e­m­ic au­thors would not re­spond or com­ply with re­view­ers and ed­i­tors,” he wrote, adding lat­er: “Clear­ly, the au­thors want­ed com­plete con­trol of their mes­sage and not to have to ac­knowl­edge the sub­stan­tial lim­i­ta­tions of their tri­als, out­comes, and in­fer­ences they make,” he wrote.

Schnei­der went on to point out flaws in the pub­li­ca­tion across five sec­tions — “Meth­ods,” “Fu­til­i­ty Analy­sis,” “Pre­spec­i­fied Analy­ses,” Cor­re­lat­ing Clin­i­cal Mea­sures with Bio­mark­ers and “The Place­bo” — with com­ments like:

  • The tri­als were not ex­e­cut­ed or an­a­lyzed as planned and were fraught with method­olog­i­cal chal­lenges and un­forced er­rors.
  • Bio­gen lat­er ar­gued that the as­sump­tions un­der­ly­ing their fu­til­i­ty analy­sis were vi­o­lat­ed. This is like say­ing, ‘Sor­ry, we did the wrong analy­sis, but nev­er mind.’
  • In any event, the au­thors want us to for­get the fu­til­i­ty analy­sis, ig­nore the En­gage tri­al, ac­cept the un­usu­al changes to the Emerge place­bo group as or­di­nary, dis­count the func­tion­al un­blind­ing and oth­er risks for bias, and sim­ply ac­cept Emerge as a pos­i­tive tri­al with “clin­i­cal­ly mean­ing­ful” out­comes. We can­not.
  • The state­ment that the study “fol­lowed pre­spec­i­fied sta­tis­ti­cal analy­ses” is faulty un­less Bio­gen had a plan for what to do af­ter stop­ping for fu­til­i­ty as knowl­edge of the fu­til­i­ty re­sults makes all these sub­set analy­ses post hoc.
  • This is a stun­ning­ly re­mark­able, false claim with­out any foun­da­tion. To say that these tiny post hoc cor­re­la­tions cho­sen among many, based on non­ran­dom­ized, con­ve­nience da­ta from on­ly those who fin­ished the tri­al and agreed to a sec­ond amy­loid-PET scan have de­ci­pher­able mean­ing, let alone is ev­i­dence that plaque re­duc­tion is a sur­ro­gate mark­er for clin­i­cal out­come is about as true as say­ing the earth is flat.

He not­ed that while late-stage da­ta from oth­er amy­loid drugs like lecanemab and gan­tenerum­ab should soon “give an­swers that will make the un­cer­tain­ties of ad­u­canum­ab moot,” new pre­ven­tion tri­als will con­tin­ue for at least five more years.

“Test­ing facets of the amy­loid cas­cade hy­poth­e­sis will grind on,” he wrote.

The ed­i­to­r­i­al was pub­lished over the week­end along­side two oth­ers that al­so took a crit­i­cal view of the man­u­script — the tar­get of Schnei­der’s fi­nal point of cri­tique, which he took to Twit­ter.

Paul Hudson, Sanofi CEO (Romuald Meigneux/Sipa via AP Images)

Sanofi and DN­Di aim to elim­i­nate sleep­ing sick­ness in Africa with promis­ing Ph II/III re­sults for new drug

The Drugs for Neglected Diseases initiative (DNDi) and Sanofi today said that their potential sleeping sickness treatment saw success rates of up to 95% from a Phase II/III study investigating the safety and efficacy of single-dose acoziborole.

The potentially transformative treatment for sleeping sickness would mainly be targeted at African countries, according to data published today in The Lancet Infectious Diseases medical journal. The clinical trial was led by DNDi and its partners in the Democratic Republic of the Congo (DRC) and Guinea, with the authors noting:

Susan Galbraith, AstraZeneca EVP, oncology R&D, at EUBIO22 (Rachel Kiki for Endpoints News)

Up­dat­ed: As­traZeneca jumps deep­er in­to cell ther­a­py 2.0 space with $320M biotech M&A

Right from the start, the execs at Neogene had some lofty goals in mind when they decided to try their hand at a cell therapy that could tackle solid tumors.

Its founders have helped hone a new approach that would pack in multiple neoantigen targets to create a personalized TCR treatment that would not just make the leap from blood to solid tumors, but do it with durability. And they managed to make their way rapidly to the clinic, unveiling their first Phase I program for advanced tumors just last May.

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Ei­sai’s ex­pand­ed Alzheimer’s da­ta leave open ques­tions about safe­ty and clin­i­cal ben­e­fit

Researchers still have key questions about Eisai’s investigational Alzheimer’s drug lecanemab following the publication of more Phase III data in the New England Journal of Medicine Tuesday night.

In the paper, which was released in conjunction with presentations at an Alzheimer’s conference, trial investigators write that a definition of clinical meaningfulness “has not been established.” And the relative lack of new information, following topline data unveiled in September, left experts asking for more — setting up a potential showdown to precisely define how big a difference the drug makes in patients’ lives.

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Pro­tect­ing its megablock­buster, Janssen chal­lenges Am­gen's Ste­lara biosim­i­lar ahead of planned 2023 launch

Johnson & Johnson unit Janssen on Wednesday sued Amgen over the company’s proposed biosimilar to its megablockbuster Stelara (ustekinumab), after Amgen said it was ready to launch next May or as soon as the FDA signs off on it.

If Amgen carries through with that plan, Janssen told the Delaware district court that the Thousand Oaks, CA-based company will infringe on at least two Janssen patents.

Emily Leproust, Twist Bioscience CEO

Twist Bio­science’s 'fac­to­ry of the fu­ture' in Ore­gon could de­liv­er with com­pet­i­tive pric­ing, SVB Se­cu­ri­ties says

The synthetic DNA manufacturer Twist Bioscience has given a peek behind the curtain to several analysts into its “factory of the future” as well as insight into the cost structure, workflow and technology at the site.

The 110,000-square-foot manufacturing site in the city of Wilsonville, OR, just south of Portland, which was announced back in 2020, will double Twist’s production capacity and bring around 400 jobs to the area.

Lex­i­con slams FDA over hear­ing de­nial fol­low­ing a CRL for its SGLT2 in­hibitor can­di­date

Lexicon Pharmaceutical is not giving up on its Type I diabetes candidate, despite FDA’s repeated rejections. This week the company laid out is argument again for a hearing on sotagliflozin in response to the FDA’s most recent denial.

The issue goes back to March 2019 when the FDA made very clear to Lexicon and its now departed partner Sanofi that it would not approve their application for a potential Type I diabetes drug because it does not appear to be safe.

Illustration: Assistant Editor Kathy Wong for Endpoints News

Twit­ter dis­ar­ray con­tin­ues as phar­ma ad­ver­tis­ers ex­tend paus­es and look around for op­tions, but keep tweet­ing

Pharma advertisers on Twitter are done — at least for now. Ad spending among the previous top spenders flattened even further last week, according to the latest data from ad tracker Pathmatics, amid ongoing turmoil after billionaire boss Elon Musk’s takeover now one month ago.

Among 18 top advertisers tracked for Endpoints News, only two are spending: GSK and Bayer. GSK spending for the full week through Sunday was minimal at just under $1,900. Meanwhile, German drugmaker Bayer remains the industry outlier upping its spending to $499,000 last week from $480,000 the previous week. Bayer’s spending also marks a big increase from a month ago and before the Musk takeover, when it spent $16,000 per week.

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Vi­a­tris with­draws ac­cel­er­at­ed ap­proval for top­i­cal an­timi­cro­bial 24 years lat­er

After 24 years without confirming clinical benefit, the FDA announced Tuesday morning that Viatris (formed via Mylan and Pfizer’s Upjohn) has decided to withdraw a topical antimicrobial agent, Sulfamylon (mafenide acetate), after the company said conducting a confirmatory study was not feasible.

Sulfamylon first won FDA’s accelerated nod in 1998 as a topical burn treatment, with the FDA noting that last December, Mylan told the agency that it wasn’t running the trial.

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John Carroll with David Chang, Allogene CEO (Credit: Jeff Rumans Photography)

Al­lo­gene takes the stage in New York to go deep on its off-the-shelf cell ther­a­pies — de­clar­ing a first for sol­id tu­mors

NEW YORK — In most cases, a biotech like Allogene would wait until the next big science conference to offer its latest series of snapshots of its data. But most biotechs aren’t like Allogene, where the veteran leaders from Kite garnered a substantial number of kudos over the years for their in-depth reviews of the company’s progress.

So on Tuesday, the leaders at Allogene converged on Manhattan once again to give a detailed breakdown of their latest steps forward, looking to stay out front in the busy off-the-shelf cell therapy arena, keep a clean bill of health on the safety front and prove that they can not only match the autologous pioneers they helped create but make the all-important leap into solid tumors. It’s another step forward in a journey that has a long way to go before even the first big regulatory finish lines appear on the track. But for CEO David Chang, who spent some time with me running through the data ahead of the Tuesday session, it all amounts to forward momentum toward the desired goal.

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