Stuart Lipton, via Scripps Research

Stu­art Lip­ton of­fers a new pos­si­ble rea­son why all the Alzheimer's drugs have failed

There are a few com­mon­ly trot­ted out rea­sons for why vir­tu­al­ly every Alzheimer’s drug of the last two decades has failed: Maybe the tri­als didn’t start ear­ly enough in the course of dis­ease, or maybe they didn’t go af­ter the right group of pa­tients?

As com­pa­nies have start­ed ear­li­er and on more se­lect groups of pa­tients, an­oth­er con­clu­sion has grown in­creas­ing­ly pop­u­lar: Maybe they’ve all gone af­ter the wrong tar­get. Maybe clear­ing the mis­fold­ed plaques that buildup in pa­tients’ brains, as these ther­a­pies have, just wipes away one symp­tom of the dis­ease but not the root cause.

Stu­art Lip­ton, though, has an al­ter­na­tive ex­pla­na­tion. A lead­ing de­men­tia ex­pert who helped de­vel­op the the last FDA-ap­proved Alzheimer’s drug, he is pub­lish­ing new re­search this week show­ing that the an­ti­bod­ies com­pa­nies de­vel­oped might be hav­ing an un­in­tend­ed side ef­fect that un­der­cuts any ben­e­fit they of­fer.

Amy­loid-clear­ing an­ti­bod­ies, he wrote in a pa­per for the Pro­ceed­ing of the Na­tion­al Acad­e­my of Sci­ence, might be set­ting off dan­ger­ous in­flam­ma­tion that, in a cru­el bit of irony, has­ten neu­ro­log­i­cal de­cline. Lip­ton called the re­sult para­dox­i­cal.

“We re­al­ized that it’s pos­si­ble these hu­man tri­als, many of which have failed, might be in part fail­ing be­cause they’re para­dox­i­cal­ly in­duc­ing more in­flam­ma­tion in the brain,” he told End­points News, “even though they’re get­ting rid of the pro­tein, which may be a good thing.”

Dorit Trudler

The re­search be­gan when a post­doc at Lip­ton’s Scripps In­sti­tute lab, Dorit Trudler, at­tempt­ed to make the in­nate im­mune cell of the brain, an oc­to­pus-look­ing goop called the mi­croglia, in the lab. It’s a dif­fi­cult task be­cause mi­croglia don’t come from the same lin­eage of stem cells in the bone mar­row that the rest of the im­mune sys­tem, B cells and T cells and macrophages, do.

In­stead, it comes from the yolk sac that bathes em­bryos in ear­ly de­vel­op­ment, mi­grat­ing from the sac to the brain. By giv­ing hu­man-de­rived stem cells a se­ries of mol­e­c­u­lar sig­nals, Trudler turned them in­to a clus­ter that re­sem­bled a yolk sac and, from it, de­vel­oped cells that, based on the mR­NA they ex­press, were in­dis­tin­guish­able from mi­croglia re­moved from hu­mans.

“They match as close­ly as pos­si­ble,” Lip­ton said.

Be­cause hu­man mi­croglia are dif­fi­cult to pro­duce, drug re­searchers have his­tor­i­cal­ly used mouse mod­els to see how the im­mune cells re­spond to drugs. Lip­ton and Trudler, though, were able to sim­u­late how hu­man mi­croglia re­spond in the brain.

They found that if you ex­posed these mi­croglia to ei­ther al­pha synu­cle­in, the hall­mark mis­fold­ed pro­tein in Parkin­son’s, the mi­croglia sent off in­flam­ma­to­ry sig­nals. And if you added amy­loid-be­ta, the in­flam­ma­tion wors­ened.

Fi­nal­ly, they man­aged to ob­tain an­ti­bod­ies that com­pa­nies had de­vel­oped to bind to and clear those mis­fold­ed pro­teins. (Lip­ton de­clined to say which an­ti­body it was, ex­cept that, de­spite his best ef­forts to con­vince the drug­mak­er, it wasn’t Bio­gen’s ad­u­canum­ab, the con­tro­ver­sial can­di­date now be­fore the FDA.)

To their sur­prise, the an­ti­bod­ies suc­cess­ful­ly bind­ed to the mis­fold­ed pro­tein but that didn’t help in­flam­ma­tion. “Rather than make things bet­ter, it ac­tu­al­ly made things worse,” Lip­ton said.

By look­ing at hu­man­ized mice that had both hu­man and mice mi­croglia, Lip­ton’s team found that the pro-in­flam­ma­to­ry re­sponse was unique to the hu­man cells, mean­ing drug­mak­ers wouldn’t have seen it in the trans­la­tion­al stud­ies. They’re still not sure why it’s caus­ing in­flam­ma­tion, but they showed the ef­fect with mul­ti­ple dif­fer­ent an­ti­bod­ies that tar­get mul­ti­ple dif­fer­ent pro­teins and they’ve nailed down the path­way, NL­RP3, that’s in­volved.

Still, Lip­ton said, they don’t nec­es­sar­i­ly have to fig­ure out the ex­act mech­a­nism. He says you could imag­ine giv­ing these amy­loid-clear­ing drugs in com­bi­na­tion with a drug that blocks in­flam­ma­tion, al­low­ing doc­tors to clear out mis­fold­ed pro­teins with­out dan­ger­ous­ly turn­ing up the heat.

In fact, it’s what his lab is work­ing on right now.

“We’re hope­ful that we can maybe de­vel­op a drug in the near fu­ture that can off­set,” Lip­ton said.

How one start­up fore­told the neu­ro­science re­nais­sance af­ter '50 years of shit­show'

In the past couple of years, something curious has happened: Pharma and VC dollars started gushing into neuroscience research.

Biogen’s controversial new Alzheimer’s drug Aduhelm has been approved on the basis of removing amyloid plaque from the brain, but the new neuro-focused pharma and biotechs have much loftier aims. Significantly curbing or even curing the most notorious disorders would prove the Holy Grail for a complex system that has tied the world’s best drug developers in knots for decades.

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Ryan Watts, Denali CEO

De­nali slips as a snap­shot of ear­ly da­ta rais­es some trou­bling ques­tions on its pi­o­neer­ing blood-brain bar­ri­er neu­ro work

Denali Therapeutics had drummed up considerable hype for their blood-brain barrier technology since launching over six years ago, hype that’s only intensified in the last 14 months following the publications of a pair of papers last spring and proof of concept data earlier this year. On Sunday, the South San Francisco-based biotech gave the biopharma world the next look at in-human data for its lead candidate in Hunter syndrome.

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Why is On­col­o­gy Drug De­vel­op­ment Re­search Late to the Dig­i­tal Bio­mark­ers Game?

During the recent Annual ASCO Meeting, thousands of cancer researchers and clinicians from across the globe joined together virtually to present and discuss the latest findings and breakthroughs in cancer research and care. There were more than 5000+ scientific abstracts presented during this event, yet only a handful involved the use of motion-tracking wearables to collect digital measures relating to activity, sleep, mobility, functional status, and/or quality of life. Although these results were a bit disappointing, they should come as no surprise to those of us in the wearable technology field.

Art Levinson (Calico)

Google-backed Cal­i­co dou­bles down on an­ti-ag­ing R&D pact with Ab­b­Vie as part­ners ante up $1B, start to de­tail drug tar­gets

Seven years after striking up a major R&D alliance, AbbVie and Google-backed anti-aging specialist Calico are doubling down on their work with a joint, $1 billion commitment to continuing their work together. And they’re also beginning to offer some details on where this project is taking them in the clinic.

According to their statement, each of the two players is putting up $500 million more to keep the labs humming.

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Busi­ness­es and schools can man­date the use of Covid-19 vac­cines un­der EUAs, DOJ says

As public and private companies stare down the reality of the Delta variant, many are now requiring that their employees or students be vaccinated against Covid-19 prior to attending school or to returning or starting a new job. Claims that such mandates are illegal or cannot be used for vaccines under emergency use authorizations have now been dismissed.

Setting the record straight, the Department of Justice on Monday called the mandates legal in a new memo, even when used for people with vaccines that remain subject to EUAs.

Ugur Sahin, BioNTech CEO (Bernd von Jutrczenka/dpa via AP Images)

BioN­Tech is spear­head­ing an mR­NA vac­cine de­vel­op­ment pro­gram for malar­ia, with a tech trans­fer planned for Africa

Flush with the success of its mRNA Covid-19 vaccine, BioNTech is now gearing up for one of the biggest challenges in vaccine development — which comes without potential profit.

The German mRNA pioneer says it plans to work on a jab for malaria, then transfer the tech to the African continent, where it will work with partners on developing the manufacturing ops needed to make this and other vaccines.

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No­var­tis reshuf­fles its wild cards; Tough sell for Bio­gen? Googling pro­teins; Ken Fra­zier's new gig; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

If you enjoy the People section in this report, you may also want to check out Peer Review, my colleagues Alex Hoffman and Kathy Wong’s comprehensive compilation of comings and goings in biopharma.

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Andrea Pfeifer, AC Immune CEO (AC Immune)

Look­ing to repli­cate Covid-19 suc­cess in neu­ro, BioN­Tech back­ers bet on AC Im­mune and its new­ly-ac­quired Parkin­son's vac­cine

The German billionaires behind BioNTech have found a new vaccine project to back.

Through their family office Athos Service, twin brothers Thomas and Andreas Strüngmann are leading a $25 million private placement into Switzerland’s AC Immune — which concurrently announced that it’s shelling out $58.7 million worth of stock to acquire Affiris’ portfolio of therapies targeting alpha-synuclein, including a vaccine candidate, for Parkinson’s disease.

Mer­ck­'s wom­en's health spin­out snags mid-stage can­di­date for preterm birth; Keytru­da nails down TNBC ap­proval af­ter March CRL

Nearly two months after spinning out from Merck, women’s health business Organon has struck its first half-billion-dollar deal.

Organon $OGN has promised $25 million upfront and another $475 million in biobucks for worldwide rights to ebopiprant, ObsEva’s investigational treatment for preterm labor. Ebopiprant, a selective prostaglandin F2α (PGF2α) receptor antagonist, was originally licensed from Merck KGaA in 2015. The candidate works by reducing inflammation and uterine contractions.