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.

Qual­i­ty Con­trol in Cell and Gene Ther­a­py – What’s Re­al­ly at Stake?

In early 2021, Bluebird Bio was forced to suspend clinical trials of its gene therapy for sickle cell disease after two patients in the trial developed cancer. As company scientists rushed to assess whether there was any causal link between the therapy and the cancer cases, Bluebird’s stock value plummeted – as did those of multiple other biopharma companies developing similar therapies.

While investigations concluded that the gene therapy was unlikely to have caused cancer, investors and the public may be more skittish regarding the safety of gene and cell therapies after this episode. This recent example highlights how delicate the fields of cell and gene therapy remain today, even as they show great promise.

Law pro­fes­sors call for FDA to dis­close all safe­ty and ef­fi­ca­cy da­ta for drugs

Back in early 2018 when Scott Gottlieb led the FDA, there was a moment when the agency seemed poised to release redacted complete response letters and other previously undisclosed data. But that initiative never gained steam.

Now, a growing chorus of researchers are finding that a dearth of public data on clinical trials and pharmaceuticals means industry and the FDA cannot be held accountable, two law professors from Yale and New York University write in an article published Wednesday in the California Law Review.

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Novavax CEO Stanley Erck at the White House in 2020 (Andrew Harnik, AP Images)

As fears mount over J&J and As­traZeneca, No­vavax en­ters a shaky spot­light

As concerns rise around the J&J and AstraZeneca vaccines, global attention is increasingly turning to the little, 33-year-old, productless, bankruptcy-flirting biotech that could: Novavax.

In the now 16-month race to develop and deploy Covid-19 vaccines, Novavax has at times seemed like the pandemic’s most unsuspecting frontrunner and at times like an overhyped also-ran. Although they started the pandemic with only enough cash to last 6 months, they leveraged old connections and believers into $2 billion and emerged last summer with data experts said surpassed Pfizer and Moderna. They unveiled plans to quickly scale to 2 billion doses. Then they couldn’t even make enough material to run their US trial and watched four other companies beat them to the finish line.

FDA of­fers scathing re­view of Emer­gent plan­t's san­i­tary con­di­tions, em­ploy­ee train­ing af­ter halt­ing pro­duc­tion

The FDA wrapped up its inspection of Emergent’s troubled vaccine manufacturing plant in Baltimore on Tuesday, after halting production there on Monday. By Wednesday morning, the agency already released a series of scathing observations on the cross contamination, sanitary issues and lack of staff training that caused the contract manufacturer to dispose of millions of AstraZeneca and J&J vaccine doses.

Brad Bolzon (Versant)

Ver­sant pulls the wraps off of near­ly $1B in 3 new funds out to build the next fleet of biotech star­tups. And this new gen­er­a­tion is built for speed

Brad Bolzon has an apology to offer by way of introducing a set of 3 new funds that together pack a $950 million wallop in new biotech creation and growth.

“I want to apologize,” says the Versant chairman and managing partner, laughing a little in the intro, “that we don’t have anything fancy or flashy to tell you about our new fund. Same team, around the same amount of capital, same investment strategy. If it ain’t broke, don’t fix it.”

But then there’s the flip side, where everything has changed. Or at least speeded into a relative blur. Here’s Bolzon:

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Sen. Patty Murray (D-WA) (Graeme Sloan/Sipa USA/Sipa via AP Images)

Sen­a­tors to NIH: Do more to pro­tect US bio­med­ical re­search from for­eign in­flu­ence

Although Thursday’s Senate health committee hearing was focused on how foreign countries and adversaries might be trying to steal or negatively influence biomedical research in the US, the only country mentioned by the senators and expert witnesses was China.

Committee chair Patty Murray (D-WA) made clear in her opening remarks that the US cannot “let the few instances of bad actors” overshadow the hard work of the many immigrant researchers in the US, many of which have won Nobel prizes for their work. But she also said, “There is more the NIH can be doing here.”

Jenny Rooke (Genoa Ventures)

Ear­ly Zymer­gen in­vestor Jen­ny Rooke re­flects on 'chimeras' in biotech, what it takes to spot a $500M gem

When Jenny Rooke first heard of Zymergen back in 2014, she knew she was looking at something different and exciting. The Emeryville, CA biotech held the promise of blending biology and technology to solve a huge unmet need for cost-effective chemicals — of all things — and a stellar founding team to boot.

But back then, West Coast venture capitalists didn’t see in Zymergen the one thing they were looking for in a winning biotech: therapeutic potential. Rooke, however, saw an opportunity and made her bets. Seven years later, that bet is paying off in a big way.

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Saurabh Saha at Endpoints News' #BIO19

On the heels of $250M launch, Centes­sa barges ahead with an IPO to fu­el its 10-in-1 Medicxi pipeline

Francesco De Rubertis made no secret of IPO plans for Centessa, his 10-in-1 legacy play. Barely two months later, the S-1 is in.

The hot-off-the-press filing depicts the same grand vision that the longtime VC touted when he did the rounds in February: Take the asset-centric mindset that he’s been preaching at Medicxi over the years, and roll up a bunch of biotech upstarts, with unrelated risk profiles, into 1 pharma company that can carry on the development at scale.

Emma Walmsley, GlaxoSmithKline CEO (Kevin Dietsch/Pool via CNP/Alamy)

Glax­o­SmithK­line hus­tles the 7th PD-1 past the fin­ish line with Jem­per­li. But how big will up­take be?

Everything came up sevens for GlaxoSmithKline on Thursday as the pharma notched the seventh PD-1 approval seven years after the first such drugs were OK’ed in Keytruda and Opdivo. But will it bring GSK good fortune?

The FDA granted accelerated approval to dostarlimab, to be branded Jemperli, to treat recurrent or advanced endometrial cancer in a specific subset of patients following platinum-based chemo. It’s a drug that came to GSK through its buyout of Tesaro, which it snapped up for $5.1 billion back in December 2018.