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.

What Will it Take to Re­al­ize the Promise and Po­ten­tial of Im­mune Cell Ther­a­pies?

What does it take to get to the finish line with a new cancer therapy – fast? With approvals in place and hundreds of immune cell therapy candidates in the pipeline, the global industry is poised to create a fundamental shift in cancer treatments towards precision medicine. At the same time, unique challenges associated with cell and process complexity present manufacturing bottlenecks that delay speed to market and heighten cost of goods sold (COGS) — these hurdles must be overcome to make precision treatments an option for every cancer patient. This series of articles highlights some of the key manufacturing challenges associated with the production of cell-based cancer therapies as well as the solutions needed to transcend them. Automation, process knowledge, scalability, and assured supply of high-quality starting material and reagents are all critical to realizing the full potential of CAR-based therapies and sustaining the momentum achieved in recent years. The articles will highlight leading-edge technologies that incorporate these features to integrate across workflows, accelerate timelines and reduce COGS – along with how these approaches are enabling the biopharmaceutical industry to cross the finish line faster with new treatment options for patients in need.

The biggest ques­tions fac­ing gene ther­a­py, the XLMTM com­mu­ni­ty, and Astel­las af­ter fourth pa­tient death

After three patients died last year in an Astellas gene therapy trial, the company halted the study and began figuring out how to safely get the program back on track. They would, executives eventually explained, cut the dose by more than half and institute a battery of other measures to try to prevent the same thing from happening again.

Then tragically, Astellas announced this week that the first patient to receive the new regimen had died, just weeks after administration.

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Lat­est news: It’s a no on uni­ver­sal boost­ers; Pa­tient death stuns gene ther­a­py field; In­side Tril­li­um’s $2.3B turn­around; 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.

Next week is shaping up to be a busy one, as our editor-in-chief John Carroll and managing editor Kyle Blankenship lead back-to-back discussions with a great group of experts to discuss the weekend news and trends. John will be spending 30 minutes with Jake Van Naarden, the CEO of Lilly Oncology, and Kyle has a brilliant panel lined up: Harvard’s Cigall Kadoch, Susan Galbraith, the new head of cancer R&D at AstraZeneca, Roy Baynes at Merck, and James Christensen at Mirati. Don’t miss out on the action — sign up here.

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Mi­rati's KRAS drug looks like the fa­vorite in colon can­cer with new da­ta, putting the pres­sure square on Am­gen

With Amgen already providing proof-of-concept for KRAS inhibitors with its sotorasib, Mirati Therapeutics is piecing together a follow-up effort in lung cancer with data it thinks are superior. But in colon cancer, where solo sotorasib has turned in a dud, Mirati may now have a strong case for superiority.

Mirati’s adagrasib, dosed solo or in combination with chemotherapy cetuximab, showed response rates grater than sotorasib solo  and as part of combination study in a similar patient population also revealed this week at #ESMO21. Mirati’s data were presented as part of a cohort update from the Phase II KRYSTAL-1 study testing adagrasib in a range of solid tumors harboring the KRAS-G12C mutation.

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President Biden and Pfizer CEO Albert Bourla (Patrick Semansky/AP Images)

Chaot­ic ad­comm sees Pfiz­er/BioN­Tech boost­ers re­ject­ed for gen­er­al pop­u­la­tion, but rec­om­mend­ed for old­er and high-risk pop­u­la­tions

With just days before President Joe Biden’s Covid-19 booster rollout is set to go into effect, an FDA advisory committee appeared on the verge of not recommending boosters for anyone in the US before a last-minute change of wording laid the groundwork for older adults to have access to a third dose.

The FDA’s adcomm on Vaccines and Related Biological Products (VRBPAC) roundly rejected Pfizer/BioNTech booster shots for all individuals older than 16 by a 16-2 vote Friday afternoon. Soon after, however, the agency posed committee members a new question limiting booster use to the 65-and-older population and individuals at high risk of disease due to occupational exposure or comorbidities.

The best of the rest: High­lights from the be­low-the-fold pre­sen­ta­tions at #ES­MO21

This year’s ESMO Congress has had a major focus on Big Pharma drugs — most notably candidates from Merck and AstraZeneca — but there have also been updates from smaller biotechs with data looking to challenge the big-name drugmakers.

Today, we’re highlighting some of the data releases that flew under the radar at #ESMO21 — whether from early-stage drugs looking to make a mark or older stalwarts with interesting follow-up data.

As­traZeneca, Dai­ichi Sanky­o's ADC En­her­tu blows away Roche's Kad­cy­la in sec­ond-line ad­vanced breast can­cer

AstraZeneca and Japanese drugmaker Daiichi Sankyo think they’ve struck gold with their next-gen ADC drug Enhertu, which has shown some striking data in late-stage breast cancer trials and early solid tumor tests. Getting into earlier patients is now the goal, starting with Enhertu’s complete walkover of a Roche drug in second-line breast cancer revealed Saturday.

Enhertu cut the risk of disease progression or death by a whopping 72% (p=<0.0001) compared with Roche’s ADC Kadcyla in second-line unresectable and/or metastatic HER2-positive breast cancer patients who had previously undergone treatment with a Herceptin-chemo combo, according to interim data from the Phase III DESTINY-Breast03 head-to-head study presented at this weekend’s #ESMO21.

Merck Research Laboratories CMO Roy Baynes

Mer­ck­'s Keytru­da un­corks full da­ta on lat­est ad­ju­vant win — this time in melanoma — adding bricks to ear­ly can­cer wall

In recent months, the battle for PD-(L)1 dominance has spilled over into early cancer with Merck’s Keytruda and Bristol Myers Squibb’s Opdivo all alone on the front lines. Keytruda now has another shell in its bandolier, and it could spell a quick approval.

Keytruda cut the risk of relapse or death by 35% over placebo (p=0.00658) in high-risk, stage 2 melanoma patients who had previously undergone surgery to remove their tumors, according to full data from the Phase III KEYNOTE-716 presented Saturday at #ESMO21.

Multiple antibiotic resistant Pseudomonas aeruginosa bacterium

A new way to in­fil­trate (and de­stroy) some of the dead­liest drug-re­sis­tant bugs

About four years ago, Ruben Tommasi, the gregarious scientific chief of antibiotics startup Entasis, walked into a meeting with his top chemist and top biologist to chew over another batch of unchanging results.

“It felt like we were running the same experiment over and over,” Tommasi told Endpoints News. “We had all sort of come to that point in time where we felt like we were banging our heads against the wall.”

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