Daphne Zohar, PureTech CEO

PureTech turns 200-year-old dis­cov­ery in­to a new ap­proach to Alzheimer's, while cling­ing to con­tro­ver­sial amy­loid hy­poth­e­sis

Be­fore MRIs or CT scans, 18th-cen­tu­ry anatomist Pao­lo Mascagni in­ject­ed his ca­dav­ers with mer­cury. Ever mo­bile, the mer­cury coursed through their veins like blood, il­lu­mi­nat­ing the body’s rivers and canals in a sil­very con­trast that Mascagni could trace up­on dis­sec­tion.

In or­nate, da Vin­ci-es­que di­a­grams, Mascagni sketched the bulk of the body’s lym­phat­ic sys­tem: The com­plex drainage net­works that as­sure im­mune cells flow to the right place and flu­id nev­er builds up in any one spot.  That in­clud­ed de­tailed draw­ings of the lym­phat­ic sys­tem in the brain — whose ex­is­tence sci­en­tists prompt­ly for­got for the next 200 years.

As Mascagni’s work, writ­ten in Latin, fell in­to ob­scu­ri­ty, re­searchers came to be­lieve the brain was cut off from the rest of the im­mune sys­tem. Now, in the few years since re­dis­cov­er­ing the Ital­ian doc­tor, sci­en­tists are be­gin­ning to im­pli­cate the sys­tem in a host of dis­eases, in­clud­ing in­tractable neu­rode­gen­er­a­tive con­di­tions such as Alzheimer’s.

“They’ve been re­dis­cov­ered and for­got­ten,” said Joseph Bolen, CSO of PureTech, a biotech that spe­cial­izes in the lym­phat­ic sys­tem. “What’s been re­al­ly well es­tab­lished in the past now six years is how im­por­tant these lym­phat­ics ac­tu­al­ly are.”

Jonathan Kip­nis

Three years ago, PureTech signed a col­lab­o­ra­tion with Jonathan Kip­nis, the Uni­ver­si­ty of Wash­ing­ton im­mu­nol­o­gist who has led the field’s re­vival. Kip­nis’ re­search showed that as mice age, the brain’s drainage sys­tem be­gins to break down. It’s as if there’s a clog and the body can’t get rid of harm­ful pro­teins as­so­ci­at­ed with Alzheimer’s or oth­er mol­e­cules that can trig­ger dan­ger­ous in­flam­ma­tion.

In a new Na­ture pa­per Wednes­day, Kip­nis demon­strat­ed that by giv­ing mice the gene for a growth fac­tor, they can stim­u­late the body to re­build that drainage sys­tem, po­ten­tial­ly im­prov­ing the ef­fi­ca­cy of drugs de­signed to clear the amy­loid plaques that build up in an Alzheimer’s pa­tient’s brain. Now con­tro­ver­sial, these treat­ments have failed near­ly every ma­jor tri­al, de­spite decades of in­dus­try in­vest­ment.

“These are great find­ings in mice by Kip­nis and col­leagues, who are re­al­ly ex­perts in this area,” Stu­art Lip­ton, an Alzheimer’s re­searcher at the Scripps In­sti­tute who was not in­volved in the re­search, said in an email.

PureTech is now try­ing to de­vel­op the ap­proach in­to a treat­ment for Alzheimer’s. It’s still ear­ly stage and the com­pa­ny is re­main­ing tight-lipped, but it would in­volve fig­ur­ing out how to de­liv­er the growth fac­tor Kip­nis used, called VEG­Fc, in­to a pa­tient’s brain at the same time they re­ceive a treat­ment like Bio­gen’s amy­loid-clear­ing ad­u­canum­ab.

The FDA is now weigh­ing an ap­proval adu­cu­nam­ab, but the drug failed one of its two ma­jor stud­ies and showed no ef­fect in low dos­es in ei­ther tri­al. If the lym­phat­ic sys­tem is re­stored, said Bolen, it should be able to clear out more amy­loid than the an­ti­body could alone.

Not every­one, though, is con­vinced. As amy­loid-clear­ing drugs have failed re­peat­ed­ly, long­time crit­ics of the amy­loid hy­poth­e­sis have be­come more vo­cal. Al­though amy­loid plaques build up in the brains of Alzheimer’s pa­tients, the plaques aren’t what dri­ve the dis­ease and clear­ing them won’t help, they ar­gue.

In the lat­est study for Eli Lil­ly’s amy­loid an­ti­body do­nanemab, 68% of pa­tients were plaque-free af­ter treat­ment. Yet they still de­te­ri­o­rat­ed sig­nif­i­cant­ly and the tri­al missed every sec­ondary end­point, rais­ing ques­tions about whether a ther­a­py that tried to clear more amy­loid could be any more ef­fec­tive.  Bolen ac­knowl­edged those re­sults, but said there’s good ev­i­dence that plaques aren’t the harm­ful part of amy­loid. In­stead, it’s like­ly oth­er, small­er amy­loid as­sem­blies, called fib­rils and oligomers.

“Yeah, but that’s just a hy­poth­e­sis,” coun­tered Nikos Robakis, a re­searcher at Mt. Sinai Med­ical Cen­ter. They need da­ta to sup­port it, he said.

Nikos Robakis

Robakis was the first per­son to clone the APP gene re­spon­si­ble for the ge­net­ic form of Alzheimer’s and he’s long been crit­i­cal of the amy­loid hy­poth­e­sis. He crit­i­cized the com­mon Alzheimer’s mod­el Kip­nis used.

To sim­u­late the neu­rode­gen­er­a­tive dis­ease, Kip­nis had bred mice to over-ex­press mu­tant pro­teins as­so­ci­at­ed with the dis­ease. But cre­at­ing a mouse brain with too much pro­tein isn’t the same as mak­ing an Alzheimer’s brain, Robakis said. It’s pos­si­ble that over-ex­pressed pro­tein are what’s dam­ag­ing the drainage sys­tem rather than the un­der­ly­ing bi­ol­o­gy you’d see in hu­mans. The in­ves­ti­ga­tors, he said, need to have a con­trol to sus out the dif­fer­ence — mice, for ex­am­ple, that have over-ex­pressed healthy pro­teins, in­stead of over-ex­pressed mu­tants.

Lip­ton de­fend­ed the Kip­nis mod­el, not­ing that it’s a com­mon one in Alzheimer’s re­search and pa­tients do in­deed show el­e­vat­ed lev­els of amy­loid ex­pres­sion. He of­fered his own cri­tique, though: It re­lies on im­mune cells in mice, but re­cent re­search from Lip­ton’s lab points to fun­da­men­tal dif­fer­ences be­tween hu­man and mouse im­mune cells when it comes to Alzheimer’s and how they re­spond to amy­loid-clear­ing an­ti­bod­ies.

“Hence, this new ap­proach still will not ad­dress the in­tense neu­roin­flam­ma­tion ob­served in hu­man but not mouse brain (im­mune cells),” he said.

Kip­nis’ tech­nol­o­gy doesn’t nec­es­sar­i­ly hinge on amy­loid be­ta. In an email, he said his ap­proach could boost an­ti-amy­loid ther­a­pies by help­ing clear out the po­ten­tial­ly tox­ic par­ti­cles that amy­loid dis­solves in­to af­ter an an­ti­body binds to it. But he al­so not­ed that it could help in oth­er ways: For ex­am­ple by help­ing re­store key struc­tures like the blood-brain bar­ri­er or clear out im­mune cells called mi­croglia that con­tribute to harm­ful in­flam­ma­tion.

Rachael Neve

“‘Un­clog­ging’ the drain, does not on­ly help with more ef­fi­cient plaque re­moval, but ac­tu­al­ly shows an im­prove­ment in oth­er as­pects of brain phys­i­ol­o­gy,” he said. “That is why we think that a syn­er­gis­tic ap­proach of im­munother­a­py+lym­phat­ic en­hancer may be more ef­fec­tive than any of them alone.”

Bolen al­so ac­knowl­edged the po­ten­tial to use the new ap­proach with ther­a­pies out­side of amy­loid ther­a­pies. Some crit­ics of the amy­loid hy­poth­e­sis agree. Rachael Neve, di­rec­tor of the Gene Tech­nol­o­gy Core at MIT’s re­searcher and Robakis’ long­time col­lab­o­ra­tor, said in an email that im­prov­ing the brain’s drainage sys­tem was a promis­ing ap­proach.

“It’s a beau­ti­ful pa­per ex­cept for their at­tempt to tie their re­sults to (amy­loid-be­ta),” she said. “That the amy­loidophiles have clung to the amy­loid hy­poth­e­sis for decades de­spite the fact that it has not been proven, and have re­fused to en­ter­tain al­ter­na­tive hy­pothe­ses, is one of the tragedies of mod­ern med­ical re­search.”

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.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 112,900+ biopharma pros reading Endpoints daily — and it's free.

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.

Endpoints Premium

Premium subscription required

Unlock this article along with other benefits by subscribing to one of our paid plans.

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.

Bob Bradway, Amgen CEO (Scott Eisen/Bloomberg via Getty Images)

Am­gen bel­lies back up to the M&A ta­ble for an­oth­er biotech buy­out, this time with a $2.5B deal for an an­ti­body play­er fo­cused on PS­MA

Five months after Amgen CEO Bob Bradway stepped up to the M&A table and acquired Five Prime for $1.9 billion, following up with the smaller Rodeo acquisition, he’s gone back in for another biotech buyout.

This time around, Amgen is paying $900 million cash while committing up to $1.6 billion in milestones to bag the privately held Teneobio, an antibody drug developer that has expertise in developing new bispecifics and multispecifics. In addition, Amgen cited Teneobio’s “T-cell engager platform, which expands on Amgen’s existing leadership position in bispecific T-cell engagers by providing a differentiated, but complementary, approach to Amgen’s current BiTE platform.”

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 112,900+ biopharma pros reading Endpoints daily — and it's free.

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.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 112,900+ biopharma pros reading Endpoints daily — and it's free.

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.

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.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 112,900+ biopharma pros reading Endpoints daily — and it's free.

Frank Pallone (Kevin Dietsch/Pool via AP Images)

House com­mit­tee seeks more from FDA on in­spec­tion back­log, when to restart work on for­eign sites

House Energy & Commerce committee leaders are raising fresh questions about the FDA’s ability to conduct foreign manufacturing site inspections and bring down its growing backlog.

“While we understand that the emergence of COVID-19 required the agency to suspend in-person inspection activities temporarily, we remain concerned that more than one year into the pandemic, the strategy for resuming all inspections and addressing the backlog of delayed inspections remains unclear,” E&C chair Frank Pallone (D-NJ) and a group of five other bipartisan leaders of the committee wrote to FDA acting commissioner Janet Woodcock.

Luciana Borio (Susan Walsh/AP Images)

UP­DAT­ED: Bob Nelsen's ARCH adds FDA, biode­fense ex­per­tise with ap­point­ment of Lu­ciana Bo­rio

Once vetted by the Biden team to lead the FDA as commissioner, Luciana Borio is now compiling quite the résumé.

Borio has now been named a venture partner at Bob Nelsen’s ARCH Venture Partners, and Nelsen told Endpoints News, “She will be involved in projects across the portfolio, including ongoing projects in manufacturing, clinical trials, gene therapy and gene editing, cell therapy, and delivery. We are exploring multiple projects in infectious disease, and next generation manufacturing.”