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.”

Biotech Half­time Re­port: Af­ter a bumpy year, is biotech ready to re­bound?

The biotech sector has come down firmly from the highs of February as negative sentiment takes hold. The sector had a major boost of optimism from the success of the COVID-19 vaccines, making investors keenly aware of the potential of biopharma R&D engines. But from early this year, clinical trial, regulatory and access setbacks have reminded investors of the sector’s inherent risks.

RBC Capital Markets recently surveyed investors to take the temperature of the market, a mix of specialists/generalists and long-only/ long-short investment strategies. Heading into the second half of the year, investors mostly see the sector as undervalued (49%), a large change from the first half of the year when only 20% rated it as undervalued. Around 41% of investors now believe that biotech will underperform the S&P500 in the second half of 2021. Despite that view, 54% plan to maintain their position in the market and 41% still plan to increase their holdings.

Covid-19 vac­cine boost­ers earn big thumbs up, but Mod­er­na draws ire over world sup­ply; What's next for Mer­ck’s Covid pill?; The C-suite view on biotech; 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.

You may remember that at the beginning of this year, Endpoints News set a goal to go broader and deeper. We are still working towards that, and are excited to share that Beth Snyder Bulik will be joining us on Monday to cover all things pharma marketing. You can sign up for her weekly Endpoints MarketingRx newsletter in your reader profile.

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No­var­tis de­vel­op­ment chief John Tsai: 'We go deep in the new plat­form­s'

During our recent European Biopharma Summit, I talked with Novartis development chief John Tsai about his experiences over the 3-plus years he’s been at the pharma giant. You can read the transcript below or listen to the exchange in the link above.

John Carroll: I followed your career for quite some time. You’ve had more than 20 years in big pharma R&D and you’ve obviously seen quite a lot. I really was curious about what it was like for you three and a half years ago when you took over as R&D chief at Novartis. Obviously a big move, a lot of changes. You went to work for the former R&D chief of Novartis, Vas Narasimhan, who had his own track record there. So what was the biggest adjustment when you went into this position?

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Roche's Tecen­triq cross­es the fin­ish line first in ad­ju­vant lung can­cer, po­ten­tial­ly kick­ing off gold rush

While falling behind the biggest PD-(L)1 drugs in terms of sales, Roche has looked to carve out a space for its Tecentriq with a growing expertise in lung cancer. The drug will now take an early lead in the sought-after adjuvant setting — but competitors are on the way.

The FDA on Friday approved Tecentriq as an adjuvant therapy for patients with Stage II-IIIA non small cell lung cancer with PD-(L)1 scores greater than or equal to 1, making it the first drug of its kind approved in an early setting that covers around 40% of all NSCLC patients.

Amit Etkin, Alto Neuroscience CEO (Alto via Vimeo)

A star Stan­ford pro­fes­sor leaves his lab for a start­up out to re­make psy­chi­a­try

About five years ago, Amit Etkin had a breakthrough.

The Stanford neurologist, a soft-spoken demi-prodigy who became a professor while still a resident, had been obsessed for a decade with how to better define psychiatric disorders. Drugs for depression or bipolar disorder didn’t work for many patients with the conditions, and he suspected the reason was how traditional diagnoses didn’t actually get at the heart of what was going on in a patient’s brain.

Susan Galbraith, Executive VP, Oncology R&D, AstraZeneca

As­traZeneca on­col­o­gy R&D chief Su­san Gal­braith: 'Y­ou're go­ing to need or­thog­o­nal com­bi­na­tion­s'


Earlier in the week we broadcast our 4th annual European Biopharma Summit with a great lineup of top execs. One of the one-on-one conversations I set up was with Susan Galbraith, the oncology research chief at AstraZeneca. In a wide-ranging discussion, Galbraith reviewed the cancer drug pipeline and key trends influencing development work at the pharma giant. You can watch the video, above, or stick with the script below. — JC

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Tillman Gerngross, Adagio CEO

Q&A: Till­man Gern­gross ex­plains why his Covid mAb will have an edge over an al­ready crowd­ed field

If anyone knows about monoclonal antibodies, it’s serial entrepreneur, Adimab CEO, and Dartmouth professor of bioengineering Tillman Gerngross.

Even the name of Gerngross’ new antibody startup Adagio Therapeutics is meant to reflect his vision behind the development of his Covid-19 mAb: slowly, he said, explaining that “everyone else, whether it’s Regeneron, Lilly, or AstraZeneca, Vir, they all valued speed over everything.”

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Susan Galbraith speaking at Endpoints News' virtual EUBIO21 summit

Imfinzi/treme­li­mum­ab com­bo scores As­traZeneca an­oth­er OS win — this time in liv­er can­cer

Is the tide turning on AstraZeneca’s battered PD-L1/CTLA4 combo?

A single priming dose of the experimental tremelimumab, followed by Imfinzi every four weeks, beat Nexavar (sorafenib) in helping a group of liver cancer patients live longer in a Phase III study, the company reported, meeting the primary endpoint.

Specifically, the two drugs extended overall survival for patients with unresectable hepatocellular carcinoma who had not received prior systemic therapy and were not eligible for localized treatment.

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FDA's vac­cine ad­comm unan­i­mous­ly sup­ports Mod­er­na's boost­er in same pop­u­la­tions as Pfiz­er's boost­er

The FDA’s vaccine advisory committee on Thursday voted 19-0 in support of expanding Moderna’s Covid-19 vaccine EUA for booster doses for certain high-risk individuals. FDA is expected to authorize the Moderna booster shortly.

Similarly to the Pfizer booster shot, Moderna’s will likely be authorized for those older than 65, adults at high risk of severe Covid-19, and adults whose frequent institutional or occupational exposure to SARS-CoV-2 puts them at high risk of serious complications of Covid-19. But unlike the Pfizer adcomm, where FDA had to scramble to get the committee to vote in favor of a booster, this committee was unanimous with the Moderna shot.