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.”

How Pa­tients with Epilep­sy Ben­e­fit from Re­al-World Da­ta

Amanda Shields, Principal Data Scientist, Scientific Data Steward

Keith Wenzel, Senior Business Operations Director

Andy Wilson, Scientific Lead

Real-world data (RWD) has the potential to transform the drug development industry’s efforts to predict and treat seizures for patients with epilepsy. Anticipating or controlling an impending seizure can significantly increase quality of life for patients with epilepsy. However, because RWD is secondary data originally collected for other purposes, the challenge is selecting, harmonizing, and analyzing the data from multiple sources in a way that helps support patients.

Jason Kelly, Ginkgo Bioworks CEO (Kyle Grillot/Bloomberg via Getty Images)

UP­DAT­ED: Gink­go Bioworks re­sizes the de­f­i­n­i­tion of go­ing big in biotech, rais­ing $2.5B in a record SPAC deal that weighs in with a whop­ping $15B-plus val­u­a­tion

Ginkgo Bioworks execs always thought big. But today should redefine just how big an upstart biotech player can dream.

In the largest SPAC deal to clear the hurdles to Nasdaq, the biotech that envisioned everything from remaking synthetic meat to a whole new approach to developing drugs has joined forces with one of the biggest disruptors in biotech to slam the Richter scale on dealmaking.

Soon after becoming the darling of the VC crew and clearing the bar on a $4 billion valuation, Ginkgo — a synthetic biotech player out to reprogram cells with industrial efficiency — has now struck a deal to go public in the latest leviathan SPAC that sets its pre-money valuation at $15 billion. In one swift vault, Ginkgo will combine with Harry Sloan’s Soaring Eagle Acquisition Corp. and leap into the public markets.

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FDA un­veils six ICH guide­lines ahead of meet­ing with Health Cana­da

A sign that the FDA’s non-Covid-related processes are beginning to normalize: The release of six guidelines from the International Council of Harmonisation.

Years in development, the ICH documents offer an international perspective on drug development, with these latest guidelines covering everything from recommendations to support the classification of drug substances, featured in the M9 guidance, to standards for nonclinical safety studies for pediatric medicines in the S11 guideline.

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Sanofi, Glax­o­SmithK­line, Boehringer ac­cused of play­ing games, de­stroy­ing emails re­lat­ed to law­suit over con­t­a­m­i­nat­ed Zan­tac

A recent court filing raises new questions about how major pharma companies like Sanofi, GlaxoSmithKline, and Boehringer Ingelheim have dealt with a lawsuit related to recalls of certain over-the-counter heartburn drugs due to the presence of a potentially cancer-causing substance found in them.

More than 70,000 people who took Sanofi’s Zantac and other heartburn drugs containing ranitidine, which have been recalled over the past two years, have sued the manufacturers, including generic drugmakers, and other retailers and distributors as part of a consolidated suit before US District Court Judge Robin Rosenberg in Florida.

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Chris Garabedian (Xontogeny)

Per­cep­tive Ad­vi­sors, Xon­toge­ny bring the band back and then some with a $515M sec­ond fund sniff­ing out lead com­pounds

When Perceptive Advisors and startup accelerator Xontogeny initially teamed up on an early-stage VC round in 2019, the partners hoped to prove their investments could be a force multiplier for early-stage companies. Now, with that proof of concept behind them, the pair have closed a second VC round worth more than double the money.

Dubbed PXV Fund II and headed by Xontogeny CEO and former Sarepta head Chris Garabedian, the $515 million fund will target 10 to 12 early-stage preclinical companies with Series A rounds in the $20 million to $40 million range with opportunities for Series B follow-ups. The oversubscribed fund is bringing the band back with initial investors from PXVI as well as new investors that include “top-tier” asset managers, endowments, foundations, family offices, and individual investors.

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A clos­er look at the FDA’s more than 700 pan­dem­ic-re­lat­ed record re­quests to re­place on­site in­spec­tions

As the pandemic constrained the FDA’s ability to travel for onsite manufacturing inspections, the agency increasingly turned to requesting records to fill the gap, even for hundreds of US-based facilities.

FDA explains in its guidance on manufacturing inspections during the pandemic that the agency can request records (not to be confused with the FDA’s remote interactive evaluations) directly from facilities “in advance of or in lieu of” certain onsite inspections. Companies are legally required to fulfill those requests because a denial may be considered limiting an inspection, which could lead to the FDA deeming a drug made at that site to be adulterated.

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Stephen Squinto, Gennao Bio CEO (Gennao)

Alex­ion co-founder Stephen Squin­to is back in the game as CEO, this time for a small gene ther­a­py play­er

With his name already behind a rare disease success story in Alexion, Stephen Squinto was looking for a great story to drive him to jump back into the biotech game. He found that in a fledging non-viral gene therapy company, and now he’s got a few backers on board as well.

On Tuesday, Gennao Bio launched with a $40 million Series A co-led by OrbiMed and Logos Capital with participation by Surveyor Capital. The biotech, which is looking to use its cell-penetrating antibody platform to deliver nucleic acid “payloads” during into the nucleus, had to rush for its initial series — and had a name change along the way.

Distribution of Moderna's Covid-19 Vaccine (Photo by Paul Sancya - Pool/Getty Images)

Opin­ion: Ado­les­cents can wait. The US needs to start do­nat­ing Covid-19 vac­cines to needy coun­tries now.

Now that the US is swimming in Covid-19 vaccines and the supply has officially eclipsed the demand, it’s time for America to lead the world and start shipping these excess doses to countries that desperately need them.

Unlike the IP waiver at the World Trade Organization, which Biden now supports and will likely take years to translate into actual shots in arms, the US could easily donate just a tiny fraction of the more than 60 million doses of Pfizer, Moderna and J&J vaccines sitting on American shelves right now.

Alvotech takes Ab­b­Vie to court over al­leged patent 'mine­field' sur­round­ing megablock­buster Hu­mi­ra

AbbVie has so far been successful in shooing away competition to its megablockbuster Humira, deploying a number of patents and settlements to keep biosimilars off the US market until 2023. But one Icelandic drugmaker doesn’t want to wait — and on Tuesday, it filed a lawsuit challenging what it called a patent “minefield.”

Alvotech has accused AbbVie of trying to “overwhelm” and “intimidate” it with “an outrageous number of patents of dubious validity,” according to court documents. The company is currently seeking approval for its Humira copycat AVT02, which AbbVie says would infringe upon 62 patents.