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.”

A new era of treat­ment: How bio­mark­ers are chang­ing the way we think about can­cer

AJ Patel was recovering from a complicated brain surgery when his oncologist burst into the hospital room yelling, “I’ve got some really great news for you!”

For two years, Patel had been going from doctor to doctor trying to diagnose his wheezing, only to be dealt the devastating news that he had stage IV lung cancer and only six months to live. And then they found the brain tumors.

“What are you talking about?” Patel asked. He had never seen an oncologist so happy.

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Mihael Polymeropoulos, Vanda Pharmaceuticals CEO

Phar­ma com­pa­ny con­tin­ues its FDA law­suit spree, this time af­ter agency de­nies fast-track des­ig­na­tion

Vanda Pharmaceuticals is making a name for itself, at least in terms of suing the FDA.

The DC-headquartered firm on Monday filed its latest suit against the agency, with the company raising concerns over the FDA’s failure to grant a fast track designation for Vanda’s potential chronic digestive disorder drug tradipitant, which is a neurokinin 1 receptor antagonist.

Specifically, Vanda said FDA’s “essential point” in its one-page denial letter on the designation pointed to “the lack of necessary safety data,” which was “inconsistent with the criteria for … Fast Track designation.”

Mod­er­na seeks to dis­miss Al­ny­lam suit over Covid-19 vac­cine com­po­nent, claim­ing wrong venue

RNAi therapeutics juggernaut Alnylam Pharmaceuticals made a splash in March when it sued and sought money from both Pfizer and Moderna regarding their use of Alnylam’s biodegradable lipids, which Alnylam claims have been integral to the way both companies’ mRNA-based Covid-19 vaccines work.

But now, Moderna lawyers are firing back, telling the same Delaware district court that Alnylam’s claims can only proceed against the US government in the Court of Federal Claims because of the way the company’s contract is set up with the US government. The US has spent almost $10 billion on Moderna’s Covid-19 vaccine so far.

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(Credit: Shutterstock)

Cracks in the fa­cade: Is phar­ma's pan­dem­ic ‘feel good fac­tor’ wan­ing?

The discordant effects of the Covid-19 pandemic on pharma reputation continues. While the overall industry still retains a respectable halo from its Covid-19 quick response and leadership, a new patient group study reveals a different story emerging in the details.

On one hand, US patient advocacy groups rated the industry higher-than-ever overall. More than two-thirds (67%) of groups gave the industry a thumbs up for 2021, a whopping 10 percentage point increase over the year before, according to the PatientView annual study, now in its 9th year.

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Michael Corbo, Pfizer CDO of inflammation & immunology

UP­DAT­ED: Plan­ning ahead for crowd­ed ul­cer­a­tive col­i­tis mar­ket, Pfiz­er spells out PhI­II da­ta on $6.7B Are­na drug

Pfizer has laid out the detailed results behind its boast that etrasimod — the S1P receptor modulator at the center of its $6.7 billion buyout of Arena Pharma — is the winner of the class, potentially leapfrogging an earlier entrant from Bristol Myers Squibb.

Pivotal data from the ELEVATE program in ulcerative colitis — which consists of two Phase III trials, one lasting 52 weeks and the other just 12 weeks — illustrate an “encouraging balance of efficacy and safety,” according to Michael Corbo, chief development officer of inflammation & immunology at Pfizer. The company is presenting the results as a late breaker at Digestive Disease Week.

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Robert Califf (Michael Brochstein/Sipa USA via AP Images)

House Re­pub­li­cans at­tack Chi­na-on­ly da­ta in FDA sub­mis­sions, seek new in­ves­ti­ga­tion in­to re­search in­spec­tions

Three Republican representatives are calling on the FDA to take a closer look at the applications including only clinical data from China.

The letter to FDA commissioner Rob Califf late last week comes as the agency recently rejected Eli Lilly’s anti-PD-1 antibody, which attempted to bring China-only data but ran into a bruising adcomm that may crush the hopes of any other companies looking to bring cheaper follow-ons based only on Chinese data.

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Amid mon­key­pox fears, biotechs spring to ac­tion; Mod­er­na’s CFO trou­ble; Cuts, cuts every­where; Craft­ing the right pro­teins; 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.

It’s always a bittersweet moment saying goodbye, but as Josh Sullivan goes off to new adventures we are grateful for the way he’s built up the Endpoints Manufacturing section — which the rest of the team will now carry forward. If you’re not already, this may be a good time to sign up for your weekly dose of drug manufacturing news. Thank you for reading and wish you a restful weekend.

Co­pay coupons gone wrong, again: Pfiz­er pays al­most $300K to set­tle com­plaints in four states

Pfizer has agreed to pay $290,000 to settle allegations of questionable copay coupon practices in Arizona, Colorado, Kansas, and Vermont from 2014 to 2018.

While the company has not admitted any wrongdoing as part of the settlement, Pfizer has agreed to issue restitution checks to about 5,000 consumers.

A Pfizer spokesperson said the company has “enhanced its co-pay coupons to alleviate the concerns raised by states and agreed to a $30,000 payment to each.”

Delaware court rules against Gilead and Astel­las in years-long patent case

A judge in Delaware has ruled against Astellas Pharma and Gilead in a long-running patent case over Pfizer-onwed Hospira’s generic version of Lexiscan.

The case kicked off in 2018, after Hospira submitted an Abbreviated New Drug Application (ANDA) for approval to market a generic version of Gilead’s Lexiscan. The drug is used in myocardial perfusion imaging (MPI), a type of nuclear stress test.