Cor­nell re­searchers to launch ear­ly tri­al of gene ther­a­py aimed — ul­ti­mate­ly — at pre­vent­ing Alzheimer's

The no­to­ri­ous dif­fi­cul­ty — if not im­pos­si­bil­i­ty — of re­vers­ing or slow­ing the pro­gres­sion of Alzheimer’s has pushed re­searchers to study much ear­li­er stages of the dis­ease, and the po­ten­tial of treat­ing pa­tients be­fore they show signs of brain dam­age. But can they go even ear­li­er than that — by tak­ing a pre­ven­tion ap­proach based on a ge­net­ic dri­ver of the dis­ease?

Ronald Crys­tal

Doc­tors at Weill Cor­nell Med­i­cine are giv­ing it a try with a gene ther­a­py de­signed to flood the brains of high-risk pa­tients with a low-risk ver­sion of the APOE gene, there­by knock­ing down their risk of get­ting Alzheimer’s to just av­er­age. In three months — pend­ing man­u­fac­tur­ing clear­ance — they will be­gin a 15-per­son tri­al to test if their in­fu­sion can in­deed lead to the right mix of genes (and sub­se­quent pro­duc­tion of pro­teins) in the brain.

Tar­get­ing the gene, prin­ci­pal in­ves­ti­ga­tor Ronald Crys­tal told MIT Tech Re­view, means his team doesn’t need to com­mit to any of the the­o­ries of what ac­tu­al­ly caus­es Alzheimer’s, whether it’s the dom­i­nant but in­creas­ing­ly shaky amy­loid-be­ta hy­poth­e­sis or the va­ri­ety of new tar­gets crop­ping up in re­cent years.

“What at­tracts us to Alzheimer’s is that the ge­net­ic epi­demi­ol­o­gy is so ob­vi­ous,” Crys­tal, a pro­fes­sor of ge­net­ic med­i­cine, said. “So the strat­e­gy is, can we bathe the brain in E2? We have the in­fra­struc­ture to do it, so we thought, why not? It gets around the prob­lem of the mech­a­nism of the dis­ease.”

By E2, he is re­fer­ring to the APOE2 gene, which is thought to low­er a per­son’s risk of de­vel­op­ing Alzheimer’s. For the tri­al, they are re­cruit­ing pa­tients with two copies of the APOE4 gene, the ver­sion of the apolipopro­tein E gene that por­tends the nasty mem­o­ry-wast­ing ail­ment. They will then in­ject bil­lions of virus­es con­tain­ing APOE2 to the pa­tients’ spinal cords.

Specif­i­cal­ly, Crys­tal told me, they are us­ing the AAV serotype rh.10 — a kind they have pre­vi­ous­ly ad­min­is­tered to chil­dren with Bat­ten dis­ease through di­rect in­fu­sion to the brain in a sep­a­rate tri­al. So while “you nev­er know un­til you do the stud­ies in hu­mans,” he is op­ti­mistic that safe­ty wouldn’t be a ma­jor con­cern.

Af­ter an­swer­ing the big ques­tions about safe­ty, the mea­sure of ef­fi­ca­cy will go as far as de­tect­ing the func­tion of the gene, since the ther­a­py is un­like­ly to al­ter the con­di­tions for a group of pa­tients al­ready di­ag­nosed with some form of cog­ni­tive im­pair­ment or de­men­tia due to Alzheimer’s.

“The con­cept is ra­tio­nal,” Crys­tal told MIT Tech Re­view. “Whether it works in a hu­man is an­oth­er thing.”

No­tably, on­ly about 2% of the world’s pop­u­la­tion are APOE4/4 ho­mozy­gotes, al­though one in four peo­ple car­ry a sin­gle copy, ac­cord­ing to the Ban­ner Alzheimer’s In­sti­tute.

Crys­tal ac­knowl­edged the small per­cent­age of po­ten­tial Alzheimer’s pa­tients with both copies of APOE4, but sug­gest­ed that E3/E4 het­erozy­gotes, who are al­so at risk (al­beit a small­er one) for the dis­ease, add to the pop­u­la­tion that the gene ther­a­py can ul­ti­mate­ly treat.

Nev­er­the­less, APOE4 is a well-known risk fac­tor that has been pop­ping up in Alzheimer’s news a num­ber of ways. Bio­gen and Ei­sai, to pick a re­cent ex­am­ple, were bashed hard when an­a­lysts found out they had pulled APOE4 car­ri­ers from a treat­ment arm of their big BAN2401 study, pos­si­bly skew­ing the re­sults in the drug’s fa­vor.

And then there’s Alzheon, whose plan to re­vive a once-failed drug by fo­cus­ing on a pop­u­la­tion of Alzheimer’s pa­tients with two copies of the APOE4 gene has been met with cold glares from pub­lic in­vestors.

Yet, be­cause the func­tion of the APOE gene re­mains some­what mys­te­ri­ous (there’s some ev­i­dence it’s as­so­ci­at­ed with amy­loid-be­ta de­po­si­tion), there have been few at­tempts to tin­ker with it di­rect­ly. One ex­cep­tion is the biotech start­up E-scape Bio, which has a plan to re­struc­ture APOE4 pro­teins in­to APOE3 — the “medi­um risk” type.

While both Voy­ager and J&J are al­so work­ing on gene ther­a­pies — most­ly still in pre­clin­i­cal stage — to com­bat Alzheimer’s, their fo­cus is on trig­ger­ing the pro­duc­tion of ther­a­peu­tic an­ti­bod­ies.

The al­most brute force ap­proach of Cyrstal’s up­com­ing study, then, makes it a some­what nov­el up­stream ap­proach aimed at pre­ven­tion.

The Alzheimer’s Drug Dis­cov­ery Foun­da­tion has com­mit­ted $3 mil­lion to the project, its largest grant to date ac­cord­ing to MIT Tech Re­view. It’s ex­pect­ed to wrap at the end of 2021.

Tesla and SpaceX founder Elon Musk gestures to the audience after being recognized by President Trump following the successful launch of a Falcon 9 rocket at the Kennedy Space Center. (via Getty Images)

Tes­la chief Elon Musk teams up with Covid-19 play­er Cure­Vac to build 'R­NA mi­cro­fac­to­ries'

Elon Musk has joined the global tech crusade now underway to revolutionize vaccine manufacturing — now aimed at delivering billions of doses of a new mRNA vaccine to fight Covid-19. And he’s cutting right to the front.

In a late-night tweet Wednesday, the Tesla chief announced:

Tesla, as a side project, is building RNA microfactories for CureVac & possibly others.

That’s not a lot to go on. But the tweet comes a year after Tesla’s German division in Grohmann and CureVac filed a patent on a “bioreactor for RNA in vitro transcription, a method for RNA in vitro transcription, a module for transcribing DNA into RNA and an automated apparatus for RNA manufacturing.” CureVac, in the meantime, has discussed a variety of plans to build microfactories that can speed up the whole process for a global supply chain.

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Sec­ond death trig­gers hold on Astel­las' $3B gene ther­a­py biotech's lead pro­gram, rais­ing fresh con­cerns about AAV

Seven months after Astellas shelled out $3 billion to acquire the gene therapy player Audentes, the biotech company’s lead program has been put on hold following the death of 2 patients taking a high dose of their treatment. And there was another serious adverse event recorded in the study as well, with a total of 3 “older” patients in the study affected.

The incidents are derailing plans to file for a near-term approval, which had been expected right about now.

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George Yancopoulos (Regeneron)

UP­DAT­ED: Re­gen­eron co-founder George Yan­copou­los of­fers a com­bat­ive de­fense of the po­lice at a high school com­mence­ment. It didn’t go well

Typically, the commencement speech at Yorktown Central School District in Westchester — like most high schools — is an opportunity to encourage students to face the future with confidence and hope. Regeneron president and co-founder George Yancopoulos, though, went a different route.

In a fiery speech, the outspoken billionaire defended the police against the “prejudice and bias against law enforcement” that has erupted around the country in street protests from coast to coast. And for many who attended the commencement, Yancopoulos struck the wrong note at the wrong time, especially when he combatively challenged someone for interrupting his speech with a honk for “another act of cowardness.”

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Elias Zerhouni (Photo by Vincent Isore/IP3/Getty Images)

Elias Zer­houni dis­cuss­es ‘am­a­teur hour’ in DC, the de­struc­tion of in­fec­tious dis­ease R&D and how we need to prep for the next time

Elias Zerhouni favors blunt talk, and in a recent discussion with NPR, the ex-Sanofi R&D and ex-NIH chief had some tough points to make regarding the pandemic response.

Rather than interpret them, I thought it would be best to provide snippets straight from the interview.

On the Trump administration response:

It was basically amateur hour. There is no central concept of operations for preparedness, for pandemics, period. This administration doesn’t want to or has no concept of what it takes to protect the American people and the world because it is codependent. You can’t close your borders and say, “OK, we’re going to be safe.” You’re not going to be able to do that in this world. So it’s a lack of vision, basically just a lack of understanding, of what it takes to protect the American people.

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Look­ing for 'ex­ter­nal in­no­va­tion,' Boehringer In­gel­heim re­serves $500M+ for new Shang­hai hub

Now that Boehringer Ingelheim’s bet on contract manufacturing in China has paid off, the German drugmaker is anteing up more to get into the research game.

Boehringer has set aside $507.9 million (€451 million) for a new External Innovation Hub to be built in Shanghai over five years. The site will become one of its “strategic pillars” as the team strives to get 71 approvals — either for new products or indications — by 2030, said Felix Gutsche, president and CEO of Boehringer Ingelheim China.

Vas Narasimhan, Novartis CEO (Patrick Straub/​EPA-EFE/​Shutterstock)

No­var­tis pays $678M for kick­back scheme as Vas Narasimhan tries to dis­tance phar­ma gi­ant from shady be­hav­ior

Novartis has reached another large settlement to resolve misconduct allegations, agreeing to pay more than $678 million to settle claims that it had spent hundreds of millions of dollars on lavish dinners, so-called speaking fees and expensive alcohol “that were nothing more than bribes” to get doctors to prescribe Novartis medications.

The top-shelf alcohol and lavish meals included a $3,250 per person night at Nobu in Dallas, a $672-per person dinner at Washington DC’s Smith & Wollensky and a $314 per person meal at Sushi Roku in Pasadena, according to the Justice Department complaint. There were at least 7 trips to Hooters and fishing trips in Alaska and off the Florida coast. Each of these events were supposed to be “speaker programs” where doctors educated other doctors on a drug, but the DOJ alleged many were “bogus” wine-and-dine events where the drug was barely mentioned, if at all.  (“Nobody presented slides on the fishing trips,” the complaint says.)

No­vavax snags Ben Machielse for CMC and pro­motes a trio of staffers; Mar­ty Du­vall lands an­oth­er CEO post at On­copep­tides

Novavax has been making waves recently by securing a $384 million commitment from CEPI to cover R&D and manufacturing for its Covid-19 vaccine while also spending $167 million on a 150,000 square-foot facility. The Maryland biotech continues to shore up its leadership team as well, bringing in Ben Machielse as their EVP of CMC just a couple weeks after nabbing AstraZeneca vet Filip Dubrovsky as their new CMO. Machielse was president and CEO of Vtesse from 2014-17, and before that, he also spent more than 11 years at MedImmune and was EVP of operations for the back half of his tenure.

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Dan Gold, MEI Pharma CEO

De­vel­op­ment part­ners at MEI, Helsinn dump a high-risk PhI­II AML study af­ter con­clud­ing it would fail sur­vival goal

Four years after Switzerland’s Helsinn put $25 million of cash on the table for an upfront and near-term milestone to take MEI Pharma’s drug pracinostat into a long-running Phase III trial for acute myeloid leukemia, the partners are walking away from a clinical pileup.

The drug — an HDAC inhibitor — failed to pass muster during a futility analysis, as researchers concluded that pracinostat combined with azacitidine wasn’t going to outperform the control group in the pivotal.

No­var­tis los­es biosim­i­lar ap­peal as court up­holds a 31-year mo­nop­oly by Am­gen's En­brel

A new court ruling has strengthened Amgen’s grip on the IP estate around Enbrel, keeping biosimilars of the autoimmune and inflammatory drug at bay until 2029.

Novartis, the patent challenger, isn’t throwing in the towel yet. In a statement noting the failed appeal, its generics division Sandoz noted its reviewing options, “including potential appeal to US Supreme Court.”

It’s been almost four years since the FDA approved Erelzi, Sandoz’s copycat version of Enbrel. While sales of the Pfizer-partnered drug in the US — the market Amgen is in charge of — have dipped slightly during that time, it remains a solid megablockbuster with 2019 revenue slightly above $5 billion.