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.

Nick Leschly via Getty

UP­DAT­ED: Blue­bird shares sink as an­a­lysts puz­zle out $1.8M stick­er shock and an un­ex­pect­ed de­lay

Blue­bird bio $BLUE has un­veiled its price for the new­ly ap­proved gene ther­a­py Zyn­te­glo (Lenti­Glo­bin), which came as a big sur­prise. And it wasn’t the on­ly un­ex­pect­ed twist in to­day’s sto­ry.

With some an­a­lysts bet­ting on a $900,000 price for the β-tha­lassemia treat­ment in Eu­rope, where reg­u­la­tors pro­vid­ed a con­di­tion­al ear­ly OK, blue­bird CEO Nick Leschly said Fri­day morn­ing that the pa­tients who are suc­cess­ful­ly treat­ed with their drug over 5 years will be charged twice that — $1.8 mil­lion — on the con­ti­nent. That makes this drug the sec­ond most ex­pen­sive ther­a­py on the plan­et, just be­hind No­var­tis’ new­ly ap­proved Zol­gens­ma at $2.1 mil­lion, with an­a­lysts still wait­ing to see what kind of pre­mi­um can be had in the US.

Ted Love. HAVERFORD COLLEGE

Glob­al Blood Ther­a­peu­tics poised to sub­mit ap­pli­ca­tion for ac­cel­er­at­ed ap­proval, with new piv­otal da­ta on its sick­le cell dis­ease drug

Global Blood Therapeutics is set to submit an application for accelerated approval in the second-half of this year, after unveiling fresh data from a late-stage trial that showed just over half the patients given the highest dose of its experimental sickle cell disease drug experienced a statistically significant improvement in oxygen-wielding hemoglobin, meeting the study's main goal.

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Gene ther­a­pies seize the top of the list of the most ex­pen­sive drugs on the plan­et — and that trend has just be­gun

Anyone looking for a few simple reasons why the gene therapy field has caught fire with the pharma giants need only look at the new list of the 10 most expensive therapies from GoodRx.

Two recently approved gene therapies sit atop this list, with Novartis’ Zolgensma crowned the king of the priciest drugs at $2.1 million. Right below is Luxturna, the $850,000 pioneer from Spark, which Roche is pushing hard to acquire as it adds a gene therapy group to the global mix.

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News­mak­ers at #EHA19: Re­gen­eron, Ar­Qule track progress on re­sponse rates

Re­gen­eron’s close­ly-watched bis­pe­cif­ic con­tin­ues to ring up high re­sponse rates

Re­gen­eron’s high-pro­file bis­pe­cif­ic REGN1979 is back in the spot­light at the Eu­ro­pean Hema­tol­ogy As­so­ci­a­tion sci­en­tif­ic con­fab. And while the stel­lar num­bers we saw at ASH have erod­ed some­what as more blood can­cer pa­tients are eval­u­at­ed, the re­sponse rates for this CD3/CD20 drug re­main high.

A to­tal of 13 out of 14 fol­lic­u­lar lym­phomas re­spond­ed to the drug, a 93% ORR, down from 100% at the last read­out. In 10 out of 14, there was a com­plete re­sponse. In dif­fuse large B-cell lym­phoma the re­sponse rate was 57% among pa­tients treat­ed at the 80 mg to 160 mg dose range. They were all com­plete re­spons­es. And 2 of these Cars were for pa­tients who had failed CAR-T ther­a­py.

Neil Woodford, Woodford Investment Management via YouTube

Un­der siege, in­vest­ment man­ag­er Wood­ford faces an­oth­er in­vest­ment shock

Em­bat­tled UK fund man­ag­er Neil Wood­ford — who has con­tro­ver­sial­ly blocked in­vestors from pulling out from his flag­ship fund to stem the blood­let­ting, af­ter a slew of dis­ap­point­ed in­vestors fled fol­low­ing a se­ries of sour bets — is now pay­ing the price for his ac­tions via an in­vestor ex­o­dus on an­oth­er fund.

Har­g­reaves Lans­down, which has in the past sold and pro­mot­ed the Wood­ford funds via its re­tail in­vest­ment plat­form, has re­port­ed­ly with­drawn £45 mil­lion — its en­tire po­si­tion — from the in­vest­ment man­ag­er’s In­come Fo­cus Fund.

Fol­low­ing CAR-T pi­o­neer­s' foot­steps, Tes­sa launch­es Chi­na JV in $120M deal

These days just about every biotech se­ri­ous about glob­al de­vel­op­ment — and not just com­mer­cial­iza­tion — has a Chi­na strat­e­gy. Tes­sa Ther­a­peu­tics, a Bay­lor as­so­ci­at­ed out­fit based out of Sin­ga­pore, is no ex­cep­tion.

Tak­ing a page out of the CAR-T pi­o­neers’ play­book, Tes­sa is es­tab­lish­ing a joint ven­ture with Chi­na-Sin­ga­pore Guangzhou Knowl­edge City, which is ini­tial­ly putting down $40 mil­lion for a 13% stake with $40 mil­lion more to come in a sec­ond stage. The biotech, which now re­tains an 87% con­trol, is al­so rolling out its own con­tri­bu­tions in two phas­es, start­ing with $20 mil­lion and all its tech­nol­o­gy li­cense rights for Chi­na.

Bain’s biotech team has cre­at­ed a $1B-plus fund — with an eye to more Big Phar­ma spin­outs

One of the biggest investors to burst onto the biotech scene in recent years has re-upped with more than a billion dollars flowing into its second fund. And this next wave of bets will likely include more of the Big Pharma spinouts that highlighted their first 3 years in action.

Adam Koppel and Jeff Schwartz got the new life sciences fund at Bain Capital into gear in the spring of 2016, as they were putting together a $720 million fund with $600 million flowing in from external investors and the rest drawn from the Bain side of the equation. This time the external investors chipped in $900 million, with Bain coming in for roughly $180 million more.

They’re not done with Fund I, with plans to add a couple more deals to the 15 they’ve already posted. And once again, they’re estimating another 15 to 20 investments over a 3- to 5-year time horizon for Fund II.

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Search­ing for the next block­buster to fol­low Darza­lex, J&J finds a $150M an­ti-CD38 drug from part­ner Gen­mab

Now that J&J and Genmab have thrust Darzalex onto the regulatory orbit for first-line use in multiple myeloma, the partners are lining up a deal for a next-gen follow-on to the leading CD38 drug.


Janssen — J&J’s biotech unit — has its eyes on HexaBody-CD38, a preclinical compound generated on Genmab’s tech platform designed to make drugs more potent via hexamerization.


Genmab is footing the bill on studies in multiple myeloma and diffuse large B-cell lymphoma; once it completes clinical proof of concept, Janssen has the option to license the drug for a $150 million exercise fee. There’s also $125 million worth of milestones in play.

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Russ­ian sci­en­tist plans to one-up Jiankui He in cre­at­ing his own CRISPR ba­bies — Na­ture

If De­nis Re­brikov has his way, the world could be ex­pect­ing more CRISPR ba­bies soon.

The Russ­ian sci­en­tist has told Na­ture he is con­sid­er­ing fol­low­ing Jiankui He’s ex­am­ple in knock­ing out the CCR5 gene in em­bryos and im­plant­i­ng them in­to women — ex­cept do­ing it in a bet­ter way. It marks the first de­c­la­ra­tion of in­ter­est in con­tin­u­ing the work when re­searchers around the world are call­ing for sus­pen­sion of hu­man germline edit­ing and stricter stan­dards, fol­low­ing a glob­al back­lash against He’s claims that he fa­cil­i­tat­ed the birth of twin girls who had been CRISPR-ed as em­bryos.