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.

Con­quer­ing a silent killer: HDV and Eiger Bio­Phar­ma­ceu­ti­cals

Hepatitis delta, also known as hepatitis D, is a liver infection caused by the hepatitis delta virus (HDV) that results in the most severe form of human viral hepatitis for which there is no approved therapy.

HDV is a single-stranded, circular RNA virus that requires the envelope protein (HBsAg) of the hepatitis B virus (HBV) for its own assembly. As a result, hepatitis delta virus (HDV) infection occurs only as a co-infection in individuals infected with HBV. However, HDV/HBV co-infections lead to more serious liver disease than HBV infection alone. HDV is associated with faster progression to liver fibrosis (progressing to cirrhosis in about 80% of individuals in 5-10 years), increased risk of liver cancer, and early decompensated cirrhosis and liver failure.
HDV is the most severe form of viral hepatitis with no approved treatment.
Approved nucleos(t)ide treatments for HBV only suppress HBV DNA, do not appreciably impact HBsAg and have no impact on HDV. Investigational agents in development for HBV target multiple new mechanisms. Aspirations are high, but a functional cure for HBV has not been achieved nor is one anticipated in the forseeable future. Without clearance of HBsAg, anti-HBV investigational treatments are not expected to impact the deadly course of HDV infection anytime soon.

No­var­tis is ax­ing 150 ear­ly dis­cov­ery jobs as CNI­BR shifts fo­cus to the de­vel­op­ment side of R&D

Novartis is axing some 150 early discover jobs in Shanghai as it swells its staff on the drug development side of the equation in China. And the company is concurrently beefing up its investment in China’s fast-growing biotech sector with a plan to add to its investments in local VCs.

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No­var­tis is eye­ing a multi­bil­lion-dol­lar Med­Co buy­out as Jer­sey biotech nears NDA — re­ports

To get from Novartis’ US headquarters to the Medicines Company, you make a left out of a square concrete building on NJ-Route 10, follow it past the sun orange veranda of Jersey’s Hot Bagels and the inexplicable green Vermont cabin that houses the Whippany Railway Museum until you turn right and immediately arrive at a rectangular glass building. It should take you about 12 minutes.

Reports are out that Novartis may be making that trip. Amid a torrent of Phase III data burnishing MedCo’s chances at a blockbuster cholesterol drug,  Bloomberg News is reporting that Novartis is looking to acquire the Jersey-based biotech.

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UP­DAT­ED: In a land­mark first glimpse of hu­man da­ta from Ver­tex, CRISPR/Cas9 gene ther­a­py sig­nals ear­ly ben­e­fit

Preliminary data on two patients with blood disorders that have been administered with Vertex and partner CRISPR Therapeutics’ gene-editing therapy suggest the technology is safe and effective, marking the first instance of the benefit of the use of CRISPR/Cas9 technology in humans suffering from disease.

Patients in these phase I/II studies give up peripheral blood from which hematopoietic stem and progenitor cells are isolated. The cells are tinkered with using CRISPR/Cas9 technology, and the edited cells — CTX001 — are infused back into the patient via a stem cell transplant. The objective of CTX001 is to fix the errant hemoglobin gene in patents with two blood disorders: beta-thalassemia and sickle cell disease, by unleashing the production of fetal hemoglobin.

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Badrul Chowdhury. FDA via Flickr

As­traZeneca los­es an­oth­er ex­ec­u­tive to biotech, as Badrul Chowd­hury moves to Savara

Another executive is migrating from the echelons of Big Pharma to the corridors of small biotech.

In April 2018, Badrul Chowdhury took his more than two decades of experience at the FDA to AstraZeneca, where he took on the role of senior vice president and chief physician-scientist for respiratory, inflammation and autoimmunity late-stage development in biopharmaceuticals R&D.

After about a year and a half in this role, Chowdhury is moving to a small Texas biotech called Savara, where he will serve as chief medical officer.

Yiannis Kiachopoulos and Artur Saudabayev, co-founders of Causaly

Lon­don AI up­start, which counts No­var­tis as a cus­tomer, can teach your com­put­er to read

When Amazon developed a machine-learning tool to make its recruitment process more efficient — the man-made system absorbed the gender-bias of its human makers, and the project was aborted. In the field of biopharmaceuticals, the way researchers train their machine learning algorithms can skew the outcome of predictions. But before those predictions can be made, the engine must learn to read to make sense of explosive volume of knowledge out there.

Burt Adelman. Novo Ventures

Here's a $25M seed fund aimed at back­ing some brash new drug ideas out of the Broad

As a former academic and a seasoned drug developer, Burt Adelman knew when he was recruited as a senior advisor to Novo Ventures in 2017 that one of his key priorities needs to be introducing the fund to the network he was so deeply embedded in.

“I was thinking long and hard on how can I, as a Boston insider, help Novo really get inside the ecosystem of Boston biotech?” he recalled in an interview with Endpoints News.

Welling­ton lines up a $393M bankroll for its next round of pri­vate biotech bets — and they’re like­ly think­ing big

Wellington Management made some uncustomary waves at the beginning of the year when it threw its considerable weight against Bristol-Myers Squibb’s $74 billion Celgene buyout. But after Bristol-Myers’ biggest investor conceded that game to the influential proxy firms involved, they’re now going to end the year by rolling out a big new investment fund for a new stable of fledgling biotechs on the private side of the industry.

As uter­ine race with Ab­b­Vie heats up, My­ovant eyes FDA ap­proval with tri­al re­sults from prostate can­cer

Myovant has long had a secret weapon in its uterine rivalry with AbbVie: Men.

While the small Swiss biotech has jockeyed with the Illinois-based giant for a foothold in the endometriosis and uterine fibroid therapy market, the company has been developing the same lead compound, relugolix, for use in one of the most common cancers for the uterus-less: prostate cancer. Today, Myovant is out with positive topline results from its big Phase III trial on the gonadotropin-releasing hormone (GnRH) antagonist. They say they’ve reached every primary and secondary endpoint with p values less than .0001.