Jennifer Doudna, AP Images

Hit­ting land­mark mile­stone, In­tel­lia shows CRISPR can ed­it genes di­rect­ly in pa­tients

In a land­mark study, re­searchers suc­cess­ful­ly used CRISPR to di­rect­ly ed­it DNA in hu­mans, a mile­stone that could pave the way for treat­ments for scores of se­ri­ous ge­net­ic and non-ge­net­ic dis­eases.

In­tel­lia, a biotech co-found­ed by 2020 No­bel lau­re­ate Jen­nifer Doud­na, used CRISPR/Cas9 to cut a gene out of the liv­er cells of pa­tients with AT­TR amy­loi­do­sis, a dead­ly dis­ease where a mis­shapen pro­tein called TTR builds up and dam­ages or­gans through­out the body. Pa­tients who re­ceived a high dose of the ther­a­py saw their pro­tein lev­els fall be­tween 80% and 96%, in­di­cat­ing the ther­a­py per­ma­nent­ly cut the genome where de­sired.

The Phase I re­sults were pub­lished Sat­ur­day in the New Eng­land Jour­nal of Med­i­cine and pre­sent­ed at a sci­en­tif­ic con­fer­ence.

“This is the re­sult that the field has been wait­ing for to re­al­ly scale up,” Fy­o­dor Urnov, a gene edit­ing ex­pert at UC Berke­ley who was not af­fil­i­at­ed with the work, told End­points News. “If any­one had a shred of doubt, that there was a fu­ture in CRISPR edit­ing as a ther­a­peu­tic that will have a broad im­pact, those doubts can be put to rest.”

This is not the first time CRISPR has been used as a ther­a­py. Ver­tex and CRISPR Ther­a­peu­tics have used it to ef­fec­tive­ly treat sick­le cell dis­ease and be­ta-tha­lassemia. Aca­d­e­mics and oth­er com­pa­nies have, with some­what less suc­cess, used it in treat­ments for can­cer and HIV. But in each case, re­searchers re­moved blood stem cells from the pa­tients, edit­ed them in a lab and then re­turned them to the pa­tient — a sim­pler, safer and more con­trol­lable pro­ce­dure.

Most con­di­tions, though, can’t be ad­dressed by edit­ing cells out­side the body. Dev­as­tat­ing ge­net­ic dis­eases such as cys­tic fi­bro­sis and Duchenne mus­cu­lar dy­s­tro­phy could be treat­ed through CRISPR gene edit­ing, but on­ly if re­searchers can de­liv­er the ther­a­py di­rect­ly in­to pa­tients. The same holds true for some of the more com­mon ail­ments where com­pa­nies are now try­ing to ap­ply the tech­nol­o­gy, such as heart dis­ease.

On Sat­ur­day, In­tel­lia be­came the first to pull it off. Doud­na hailed it as a proof-of-con­cept for the en­tire field.

“While these are ear­ly da­ta, they show us that we can over­come one of the biggest chal­lenges with ap­ply­ing CRISPR clin­i­cal­ly so far, which is be­ing able to de­liv­er it sys­tem­i­cal­ly and get it to the right place,” Doud­na said in an email. “It’s a crit­i­cal first step in be­ing able to in­ac­ti­vate, re­pair or re­place any gene that caus­es dis­ease, any­where in the body. This opens up the pos­si­bil­i­ty to treat a wide range of dis­eases that we haven’t been able to ad­dress so far.”

In­tel­lia’s stock $NT­LA jumped 52% when pre-mar­ket trad­ing be­gan Mon­day, rais­ing their mar­ket cap by $3 bil­lion. The oth­er so-called “CRISPR com­pa­nies,” in­clud­ing Beam, CRISPR Ther­a­peu­tics, and Ed­i­tas, all rose be­tween 15% and 25%.

In­tel­lia be­gan work­ing on the AT­TR pro­gram not long af­ter it was found­ed in 2014, said CEO John Leonard. They tin­kered for years, af­ter the first ver­sions edit­ed less than 2% of tar­get­ed cells in mice. Even­tu­al­ly, they de­vised two RNA strands, one that codes for the DNA-cut­ting en­zyme Cas9 and an­oth­er, the guide RNA, that tells Cas9 which gene to cut.

Lau­ra Sepp-Loren­zi­no

They en­cased the RNA in a lipid nanopar­ti­cle, the mi­cro­scop­ic bub­bles of fat that have now been used around the world to de­liv­er mR­NA Covid-19 vac­cines. Af­ter the LNPs are ad­min­is­tered to pa­tients, they go to the liv­er, ex­press Cas9, which slices the DNA, and flush out with­in hours, said CSO Lau­ra Sepp Loren­zi­no.

“Part of our de­sign cri­te­ria was rapid elim­i­na­tion,” Loren­zi­no told End­points.

The first three AT­TR pa­tients, who re­ceived a low dose of the ther­a­py, saw their pro­duc­tion of TTR pro­tein fall by an av­er­age of 57%. When they es­ca­lat­ed for the next three pa­tients, they saw an av­er­age re­duc­tion of 87%.

The lat­ter fig­ure close­ly ri­vals the da­ta from Al­ny­lam’s RNAi drug On­pat­tro, one of three drugs re­cent­ly ap­proved for the dis­ease. But In­tel­lia’s ap­proach on­ly has to be dosed once in a life­time, as op­posed to once every three weeks.

“The lev­el of TTR pro­tein re­duc­tion is im­pres­sive,” Har­vard bio­chemist David Liu, who co-found­ed CRISPR com­pa­nies Beam and Prime, said in an email. The da­ta “serve as a com­pelling re­minder that the era of in vi­vo ther­a­peu­tic hu­man gene edit­ing is al­ready up­on us.”

David Liu

Liu not­ed In­tel­lia got re­sults de­spite us­ing less than 1/10th the dose they used in mon­keys. The com­pa­ny plans to up the dosage fur­ther to try to com­plete­ly elim­i­nate pro­tein pro­duc­tion — a bench­mark they hope will not on­ly stop the dis­ease’s pro­gres­sion but po­ten­tial­ly re­verse it, giv­ing the body time to clean up that mis­shapen pro­tein that ac­cu­mu­lat­ed in the years pri­or to ther­a­py.

Out­side ex­perts took par­tic­u­lar note of the safe­ty da­ta. It was not clear what would hap­pen when re­searchers first ad­min­is­tered Cas9, a pro­tein de­rived from bac­te­ria, through­out the body. Some feared that the im­mune sys­tem would rec­og­nize it as for­eign and go in­to dan­ger­ous over­drive.

“The safe­ty da­ta look re­al­ly good,” Alex­is Ko­mor, who runs a gene edit­ing lab at UC San Diego, told End­points. “There’s no crazy im­mune re­sponse. That was a ques­tion that every­body’s had for a while.”

Alex­is Ko­mor

Still, there are key safe­ty ques­tions that can on­ly be an­swered with time. Over the last decade, CRISPR re­searchers have doc­u­ment­ed in nu­mer­ous lab stud­ies that, by break­ing the DNA in two, Cas9 can in­flict un­in­tend­ed dam­age on the genome.

So far those have not born out in pa­tients and ex­perts say there are no red flags in In­tel­lia’s da­ta. But it will be hard­er for In­tel­lia to mon­i­tor than for pre­vi­ous com­pa­nies who edit­ed blood cells; they were able to check in the lab how the cells re­spond­ed ini­tial­ly and take sub­se­quent sam­ples from pa­tients to mon­i­tor.

By con­trast, doc­tors can’t just re­move a pa­tient’s liv­er to mon­i­tor for ear­ly signs of can­cer. “There’s just a fun­da­men­tal ques­tion of how we do long-term fol­lowup,” Urnov said.

The com­pa­ny will now look to ap­ply the same strat­e­gy they used for AT­TR to an­oth­er ge­net­ic dis­ease, hered­i­tary an­gioede­ma, swap­ping out the guide RNA for TTR and re­plac­ing it with one for a gene called KLB1.

Fy­o­dor Urnov

Urnov said the tech­nol­o­gy will work like mR­NA vac­cines: Once proven, the plat­form can be re­de­ployed for an­oth­er dis­ease by swap­ping out one set of ge­net­ic in­struc­tions for an­oth­er. It pro­vides a proof of prin­ci­ple for Verve Ther­a­peu­tics, which is try­ing to pre­vent heart dis­ease by knock­ing out a gene in the liv­er that strong­ly af­fects cho­les­terol lev­els.

For these com­pa­nies, he said, “the ball is in your court,” he said, “to do it and just not drop the ball.”

But that on­ly ap­plies to a sub­set of ther­a­pies and dis­eases. In­tel­lia ef­fec­tive­ly went af­ter the low­est hang­ing fruit for sys­temic CRISPR treat­ments. They di­rect­ed the treat­ment against the liv­er, the body’s in­ter­nal fil­ter and the eas­i­est or­gan to di­rect ge­net­ic ther­a­pies. And they on­ly tried to crip­ple a gene, rather than re­pair one.

To tack­le most of the dis­eases sci­en­tists en­vi­sioned cur­ing when CRISPR was first pi­o­neered a decade ago, re­searchers will have to prove they can de­liv­er through­out the body and, once there, turn a mu­tant gene in­to a healthy one — a pair of sig­nif­i­cant­ly high­er hur­dles.

Rodolphe Bar­ran­gou

Ear­ly tests for those hur­dles will ar­rive in the com­ing years, as ther­a­pies for Duchenne and HIV, among oth­ers, en­ter the clin­ic.

“It’s an ex­cit­ing day, it’s an ex­cit­ing mile­stone,” Rodolphe Bar­ran­gou, an ear­ly CRISPR re­searcher and a co-founder of In­tel­lia, told End­points. “But we have a ways to go.”

Biotech Half­time Re­port: Af­ter a bumpy year, is biotech ready to re­bound?

The biotech sector has come down firmly from the highs of February as negative sentiment takes hold. The sector had a major boost of optimism from the success of the COVID-19 vaccines, making investors keenly aware of the potential of biopharma R&D engines. But from early this year, clinical trial, regulatory and access setbacks have reminded investors of the sector’s inherent risks.

RBC Capital Markets recently surveyed investors to take the temperature of the market, a mix of specialists/generalists and long-only/ long-short investment strategies. Heading into the second half of the year, investors mostly see the sector as undervalued (49%), a large change from the first half of the year when only 20% rated it as undervalued. Around 41% of investors now believe that biotech will underperform the S&P500 in the second half of 2021. Despite that view, 54% plan to maintain their position in the market and 41% still plan to increase their holdings.

No­vo CEO Lars Fruer­gaard Jør­gensen on R&D risk, the deal strat­e­gy and tar­gets for gen­der di­ver­si­ty

 

I kicked off our European R&D summit last week with a conversation involving Novo Nordisk CEO Lars Fruergaard Jørgensen. Novo is aiming to launch a new era of obesity management with a new approval for semaglutide. And Jørgensen had a lot to say about what comes next in R&D, how they manage risk and gender diversity targets at the trendsetting European pharma giant.

John Carroll: I’m here with Lars Jørgensen, the CEO of Novo Nordisk. Lars, it’s been a really interesting year so far with Novo Nordisk, right? You’ve projected a new era of growing sales. You’ve been able to expand on the GLP-1 franchise that was already well established in diabetes now going into obesity. And I think a tremendous number of people are really interested in how that’s working out. You have forecast a growing amount of sales. We don’t know specifically how that might play out. I know a lot of the analysts have different ideas, how those numbers might play out, but that we are in fact embarking on a new era for Novo Nordisk in terms of what the company’s capable of doing and what it’s able to do and what it wants to do. And I wanted to start off by asking you about obesity in particular. Semaglutide has been approved in the United States for obesity. It’s an area of R&D that’s been very troubled for decades. There have been weight loss drugs that have come along. They’ve attracted a lot of attention, but they haven’t actually ever gained traction in the market. My first question is what’s different this time about obesity? What is different about this drug and why do you expect it to work now whereas previous drugs haven’t?

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Sur­geons suc­cess­ful­ly at­tach pig kid­ney to a hu­man for the first time, us­ing tech from Unit­ed's Re­vivi­cor

In a first, researchers reportedly successfully transplanted a pig kidney into a human without triggering an immediate immune response this week. And the technology came from the biotech United Therapeutics.

Surgeons spent three days attaching the kidney to the patient’s blood vessels, but when all was said and done, the kidney appeared to be functioning normally in early testing, Reuters and the New York Times were among those to report. The kidney came from a genetically altered pig developed through United’s Revivicor unit.

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David Livingston (Credit: Michael Sazel for CeMM)

Renowned Dana-Far­ber sci­en­tist, men­tor and bio­phar­ma ad­vi­sor David Liv­ingston has died

David Livingston, the Dana-Farber/Harvard Med scientist who helped shine a light on some of the key molecular drivers of breast and ovarian cancer, died unexpectedly last Sunday.

One of the senior leaders at Dana-Farber during his nearly half century of work there, Livingston was credited with shedding light on the genes that regulate cell growth, with insights into inherited BRCA1 and BRCA2 mutations that helped lay the scientific foundation for targeted therapies and earlier detection that have transformed the field.

Carl June (Brian Ach/Getty Images for TIME 100 Health Summit)

Carl June lends 'wings' to Chi­nese CAR-T start­up led by for­mer post­doc, pur­su­ing off-the-shelf ap­proach with CRISPR fla­vor

Carl June still has plenty of energy to bring forth new iterations of CAR-T technology — wherever they’re coming from.

Adding another role to his already lengthy list of titles, June is joining the scientific advisory board at Nanjing Bioheng Biotech, where he will serve as chairman.

The appointment, if slightly out of the ordinary, is both a testament to the fruitfulness of June’s lab at the University of Pennsylvania and China’s increasing appeal to biotech entrepreneurs educated overseas.

Man­u­fac­tur­ing woes for No­vavax’s Covid jab bad­ly dis­rupt plans for roll­out to the poor — re­port

Production problems at a Novavax facility in Maryland have led to delays in the Covax vaccine sharing program. Now, a shortage of 1 billion doses is expected, as the supplier tries to navigate producing a shot up to regulators’ standards, Politico reported Tuesday.

The company has run into trouble with the purity of the vaccine. Novavax has had trouble proving it can produce a shot consistently up to standards, and it has caused significant delays in the rollout to low- and middle-income countries. This follows several delays at Novavax that has put the executive crew on the defensive.

Break­ing: Bio­gen sells just $300K worth of Aduhelm in Q3, as ques­tions on long term vi­a­bil­i­ty re­main

Barely anyone is accessing Biogen’s controversial Alzheimer’s treatment, with the company reporting just $0.3 million in Aduhelm sales in the third quarter. Although investors will be looking to the longer term, when CMS may decide to cover the drug and open the floodgates for more coverage, use of the drug is currently stalled.

Since June, when the FDA first signed off on the drug under its accelerated pathway, Biogen said Wednesday that it’s sold a total of $2 million worth of Aduhelm. Biogen said on its earnings call that about 120 sites so far have infused at least one patient with Aduhelm, which is priced at $56,000 annually. Morgan Stanley previously predicted about 14,000 patients will access Aduhelm by the end of 2022.

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Bill Gates at the Global Investment Summit in London, Oct. 19, 2021 (Leon Neal/Pool via AP Images)

Gates Foun­da­tion pledges $120M to ramp up gener­ic sup­ply of Mer­ck­'s Covid-19 pill while ac­tivists blast Pfiz­er's dis­pro­por­tion­ate pow­er

Merck’s molnupiravir may not be officially authorized anywhere in the world yet, but who will get access to it has shaped up to be a huge issue. The Bill & Melinda Gates Foundation is now stepping up to ensure lower-income countries won’t be left behind — and calling on others to follow its lead.

The oral antiviral pill, which was shown to dramatically cut the risk of severe Covid-19 disease and death in a Phase III study, is the latest rallying symbol in the battle against not just the coronavirus but the inequality it’s exposed.

With hun­dreds of mil­lions spent on failed ac­cel­er­at­ed ap­provals, re­searchers call for faster FDA with­drawals

Between 2017 and 2019, Medicare spent more than $220 million on cancer drugs for which the indications were either voluntarily pulled by their applicants or FDA’s oncology adcomm had recommended their withdrawal.

That kind of massive spending on cancer drugs lacking overall survival benefit is wasteful and risks harming people’s health, a research letter published in JAMA Internal Medicine on Monday said. The researchers from Harvard and the London School of Economics called on the FDA to move faster in both requiring timely postmarketing trials and accelerating the speed in pulling these dangling approvals when the confirmatory studies fail.

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