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.”

No­var­tis reshuf­fles its wild cards; Tough sell for Bio­gen? Googling pro­teins; Ken Fra­zier's new gig; 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.

If you enjoy the People section in this report, you may also want to check out Peer Review, my colleagues Alex Hoffman and Kathy Wong’s comprehensive compilation of comings and goings in biopharma.

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Demis Hassabis, DeepMind CEO (Qianlong/Imaginechina via AP Images)

Google's Deep­Mind opens its pro­tein data­base to sci­ence — po­ten­tial­ly crack­ing drug R&D wide open

Nearly a year ago, Google’s AI outfit DeepMind announced they had cracked one of the oldest problems in biology: predicting a protein’s structure from its sequence alone. Now they’ve turned that software on nearly every human protein and hundreds of thousands of additional proteins from organisms important to medical research, such as fruit flies, mice and malaria parasite.

The new database of roughly 350,000 protein sequences and structures represents a potentially monumental achievement for the life sciences, one that could hasten new biological insights and the development of new drugs. DeepMind said it will be free and accessible to all researchers and companies.

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Vas Narasimhan, Novartis CEO (Jason Alden/Bloomberg via Getty Images)

No­var­tis dis­cards one of its ‘wild card’ drugs af­ter it flops in key study. But it takes one more for the hand

Always remember just how risky it is to gamble big on small studies.

A little more than 4 years ago, Novartis reportedly put up a package worth up to $1 billion for the dry eye drug ECF843 after a small biotech called Lubris put it through its paces in a tiny study of 40 moderate to severe patients, tracking some statistically significant markers of efficacy.

By last fall, the program had risen up to become one of CEO Vas Narasimhan’s top “wild card” programs in line for a potential breakthrough year in 2021. These drugs were all considered high-risk, high-reward efforts. And in this case, risk won.

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6 top drug­mak­ers of­fer per­spec­tives on FDA's new co­vari­ates in RCTs guid­ance

Back in May, the FDA revised and expanded a 2019 draft guidance that spells out how to adjust for covariates in the statistical analysis of randomized controlled trials.

Building on the ICH’s E9 guideline on the statistical principles for clinical trials, the 3-page draft was transformed into an 8-page draft, with more detailed recommendations on linear and nonlinear models to analyze the efficacy endpoints in RCTs.

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In­side Bio­gen's scram­ble to sell Aduhelm: Pro­ject 'Javelin' and pres­sure to ID as many pa­tients as pos­si­ble

In anticipation of Aduhelm’s approval for Alzheimer’s in June, Biogen employees were directed to identify and guarantee treatment centers would administer the drug through a program called “Javelin,” a senior Biogen employee told Endpoints News.

The program identified about 800 centers for use, he said, and Biogen now pays for the use of bioassays to identify beta amyloid in potential patients having undergone a lumbar puncture procedure, the employee said — and one center preparing to administer the drug confirmed its participation in the bioassay program.

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Laurent Fischer, Adverum CEO

Ad­verum faces murky fu­ture af­ter re­view turns up deep­er safe­ty is­sues for gene ther­a­py

Three months after revealing that a patient lost significant vision in one eye after receiving its experimental gene therapy, Adverum announced it found the safety issues were more widespread: Five of 12 patients who received a high dose of the therapy saw “similar clinically-relevant events.”

Three required surgery on their treated eye. And all 12 are being recommended “aggressive immunomodulatory treatments” to prevent further injury.

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EMA re­jects FDA-ap­proved Parkin­son's drug, signs off on Mod­er­na vac­cine use in ado­les­cents ahead of FDA

The European Medicines Agency on Friday rejected Kyowa Kirin’s Parkinson’s disease drug Nouryant (istradefylline), which the US FDA approved in 2019 under the brand name Nourianz.

EMA said it considered that the results of the clinical studies used to support the application “were inconsistent and did not satisfactorily show that Nouryant was effective at reducing the ‘off’ time. Only four out of the eight studies showed a reduction in ‘off’ time, and the effect did not increase with an increased dose of Nouryant.”

Mol­e­c­u­lar Di­ag­nos­tics Can Trans­form Can­cer Care. Let’s Make It Hap­pen.

Like so many people around the world, my life has been profoundly shaped by cancer. Those personal experiences, along with a deep love of clinical laboratory science and a passion to apply the power of genomics in medicine, motivated me to launch a company that would improve cancer care through better diagnostics. Thirteen years later, I am proud that we are delivering more accurate information at multiple points along the patient journey, with a focus on eight of the 10 cancers that are most commonly diagnosed in the United States.

FDA lev­els clin­i­cal hold on Ma­gen­ta's sec­ond lead drug, ask­ing for an ad­di­tion­al bioas­say be­fore it gets to hu­mans

Earlier this summer, Magenta Therapeutics was forced to say goodbye to its head of R&D at a pivotal time as the biotech read out data for its lead stem cell conditioning hopeful. Just weeks later, the company’s second drug is facing a clinical hold from the FDA as the agency demands more info on how the candidate works in humans.

Magenta will be required to submit an additional bioassay to help determine the best path forward on dose escalation for the biotech’s Phase I/II study of MGTA-117, an antibody-drug conjugate used to deplete hematopoietic stem cells prior to a transplant of HSC-based gene therapy, the biotech said Wednesday.

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