Derek Jantz, Precision Biosciences

Jim Wilson's team hands Pre­ci­sion Bio a big proxy win for its PC­SK9 gene edit­ing tech with 3-year mon­key da­ta

James Wil­son

James Wil­son and his gene edit­ing team at UPenn have pub­lished a new pa­per in­to a one-time PC­SK9 ther­a­py, one that Pre­ci­sion Bio­sciences hopes can turn up the heat on its com­peti­tors at Verve.

Us­ing Pre­ci­sion’s pro­pri­etary AR­CUS gene edit­ing plat­form, Wil­son was able to demon­strate that PC­SK9 pro­tein and LDL cho­les­terol re­duc­tions could be sus­tained in mon­keys for at least three years af­ter treat­ment, Pre­ci­sion an­nounced Fri­day. Re­searchers ad­min­is­tered the ther­a­py to 10 mon­keys back in 2017 and re­port­ed re­duc­tions of up to 85% in PC­SK9 pro­tein lev­els and a 56% re­duc­tion of LDL cho­les­terol lev­els.

Those lev­els are slight­ly low­er than the fig­ures post­ed by Verve last month at JP Mor­gan, when the Sek Kathire­san-led biotech said it ob­served a 61% LDL cho­les­terol re­duc­tion and 89% cut in av­er­age blood PC­SK9 pro­tein lev­el. But Verve’s da­ta was record­ed af­ter on­ly six months — or one-sixth the time of Pre­ci­sion’s.

That dif­fer­ence in time is sig­nif­i­cant be­cause Pre­ci­sion’s mon­keys have had the chance to go through sev­er­al gen­er­a­tions of liv­er cell turnover, and the cho­les­terol and PC­SK9 pro­tein re­duc­tions have re­mained sta­ble, CSO Derek Jantz told End­points News. Liv­er cells, or he­pa­to­cytes, typ­i­cal­ly on­ly live for about 200 days be­fore they die off and are re­plen­ished.

“What we’ve been able to show is that those sub­se­quent gen­er­a­tions of cells are in­her­it­ing the gene ed­it,” Jantz said. “We are be­yond the life­time of a typ­i­cal non-hu­man pri­mate he­pa­to­cyte.”

Fri­day’s study is a fol­low-up from a pa­per pub­lished in 2018, which Jantz said demon­strat­ed short-term ben­e­fits of their gene edit­ing treat­ment. At that time, Pre­ci­sion saw PC­SK9 re­duc­tions of more than 90% at the high­est dose, af­ter which they fell slight­ly over the first nine months when the first liv­er cells were be­ing re­placed.

Since then, the lev­els have plateaued, giv­ing Pre­ci­sion what it says is ear­ly ev­i­dence that the treat­ment can be per­ma­nent. Even more promis­ing is that re­searchers didn’t see any ma­jor safe­ty is­sues man­i­fest in the three years since the mon­keys were dosed, Jantz said.

Pre­ci­sion used its AR­CUS genome edit­ing plat­form, com­ing from a group of North Car­oli­na sci­en­tists, which they claim has a bet­ter way to ac­com­plish DNA hack­ing than the gene edit­ing pro­mot­ed by biotechs work­ing on CRISPR/Cas9 tech­nolo­gies. AR­CUS deals with what’s known as the ARC nu­cle­ase, and the com­pa­ny says it pro­vides a sim­pler, more ef­fec­tive way of com­plet­ing the gene edit­ing process to al­low for low­er costs when pro­duc­tion even­tu­al­ly has to scale up, as well as low­er rates of off-tar­get edit­ing.

AR­CUS can be used to ei­ther in­sert, re­move or re­pair DNA in in vi­vo set­tings. In this in­stance, the PC­SK9 gene was “knocked out,” re­sult­ing in low­er lev­els of the pro­tein, Jantz said.

That’s a dif­fer­ent ap­proach than the one used by Verve, which is aim­ing to uti­lize the next-gen­er­a­tion gene edit­ing tool called base edit­ing. Where­as the first gen­er­a­tion of CRISPR gene edit­ing mol­e­cules would snip the DNA se­quence and let it re­pair on its own, base edit­ing works by con­vert­ing one let­ter on the genome to an­oth­er.

In Verve’s case, re­searchers made a sin­gle change from A to G in the ge­net­ic se­quence of the PC­SK9 gene in the liv­er.

Both com­pa­nies are look­ing at fa­mil­ial hy­per­c­ho­les­terolemia as a po­ten­tial in­di­ca­tion, with Verve aim­ing to dose its first pa­tient in the het­erozy­gous form of the dis­ease some­time in 2022. Pre­ci­sion, how­ev­er, isn’t giv­ing any timeta­bles as to when it could launch an in-hu­man tri­al, with Jantz say­ing any such study is still “a ways away.” Both are aim­ing to re­place chron­ic treat­ments for dis­ease with one-time in­jec­tions.

Though ex­cit­ed by Fri­day’s re­sults, Pre­ci­sion is not tar­get­ing PC­SK9 as its lead pro­gram. That would be an off-the-shelf CAR-T ther­a­py for acute lym­phoblas­tic leukemia and non-Hodgkin lym­phoma, aim­ing to tar­get CD19. The pro­gram read out in­ter­im re­sults from a Phase I/IIa tri­al last De­cem­ber.

The Fac­tors Dri­ving a Rapid Evo­lu­tion of Gene & Cell Ther­a­py and CAR-T Clin­i­cal Re­search in APAC

APAC is the fastest growing region globally for cell & gene therapy trials representing more than a third of all cell & gene studies globally, with China leading in the region. 

APAC is the leading location globally for CAR-T trials with China attracting ~60% of all CAR-T trials globally between 2015-2022. The number of CAR-T trials initiated by Western companies has rapidly increased in recent years (current CAGR of about 60%), with multiple targets being explored including CD19, CD20, CD22, BCMA, CD30, CD123, CD33, CD38, and CD138.

The End­points 11; blue­bird's $3M gene ther­a­py; Bio­gen tout new neu­ro da­ta; Harsh re­views for can­cer drugs; 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.

Reading about John Carroll’s pick of biotech’s most promising startups has become a treasured tradition. If you ever get curious about previous classes of the Endpoints 11, you can find all of them (plus a number of our other regular specials) here.

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EMA warns of short­ages of two Boehringer heart drugs due to a spike in de­mand

The EMA is putting EU member states on alert over the shortage of two drugs that counter heart attacks due to an uptick in demand.

On Friday, the EMA sent out a warning that two Boehringer Ingelheim drugs are experiencing a shortage: Actilyse and Metalyse. The drugs are used as emergency treatments for adults experiencing acute myocardial infarction, or a heart attack, by dissolving blood clots that have formed in the blood vessels.

The End­points 11: The top pri­vate biotechs in pur­suit of new drugs. Push­ing the en­ve­lope with pow­er­ful new tech­nolo­gies

Right around the beginning of the year, we got a close-up look at what happens after a boom ripples through biotech. The crash of life sciences stocks in Q1 was heard around the world.

In the months since, we’ve seen the natural Darwinian down cycle take effect. Reverse mergers made a comeback, with more burned out shells to go public at a time IPOs and road shows are out of favor. And no doubt some of the more recent arrivals on the investing side of the business are finding greener pastures.

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Solicitor General Elizabeth Prelogar

Should SCO­TUS hear Am­gen's Repatha case? So­lic­i­tor gen­er­al says no

Back in April, Amgen said it was encouraged by the solicitor general’s anticipated review of its Supreme Court petition to rehear a Repatha patent case. They’re likely much less optimistic about the outcome now.

Solicitor General Elizabeth Prelogar wrote in a recent 27-page brief that Amgen’s arguments “lack merit and further review is not warranted.”

The case traces back to a suit filed in 2014 against Sanofi and Regeneron’s Praluent, which ended up beating Amgen’s PCSK9 blockbuster Repatha to market by a month just a year later.

As­traZeneca, Mer­ck cull one Lyn­parza in­di­ca­tion in heav­i­ly pre­treat­ed ovar­i­an can­cer pa­tients

Just one day after blockbuster Lynparza got access to another indication in China, its Big Pharma owners have decided to withdraw it in certain patients after reviewing Phase III data.

The two companies that work together on Lynparza decided to recall one of the indications several weeks ago in a specific type of ovarian cancer, Lynparza’s first indication when it was first FDA-approved in 2014. Initial data showed that rates of overall survival in patients with at least three rounds of chemo before getting on the PARP inhibitor were lower than in patients with less previous chemo treatment.

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Fu­ji­film con­tin­ues CD­MO ex­pan­sion, break­ing ground on $435M UK site

Fujifilm’s CDMO arm, Fujifilm Diosynth, has been on a roll this month as the company has recently broken ground on a major project in Europe and it appears to be keeping up the momentum.

Fujifilm Diosynth announced that it has kicked off an expansion project for its microbial manufacturing facility at its campus in the town of Billingham, UK, in the northeast of England.

The 20,000 square-foot, £400 million ($435 million) expansion will add clean rooms, purification suites and a packing area along with more space for the manufacturing itself.

An­oth­er Cipla site lands a Form 483 over clean­ing is­sues and QC con­trols

A Cipla drug manufacturing site in India has once again landed in the crosshairs of FDA inspectors.

The facility in question is Cipla’s drug manufacturing facility in the village of Verna, in the state of Goa in India’s southwest. In a sign that foreign inspections might ramp up again, the FDA’s visit from Aug. 16 to Aug. 22 uncovered six observations.

The 11-page report noted that environmental monitoring at the site did not properly ensure that microbial contaminants were not making any impact in the aseptic filling areas. It also found that procedures meant to stop microbial contamination were not adequately conducted in aseptic areas of the facility.

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FDA ad­comm takes down Se­cu­ra Bio's leukemia drug af­ter fi­nal tri­al re­sults show po­ten­tial OS detri­ment

The FDA’s Oncologic Drugs Advisory Committee on Friday voted 8-4 against the benefit-risk profile of Secura Bio’s PI3K inhibitor Copiktra (duvelisib), which won approval in September 2018 as a third-line treatment for relapsed or refractory CLL or SLL, but updated pivotal trial results raised safety questions.

In addition to the serious and fatal toxicities of duvelisib, FDA speakers at the ODAC meeting pointed to an evolved treatment landscape for CLL and SLL, with targeted BTK or BCL2 inhibitors (front-line or second-line), and data pointing to a “potential detriment” in overall survival for duvelisib. But some ODAC members noted that the detriment was likely small and that there is some efficacy even as the data are difficult to interpret.

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