Ap­ply­ing CRISPR to Duchenne, Duke re­searchers spot­light 1-year mouse da­ta in Sarep­ta-spon­sored study

Char­lie Gers­bach (Duke Uni­ver­si­ty)

As Sarep­ta hus­tles its gene ther­a­py for Duchenne mus­cu­lar dy­s­tro­phy in­to a piv­otal study, one of its aca­d­e­m­ic col­lab­o­ra­tors has some longterm mouse da­ta to re­port on an at­tempt to treat the dis­ease through gene edit­ing.

One year af­ter a sin­gle dose of the CRISPR-based treat­ment, the adult mice in the study main­tained a high lev­el of dy­s­trophin ex­pres­sion, ac­cord­ing to re­searchers led by Pro­fes­sor Charles Gers­bach at Duke Uni­ver­si­ty.

In the study, which was spon­sored by Sarep­ta, the NIH and sev­er­al oth­er groups, sci­en­tists used CRISPR/Cas9 to snip out dy­s­trophin ex­ons around the DMD-caus­ing ge­net­ic mu­ta­tion so that the body would “stitch the re­main­ing gene back to­geth­er to cre­ate a short­ened — but func­tion­al — ver­sion of the dy­s­trophin gene.” While the in­jec­tion was found to trig­ger an im­mune re­sponse and in­duce un­in­tend­ed, al­ter­na­tive ed­its on the tar­get, they didn’t turn out to be cause for con­cern.

Christo­pher Nel­son

“The good news is that even though we ob­served both an­ti­body and T cell re­spons­es to Cas9, nei­ther ap­peared to re­sult in any tox­i­c­i­ty in these mice,” said Christo­pher Nel­son, a post-doc who led the work. “The re­sponse al­so did not pre­vent the ther­a­py’s abil­i­ty to suc­cess­ful­ly ed­it the dy­s­trophin gene and pro­duce long-term pro­tein ex­pres­sion.”

Nev­er­the­less, both Gers­bach and Nel­son said the im­mune re­sponse and al­ter­na­tive se­quence changes re­main po­ten­tial chal­lenges to be mon­i­tored and over­come.

One the­o­ry emerg­ing from these re­sults is that edit­ing the genes of in­fants be­fore their im­mune sys­tems are ful­ly de­vel­oped can cir­cum­vent any un­want­ed im­mune re­sponse, based on the ob­ser­va­tion that mice treat­ed when they were two days old (and lacked a ful­ly de­vel­oped im­mune sys­tem) didn’t seem to ex­pe­ri­ence an im­mune re­sponse to the Cas9 pro­tein.

Mov­ing from an­i­mal to hu­man stud­ies with this fu­tur­is­tic tech won’t be quick. Mean­while, Sarep­ta — which al­ready mar­kets a con­tro­ver­sial DMD treat­ment — is ar­guably in the lead of a tight race to de­vel­op a gene ther­a­py for the dis­ease which works by in­sert­ing a mi­cro-dy­s­trophin trans­gene via an AAV. Pfiz­er al­so has a clin­i­cal study un­der­way, while Sol­id Bio is trudg­ing along af­ter ini­tial biop­sies sug­gest­ed a flop in an ear­ly study.

BiTE® Plat­form and the Evo­lu­tion To­ward Off-The-Shelf Im­muno-On­col­o­gy Ap­proach­es

Despite rapid advances in the field of immuno-oncology that have transformed the cancer treatment landscape, many cancer patients are still left behind.1,2 Not every person has access to innovative therapies designed specifically to treat his or her disease. Many currently available immuno-oncology-based approaches and chemotherapies have brought long-term benefits to some patients — but many patients still need other therapeutic options.3

Gilead re­leas­es an­oth­er round of murky remde­sivir re­sults

A month after the NIH declared the first trial on remdesivir in Covid-19 a success, Gilead is out with new results on their antiviral. But although the study met one of its primary endpoints, the data are likely to only add to a growing debate over how effective the drug actually is.

In a Phase III trial, patients given a 5-day dose of remdesivir were 65% more likely to show “clinical improvement” compared to an arm given standard-of-care. The trial, though, gave little indication for whether the drug had an impact on key endpoints such as survival or time-to-recovery. And in a surprising twist, a 10-day dosing arm of remdesivir didn’t lead to a statistically significant improvement over standard of care.

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Fangliang Zhang (Imaginechina via AP Images)

The big mon­ey: Poised to make drug R&D his­to­ry, a Chi­na biotech un­veils uni­corn rac­ing am­bi­tions in a bid to raise $350M-plus on Nas­daq

Almost exactly three years after Shanghai-based Legend came out of nowhere to steal the show at ASCO with jaw-dropping data on their BCMA-targeted CAR-T for multiple myeloma, the little player with Big Pharma connections is taking a giant step toward making it big on Wall Street. And this time they want to seal the deal on a global rep after staking out a unicorn valuation in what’s turned out to be a bull market for biotech IPOs — in the middle of a pandemic.

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Federico Mingozzi (Spark)

Spark touts an­i­mal da­ta for a so­lu­tion to AAV gene ther­a­py's an­ti­body prob­lem

Among all the limitations of using an adeno-associated virus as a vector to deliver a gene — still the most established modality in gene therapy given years of trial and error and finally success — the presence of neutralizing antibodies, whether pre-existing or induced, looms large.

“When I think about the immune responses in AAV, I try to sort of layer them,” Federico Mingozzi, the CSO at Spark Therapeutics, told Endpoints News. “The antibody is the first layer. It’s the first block that you find when you’re trying to do gene transfer.”

Len Schleifer (left) and George Yancopoulos, Regeneron (Vimeo)

Eyes on he­mo­phil­ia prize, Re­gen­eron adds a $100M wa­ger on joint de­vel­op­ment cam­paign with In­tel­lia

When George Yancopoulos first signed up Intellia to be its CRISPR/Cas9 partner on gene editing projects 4 years ago, the upstart smartly ramped up its IPO at the same time. Today, Regeneron $REGN is coming back in, adding $100 million in an upfront fee and equity to significantly boot up a whole roster of new development projects.

And they’re highlighting some clinical hemophilia research plans in the process.

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Covid-19 roundup: Did in­sid­ers cash in on pos­i­tive news re­port about Gilead be­fore pub­li­ca­tion?

A series of bullish trades on Gilead options just before the release of a favorable news story is raising questions among regulatory experts, Reuters reported.

On April 16, just hours before STAT published anecdotes from a Chicago hospital that served as one of the clinical sites to test Gilead’s remdesivir in Covid-19 patients, the California-based company’s shares were trading at around $75. Four large blocks of options were purchased for about $1.5 million each, betting that the stock would rise beyond that to as much as $87.5 by mid-August.

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Jean-Jacques Bienaimé, BioMarin chairman and CEO

Bio­Marin holds the line on bleeds with 4-year val­rox up­date on he­mo­phil­ia A — but what's this about an­oth­er de­cline in Fac­tor 8 lev­els?

BioMarin has posted some top-line results for their 4-year followup on the most advanced gene therapy for hemophilia A — extending its streak on keeping a handful of patients free of bleeds and off Factor VIII therapy, but likely stirring fresh worries over a continued drop in Factor VIII levels.

We just don’t know how big a drop.

We’ll see more data when the results are presented at the World Federation of Hemophilia in a couple of weeks. But in a statement out Sunday night, BioMarin $BMRN reported that none of the patients required Factor VIII treatment, adding:

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As­traZeneca trum­pets the 'mo­men­tous' da­ta they found for Tagris­so in an ad­ju­vant set­ting for NSCLC — but many of the ex­perts aren’t cheer­ing along

AstraZeneca is rolling out the big guns this evening to provide a salute to their ADAURA data on Tagrisso at ASCO.

Cancer R&D chief José Baselga calls the disease-free survival data for their drug in an adjuvant setting of early stage, epidermal growth factor receptor-mutated NSCLC patients following surgery “momentous.” Roy Herbst, the principal investigator out of Yale, calls it “transformative.”

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Pablo Legorreta, founder and CEO of Royalty Pharma AG, speaks at the annual Milken Institute Global Conference in Beverly Hills, California (Patrick T. Fallon/Bloomberg via Getty Images)

Cap­i­tal­iz­ing Pablo: The world’s biggest drug roy­al­ty buy­er is go­ing pub­lic. And the low-key CEO di­vulges a few se­crets along the way

Pablo Legorreta is one of the most influential players in biopharma you likely never heard of.

Over the last 24 years, Legorreta’s Royalty Pharma group has become, by its own reckoning, the biggest buyer of drug royalties in the world. The CEO and founder has bought up a stake in a lengthy list of the world’s biggest drug franchises, spending $18 billion in the process — $2.2 billion last year alone. And he’s become one of the best-paid execs in the industry, reaping $28 million from the cash flow last year while reserving 20% of the cash flow, less expenses, for himself.

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