A CRISPR/Cas9 start­up launch­es on the R&D fron­tier, work­ing on a one-time fix for Duchenne MD


Af­ter ex­per­i­ment­ing with CRISPR/Cas9 tech, per­fect­ing ge­net­ic surgery on mus­cle cells in mice to snip out the faulty ex­ons that are the cause of the lethal mus­cle wast­ing dis­ease, UT South­west­ern’s Er­ic Ol­son is ready to move in­to the late pre­clin­i­cal stage of de­vel­op­ment. His work is be­ing spun out in­to a start­up which Ol­son hopes will play a big role in even­tu­al­ly cor­rect­ing the fa­tal ge­net­ic flaws for most of the boys who have this dis­ease.

Cure­Duchenne Ven­tures is bankrolling the start­up — dubbed Ex­on­ics Ther­a­peu­tics — with $5 mil­lion in seed mon­ey. That’s not a huge amount in biotech these days. But it is enough to take their pro­gram for Duchenne’s in­to large an­i­mals, mon­keys as well as dogs, as they get a bet­ter grasp of the po­ten­tial ef­fi­ca­cy as well as a clean­er safe­ty pro­file on this ther­a­py.

“We’ve con­tin­ued to op­ti­mize the method for AAV de­liv­ery for cor­rec­tion of Duchenne mu­ta­tions in mouse mod­els,” Ol­son tells me. “We’re now look­ing at 80% restora­tion of dy­s­trophin.”

Even a much small­er, par­tial re­sponse in hu­mans would be a re­mark­able achieve­ment, as the ab­sence of dy­s­trophin is what trig­gers the dis­ease, which first puts these boys in­to a wheel­chair and then kills them.

Keep in mind, ro­dent mod­els can be a poor sub­sti­tute for hu­mans. And no one should think we’re right around the sci­en­tif­ic cor­ner from a cure. But Ol­son — who’s al­so been test­ing this tech on pa­tients’ cells — be­lieves that his hu­man­ized mice are a good in­di­ca­tor of fu­ture suc­cess for an ap­proach po­ten­tial­ly leagues ahead of the con­tro­ver­sial ex­on-skip­ping tech that’s been ad­vanced by Sarep­ta and PTC Ther­a­peu­tics.

Both of those ther­a­pies are now be­ing sold in the US and Eu­rope, re­spec­tive­ly, de­spite a lack of ef­fi­ca­cy da­ta. And Ol­son’s had a chance to per­fect the de­liv­ery method, to ex­pand the po­ten­tial tar­get group of pa­tients to a num­ber dra­mat­i­cal­ly high­er than the cur­rent ther­a­pies tar­get­ed at spe­cif­ic mu­ta­tions.

“You don’t have to have a pre­cise cor­rec­tion,” notes Ol­son. “You can use a sim­ple gene-edit­ing strat­e­gy to skip over mu­tant ex­on.”

Tai­lor­ing a gene-edit­ing fix for Duchenne seems like a nat­ur­al ear­ly tar­get for the field. If you can use CRISPR to guide Cas9 to ed­it out the ge­net­ic de­fects in pa­tients’ DNA, get­ting to a large enough con­cen­tra­tion of mus­cle cells to make a sig­nif­i­cant dif­fer­ence in dy­s­trophin pro­duc­tion, you have the po­ten­tial to cre­ate a once-and-done ther­a­peu­tic that could make a huge dif­fer­ence in the lives of many of the 15,000 boys in the US who have this dis­ease, along with the rest of the world’s pa­tients.

Based on his work so far, Ol­son be­lieves the pro­gram could large­ly fix Duchenne MD for 80% of the boys with this dis­ease.

Ol­son is about to pub­lish more about his re­search, fol­low­ing up a re­port in Sci­ence in late 2015 that marked his ear­ly progress and snared broad at­ten­tion in the biotech world for his work.

 

“Ex­on­ics is clear­ly well po­si­tioned, as we climb the species lad­der,” says Cristi­na Csim­ma, the for­mer CEO at Cy­dan who’s now ex­ec­u­tive chair­man at Ex­on­ics. And the com­pa­ny can take some time to bal­ance ei­ther a Se­ries A or pur­sue talks with oth­er play­ers in the field.

Jak Knowles, the man­ag­ing di­rec­tor of Cure Duchenne Ven­tures and VP of sci­en­tif­ic af­fairs at Cure­Duchenne, is tak­ing the reins as CEO of the com­pa­ny, now based in Boston near South Sta­tion.

No one is giv­ing out a time­line here on how long it’s go­ing to take to get through an IND-en­abling pro­gram and up to the thresh­old of a first-in-man study. But when Ol­son talked to MIT Tech­nol­o­gy Re­view late last year, he told An­to­nio Re­gal­a­do that a clin­i­cal ef­fort could get un­der­way in about two years, not out of line for a pro­gram en­ter­ing the late pre­clin­i­cal stage.

But they might not be alone. Ed­i­tas, one of the three pi­o­neers with CRISPR Ther­a­peu­tics and In­tel­lia to leap in­to the field with hun­dreds of mil­lions of dol­lars each in in­vestors’ cash, has point­ed to Duchenne MD as an area of in­ter­est. Ol­son al­so told Re­gal­a­do that he had been in touch with Ed­i­tas — which has been keep­ing its pipeline plans close to the vest — as he ex­plored a com­mer­cial deal with one of the ex­ist­ing play­ers.

One of the time­lines you hear a lot when talk­ing to peo­ple about CRISPR re­search is that it could eas­i­ly take 10 years be­fore you see the first new ther­a­py. And that could be am­bi­tious. This is a new and evolv­ing fo­cus in biotech, where re­searchers are still care­ful­ly look­ing for un­in­tend­ed off-tar­get ef­fects that could raise un­ex­pect­ed safe­ty is­sues. But in a few weeks we’ll see a new FDA com­mis­sion­er step in with a man­date to speed new reme­dies like this. Scott Got­tlieb has talked about cre­at­ing a kind of Skunkworks in the FDA for rare dis­eases that might sig­nif­i­cant­ly short­en the de­vel­op­ment time­lines for new drugs to treat lethal rare dis­eases.

So it’s con­ceiv­able that it could be done in less than 10 years.

The race is on. We just don’t know right now where the fin­ish line is.

Health­care Dis­par­i­ties and Sick­le Cell Dis­ease

In the complicated U.S. healthcare system, navigating a serious illness such as cancer or heart disease can be remarkably challenging for patients and caregivers. When that illness is classified as a rare disease, those challenges can become even more acute. And when that rare disease occurs in a population that experiences health disparities, such as people with sickle cell disease (SCD) who are primarily Black and Latino, challenges can become almost insurmountable.

David Meek, new Mirati CEO (Marlene Awaad/Bloomberg via Getty Images)

Fresh off Fer­Gene's melt­down, David Meek takes over at Mi­rati with lead KRAS drug rac­ing to an ap­proval

In the insular world of biotech, a spectacular failure can sometimes stay on any executive’s record for a long time. But for David Meek, the man at the helm of FerGene’s recent implosion, two questionable exits made way for what could be an excellent rebound.

Meek, most recently FerGene’s CEO and a past head at Ipsen, has become CEO at Mirati Therapeutics, taking the reins from founding CEO Charles Baum, who will step over into the role of president and head of R&D, according to a release.

Who are the women su­per­charg­ing bio­phar­ma R&D? Nom­i­nate them for this year's spe­cial re­port

The biotech industry has faced repeated calls to diversify its workforce — and in the last year, those calls got a lot louder. Though women account for just under half of all biotech employees around the world, they occupy very few places in C-suites, and even fewer make it to the helm.

Some companies are listening, according to a recent BIO survey which showed that this year’s companies were 2.5 times more likely to have a diversity and inclusion program compared to last year’s sample. But we still have a long way to go. Women represent just 31% of biotech executives, BIO reported. And those numbers are even more stark for women of color.

Jacob Van Naarden (Eli Lilly)

Ex­clu­sives: Eli Lil­ly out to crash the megablock­buster PD-(L)1 par­ty with 'dis­rup­tive' pric­ing; re­veals can­cer biotech buy­out

It’s taken 7 years, but Eli Lilly is promising to finally start hammering the small and affluent PD-(L)1 club with a “disruptive” pricing strategy for their checkpoint therapy allied with China’s Innovent.

Lilly in-licensed global rights to sintilimab a year ago, building on the China alliance they have with Innovent. That cost the pharma giant $200 million in cash upfront, which they plan to capitalize on now with a long-awaited plan to bust up the high-price market in lung cancer and other cancers that have created a market worth tens of billions of dollars.

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When ef­fi­ca­cy is bor­der­line: FDA needs to get more con­sis­tent on close-call drug ap­provals, agency-fund­ed re­search finds

In the exceedingly rare instances in which clinical efficacy is the only barrier to a new drug’s approval, new FDA-funded research from FDA and Stanford found that the agency does not have a consistent standard for defining “substantial evidence” when flexible criteria are used for an approval.

The research comes as the FDA is at a crossroads with its expedited-review pathways. The accelerated approval pathway is under fire as the agency recently signed off on a controversial new Alzheimer’s drug, with little precedent to explain its decision. Meanwhile, top officials like Rick Pazdur have called for a major push to simplify and clarify all of the various expedited pathways, which have grown to be must-haves for sponsors of nearly every newly approved drug.

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Af­ter sell­ing to Genen­tech, the old Je­cure team is back at an RNA-fo­cused start­up — and more en­thu­si­as­tic than ever

When Genentech swooped in to buy NASH-focused Jecure Therapeutics back in 2018, a handful of the startup’s executives weren’t quite ready to disperse.

It had been just three years since Jecure launched with a preclinical portfolio of NLRP3 inhibitors — and the takeover came sooner than anyone, including CEO Jeff Stafford, had expected. So he got talking with James Veal and Gretchen Bain, two serial entrepreneurs in charge of Jecure’s R&D.

Jay Bradner (Jeff Rumans for Endpoints News)

Div­ing deep­er in­to in­her­it­ed reti­nal dis­or­ders, No­var­tis gob­bles up an­oth­er bite-sized op­to­ge­net­ics biotech

Right about a year ago, a Novartis team led by Jay Bradner and Cynthia Grosskreutz at NIBR swooped in to scoop up a Cambridge, MA-based opthalmology gene therapy company called Vedere. Their focus was on a specific market niche: inherited retinal dystrophies that include a wide range of genetic retinal disorders marked by the loss of photoreceptor cells and progressive vision loss.

But that was just the first deal that whet their appetite.

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FDA hands ac­cel­er­at­ed nod to Seagen, Gen­mab's so­lo ADC in cer­vi­cal can­cer, but com­bo stud­ies look even more promis­ing

Biopharma’s resident antibody-drug conjugate expert Seagen has scored a clutch of oncology approvals in recent years, finding gold in what are known as “third-gen” ADCs. Now, another of their partnered conjugates is ready for prime time.

The FDA on Monday handed an accelerated approval to Seagen and Genmab’s Tivdak (tisotumab vedotin-tftv, or “TV”) in second-line patients with recurrent or metastatic cervical cancer who previously progressed after chemotherapy rather than PD-(L)1 systemic therapy, the companies said in a release.

Take­da snaps up the Japan­ese rights to an old Shire cast-off; Boehringer In­gel­heim ac­quires Abexxa Bi­o­log­ics

A week before the FDA is set to decide on Mirum Pharmaceuticals’ lead liver disease drug — an old Shire cast-off called maralixibat — Takeda is swooping in to secure the rights in Japan.

Maralixibat’s roots trace back to Lumena, which was snapped up by Shire for $260 million-plus back in 2014. While the candidate had failed mid-stage studies at Shire, Mirum believes better trial design and patient selection will deliver the wins it needs. The drug is currently in development for Alagille syndrome (a condition called ALGS in which bile builds up in the liver), progressive familial intrahepatic cholestasis (PFIC, which causes progressive liver disease) and biliary atresia (a blockage in the ducts that carry bile from the liver to the gallbladder).