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.

A New Fron­tier: The In­ner Ear

What happens when a successful biotech venture capitalist is unexpectedly diagnosed with a chronic, life-disrupting vertigo disorder? Innovation in neurotology.

That venture capitalist was Jay Lichter, Ph.D., and after learning there was no FDA-approved drug treatment for his condition, Ménière’s disease, he decided to create a company to bring drug development to neurotology. Otonomy was founded in 2008 and is dedicated to finding new drug treatments for the hugely underserved community living with balance and hearing disorders. Helping patients like Jay has been the driving force behind Otonomy, a company heading into a transformative 2020 with three clinical trial readouts: Phase 3 in Ménière’s disease, Phase 2 in tinnitus, and Phase 1/2 in hearing loss. These catalysts, together with others in the field, highlight the emerging opportunity in neurotology.
Otonomy is leading the way in neurotology
Neurotology, or the treatment of inner ear neurological disorders, is a large and untapped market for drug developers: one in eight individuals in the U.S. have moderate-to-severe hearing loss, tinnitus or vertigo disorders such as Ménière’s disease.1 With no FDA-approved drug treatments available for these conditions, the burden on patients—including social anxiety, lower quality of life, reduced work productivity, and higher rates of depression—can be significant.2, 3, 4

Joe Jimenez, Getty

Ex-No­var­tis CEO Joe Jimenez is tak­ing an­oth­er crack at open­ing a new chap­ter in his ca­reer — and that in­cludes a new board seat and a $250M start­up

Joe Jimenez is back.

The ex-CEO of Novartis has taken a board seat on Century Therapeutics, the Versant and Bayer-backed startup focused on coming up with a brand new twist on cell therapies for cancer — a field where Jimenez made his mark backing the first personalized CAR-T approved for use.

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Can we make the an­tibi­ot­ic mar­ket great again?

The standard for-profit model in drug development is straightforward. Spend millions, even billions, to develop a medicine from scratch. The return on investment (and ideally a tidy profit) comes via volume and/or price, depending on the disease. But the string of big pharma exits and slew of biotech bankruptcies indicate that the model is sorely flawed when it comes to antibiotics.

The industry players contributing to the arsenal of antimicrobials are fast dwindling, and the pipeline for new antibiotics is embarrassingly sparse, the WHO has warned. Drugmakers are enticed by greener pastures, compared to the long, arduous and expensive path to antibiotic approval that offers little financial gain as treatments are typically priced cheaply, and often lose potency over time as microbes grow resistant to them.

Top Har­vard chemist caught up in FBI’s 'T­hou­sand Tal­ents' drag­net, ac­cused of ly­ing about Chi­nese con­nec­tions, pay

The FBI’s probe into the alleged theft of R&D secrets by Chinese authorities has drawn Harvard’s top chemist into its net.

The agency accused Charles M. Lieber, who chairs the university’s chemistry and chemical biology department, with lying about his involvement in China’s Thousand Talents campaign, which was established as a way of drawing in innovators from around the world. And the scientist, 60, was charged with making false statements about his ties to China.

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Eye­ing a trio of tri­al ini­ti­a­tions, Jim Wilson's gene ther­a­py start­up woos Bruce Gold­smith from Deer­field as CEO

Passage Bio — Jim Wilson’s self-described “legacy company” — has wooed a seasoned biotech executive to steer the clinical entry of its first three gene therapy programs.

Bruce Goldsmith jumps to the helm of Passage after a brief CEO stint at Civetta, a cancer-focused startup he helped launch while a venture partner at Deerfield. He takes over from OrbiMed partner and interim chief Stephen Squinto, who will now lead the R&D team.

The FTC and New York state ac­cuse Mar­tin Shkre­li of run­ning a drug mo­nop­oly. They plan to squash it — and per­ma­nent­ly ex­ile him

Pharma bro Martin Shkreli was jailed, publicly pilloried and forced to confront some lawmakers in Washington riled by his move to take an old generic and move the price from $17.50 per pill to $750. But through 4 years of controversy and public revulsion, his company never backed away from the price — left uncontrolled by a laissez faire federal policy on a drug’s cost.

Now the FTC and the state of New York plan to pry his fingers off the drug once and for all and open it up to some cheap competition. And their lawsuit is asking that Shkreli — with several years left on his prison sentence — be banned permanently from the pharma industry.

UP­DAT­ED: Ac­celeron res­ur­rects block­buster hopes for so­tater­cept with pos­i­tive PhII — and shares rock­et up

Acceleron $XLRN says that its first major trial readout of 2020 is a success.

In a Phase II study of 106 patients with pulmonary arterial hypertension (PAH), Acceleron’s experimental drug sotatercept hit its primary endpoint: a significant reduction in pulmonary vascular resistance. The drug also met three different secondary endpoints, including the 6-minute walking test.

“We’re thrilled to report such positive topline results from the PULSAR trial,” Acceleron CEO Habib Dable said in a statement. The company said in a conference call they plan on discussing a Phase III trial design with regulators.

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Short at­tack­er Sahm Ad­ran­gi draws crosshairs over a fa­vorite of Sanofi’s new CEO — with PhII da­ta loom­ing

Sahm Adrang Kerrisdale

Kerrisdale chief Sahm Adrangi took a lengthy break from his series of biotech short attacks after his chief analyst in the field pulled up stakes and went solo. But he’s making a return to drug development this morning, drawing crosshairs over a company that’s one of new Sanofi CEO Paul Hudson’s favorite collaborators.

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Amber Saltzman (Ohana)

Flag­ship's first ven­ture of 2020 is out, and it's all about sperm

A couple years ago, Amber Salzman got a call as she was returning East full-time after a two-year stint running a gene therapy company in California.

It was from someone at Flagship Pioneering, the deep-pocketed biotech venture firm. They had a new company with a new way of thinking about sperm. It had been incubating for over a year, and now they wanted her to run it.

“It exactly fit,” Salzman told Endpoints News. “I just thought I had to do something.”