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.

George Yancopoulos (Regeneron)

Re­gen­eron co-founder George Yan­copou­los of­fers a com­bat­ive de­fense of the po­lice at a high school com­mence­ment. It didn’t go well

Typically, the commencement speech at Yorktown Central School District in Westchester — like most high schools — is an opportunity to encourage students to face the future with confidence and hope. Regeneron president and co-founder George Yancopoulos, though, went a different route.

In a fiery speech, the outspoken billionaire defended the police against the “prejudice and bias against law enforcement” that has erupted around the country in street protests from coast to coast. And for many who attended the commencement, Yancopoulos struck the wrong note at the wrong time, especially when he combatively challenged someone for interrupting his speech with a honk for “another act of cowardness.”

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Elias Zerhouni (Photo by Vincent Isore/IP3/Getty Images)

Elias Zer­houni dis­cuss­es ‘am­a­teur hour’ in DC, the de­struc­tion of in­fec­tious dis­ease R&D and how we need to prep for the next time

Elias Zerhouni favors blunt talk, and in a recent discussion with NPR, the ex-Sanofi R&D and ex-NIH chief had some tough points to make regarding the pandemic response.

Rather than interpret them, I thought it would be best to provide snippets straight from the interview.

On the Trump administration response:

It was basically amateur hour. There is no central concept of operations for preparedness, for pandemics, period. This administration doesn’t want to or has no concept of what it takes to protect the American people and the world because it is codependent. You can’t close your borders and say, “OK, we’re going to be safe.” You’re not going to be able to do that in this world. So it’s a lack of vision, basically just a lack of understanding, of what it takes to protect the American people.

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Pfiz­er shares surge on pos­i­tive im­pact of their mR­NA Covid-19 vac­cine — part­nered with BioN­Tech — in an ear­ly-stage study

Pfizer and their partners at the mRNA specialist BioNTech have published the first glimpse of biomarker data from an early-stage study spotlighting the “robust immunogenicity” triggered by their Covid-19 vaccine, which is one of the leaders in the race to vanquish the global pandemic.

Researchers selected 45 healthy volunteers 18-55 years of age for the study. They were randomized to receive 2 doses, separated by 21 days, of 10 µg, 30 µg, or 100 µg of BNT162b1, “a lipid nanoparticle-formulated, nucleoside-modified, mRNA vaccine that encodes trimerized SARS-CoV-2 spike glycoprotein RBD.” Their responses were compared against the effect of a natural, presumably protective defense offered by a regular infection.

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An ex­pe­ri­enced biotech is stitched to­geth­er from transpa­cif­ic parts, with 265 staffers and a fo­cus on ‘new bi­ol­o­gy’

Over the past few years, different teams at a pair of US-based biotechs and in labs in Japan have labored to piece together a group of cancer drug programs, sharing a single corporate umbrella with research colleagues in Japan. But now their far-flung operations have been knit together into a single unit, creating a pipeline with 10 cancer drug development programs — going from early-stage right into Phase III — and a host of discovery projects managed by a collective staff of some 265 people.

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New stan­dard of care? FDA hands Pfiz­er, Mer­ck KGaA an OK for Baven­cio in blad­der can­cer

The breakthrough therapy designation Pfizer and Merck KGaA notched for Bavencio in bladder cancer has quickly paved way for a full approval.

The PD-L1 drug is now sanctioned as a first-line maintenance treatment for patients with locally advanced or metastatic urothelial carcinoma, applicable in cases where cancer hasn’t progressed after platinum-containing chemotherapy.

Petros Grivas, the principal investigator of the supporting Phase III JAVELIN Bladder 100, called the approval “one of the most significant advances in the treatment paradigm in this setting in 30 years.”

Sec­ond death trig­gers hold on Astel­las' $3B gene ther­a­py biotech's lead pro­gram, rais­ing fresh con­cerns about AAV

Seven months after Astellas shelled out $3 billion to acquire the gene therapy player Audentes, the biotech company’s lead program has been put on hold following the death of 2 patients taking a high dose of their treatment. And there was another serious adverse event recorded in the study as well, with a total of 3 “older” patients in the study affected.

The incidents are derailing plans to file for a near-term approval, which had been expected right about now.

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Covid-19 roundup: Vac­cines will need to beat place­bo by 50% to qual­i­fy for FDA OK; UK tri­al drops Kale­tra

The FDA will set the bar for approving a Covid-19 vaccine at 50% efficacy, the Wall Street Journal reported, meaning any successful candidate will have to reduce the risk of coronavirus disease by at least half compared to placebo.

That requirement is part of guidance that the agency is set to release later today, laying out detailed criteria for vaccine developers — some of whom are eyeing an OK by the end of the year, in line with expectations at Operation Warp Speed.

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Joseph Kim, Inovio CEO (Andrew Harnik, AP Images)

Pos­i­tive Covid-19 vac­cine da­ta? New mouse study? OWS in­clu­sion? Yep, but some­how, the usu­al tid­bits from In­ovio back­fire

You don’t go more than 40 years in biotech without ever getting a product to market unless you can learn the art of writing a promotional press release. And Inovio captures the prize in baiting the hook.

Tuesday morning Inovio, which has been struggling to get its Covid-19 vaccine lined up for mass manufacturing, put out a release that touched on virtually every hot button in pandemic PR.

There was, first and foremost, an interim snapshot of efficacy from their Phase I program for INO-4800.

On a roll, Mer­ck blazes through a new seg­ment of the bio­mark­er trail

Merck has notched an approval for using Keytruda to treat a biomarker-based subset of first-line colorectal cancer patients with unresectable or metastatic tumors, as the pharma giant continues to find new niches for its blockbuster PD-1 star.

The OK is significant in a number of ways. Not only does it build on an accelerated approval for all tumors characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR); it also marks the first single treatment for colorectal cancer that doesn’t contain chemotherapy.