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.

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Uğur Şahin, BioNTech CEO (Kay Nietfeld/picture-alliance/dpa/AP Images)

De­spite falling Covid-19 sales, BioN­Tech main­tains '22 sales guid­ance

While Pfizer raked in almost $28 billion last quarter, its Covid-19 vaccine partner BioNTech reported a rise in total dose orders but a drop in sales.

The German biotech reported over $3.2 billion in revenue in Q2 on Monday, down from more than $6.7 billion in Q1, in part due to falling Covid sales. While management said last quarter that they anticipated a Covid sales drop — CEO Uğur Şahin said at the time that “the pandemic situation is still very much uncertain” — Q2 sales still missed consensus by 14%.

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Ted Love, Global Blood Therapeutics CEO

Up­dat­ed: Pfiz­er scoops up Glob­al Blood Ther­a­peu­tics and its sick­le cell ther­a­pies for $5.4B

Pfizer is dropping $5.4 billion to acquire Global Blood Therapeutics.

Just ahead of the weekend, word got out that Pfizer was close to clinching a $5 billion buyout — albeit with other potential buyers still at the table. The pharma giant, flush with cash from Covid-19 vaccine sales, apparently got out on top.

The deal immediately swells Pfizer’s previously tiny sickle cell disease portfolio from just a Phase I program to one with an approved drug, Oxbryta, plus a whole pipeline that, if all approved, the company believes could make for a $3 billion franchise at peak.

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FDA commissioner Rob Califf (Tom Williams/CQ Roll Call via AP Images)

With drug pric­ing al­most done, Con­gress looks to wrap up FDA user fee leg­is­la­tion

The Senate won’t return from its summer recess until Sept. 6, but when it does, it officially has 18 business days to finalize the reauthorization of the FDA user fee programs for the next 5 years, or else thousands of drug and biologics reviewers will be laid off and PDUFA dates will vanish in the interim.

FDA commissioner Rob Califf recently sent agency staff a memo explaining how, “Our latest estimates are that we have carryover for PDUFA [Prescription Drug User Fee Act], the user fee funding program that will run out of funding first, to cover only about 5 weeks into the next fiscal year.”

Pascal Soriot, AstraZeneca CEO (David Zorrakino/Europa Press via AP Images)

As­traZeneca and Dai­ichi Sankyo sprint to mar­ket af­ter FDA clears En­her­tu in just two weeks

Regulators didn’t keep AstraZeneca and Daiichi Sankyo waiting long at all for their latest Enhertu approval.

The partners pulled a win on Friday in HER2-low breast cancer patients who’ve already failed on chemotherapy, just two weeks after submitting a supplemental BLA. While this isn’t the FDA’s fastest approval — Bristol Myers Squibb won an OK for its blockbuster checkpoint inhibitor Opdivo in just five days back in March — it comes well ahead of Enhertu’s original Q4 PDUFA date.

David Reese, Amgen R&D chief

UP­DAT­ED: In a fresh dis­ap­point­ment, Am­gen spot­lights a ma­jor safe­ty is­sue with KRAS com­bo

Amgen had hoped that its latest study matching its landmark KRAS G12C drug Lumakras with checkpoint inhibitors would open up its treatment horizons and expand its commercial potential. Instead, the combo spurred safety issues that blunted efficacy and forced the pharma giant to alter course on its treatment strategy, once again disappointing analysts who have been tracking the drug’s faltering sales and limited therapeutic reach.

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GSK and IQVIA launch plat­form of US vac­ci­na­tion da­ta, show­ing drop in adult rates

Throughout the Covid-19 pandemic, the issue of vaccine uptake has been a point of contention, but a new platform from GSK and IQVIA is hoping to shed more light on vaccine data, via new transparency and general awareness.

The two companies have launched Vaccine Track, a platform intended to be used by public health officials, medical professionals and others to strengthen data transparency and display vaccination trends. According to the companies, the platform is intended to aid in increasing vaccine rates and will provide data on trends to assist public health efforts.

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Ab­b­Vie sur­veys emo­tion­al im­pact of chron­ic leukemia con­di­tion, finds 'roller coast­er' of emo­tions

Rare diseases often have more than just physical effects on patients — especially when it comes to chronic conditions. In the case of the rare slow-growing blood cancer chronic lymphocytic leukemia (CLL), AbbVie wanted to try to assess the mental and emotional toll on patients.

So it surveyed more than 300 CLL patients, caregivers and physicians. While each group differed in how they felt — caregivers overwhelmingly (81%) felt positive about their role, for instance — patients described a “roller coaster” of emotions traversing diagnosis to treatment to remission and even relapse for some.

Bernhardt Zeiher, outgoing Astellas CMO (Astellas)

Q&A: Astel­las' re­tir­ing head of de­vel­op­ment re­flects on gene ther­a­py deaths

For anyone who’s been following discussions about the safety alarms surrounding the adeno-associated viruses (AAV) commonly used to deliver gene therapy, Astellas should be a familiar name.

The Japanese pharma — which bought out Audentes Therapeutics near the end of 2019 and later built a gene therapy unit around the acquisition — rocked the field when it reported three patient deaths in a trial testing AT132, the lead program from Audentes designed to treat a rare muscle disease called X-linked myotubular myopathy (XLMTM).

When the company restarted the trial, it adjusted the dose and instituted a battery of other measures to try to prevent the same thing from happening again. But tragically, the first patient to receive the new regimen died just weeks after administration. The therapy remains under clinical hold, and just weeks ago, Astellas flagged another safety-related hold for a separate gene therapy candidate. In the process of investigating the deaths, the company has also taken flak about the way it disclosed information.

Big questions remain — questions that can have big implications about the future of AAV gene therapies.

Bernhardt Zeiher did not imagine any of it when he first joined Astellas as the therapeutic area leader in inflammation, immunology and infectious diseases. But his ascent to chief medical officer and head of development coincided almost exactly with Astellas’ big move into gene therapy, putting him often in the driver’s seat to grapple with the setbacks.

As Zeiher prepares to retire next month after a 12-year tenure — leaving the unfinished tasks to his successor, a seasoned cancer drug developer — he chatted with Endpoints News, in part, to discuss the effort to understand what happened, lessons learned and the criticism along the way.

The transcript has been lightly edited for length and clarity.

Endpoints: I want to also ask you a bit about the gene therapy efforts you’ve been working on. Astellas has really been at the forefront of discovering the safety concerns associated with AAV gene therapy. What’s that been like for you?

Zeiher: Well, I have to admit, it’s been a bit of a roller coaster. We acquired Audentes. Huge amount of enthusiasm. What we saw with AT132 — that was the lead program in XLMTM — was just remarkable efficacy. I mean, kids who went from being on ventilators, not able to eat for themselves, sit up, do things like that, to off ventilators, walking, you know, really — one investigator called it this Lazarus-like effect. It was just really dramatic efficacy. And then to have the safety events that occurred. So they actually occurred within that first year of the acquisition. So we had the three patient deaths. Me and my organization became very, very much involved. In fact, Ed Conner, who had been the chief medical officer, he left after some of the deaths, but I stepped in as the kind of acting chief medical officer, we had another chief medical officer who was involved, and then we had a fourth death, and I became acting again for a period of time.

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