As R&D set­backs mul­ti­ply, a pi­o­neer­ing CRISPR/Cas9 pro­gram for Duchenne MD con­tin­ues to im­press in new dog study

While one drug af­ter the next seems to get reg­u­lar­ly shot down in Duchenne mus­cu­lar dy­s­tro­phy, as we saw to­day with Pfiz­er’s failed Phase II, a pre­clin­i­cal CRISPR gene edit­ing pro­gram has been mak­ing some im­pres­sive progress in an­i­mal stud­ies.

Thurs­day af­ter­noon, Ex­on­ics pro­vid­ed some in­trigu­ing de­tails to show how their gene-edit­ing ap­proach works in dogs. Dis­patch­ing a Cas9 scalpel with guide RNA in­side an AAV de­liv­ery ve­hi­cle straight to mus­cle cells, the re­searchers say that their ap­proach was able to re­store dy­s­trophin pro­duc­tion that reached up to 92% of nor­mal in a ca­nine mod­el for the dis­ease.

That was for the high­est dose used.

John Rip­ple

“Typ­i­cal­ly,” Ex­on­ics CEO John Rip­ple tells me, the re­sponse in dy­s­trophin pro­duc­tion “was above 50%.”

That’s a big deal, he says, par­tic­u­lar­ly when re­searchers in the field see pa­tients turn asymp­to­matic at around 20% of nor­mal dy­s­trophin pro­duc­tion.

Ex­on­ics has been mak­ing mea­sured ad­vances in this field, start­ing with the lab work done by UT South­west­ern’s Er­ic Ol­son, who did the ear­ly sci­en­tif­ic in­ves­ti­ga­tion us­ing CRISPR on cells and mice. We made con­tact ear­ly on, as he dis­cussed the progress he had been mak­ing. Ol­son co-au­thored the study out to­day.

“Ca­nines have clin­i­cal and patho­log­i­cal fea­tures sim­i­lar to the hu­man pre­sen­ta­tion of Duchenne, in­clud­ing mus­cle weak­ness, at­ro­phy and fi­bro­sis,” Ol­son not­ed to­day, as the lat­est work ap­peared in Sci­ence.

Late last year a $40 mil­lion launch round helped the com­pa­ny get start­ed with a vir­tu­al crew, which is now grow­ing fast. From a hand­ful of staffers, Ex­on­ics ros­ter has now grown to 11, with plans to dou­ble that when they move in­to a new lab and of­fices in Wa­ter­town lat­er this year. 

In many ways, Duchenne MD could prove one of the best fields for a CRISPR team to work in — es­pe­cial­ly in the ear­ly days.

In this case, they’re look­ing for a sim­ple cut and re­pair re­sponse need­ed to cor­rect er­rant cells that trig­ger the ail­ment, which slow­ly but sure­ly crip­ples and then kills its vic­tims. Tar­get­ing mus­cles and heart tis­sue gives them a sta­ble group of non-di­vid­ing cells to work with, which may well re­duce the chances of any off-tar­get im­pact — a top­ic that rou­tine­ly sparks near pan­ic in CRISPR/Cas9 in­vest­ment cir­cles.

It should be not­ed, though, that be­fore we start spot­light­ing a po­ten­tial cure for Duchenne, or spe­cif­ic ge­net­ic pa­tient pop­u­la­tions with the dis­ease, the drug is still not ready for a prime time hu­man tri­al.

“Our next step is to con­tin­ue pre­clin­i­cal work, ad­vanc­ing in the clin­ic,” adds the CEO. “We need to do longer an­i­mal stud­ies, main­tain dy­s­trophin pro­tein over a long pe­ri­od of time.”

That way, by the time they sit down with reg­u­la­tors and start talk­ing hu­man stud­ies, they’ll be able to make a sol­id case built on ex­ten­sive pre­clin­i­cal work. When­ev­er that day ar­rives.

There’s not an un­lim­it­ed amount of time avail­able, though. Pa­tients are still in des­per­ate need, and oth­er biotechs are al­so work­ing on a cure.

Ex­on­ics is one of sev­er­al de­vel­op­ers look­ing to carve a new re­search path to this dis­ease. Mus­cle drugs have proven very prob­lem­at­ic in ad­dress­ing a se­vere dis­ease like this. And Sarep­ta’s eteplirsen was ap­proved with­out sig­nif­i­cant ef­fi­ca­cy da­ta, un­der­scor­ing a dra­mat­ic need for new drugs. Sarep­ta, Sol­id Bio and oth­ers are ex­plor­ing gene ther­a­py ap­proach­es, which have al­so high­light­ed some im­pres­sive ear­ly re­sults.


Im­age: Er­ic Ol­son. Jane Cof­fin Childs Memo­r­i­al Fund for Med­ical Re­search

Brian Kaspar. AveXis via Twitter

AveX­is sci­en­tif­ic founder fires back at No­var­tis CEO Vas Narasimhan, 'cat­e­gor­i­cal­ly de­nies any wrong­do­ing'

Brian Kaspar’s head was among the first to roll at Novartis after company execs became aware of the fact that manipulated data had been included in its application for Zolgensma, now the world’s most expensive therapy.

But in his first public response, the scientific founder at AveXis — acquired by Novartis for $8.7 billion — is firing back. And he says that not only was he not involved in any wrongdoing, he’s ready to defend his name as needed.

I reached out to Brian Kaspar after Novartis put out word that he and his brother Allen had been axed in mid-May, two months after the company became aware of the allegations related to manipulated data. His response came back through his attorneys.

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Novartis CEO Vas Narasimhan [via Bloomberg/Getty]

I’m not per­fect: No­var­tis chief Vas Narasimhan al­most apol­o­gizes in the wake of a new cri­sis

Vas Narasimhan has warily stepped up with what might pass as something close to a borderline apology for the latest scandal to engulf Novartis.

But he couldn’t quite get there.

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UP­DAT­ED: Pay­back? An­a­lysts say Sarep­ta was blind­sided by an FDA re­jec­tion dri­ven by reg­u­la­to­ry re­venge

In one of the least anticipated moves of the year, the FDA has rejected Sarepta’s application for an accelerated approval of its Duchenne MD drug golodirsen after fretting over safety issues.

In a statement that arrived after the bell on Monday, Sarepta explained the CRL, saying:

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FDA de­ci­sion on Ver­tex's CF triple will come just ahead of planned CEO shake­up

Vertex has clinched a priority review for the all-important cystic fibrosis triple that will blaze the trail for treating a large group of patients unhelped by its current drugs.

FDA regulators have set a PDUFA date of March 19, 2020, just a year after the Boston biotech posted positive Phase III results showing that people with two F508del mutations experienced statistically significant improvements in lung function after a 4-week regimen of VX-445, tezacaftor and ivacaftor. After reviewing 24-week data among patients with one F508del mutation and one minimal function mutation — and thoroughly comparing the VX-445 triple with another combo featuring VX-659 on scores like safety, drug-drug interactions, and photosensitivity — Vertex ultimately went with VX-445.

An MIT spin­out kills one of its ‘liv­ing ther­a­peu­tics’ af­ter flunk­ing an ear­ly-stage study — shares rout­ed

Just a few weeks after bagging $80 million in a deal to collaborate with Gingko Bioworks on its special blend of engineered bacteria used for “living therapeutics,” little Synlogic in Boston $SYBX is tossing one of its two clinical programs after watching an early-stage study go down in defeat.

Their Phase Ib/IIa study for SYNB1020 to counter the accumulation of ammonia in the body, a condition called hyperammonemia or urea cycle disorder, floundered at the interim readout, forcing the biotech to kill it and reserve its cash for pipeline therapies with greater potential.

Elan­co to buy Bay­er's an­i­mal health busi­ness for $7.6B, as deal­mak­ing gath­ers steam in the sec­tor

Last week, Elanco explicitly dodged answering questions about its rumored interest in Bayer’s animal health business in its post-earnings call. On Tuesday, the Eli Lilly spinoff disclosed it was purchasing the German drug maker’s veterinary unit in a cash-and-stock deal worth $7.6 billion. 

Elanco $ELAN has been busy on the deal-making front. In April, it laid out plans to swallow its partner, Kansas-based pet therapeutics company Aratana $PETX. A July report by Reuters suggested a potential Bayer deal was being explored, and Bloomberg last week said the deal was imminent, citing sources. 

As­traZeneca's di­a­betes drug Farx­i­ga helps pa­tients with heart dis­ease and with­out di­a­betes in land­mark tri­al

Months ago, data on J&J’s $JNJ Invokana indicated the diabetes drug conferred cardiovascular (CV) benefit in patients who do and do not have preexisting CV disease. On Tuesday, AstraZeneca’s $AZN rival treatment, Farxiga, was shown to cut the risk of CV death or the worsening of heart failure in patients with heart disease, in a landmark trial.

The treatments, in addition to Jardiance from Eli Lilly $LLY, belong to a class of diabetes drugs called sodium-glucose co-transporter 2 (SGLT2) inhibitors, which work by curbing the absorption of glucose via the kidneys so that surplus glucose is excreted through urination.

Levi Garraway. Broad Institute via Youtube

Roche raids Eli Lil­ly for its next chief med­ical of­fi­cer as San­dra Horn­ing plans to step down

We found out Monday morning where Levi Garraway was headed after he left Eli Lilly as head of oncology R&D a few days ago. Roche named Garraway as their new chief medical officer, replacing Sandra Horning, who they say is retiring from the company.

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Af­ter a posse of Wall Street an­a­lysts pre­dict a like­ly new win for Sarep­ta, we're down to the wire on a crit­i­cal FDA de­ci­sion

As Bloomberg notes, most of the Wall Street analysts that cover Sarepta $SRPT are an upbeat bunch, ready to cheer on the team when it comes to their Duchenne MD drugs, or offer explanations when an odd setback occurs — as happened recently with a safety signal that was ‘erroneously’ reported last week.

Ritu Baral Cowen
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