Ap­ply­ing CRISPR to Duchenne, Duke re­searchers spot­light 1-year mouse da­ta in Sarep­ta-spon­sored study

Char­lie Gers­bach (Duke Uni­ver­si­ty)

As Sarep­ta hus­tles its gene ther­a­py for Duchenne mus­cu­lar dy­s­tro­phy in­to a piv­otal study, one of its aca­d­e­m­ic col­lab­o­ra­tors has some longterm mouse da­ta to re­port on an at­tempt to treat the dis­ease through gene edit­ing.

One year af­ter a sin­gle dose of the CRISPR-based treat­ment, the adult mice in the study main­tained a high lev­el of dy­s­trophin ex­pres­sion, ac­cord­ing to re­searchers led by Pro­fes­sor Charles Gers­bach at Duke Uni­ver­si­ty.

In the study, which was spon­sored by Sarep­ta, the NIH and sev­er­al oth­er groups, sci­en­tists used CRISPR/Cas9 to snip out dy­s­trophin ex­ons around the DMD-caus­ing ge­net­ic mu­ta­tion so that the body would “stitch the re­main­ing gene back to­geth­er to cre­ate a short­ened — but func­tion­al — ver­sion of the dy­s­trophin gene.” While the in­jec­tion was found to trig­ger an im­mune re­sponse and in­duce un­in­tend­ed, al­ter­na­tive ed­its on the tar­get, they didn’t turn out to be cause for con­cern.

Christo­pher Nel­son

“The good news is that even though we ob­served both an­ti­body and T cell re­spons­es to Cas9, nei­ther ap­peared to re­sult in any tox­i­c­i­ty in these mice,” said Christo­pher Nel­son, a post-doc who led the work. “The re­sponse al­so did not pre­vent the ther­a­py’s abil­i­ty to suc­cess­ful­ly ed­it the dy­s­trophin gene and pro­duce long-term pro­tein ex­pres­sion.”

Nev­er­the­less, both Gers­bach and Nel­son said the im­mune re­sponse and al­ter­na­tive se­quence changes re­main po­ten­tial chal­lenges to be mon­i­tored and over­come.

One the­o­ry emerg­ing from these re­sults is that edit­ing the genes of in­fants be­fore their im­mune sys­tems are ful­ly de­vel­oped can cir­cum­vent any un­want­ed im­mune re­sponse, based on the ob­ser­va­tion that mice treat­ed when they were two days old (and lacked a ful­ly de­vel­oped im­mune sys­tem) didn’t seem to ex­pe­ri­ence an im­mune re­sponse to the Cas9 pro­tein.

Mov­ing from an­i­mal to hu­man stud­ies with this fu­tur­is­tic tech won’t be quick. Mean­while, Sarep­ta — which al­ready mar­kets a con­tro­ver­sial DMD treat­ment — is ar­guably in the lead of a tight race to de­vel­op a gene ther­a­py for the dis­ease which works by in­sert­ing a mi­cro-dy­s­trophin trans­gene via an AAV. Pfiz­er al­so has a clin­i­cal study un­der­way, while Sol­id Bio is trudg­ing along af­ter ini­tial biop­sies sug­gest­ed a flop in an ear­ly study.

It’s fi­nal­ly over: Bio­gen, Ei­sai scrap big Alzheimer’s PhI­I­Is af­ter a pre­dictable BACE cat­a­stro­phe rais­es safe­ty fears

Months after analysts and investors called on Biogen and Eisai to scrap their BACE drug for Alzheimer’s and move on in the wake of a string of late-stage failures and rising safety fears, the partners have called it quits. And they said they were dropping the drug — elenbecestat — after the independent monitoring board raised concerns about…safety.

We don’t know exactly what researchers found in this latest catastrophe, but the companies noted in their release that investigators had determined that the drug was flunking the risk/benefit analysis.

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It's not per­fect, but it's a good start: FDA pan­elists large­ly en­dorse Aim­mune's peanut al­ler­gy ther­a­py

Two days after a fairly benign review from FDA staff, an independent panel of experts largely endorsed the efficacy and safety of Aimmune’s peanut allergy therapy, laying the groundwork for approval with a risk evaluation and mitigation strategy (REMS).

Traditionally, peanut allergies are managed by avoidance, but the threat of accidental exposure cannot be nullified. Some allergists have devised a way to dose patients off-label with peanut protein derived from supermarket products to wean them off their allergies. But the idea behind Aimmune’s product was to standardize the peanut protein, and track the process of desensitization — so when accidental exposure in the real world invariably occurs, patients are less likely to experience a life-threatening allergic reaction.

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Rit­ter bombs fi­nal PhI­II for sole lac­tose in­tol­er­ance drug — shares plum­met

More than two years ago Ritter Pharmaceuticals managed to find enough silver lining in its Phase IIb/III study — after missing the top-line mark — to propel its lactose intolerance toward a confirmatory trial. But as it turned out, the enthusiasm only set the biotech and its investors up to be sorely disappointed.

This time around there’s little left to salvage. Not only did RP-G28 fail to beat placebo in reducing lactose intolerance symptoms, patients in the treatment group actually averaged a smaller improvement. On a composite score measuring symptoms like abdominal pain, cramping, bloating and gas, patients given the drug had a mean reduction of 3.159 while the placebo cohort saw a 3.420 drop on average (one-sided p-value = 0.0106).

Ear­ly snap­shot of Ad­verum's eye gene ther­a­py sparks con­cern about vi­sion loss

An early-stage update on Adverum Biotechnologies’ intravitreal gene therapy has triggered investor concern, after patients with wet age-related macular degeneration (AMD) saw their vision deteriorate, despite signs that the treatment is improving retinal anatomy.

Adverum, on Wednesday, unveiled 24-week data from the OPTIC trial of its experimental therapy, ADVM-022, in six patients who have been administered with one dose of the therapy. On average, patients in the trial had severe disease with an average of 6.2 anti-VEGF injections in the eight months prior to screening and an average annualized injection frequency of 9.3 injections.

Alex Ar­faei trades his an­a­lyst's post for a new role as biotech VC; Sanofi vet heads to Vi­for

Too often, Alex Arfaei arrived too late. 

An analyst at BMO Capital Markets, he’d meet with biotech or pharmaceutical heads for their IPO or secondary funding and his brain, trained on a biology degree and six years at Merck and Endo, would spring with questions: Why this biomarker? Why this design? Why not this endpoint? Not that he could do anything about it. These execs were coming for clinical money; their decisions had been made and finalized long ago.

Lisa M. DeAngelis, MSKCC

MSK picks brain can­cer ex­pert Lisa DeAn­ge­lis as its next CMO — fol­low­ing José Basel­ga’s con­tro­ver­sial ex­it

It’s official. Memorial Sloan Kettering has picked a brain cancer expert as its new physician-in-chief and CMO, replacing José Baselga, who left under a cloud after being singled out by The New York Times and ProPublica for failing to properly air his lucrative industry ties.

His replacement, who now will be in charge of MSK’s cutting-edge research work as well as the cancer care delivered by hundreds of practitioners, is Lisa M. DeAngelis. DeAngelis had been chair of the neurology department and co-founder of MSK’s brain tumor center and was moved in to the acting CMO role in the wake of Baselga’s departure.

Penn team adapts CAR-T tech, reengi­neer­ing mouse cells to treat car­diac fi­bro­sis

After establishing itself as one of the pioneer research centers in the world for CAR-T cancer therapies, creating new attack vehicles to eradicate cancer cells, a team at Penn Medicine has begun the tricky transition of using the basic technology for heart repair work.

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Tal Zaks. Moderna

The mR­NA uni­corn Mod­er­na has more ear­ly-stage hu­man da­ta it wants to show off — reach­ing new peaks in prov­ing the po­ten­tial

The whole messenger RNA field has attracted billions of dollars in public and private investor cash gambled on the prospect of getting in on the ground floor. And this morning Boston-based Moderna, one of the leaders in the field, wants to show off a few more of the cards it has to play to prove to you that they’re really in the game.

The whole hand, of course, has yet to be dealt. And there’s no telling who gets to walk with a share of the pot. But any cards on display at this point — especially after being accused of keeping its deck under lock and key — will attract plenty of attention from some very wary, and wired, observers.

“In terms of the complexity and unmet need,” says Tal Zaks, the chief medical officer, “this is peak for what we’ve accomplished.”

Moderna has two Phase I studies it wants to talk about now.

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Sanofi takes a $260M hit to ex­tri­cate it­self from a dis­as­trous al­liance with Lex­i­con

Sanofi spent $300 million in cash to get into a $1.7 billion alliance with Lexicon on their SGLT1/2 diabetes drug sotagliflozin. And now that the drug has been spurned by the FDA after burning through a program that provided mixed late-stage data and a late shot at a last-place finish, the French pharma giant is forking over another $260 million to get out of the deal.

Sanofi’s unhappiness was already apparent when the company — now under new CEO Paul Hudson — posted a statement back in July that they were dropping the deal. But it wasn’t that simple. 

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