Federico Mingozzi (Spark)

Spark touts an­i­mal da­ta for a so­lu­tion to AAV gene ther­a­py's an­ti­body prob­lem

Among all the lim­i­ta­tions of us­ing an ade­no-as­so­ci­at­ed virus as a vec­tor to de­liv­er a gene — still the most es­tab­lished modal­i­ty in gene ther­a­py giv­en years of tri­al and er­ror and fi­nal­ly suc­cess — the pres­ence of neu­tral­iz­ing an­ti­bod­ies, whether pre-ex­ist­ing or in­duced, looms large.

“When I think about the im­mune re­spons­es in AAV, I try to sort of lay­er them,” Fed­eri­co Min­gozzi, the CSO at Spark Ther­a­peu­tics, told End­points News. “The an­ti­body is the first lay­er. It’s the first block that you find when you’re try­ing to do gene trans­fer.”

Pre-ex­ist­ing an­ti­bod­ies ac­quired from in­fec­tions by wild-type AAV dis­qual­i­fy any­where from 30% to 70% of pa­tients from clin­i­cal tri­als; high titers of an­ti­bod­ies trig­gered by a first ad­min­is­tra­tion of a gene ther­a­py ren­der re­dos­ing es­sen­tial­ly im­pos­si­ble. But Min­gozzi and his team — now work­ing as a sub­sidiary of Roche — said they have found a tech­nol­o­gy that can dis­man­tle this lay­er.

They didn’t in­vent IdeS, short for im­munoglob­u­lin G-de­grad­ing en­zyme of Strep­to­coc­cus pyo­genes. In fact, the re­searchers said the “ex­cel­lent” safe­ty pro­file the en­zyme has ac­crued in clin­i­cal tri­als for IgG-me­di­at­ed au­toim­mune dis­eases and in trans­plant pa­tients boost­ed their con­fi­dence in car­ry­ing out the new work. Pre­vi­ous stud­ies al­so sug­gest that IdeS cleaves an­ti­bod­ies in the blood­stream, but on­ly tran­sient­ly — which Min­gozzi said is per­fect for gene ther­a­py.

“Ba­si­cal­ly all you need is a win­dow of time that al­lows you to in­ject the vec­tor and al­low the vec­tor to get to the tar­get tis­sue, and then the vec­tor once it’s in­side the cell is pro­tect­ed from an­ti­bod­ies, so you don’t care any longer,” he said. “And this win­dow of time is on­ly a cou­ple of hours.”

Re­port­ing in Na­ture Med­i­cine, the team wrote that IdeS treat­ment de­creased the lev­els of IgG in both mice, non-hu­man pri­mates that were then giv­en an AAV8 vec­tor car­ry­ing a gene for fac­tor IX. Trans­gene ex­pres­sion and liv­er gene trans­duc­tion al­so ap­peared to be high­er. The same ef­fects were ob­served in ex­per­i­ments with hu­man plas­ma sam­ples, in­clud­ing some from prospec­tive clin­i­cal tri­al par­tic­i­pants, they added.

The find­ing that IdeS worked not just against an­ti­bod­ies that were al­ready there but al­so new ones de­vel­oped as a re­sult of vec­tor ad­min­is­tra­tion is sur­pris­ing, Min­gozzi said, as the lat­ter of­ten stirs up high and long-last­ing titers.

Re­dos­ing of gene ther­a­py has been on the wish list of sci­en­tists who are con­cerned about the ef­fects wan­ing over time, an is­sue that could be es­pe­cial­ly per­ti­nent for pa­tients re­ceiv­ing an in­jec­tion as in­fants.

Oth­er im­mu­ni­ty-re­lat­ed is­sues, of course, may still crop up, such as T cell re­spons­es that are cur­rent­ly be­ing con­trolled by cor­ti­cos­teroids. But Min­gozzi is hope­ful that the tech­nol­o­gy will go a long way in ex­tend­ing the reach of these po­ten­tial­ly cu­ra­tive treat­ments, with the most im­me­di­ate ap­pli­ca­tion in liv­er gene trans­fer.

While oth­er com­pa­nies are de­vel­op­ing IdeS for oth­er con­di­tions, Spark has filed for IP around this par­tic­u­lar use, he said. Pre­clin­i­cal work, in­clud­ing GLP tox­i­col­o­gy stud­ies, is on­go­ing to push it to­ward the clin­ic — at which point the de­vel­op­ment team will have to fig­ure out with reg­u­la­tors how they can re­design and as­sess tri­als that will in­clude an­ti-AAV an­ti­body seropos­i­tive pa­tients.

Secretary of health and human services Alex Azar speaking in the Rose Garden at the White House (Photo: AFP)

Trump’s HHS claims ab­solute au­thor­i­ty over the FDA, clear­ing path to a vac­cine EUA

The top career staff at the FDA has vowed not to let politics overrule science when looking at vaccine data this fall. But Alex Azar, who happens to be their boss’s boss, apparently won’t even give them a chance to stand in the way.

In a new memorandum issued Tuesday last week, the HHS chief stripped the FDA and other health agencies under his purview of their rule making ability, asserting all such power “is reserved to the Secretary.” Sheila Kaplan of the New York Times first obtained and reported the details of the September 15 bulletin.

President Donald Trump (via AP Images)

Signs of an 'Oc­to­ber Vac­cine Sur­prise' alarm ca­reer sci­en­tists

President Donald Trump, who seems intent on announcing a COVID-19 vaccine before Election Day, could legally authorize a vaccine over the objections of experts, officials at the FDA and even vaccine manufacturers, who have pledged not to release any vaccine unless it’s proved safe and effective.

In podcasts, public forums, social media and medical journals, a growing number of prominent health leaders say they fear that Trump — who has repeatedly signaled his desire for the swift approval of a vaccine and his displeasure with perceived delays at the FDA — will take matters into his own hands, running roughshod over the usual regulatory process.

#ES­MO20: Push­ing in­to front­line, Mer­ck and Bris­tol My­ers duke it out with new slate of GI can­cer da­ta

Having worked in parallel for years to move their respective PD-1 inhibitors up to the first-line treatment of gastrointestinal cancers, Merck and Bristol Myers Squibb finally have the data at ESMO for a showdown.

Comparing KEYNOTE-590 and CheckMate-649, of course, comes with the usual caveats. But a side-by-side look at the overall survival numbers also offer some perspective on a new frontier for the reigning checkpoint rivals, both of whom are claiming to have achieved a first.

Frank Zhang (AP Images)

Rocked by cus­toms in­ves­ti­ga­tion, Leg­end's CFO takes over as CEO Frank Zhang placed un­der house ar­rest

When Frank Zhang stepped down from GenScript — the contract research group he’s run for 18 years — to take up the CEO post at its CAR-T focused spinout Legend Biotech, he assured analysts that he was in for the long haul.

Just 49 days later, though, he’s been forced to hand back the title.

In a dramatic turn of events, Legend disclosed that Zhang is under house arrest in China as part of a customs investigation involving GenScript. While he remains the chairman, CFO Ying Huang has been tapped to double as interim CEO.

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UP­DAT­ED: Two wild weeks for Grail end in $8B Il­lu­mi­na buy­out

Grail’s whirlwind two weeks have ended in the wealthy arms of its former founder and benefactors.

Illumina has shelled out $8 billion to reacquire the closely-watched liquid biopsy startup they spun out just 5 years ago and sold off much of its shares just 3 years ago. The deal comes nearly two weeks after the well-heeled startup filed for a potentially massive IPO — one that was disrupted just a week later when Bloomberg reported that Illumina was in talks to buy their former spinout for up to $8 billion.

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Roche vaults to the front of the NL­RP3 clin­i­cal race, pay­ing $448M up­front to bag In­fla­zome

Roche is going all in on NLRP3.

The pharma giant is putting down $448 million (€380 million) upfront to snatch Novartis-backed Inflazome, which makes it a clinical player in the space overnight.

Dublin and Cambridge, UK-based Inflazome is the second NLRP3-focused biotech Roche has acquired in less than two years, and although no numbers were disclosed in the Jecure buyout, this is almost certainly a much larger deal.

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Anthony Fauci (AP Images)

A press of­fi­cer at An­tho­ny Fau­ci’s NI­AID was un­masked as a hard-right Covid troll. He just re­tired to­day

William B Crews had been a public affairs specialist at the NIH’s National Institute of Allergy and Infectious Diseases.

That ended today when he informed the agency of his decision to retire, after he was identified as the managing editor at RedState, a prominent Trump loyalist website.

Crews’ RedState duties are performed under the alias streiff. While enjoying the benefits of pseudonymity, he disparaged and worked against NIAID with an incendiary level of rhetoric in the midst of a pandemic.

#ES­MO20: Bris­tol My­ers marks Op­di­vo's sec­ond ad­ju­vant win — eye­ing a stan­dard of care gap

Moving into earlier and earlier treatment lines, Bristol Myers Squibb is reporting that adjuvant treatment with Opdivo has doubled the time that esophageal or gastroesophageal junction cancer patients stay free of disease.

With the CheckMate-577 data at ESMO, CMO Samit Hirawat said, the company believes it can change the treatment paradigm.

While a quarter to 30% of patients typically achieve a complete response following chemoradiation therapy and surgery, the rest do not, said Ronan Kelly of Baylor University Medical Center. The recurrence rate is also high within the first year, Hirawat added.

Donald Trump, AP

Covid-19 roundup: Trump sug­gests Pfiz­er vac­cine could be first ap­proved; VBI Vac­cines inks de­vel­op­ment deal with Cana­da

President Donald Trump commented Monday morning that Pfizer’s Covid-19 vaccine candidate could be the first to win approval by regulators.

During an interview on a Fox News’ morning show, the president said Pfizer was doing “very well” when asked which candidate could be approved, according to a Reuters report. He added that J&J could follow up afterward, saying “they’ll probably be a little later.”