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.

Covid-19 roundup: Eu­rope pur­chas­es 80M dos­es of Mod­er­na's vac­cine; CO­V­AXX se­cures $2.8B in emerg­ing mar­ket pre-or­ders

With the announcement of its vaccine efficacy data last week, Moderna is starting to line up customers for its Covid-19 mRNA jabs.

The Massachusetts-based biotech announced Wednesday it has agreed to sell an initial round of 80 million doses to the European Commission, with the option to double the amount to 160 million. Once the member states rubber stamp the approval, the deal will be finalized.

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Pascal Soriot (AP Images)

UP­DAT­ED: As­traZeneca, Ox­ford on the de­fen­sive as skep­tics dis­miss 70% av­er­age ef­fi­ca­cy for Covid-19 vac­cine

On the third straight Monday that the world wakes up to positive vaccine news, AstraZeneca and Oxford are declaring a new Phase III milestone in the fight against the pandemic. Not everyone is convinced they will play a big part, though.

With an average efficacy of 70%, the headline number struck analysts as less impressive than the 95% and 94.5% protection that Pfizer/BioNTech and Moderna have boasted in the past two weeks, respectively. But the British partners say they have several other bright spots going for their candidate. One of the two dosing regimens tested in Phase III showed a better profile, bringing efficacy up to 90%; the adenovirus vector-based vaccine requires minimal refrigeration, which may mean easier distribution; and AstraZeneca has pledged to sell it at a fraction of the price that the other two vaccine developers are charging.

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Jason Kelly, Ginkgo Bioworks CEO (Kyle Grillot/Bloomberg via Getty Images)

Af­ter Ko­dak de­ba­cle, US lends $1.1B to a syn­thet­ic bi­ol­o­gy com­pa­ny and their big Covid-19, mR­NA plans

In mid-August, as Kodak’s $765 million government-backed push into drug manufacturing slowly fell apart in national headlines, Ginkgo Bioworks CEO Jason Kelly got a message from his company’s government liaison: HHS wanted to know if they, too, might want a loan.

The government’s decision to lend Kodak three quarters of a billion dollars raised eyebrows because Kodak had never made drugs before. But Ginkgo, while not a manufacturing company, had spent the last decade refining new ways to produce materials inside cells and building automated facilities across Boston.

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FDA hands Liq­uidia and Re­vance a CRL and de­fer­ral, re­spec­tive­ly, as Covid-19 cre­ates in­spec­tion chal­lenge

Two biotechs said they got turned away by the FDA on Wednesday, in part due to pandemic-related travel restrictions.

North Carolina-based Liquidia Technologies was handed a CRL for its lead pulmonary arterial hypertension drug, citing the need for more CMC data and on-site pre-approval inspections, which the FDA hasn’t been able to conduct due to travel restrictions. The agency also deferred its decision on Revance Therapeutics’ BLA for its frown line treatment, because it needs to inspect the company’s northern California manufacturing facility. The action, Revance emphasized, was not a CRL.

News brief­ing: FDA re­quests new tri­al for Reata's Friedre­ich's atax­ia pro­gram; J&J's Trem­fya picks up ex­pand­ed la­bel in Eu­rope

Three months after Reata Pharmaceuticals suggested its Friedreich’s ataxia program omaveloxolone could be delayed, the company revealed that is indeed going to be the case.

Reata $RETA shares took a nosedive Wednesday after the biotech revealed that the FDA said supplemental data for its pivotal trial did not strengthen the case for approval. As a result, the drug is likely to need another study before the FDA takes up the case.

Jef­frey Hat­field takes over from Diego Mi­ralles as CEO of Vi­vid­ion; Drag­on­fly scores a new ex­ec with COO Alex Lu­gov­skoy

→ San Diego protein degradation startup Vividion Therapeutics has made a change at the top with Jeffrey Hatfield taking the helm as CEO, replacing Diego Miralles six months after Roche forked over $135 million to collaborate with Vividion on their small molecule degraders. Hatfield is chairman of the board at miRagen Therapeutics and previously held the CEO job at Zafgen and Vitae Pharmaceuticals. He also had a series of leadership roles at Bristol Myers Squibb from 1996-2004, including SVP, immunology and virology divisions.

Chi­na opens the door for biotech in­vestors in Hong Kong to buy Shang­hai stocks, and vice ver­sa

When Shanghai’s STAR board began opening its doors to biotech, it was considered not just a rival to Nasdaq but also the stock exchange in Hong Kong. Those perceptions may take an amicable turn as China expands a mutual access program with the city.

The changes mean investors in mainland China will be able to own Hong Kong biotech chapter stocks, while those in Hong Kong — a much more internationally connected group — would have access to those listed on STAR. In effect, it turns the Shanghai market into a globally accessible exchange overnight while also broadening a key source of revenue for HKEX.

Bax­ter con­tin­ues on-shoring push with $50M In­di­ana ex­pan­sion

It’s been a banner year for the once humdrum business of manufacturing drugs, particularly vaccines. Billions have been spent ramping up facilities for Covid-19 jabs, while individual CDMOs have expanded their facilities, apparently anticipating demand or responding to a government-led push to onshore drug manufacturing.

Now Baxter Biopharma Solutions, the CDMO wing of the many-armed healthcare giant Baxter, is getting in on the game. On Tuesday, they announced plans to spend $50 million to expand their flagship, 600,000 square-foot facility in Bloomington, IN.

Eu­ro­pean Union aims to es­tab­lish patent workaround in case of emer­gen­cies while try­ing to strength­en its own IP

The European Union is looking at ways to bypass patent protections and make it easier to make generic drugs in cases of emergency such as the Covid-19 pandemic, a new document says.

Normally, under WTO regulations, the practice known as “compulsory licensing” is allowed in exceptional circumstances and could be applied as a waiver to bypass patent holders. Wednesday’s document was published as part of the EU’s plan to shore up the intellectual property rights of its member states.