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.

Bio­mark­er 'roadmap­s' and the fu­ture of can­cer R&D; Cur­tain rais­es on #AS­CO22; Pfiz­er, No­var­tis tack­le drug ac­cess; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

While this was not a week for earth-shattering news, there were certainly a lot of interesting tidbits. If you found this recap helpful, please recommend it to your friends and colleagues. We’ll see you on the other side of the long weekend.

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Keep­ing pres­sure on Am­gen, Mi­rati draws mixed re­views on lat­est cut of KRAS da­ta

As the close runner-up to Amgen’s Lumakras in the KRAS race, any data cut from Mirati’s adagrasib continues to draw scrutiny from analysts. And the latest batch of numbers from ASCO is a decidedly mixed bag.

While a quick comparison suggests that adagrasib spurred slightly more responses and led to a longer overall survival than Lumakras among a group of non-small cell lung cancer patients, its duration of response appears shorter and the safety profile continues to spark concern.

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Ann is one of ViiV Healthcare's newest spokespeople as the retired school administrator speaks up about her HIV status.

GSK's Vi­iV de­buts next evo­lu­tion in HIV med Dova­to cam­paign with new spokes­peo­ple and new mes­sage

When Ann saw the first TV commercials for HIV medicine Dovato, she didn’t see herself represented. So the 74-year-old retired school administrator who’s been living with HIV since 1998, reached out to GSK’s ViiV Healthcare and asked why not?

Now Ann is one of three people starring in ViiV’s latest Dovato campaign called “Detect This.” The next-step evolution in the branded campaign plays on the word “detect” — often used in describing HIV status under control as undetectable — but in this case, uses the word as a directive for people to understand they can use fewer medicines.

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Tran­si­tion to new Eu­ro­pean clin­i­cal tri­als in­fo sys­tem starts slow­ly

At the end of January, the European Medicines Agency officially launched its new clinical trials info system (CTIS), although the migration to the new platform has only really just begun, and sponsors have until the end of January 2023 before all initial trial applications must be submitted through CTIS.

Overall, 56 clinical trial applications have been submitted in CTIS during the first 3 months since the launch of the system on Jan. 31, according to new data posted by the EMA. By comparison, about 4,000 new trials are authorized each year across Europe.

Switzer­land to de­stroy over 600,000 ex­pired dos­es of Mod­er­na Covid vac­cine

As concerns related to uptake and distribution continue to linger, Switzerland is among the first countries that plans to destroy hundreds of thousands of expired and unused Covid-19 vaccine doses.

The European country said it plans to destroy more than 600,000 doses of Moderna’s Spikevax Covid-19 vaccine as the doses have reached their expiration date.

However, Moderna CEO Stéphane Bancel told the World Economic Forum in Davos, Switzerland that he’s in the process of throwing 30 million doses in the garbage, exclaiming, “We have a big demand problem.”

Nassim Usman, Catalyst Biosciences CEO

Af­ter $60M Ver­tex deal, group of Cat­a­lyst share­hold­ers claims biotech could’ve sold as­sets three years ago

Catalyst Biosciences was down to five employees in March, and the biotech needed to do something after two rounds of layoffs, a nixed collaboration and a culling of its hemophilia program.

In came Vertex, with $60 million to buy up the South San Francisco biotech’s preclinical complement drugs, which target the system that bridges the body’s innate and adaptive immune response and a class most known for Ultomiris and Soliris. The deal includes CB 2782-PEG, the dry AMD drug that Biogen no longer wanted in March.

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Lina Khan, FTC chair (Graeme Jennings/Pool via AP Images)

Pile-on over PBMs con­tin­ues with FTC com­ments and a new bi­par­ti­san Sen­ate bill

More than 500 stakeholders sent comments to the FTC on whether the commission should look further into pharma middlemen, known as PBMs, with many of the commenters calling for more federal oversight.

Similar to the critical open comment period in a deadlocked FTC session last February, pharmacies and pharmacy groups are continuing to call out the lack of transparency among the top 3 PBMs, which control about 80% of the market.

Pharma brands are losing their shine with US consumers who are now thinking about the economy and inflation instead of Covid. (Credit: Shutterstock)

Phar­ma brands fade in an­nu­al Har­ris con­sumer vis­i­bil­i­ty poll: Mod­er­na drops off and Pfiz­er dips

As Covid-19 concerns are fading in the US, so is biopharma visibility. The annual Axios Harris Poll survey to determine and rank the 100 most top-of-mind brands in the US finds Moderna, which was No. 3 last year, not on the list at all for 2022, and Pfizer sinking 37 spots.

However, it’s not that Moderna or Pfizer did anything wrong, it’s just that Americans have moved on to other worries beyond Covid.

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HHS Secretary Xavier Becerra (Jacquelyn Martin/AP Images)

HHS fin­ish­es off Trump-era rule that would've erased ba­sic FDA regs with­out fre­quent re­views

HHS on Thursday finalized its decision to withdraw a rule, proposed just before former President Donald Trump left office, that would’ve caused thousands of HHS and FDA regulations to automatically expire if they weren’t reviewed within two years, and every 10 years thereafter.

The decision follows the filing of a lawsuit last March, in which several nonprofits alleged that the outgoing administration planted “a ticking timebomb” for HHS, essentially forcing it to devote an enormous amount of resources to the unprecedented and infeasible task of reviewing thousands of regulations regularly.