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.

Andrew Kruegel, Kures president and co-founder (Columbia Tech Ventures via Vimeo)

Af­ter psilo­cy­bin and ke­t­a­mine, a new biotech comes along de­vel­op­ing a drug Scott Got­tlieb fought

Andrew Kruegel was six years into his chemistry work at Columbia University, when, one day in August 2016, he learned he might have only 30 days before the government made him destroy his research.

Kruegel had been studying kratom, a leaf long used in Southeast Asia as a stimulant or for pain. It had opioid-like properties, he found, but seemed to offer pain relief without the addictive potential or respiratory side effects of traditional opioids — a riddle that might help illuminate how human opioid receptors work.

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Regeneron CEO Leonard Schleifer speaks at a meeting with President Donald Trump, members of the Coronavirus Task Force, and pharmaceutical executives in the Cabinet Room of the White House (AP Photo/Andrew Harnik)

OWS shifts spot­light to drugs to fight Covid-19, hand­ing Re­gen­eron $450M to be­gin large scale man­u­fac­tur­ing in the US

The US government is on a spending spree. And after committing billions to vaccines defense operations are now doling out more of the big bucks through Operation Warp Speed to back a rapid flip of a drug into the market to stop Covid-19 from ravaging patients — possibly inside of 2 months.

The beneficiary this morning is Regeneron, the big biotech engaged in a frenzied race to develop an antibody cocktail called REGN-COV2 that just started a late-stage program to prove its worth in fighting the virus. BARDA and the Department of Defense are awarding Regeneron a $450 million contract to cover bulk delivery of the cocktail starting as early as late summer, with money added for fill/finish and storage activities.

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The home run count: The $100M+ mega-round boom in biotech in­spired a $7.3B feed­ing fren­zy — so far this year

Over the last 6 months there’s been a blizzard of money piling up drifts of the green stuff through the biotech landscape. And the forecast calls for more cash windfalls ahead.

Even as a global pandemic has killed more than half a million people, blighted economies and divided nations over the proper response, it’s also helped ignite an unprecedented burst of big-time investing. And not just in Covid-19 deals, as we’ve looked at before.

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UP­DAT­ED: Bio­gen shares spike as ex­ecs com­plete a de­layed pitch for their con­tro­ver­sial Alzheimer's drug — the next move be­longs to the FDA

Biogen is stepping out onto the high wire today, reporting that the team working on the controversial Alzheimer’s drug aducanumab has now completed their submission to the FDA. And they want the agency to bless it with a priority review that would cut the agency’s decision-making time to a mere 6 months.

The news drove a 10% spike in Biogen’s stock $BIIB ahead of the bell.

Part of that spike can be attributed to a relief rally. Biogen execs rattled backers and a host of analysts earlier in the year when they unexpectedly delayed their filing to the third quarter. That delay provoked all manner of speculation after CEO Michel Vounatsos and R&D chief Al Sandrock failed to persuade influential observers that the pandemic and other factors had slowed the timeline for filing. Actually making the pitch at least satisfies skeptics that the FDA was not likely pushing back as Biogen was pushing in. From the start, Biogen execs claimed that they were doing everything in cooperation with the FDA, saying that regulators had signaled their interest in reviewing the submission.

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For­bion spot­lights late-stage plays, carves out new €250M growth fund

Having staked its rep on picking out a mix of biotech investment opportunities across the “build,” “enable,” “growth” continuum, Forbion is launching its first fund dedicated to late-stage opportunities.

Forbion Growth Opportunities Fund’s first close brought in €185 million ($208 million). Existing investors Pantheon, KfW Capital and the European Investment Fund came on board, joined by new backers Eli Lilly, Horizon Therapeutics, Belgian Growth Fund and New Waves Investments.

Mer­ck ex­pands scope of Zymeworks an­ti­body al­liance, adding close to $900M in mile­stones

Nearly a decade after first partnering with Merck, Vancouver-based biotech Zymeworks has expanded its collaboration with the pharma giant once again.

Zymeworks re-upped with Merck in a new licensing agreement, granting the New Jersey pharma giant the right to develop up to 3 additional multispecific antibody candidates. In exchange, the biotech will receive an undisclosed upfront payment — Merck is always loath to discuss cash terms — and nearly $900 million in combined regulatory ($411 million) and commercial ($480 million) milestones.

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Nello Mainolfi (Kymera via YouTube)

Out to re­vive R&D, a resur­gent Sanofi pays $150M cash to part­ner up with a pi­o­neer­ing pro­tein degra­da­tion play­er

Frank Nestle was appointed Sanofi’s global head of immunology and inflammation research therapeutic area just days before dupilumab, the blockbuster-to-be IL-4 antibody, would be accepted for priority review. After four years of consolidating immunology expertise from multiple corners of the Sanofi family and recruiting new talents to build the discovery engine, he’s set eyes on a Phase I-ready program that he believes can grow into a Dupixent-sized franchise.

Atul Deshpande, Harbour BioMed chief strategy officer & head, US operations (Harbour BioMed)

An­oth­er biotech IPO set-up? Multi­na­tion­al biotech leaps from round to round, scoop­ing up cash at a blis­ter­ing pace

A short four months after announcing a $75 million haul in Series B+ fundraising, the multinational biotech Harbour BioMed pulled in another round of investments and eclipsed the nine-digit mark in the process.

Harbour completed its Series C financing, the company announced Thursday morning, raising $102.8 million and bringing its total investment sum to over $300 million since its founding in late 2016. The biotech plans to use the money to transition early-stage candidates from the discovery phase, fund candidates already in the clinic, and prep late-stage candidates for commercialization.

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Covid-19 roundup: CDC de­bat­ing who should get first avail­able vac­cines; EU in Gilead talks af­ter US gob­bled first remde­sivir dos­es

The federal government has now spent billions of dollars accelerating the development of a Covid-19 vaccine, and yet they’ve remained hush-hush on who, precisely, would actually get inoculated once the first doses are approved and available. Internally, though, they have been debating it.

The CDC and an advisory committee of outside health experts have been working since April to devise a ranking system that would determine who receives a vaccine and when, The New York Times reported. The question of who is first in line for inoculation is important because no matter how many doses developers can make or how quickly they can make them, doses will still come out in batches; 300 million inoculations will not appear overnight.

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