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.

Donald and Melania Trump watch the smoke of fireworks from the South Lawn of the White House on July 4, 2020 (via Getty)

Which drug de­vel­op­ers of­fer Trump a quick, game-chang­ing ‘so­lu­tion’ as the pan­dem­ic roars back? Eli Lil­ly and Ab­Cellera look to break out of the pack

We are unleashing our nation’s scientific brilliance and will likely have a therapeutic and/or vaccine solution long before the end of the year.

— Donald Trump, July 4

Next week administration officials plan to promote a new study they say shows promising results on therapeutics, the officials said. They wouldn’t describe the study in any further detail because, they said, its disclosure would be “market-moving.”

— NBC News, July 3

Something’s cooking. And it’s not just July 4 leftovers involving stale buns and uneaten hot dogs.

Over the long weekend observers picked up signs that the focus in the Trump administration may swiftly shift from the bright spotlight on vaccines being promised this fall, around the time of the election, to include drugs that could possibly keep patients out of the hospital and take the political sting out of the soaring Covid-19 numbers causing embarrassment in states that swiftly reopened — as Trump cheered along.

So far, Gilead has been the chief beneficiary of the drive on drugs, swiftly offering enough early data to get remdesivir an emergency authorization and into the hands of the US government. But their drug, while helpful in cutting stays, is known for a limited, modest effect. And that won’t tamp down on the hurricane of criticism that’s been tearing at the White House, and buffeting the president’s most stalwart core defenders as the economy suffers.

We’ve had positive early-stage vaccine data, most recently from Pfizer and BioNTech, playing catchup on an mRNA race led by Moderna — where every little sign of potential trouble is magnified into a lethal threat, just as every advance excites a frenzy of support. But that race still has months to play out, with more Phase I data due ahead of the mid-stage numbers looming ahead. A vaccine may not be available in large enough quantities until well into 2021, which is still wildly ambitious.

So what about a drug solution?

Trump’s initial support for a panacea focused on hydroxychloroquine. But that fizzled in the face of data underscoring its ineffectiveness — killing trials that aren’t likely to be restarted because of a recent population-based study offering some support. And there are a number of existing drugs being repurposed to see how they help hospitalized patients.

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Sec­ond death trig­gers hold on Astel­las' $3B gene ther­a­py biotech's lead pro­gram, rais­ing fresh con­cerns about AAV

Seven months after Astellas shelled out $3 billion to acquire the gene therapy player Audentes, the biotech company’s lead program has been put on hold following the death of 2 patients taking a high dose of their treatment. And there was another serious adverse event recorded in the study as well, with a total of 3 “older” patients in the study affected.

The incidents are derailing plans to file for a near-term approval, which had been expected right about now.

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George Yancopoulos (Regeneron)

UP­DAT­ED: Re­gen­eron co-founder George Yan­copou­los of­fers a com­bat­ive de­fense of the po­lice at a high school com­mence­ment. It didn’t go well

Typically, the commencement speech at Yorktown Central School District in Westchester — like most high schools — is an opportunity to encourage students to face the future with confidence and hope. Regeneron president and co-founder George Yancopoulos, though, went a different route.

In a fiery speech, the outspoken billionaire defended the police against the “prejudice and bias against law enforcement” that has erupted around the country in street protests from coast to coast. And for many who attended the commencement, Yancopoulos struck the wrong note at the wrong time, especially when he combatively challenged someone for interrupting his speech with a honk for “another act of cowardness.”

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Elias Zerhouni (Photo by Vincent Isore/IP3/Getty Images)

Elias Zer­houni dis­cuss­es ‘am­a­teur hour’ in DC, the de­struc­tion of in­fec­tious dis­ease R&D and how we need to prep for the next time

Elias Zerhouni favors blunt talk, and in a recent discussion with NPR, the ex-Sanofi R&D and ex-NIH chief had some tough points to make regarding the pandemic response.

Rather than interpret them, I thought it would be best to provide snippets straight from the interview.

On the Trump administration response:

It was basically amateur hour. There is no central concept of operations for preparedness, for pandemics, period. This administration doesn’t want to or has no concept of what it takes to protect the American people and the world because it is codependent. You can’t close your borders and say, “OK, we’re going to be safe.” You’re not going to be able to do that in this world. So it’s a lack of vision, basically just a lack of understanding, of what it takes to protect the American people.

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Tesla and SpaceX founder Elon Musk gestures to the audience after being recognized by President Trump following the successful launch of a Falcon 9 rocket at the Kennedy Space Center. (via Getty Images)

Tes­la chief Elon Musk teams up with Covid-19 play­er Cure­Vac to build 'R­NA mi­cro­fac­to­ries'

Elon Musk has joined the global tech crusade now underway to revolutionize vaccine manufacturing — now aimed at delivering billions of doses of a new mRNA vaccine to fight Covid-19. And he’s cutting right to the front.

In a late-night tweet Wednesday, the Tesla chief announced:

Tesla, as a side project, is building RNA microfactories for CureVac & possibly others.

That’s not a lot to go on. But the tweet comes a year after Tesla’s German division in Grohmann and CureVac filed a patent on a “bioreactor for RNA in vitro transcription, a method for RNA in vitro transcription, a module for transcribing DNA into RNA and an automated apparatus for RNA manufacturing.” CureVac, in the meantime, has discussed a variety of plans to build microfactories that can speed up the whole process for a global supply chain.

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Paul Tesar (Convelo Therapeutics)

Io­n­is, lead­ing MS re­searcher throw an­ti­sense at a new type of brain cells

No matter how many molecules he threw at them, Paul Tesar couldn’t get the brain cells to survive. Or he got them to survive, but then — to everyone’s bafflement — they still couldn’t do what they were supposed to.

Tesar, a professor of innovative therapeutics at Case Western University, had spent years building stem cell models for multiple sclerosis, growing brain organoids in dishes and then seeing what small molecules restored myelin production. Now he was trying to do the same for other myelin diseases, particularly an ultra-rare genetic condition called Pelizaeus-Merzbacher disease, where a single mutation leads to the death of the myelin-producing neurons, called oligodendrocytes, and can kill patients in infancy.

Pfiz­er shares surge on pos­i­tive im­pact of their mR­NA Covid-19 vac­cine — part­nered with BioN­Tech — in an ear­ly-stage study

Pfizer and their partners at the mRNA specialist BioNTech have published the first glimpse of biomarker data from an early-stage study spotlighting the “robust immunogenicity” triggered by their Covid-19 vaccine, which is one of the leaders in the race to vanquish the global pandemic.

Researchers selected 45 healthy volunteers 18-55 years of age for the study. They were randomized to receive 2 doses, separated by 21 days, of 10 µg, 30 µg, or 100 µg of BNT162b1, “a lipid nanoparticle-formulated, nucleoside-modified, mRNA vaccine that encodes trimerized SARS-CoV-2 spike glycoprotein RBD.” Their responses were compared against the effect of a natural, presumably protective defense offered by a regular infection.

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An ex­pe­ri­enced biotech is stitched to­geth­er from transpa­cif­ic parts, with 265 staffers and a fo­cus on ‘new bi­ol­o­gy’

Over the past few years, different teams at a pair of US-based biotechs and in labs in Japan have labored to piece together a group of cancer drug programs, sharing a single corporate umbrella with research colleagues in Japan. But now their far-flung operations have been knit together into a single unit, creating a pipeline with 10 cancer drug development programs — going from early-stage right into Phase III — and a host of discovery projects managed by a collective staff of some 265 people.

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New stan­dard of care? FDA hands Pfiz­er, Mer­ck KGaA an OK for Baven­cio in blad­der can­cer

The breakthrough therapy designation Pfizer and Merck KGaA notched for Bavencio in bladder cancer has quickly paved way for a full approval.

The PD-L1 drug is now sanctioned as a first-line maintenance treatment for patients with locally advanced or metastatic urothelial carcinoma, applicable in cases where cancer hasn’t progressed after platinum-containing chemotherapy.

Petros Grivas, the principal investigator of the supporting Phase III JAVELIN Bladder 100, called the approval “one of the most significant advances in the treatment paradigm in this setting in 30 years.”