In race for in vi­vo sick­le cell cure, In­tel­lia un­veils (very) ear­ly proof-of-con­cept

Ver­tex and CRISPR Ther­a­peu­tics have shown they can use the gene edit­ing tool to cure, for at least a cou­ple years, a hand­ful of pa­tients with sick­le cell dis­ease and are now en­ter­ing late-stage de­vel­op­ment.

It’s a ma­jor ad­vance, but it comes with the same caveats that have plagued oth­er gene ther­a­pies for sick­le cell. You have to give pa­tients what amounts to a bone mar­row trans­plant: a la­bo­ri­ous, ex­pen­sive and oc­ca­sion­al­ly risky pro­ce­dure that in­volves re­mov­ing stem cells from their mar­row, edit­ing them in a fa­cil­i­ty and then re-in­ject­ing them. Any com­pa­ny that could find a way to ed­it cells with a sim­ple IV in­fu­sion could make those old­er ap­proach­es ob­so­lete.

In­tel­lia, one of the first big CRISPR com­pa­nies, un­veiled one new ap­proach to reach­ing that sim­ple IV at a sci­en­tif­ic con­fer­ence Wednes­day. The biotech used cus­tom lipid nanopar­ti­cles — those nowfa­mous tiny bub­bles of fat — to car­ry CRISPR in­to the bone mar­row of mice and ed­it stem cells there. Af­ter re­peat­ed dos­ing, the com­pa­ny’s sci­en­tists said they were able to ed­it more than enough cells to pro­vide a func­tion­al cure for sick­le cell.

John Leonard

“This new da­ta sup­ports the pos­si­bil­i­ty of de­liv­er­ing a safer so­lu­tion to treat blood dis­or­ders, in­clud­ing sick­le cell dis­ease, by avoid­ing the need for bone mar­row trans­plan­ta­tion,” In­tel­lia CEO John Leonard said in a state­ment.

The re­sults pro­vide a (very) ear­ly proof of con­cept for an ap­proach the Gates Foun­da­tion has al­ready bet on. In the fall, they award­ed In­tel­lia a grant of $2.8 mil­lion to de­vel­op their lipid nanopar­ti­cle CRISPR sys­tem for sick­le cell dis­ease and HIV, an­oth­er dead­ly dis­ease that might be cured by edit­ing stem cells in the bone mar­row.

Still, In­tel­lia is far from alone in that race. Their cross-town gene edit­ing ri­vals CRISPR Ther­a­peu­tics al­so re­ceived a sim­i­lar­ly sized grant from the foun­da­tion to de­vel­op lipid nanopar­ti­cles that tar­get the bone mar­row, al­though theirs is ex­clu­sive­ly HIV-fo­cused. And oth­ers, most no­tably Fred Hutch’s Hans Pe­ter-Kiem and Uni­ver­si­ty of Wash­ing­ton’s An­dré Lieber, have gone much fur­ther on an ap­proach that us­es a mod­i­fied virus to de­liv­er a gene for func­tion­ing he­mo­glo­bin di­rect­ly in­to pa­tients’ stem cells, show­ing proof-of-con­cept in mon­keys. A well-heeled biotech called En­so­ma, launched last month, is de­vel­op­ing their ap­proach fur­ther.

In­tel­lia, though, is the on­ly com­pa­ny to date to use lipid nanopar­ti­cles for gene edit­ing or gene ther­a­py in pa­tients. Last year, they start­ed dos­ing pa­tients with a CRISPR ther­a­py meant to knock out the cen­tral gene in a rare liv­er dis­ease.

While gene ther­a­py com­pa­nies have re­lied large­ly on mod­i­fied virus­es to de­liv­er new genes in­to hu­man cells, gene edit­ing com­pa­nies have re­lied much more heav­i­ly on nanopar­ti­cles. CRISPR ma­chin­ery is of­ten too large and clunky to fit in­to those virus­es. And al­though gene ther­a­py com­pa­nies need virus­es to get the ther­a­peu­tic gene to stay in­side a cell for years, CRISPR com­pa­nies just need their ther­a­py to hit once and per­ma­nent­ly al­ter the DNA.

The biggest hur­dle is that most lipid nanopar­ti­cles go di­rect­ly to the liv­er. Com­pa­nies have spent hun­dreds of mil­lions of dol­lars try­ing to de­vel­op ones that are tar­get­ed to oth­er re­gions of the body, such as the brain or mus­cle. Beam Ther­a­peu­tics re­cent­ly spent up to $420 mil­lion to pur­chase an aca­d­e­m­ic spin­out de­vot­ed sole­ly to build­ing tar­get­ed lipid nanopar­ti­cles.

In­tel­lia de­vel­oped lipid nanopar­ti­cles that tar­get the bone mar­row. They pre­dict, based on stud­ies from ear­ly sick­le cell gene ther­a­pies, that they would need to ed­it 20% of cells to of­fer a func­tion­al cure. Af­ter a sin­gle dose in­to mice, they were able to ed­it about 10%.

Un­like oth­er de­liv­ery meth­ods, lipid nanopar­ti­cles can be giv­en re­peat­ed­ly. Af­ter a sec­ond dose, they had edit­ed about 25% of bone mar­row cells. Af­ter the 4th dose, they had edit­ed more than 40% of cells.

In a note to in­vestors, Chardan’s Geu­lah Livshits said the da­ta were quite ear­ly but en­cour­ag­ing.

“We could en­vi­sion such strate­gies emerg­ing in com­ing years and, while many un­knowns re­main, see In­tel­lia’s ear­ly da­ta as a step in that di­rec­tion,” she said.

Qual­i­ty Con­trol in Cell and Gene Ther­a­py – What’s Re­al­ly at Stake?

In early 2021, Bluebird Bio was forced to suspend clinical trials of its gene therapy for sickle cell disease after two patients in the trial developed cancer. As company scientists rushed to assess whether there was any causal link between the therapy and the cancer cases, Bluebird’s stock value plummeted – as did those of multiple other biopharma companies developing similar therapies.

While investigations concluded that the gene therapy was unlikely to have caused cancer, investors and the public may be more skittish regarding the safety of gene and cell therapies after this episode. This recent example highlights how delicate the fields of cell and gene therapy remain today, even as they show great promise.

Law pro­fes­sors call for FDA to dis­close all safe­ty and ef­fi­ca­cy da­ta for drugs

Back in early 2018 when Scott Gottlieb led the FDA, there was a moment when the agency seemed poised to release redacted complete response letters and other previously undisclosed data. But that initiative never gained steam.

Now, a growing chorus of researchers are finding that a dearth of public data on clinical trials and pharmaceuticals means industry and the FDA cannot be held accountable, two law professors from Yale and New York University write in an article published Wednesday in the California Law Review.

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Novavax CEO Stanley Erck at the White House in 2020 (Andrew Harnik, AP Images)

As fears mount over J&J and As­traZeneca, No­vavax en­ters a shaky spot­light

As concerns rise around the J&J and AstraZeneca vaccines, global attention is increasingly turning to the little, 33-year-old, productless, bankruptcy-flirting biotech that could: Novavax.

In the now 16-month race to develop and deploy Covid-19 vaccines, Novavax has at times seemed like the pandemic’s most unsuspecting frontrunner and at times like an overhyped also-ran. Although they started the pandemic with only enough cash to last 6 months, they leveraged old connections and believers into $2 billion and emerged last summer with data experts said surpassed Pfizer and Moderna. They unveiled plans to quickly scale to 2 billion doses. Then they couldn’t even make enough material to run their US trial and watched four other companies beat them to the finish line.

FDA of­fers scathing re­view of Emer­gent plan­t's san­i­tary con­di­tions, em­ploy­ee train­ing af­ter halt­ing pro­duc­tion

The FDA wrapped up its inspection of Emergent’s troubled vaccine manufacturing plant in Baltimore on Tuesday, after halting production there on Monday. By Wednesday morning, the agency already released a series of scathing observations on the cross contamination, sanitary issues and lack of staff training that caused the contract manufacturer to dispose of millions of AstraZeneca and J&J vaccine doses.

Brad Bolzon (Versant)

Ver­sant pulls the wraps off of near­ly $1B in 3 new funds out to build the next fleet of biotech star­tups. And this new gen­er­a­tion is built for speed

Brad Bolzon has an apology to offer by way of introducing a set of 3 new funds that together pack a $950 million wallop in new biotech creation and growth.

“I want to apologize,” says the Versant chairman and managing partner, laughing a little in the intro, “that we don’t have anything fancy or flashy to tell you about our new fund. Same team, around the same amount of capital, same investment strategy. If it ain’t broke, don’t fix it.”

But then there’s the flip side, where everything has changed. Or at least speeded into a relative blur. Here’s Bolzon:

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Sen. Patty Murray (D-WA) (Graeme Sloan/Sipa USA/Sipa via AP Images)

Sen­a­tors to NIH: Do more to pro­tect US bio­med­ical re­search from for­eign in­flu­ence

Although Thursday’s Senate health committee hearing was focused on how foreign countries and adversaries might be trying to steal or negatively influence biomedical research in the US, the only country mentioned by the senators and expert witnesses was China.

Committee chair Patty Murray (D-WA) made clear in her opening remarks that the US cannot “let the few instances of bad actors” overshadow the hard work of the many immigrant researchers in the US, many of which have won Nobel prizes for their work. But she also said, “There is more the NIH can be doing here.”

Jenny Rooke (Genoa Ventures)

Ear­ly Zymer­gen in­vestor Jen­ny Rooke re­flects on 'chimeras' in biotech, what it takes to spot a $500M gem

When Jenny Rooke first heard of Zymergen back in 2014, she knew she was looking at something different and exciting. The Emeryville, CA biotech held the promise of blending biology and technology to solve a huge unmet need for cost-effective chemicals — of all things — and a stellar founding team to boot.

But back then, West Coast venture capitalists didn’t see in Zymergen the one thing they were looking for in a winning biotech: therapeutic potential. Rooke, however, saw an opportunity and made her bets. Seven years later, that bet is paying off in a big way.

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Saurabh Saha at Endpoints News' #BIO19

On the heels of $250M launch, Centes­sa barges ahead with an IPO to fu­el its 10-in-1 Medicxi pipeline

Francesco De Rubertis made no secret of IPO plans for Centessa, his 10-in-1 legacy play. Barely two months later, the S-1 is in.

The hot-off-the-press filing depicts the same grand vision that the longtime VC touted when he did the rounds in February: Take the asset-centric mindset that he’s been preaching at Medicxi over the years, and roll up a bunch of biotech upstarts, with unrelated risk profiles, into 1 pharma company that can carry on the development at scale.

Why re­mote drug man­u­fac­tur­ing eval­u­a­tions won't re­al­ly re­duce FDA's back­log of in­spec­tions

For the first several months of the pandemic last spring, the FDA continued to plow through its user fee-enabled work on new drug and biologic applications, meeting nearly all of its goal dates.

But by last fall and into the winter, complete response letters and other delays began arriving in companies’ mailboxes as the agency struggled to catch up to a growing backlog of both domestic and foreign drug manufacturing inspections.

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