New NIH vi­ral vec­tor flips the script on sick­le cell dis­ease gene ther­a­py

Re­searchers at the NIH have rolled out a new ve­hi­cle for sick­le cell gene ther­a­py with high­er speeds and bet­ter horse­pow­er, po­ten­tial­ly al­low­ing vast­ly more ef­fi­cient gene trans­fer and a much larg­er car­ry­ing ca­pac­i­ty. The best part? Un­like cur­rent sick­le cell gene ther­a­py mod­els, the NIH one doesn’t have to dri­ve in re­verse.

In mice and mon­keys, the new ve­hi­cle was up to 10 times more ef­fi­cient and had a car­ry­ing ca­pac­i­ty – the amount of DNA it can haul – of up to 6 times that of the con­ven­tion­al vec­tors cur­rent­ly de­ployed in gene ther­a­py tri­als across the coun­try. Most no­tably, the new vec­tor can read the ther­a­peu­tic gene se­quence for­ward rather than read­ing them back­ward — a counter-in­tu­itive trick re­searchers had used to over­come long-run­ning bar­ri­ers to gene ther­a­py but which sac­ri­ficed ef­fi­cien­cy. The re­sults were pub­lished open ac­cess in Na­ture Com­mu­ni­ca­tions.

John Tis­dale NIH

“Our new vec­tor is an im­por­tant break­through in the field of gene ther­a­py for sick­le cell dis­ease,” said study se­nior au­thor John Tis­dale, chief of the Cel­lu­lar and Mol­e­c­u­lar Ther­a­peu­tic Branch at the Na­tion­al Heart, Lung, and Blood In­sti­tute (NHLBI). “It’s the new kid on the block and rep­re­sents a sub­stan­tial im­prove­ment in our abil­i­ty to pro­duce high ca­pac­i­ty, high-ef­fi­cien­cy vec­tors for treat­ing this dev­as­tat­ing dis­or­der.”

Gene ther­a­py tri­als for SCD have launched the past few years, bring­ing a hand­ful of well-cov­ered cas­es of pa­tients re­spond­ing strong­ly to the treat­ment, even as more da­ta shows cur­rent tech­niques are no cure-all. One of the big­ger long­stand­ing ques­tions, though, is how to best de­liv­er the ge­net­ic fix.

The sim­ple ge­net­ic un­der­pin­nings of the dis­ease have been well-un­der­stood since the 1950s — one A-T sub­sti­tu­tion in the β-glo­bin gene — and re­searchers have ac­cord­ing­ly tar­get­ed it since the first gene ther­a­py re­search in the 1980s. But the par­tic­u­lar prob­lems of build­ing a prop­er vec­tor for the he­mo­glo­bin gene, in ad­di­tion to the myr­i­ad oth­er ob­sta­cles to gene ther­a­py broad­ly, have im­ped­ed progress.

The steps in gene ther­a­py for sick­le cell dis­ease. Na­tion­al Heart, Lung, and Blood In­sti­tute

Click on the im­age to see the full-sized ver­sion

The lentivi­ral vec­tor blue­bird bio has used to bring its sick­le cell gene ther­a­py to tri­al is a workaround to an ear­ly prob­lem unique to sick­le cell ther­a­py. RNA splic­ing – a nat­ur­al process crit­i­cal to prepar­ing the vec­tor – will re­move “in­trons” that are key to ex­press­ing the genes to pro­duce he­mo­glo­bin. De­vel­op­ers have been able to get around this by us­ing a vec­tor that reads the DNA back­wards, last gene to first. Most gene ther­a­py tech­niques read as you would a sen­tence, first word to last.

The re­searchers al­so not­ed their vec­tors were cheap­er to pro­duce.

De­vel­op­ment of the Next Gen­er­a­tion NKG2D CAR T-cell Man­u­fac­tur­ing Process

Celyad’s view on developing and delivering a CAR T-cell therapy with multi-tumor specificity combined with cell manufacturing success
Transitioning potential therapeutic assets from academia into the commercial environment is an exercise that is largely underappreciated by stakeholders, except for drug developers themselves. The promise of preclinical or early clinical results drives enthusiasm, but the pragmatic delivery of a therapy outside of small, local testing is most often a major challenge for drug developers especially, including among other things, the manufacturing challenges that surround the production of just-in-time and personalized autologous cell therapy products.

Paul Hudson, Getty Images

UP­DAT­ED: Sanofi CEO Hud­son lays out new R&D fo­cus -- chop­ping di­a­betes, car­dio and slash­ing $2B-plus costs in sur­gi­cal dis­sec­tion

Earlier on Monday, new Sanofi CEO Paul Hudson baited the hook on his upcoming strategy presentation Tuesday with a tell-tale deal to buy Synthorx for $2.5 billion. That fits squarely with hints that he’s pointing the company to a bigger future in oncology, which also squares with a major industry tilt.

In a big reveal later in the day, though, Hudson offered a slate of stunners on his plans to surgically dissect and reassemble the portfoloio, saying that the company is dropping cardio and diabetes research — which covers two of its biggest franchise arenas. Sanofi missed the boat on developing new diabetes drugs, and now it’s pulling out entirely. As part of the pullback, it’s dropping efpeglenatide, their once-weekly GLP-1 injection for diabetes.

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Roger Perlmutter, Merck

#ASH19: Here’s why Mer­ck is pay­ing $2.7B to­day to grab Ar­Qule and its next-gen BTK drug, lin­ing up Eli Lil­ly ri­val­ry

Just a few months after making a splash at the European Hematology Association scientific confab with an early snapshot of positive data for their BTK inhibitor ARQ 531, ArQule has won a $2.7 billion buyout deal from Merck.

Merck is scooping up a next-gen BTK drug — which is making a splash at ASH today — from ArQule in an M&A pact set at $20 a share $ARQL. That’s more than twice Friday’s $9.66 close. And Merck R&D chief Roger Perlmutter heralded a deal that nets “multiple clinical-stage oral kinase inhibitors.”

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Left top to right: Mark Timney, Alex Denner, Vas Narasimhan. (The Medicines Company, Getty, AP/Endpoints News)

In a play-by-play of the $9.7B Med­Co buy­out, No­var­tis ad­mits it over­paid while of­fer­ing a huge wind­fall to ex­ecs

A month into his tenure at The Medicines Company, new CEO Mark Timney reached out to then-Novartis pharma chief Paul Hudson: Any interest in a partnership?

No, Hudson told him. Not now, at least.

Ten months later, Hudson had left to run Sanofi and Novartis CEO Vas Narasimhan was paying $9.7 billion for the one-drug biotech – the largest in the string of acquisitions Narasimhan has signed since his 2017 appointment.

The deal was the product of an activist investor and his controversial partner working through nearly a year of cat-and-mouse negotiations to secure a deal with Big Pharma’s most expansionist executive. It represented a huge bet in a cardiovascular field that already saw two major busts in recent years and brought massive returns for two of the industry’s most eye-raising names.

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Paul Hudson. Sanofi

New Sanofi CEO Hud­son adds next-gen can­cer drug tech to the R&D quest, buy­ing Syn­thorx for $2.5B

When Paul Hudson lays out his R&D vision for Sanofi tomorrow, he will have a new slate of interleukin therapies and a synthetic biology platform to boast about.

The French pharma giant announced early Monday that it is snagging San Diego biotech Synthorx in a $2.5 billion deal. That marks an affordable bolt-on for Sanofi but a considerable return for Synthorx backers, including Avalon, RA Capital and OrbiMed: At $68 per share, the price represents a 172% premium to Friday’s closing.

Synthorx’s take on alternative IL-2 drugs for both cancer and autoimmune disorders — enabled by a synthetic DNA base pair pioneered by Scripps professor Floyd Romesberg — “fits perfectly” with the kind of innovation that he wants at Sanofi, Hudson said.

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Jake Van Naarden, Josh Bilenker, Nisha Nanda (Credit: Loxo, Aisling Capital)

Josh Bilenker and his Loxo crew are tak­ing the reins on on­col­o­gy R&D at Eli Lil­ly, culling the weak and map­ping a new path

Josh Bilenker, Jake Van Naarden and Nisha Nanda came out of Eli Lilly’s $8 billion Loxo Oncology buyout with a bundle of cash and plenty of choices on what they could do next. Start a new company, go public. Live on the beach in 5-star luxury. Contemplate the stars — in their own observatory.

So what are they doing?

They formed a new executive team that is taking over the management of Eli Lilly’s hundreds-strong oncology R&D group — essentially using Loxo as a base for a bold new experiment in Big Pharma R&D in an attempt to create a true biotech environment with the deep pockets of a top-15 industry player. They’ve recruited David Hyman from Memorial Sloan Kettering to join the team as chief medical officer. And the mandate includes culling out the oncology pipeline, highlighting their star prospects and going after new programs wherever they can find the best prospects.

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Game on: Re­gen­eron's BC­MA bis­pe­cif­ic makes clin­i­cal da­ta de­but, kick­ing off mul­ti­ple myelo­ma matchup with Bris­tol-My­ers

As J&J attempts to jostle past Bristol-Myers Squibb and bluebird for a landmark approval of its anti-BCMA CAR-T — and while GlaxoSmithKline maps a quick path to the FDA riding on its own BCMA-targeting antibody-drug conjugates — the bispecifics are arriving on the scene to stake a claim for a market that could cross $10 billion per year.

The main rivalry in multiple myeloma is shaping up to be one between Regeneron and Bristol-Myers, which picked up a bispecific antibody to BCMA through its recently closed $74 billion takeover of Celgene. Both presented promising first-in-human data at the ASH 2019 meeting.

FDA lifts hold on Abeon­a's but­ter­fly dis­ease ther­a­py, paving way for piv­otal study

It’s been a difficult few years for gene and cell therapy startup Abeona Therapeutics. Its newly crowned chief Carsten Thiel was forced out last year following accusations of unspecified “personal misconduct,” and this September, the FDA imposed a clinical hold on its therapy for a form of “butterfly” disease. But things are beginning to perk up. On Monday, the company said the regulator had lifted its hold and the experimental therapy is now set to be evaluated in a late-stage study.

Roche faces an­oth­er de­lay in strug­gle to nav­i­gate Spark deal past reg­u­la­tors — but this one is very short

Roche today issued the latest in a long string of delays of its $4.3 billion buyout of Philadelphia-based Spark Therapeutics. The delay comes as little surprise — it is their 10th in as many months — as their most recent delay was scheduled to expire before a key regulatory deadline.

But it is notable for its length: 6 days.

Previous extensions had moved the goalposts by about 3 weeks to a month, with the latest on November 22 expiring tomorrow. The new delay sets a deadline for next Monday, December 16, the same day by which the UK Competition and Markets Authority has to give its initial ruling on the deal. And they already reportedly have lined up an OK from the FTC staff – although that’s only one level of a multi-step process.

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