An au­toim­mune up­start turns PD-L1 around to blaze a new ap­proach to di­a­betes, mul­ti­ple scle­ro­sis

PD-L1 has be­come one of the most fa­mil­iar tar­gets in the glob­al can­cer re­search world, a key play­er in me­di­at­ing a co­or­di­nat­ed im­mune sys­tem as­sault on can­cer cells. 

But what if you could al­so turn it around, use el­e­vat­ed PD-L1 to muf­fle an au­toim­mune re­sponse by T cells, hit­ting the brakes on the im­mune sys­tem and avoid­ing an as­sault on healthy tis­sue — rather than tak­ing your foot off the brake and tar­get­ing can­cer­ous cells?

A promi­nent Ital­ian in­ves­ti­ga­tor named Pao­lo Fio­r­i­na based, in part, at Boston Chil­dren’s put that idea to the test in PD-L1 de­fi­cient mice last year — adapt­ing blood stem cells — and found that it could co­or­di­nate an ef­fec­tive re­ver­sal of hy­per­glycemia and Type 1 di­a­betes, the in­her­it­ed form of the dis­ease in which the im­mune sys­tem at­tacks in­sulin-pro­duc­ing cells in the pan­creas.

He pub­lished his work in Sci­ence Trans­la­tion­al Med­i­cine.

In this case, Fio­r­i­na and his team used dif­fer­ent ap­proach­es, one of which in­volved de­liv­er­ing a gene with a healthy copy of PD-L1 in­to stem cells to reengi­neer them for a new role play­ing de­fense. Now, they’re us­ing that suc­cess­ful an­i­mal ex­per­i­ment to start a new biotech — dubbed Al­theia Sci­ence — which will look to try it in hu­mans in about 2.5 to 3 years.

Pao­lo Riz­zar­di

This isn’t the first time di­a­betes has been cured in mice. Hu­mans still face plen­ty of ob­sta­cles, so some healthy skep­ti­cism is al­ways war­rant­ed. But Pao­lo Riz­zar­di, who heads up the Mi­lan-based tech trans­fer group Au­ro­rA-TT, is a be­liev­er. 

Riz­zar­di has just lined up an $11 mil­lion launch round to com­plete the trans­la­tion­al work need­ed to de­vel­op an ef­fec­tive, com­mer­cial­ly vi­able, gene ther­a­py ap­proach that could adapt pa­tient stem cells to do the work with PD-L1.

“I like the idea,” Riz­zar­di tells me. “The con­cept was quite sim­ple,” where the sci­en­tists rec­og­nized a com­mon bi­o­log­ic mech­a­nism that worked across mul­ti­ple in­di­ca­tions.

And they are by no means lim­it­ing the ap­proach to di­a­betes. Al­theia’s team is work­ing on the be­lief that mul­ti­ple scle­ro­sis should be an ear­ly fo­cus at the com­pa­ny. And rheuma­toid arthri­tis as well as oth­er au­toim­mune con­di­tions could be added lat­er.

Di­a­betes, MS, rheuma­toid arthri­tis; these are all dis­eases with ma­jor pop­u­la­tions. But Riz­zar­di be­lieves that the ex­perts in the field are giv­ing birth to gen­er­a­tion 2.0 of gene ther­a­py, which can be adapt­ed to large num­bers with an econ­o­my of scale.

Mi­lan, which was home to the gene ther­a­py work that Glax­o­SmithK­line re­cent­ly spun out to Or­chard, has a broad group of ex­perts in gene ther­a­py op­er­at­ing at the San Raf­faele Sci­en­tif­ic In­sti­tute. But with gene ther­a­py ex­per­tise lined up along the East Coast, a group of po­ten­tial part­ners along with in­vestors who are hap­py to back pre­clin­i­cal work like this, Riz­zar­di felt the 3-mem­ber team do­ing the ini­tial work should have an of­fice in New York.

Some pri­vate in­vestors joined the Rovati fam­i­ly’s Fidim/Rot­tapharm Biotech group in pro­vid­ing the first $11 mil­lion, which could range up to $17 mil­lion as the project de­vel­ops.

“These num­bers are not that fas­ci­nat­ing for the US,” Riz­zar­di read­i­ly con­cedes, but they are “pret­ty good” for Eu­rope. And it’s enough for a lean-and-mean team to get through the proof-of-con­cept stage for this, when they’ll know if they have some­thing that could com­plete­ly dis­rupt ma­jor mar­kets.

That’s pret­ty good, too.

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.

“To be out of cardiovascular and diabetes is not easy for a company like ours with an incredibly proud history,” Hudson said on a call with reporters, according to the Wall Street Journal. “As tough a choice as that is, we’re making that choice.”

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What does $6.9B buy these days in on­col­o­gy R&D? As­traZeneca has a land­mark an­swer

Given the way the FDA has been whisking through new drug approvals months ahead of their PDUFA date, AstraZeneca and their partners Daiichi Sankyo may not have to wait until Q2 of next year to get a green light on trastuzumab deruxtecan (DS-8201).

The pharma giant this morning played their ace in the hole, showing off why they were willing to commit to a $6.9 billion deal — with $1.35 billion in a cash upfront — to partner on the drug.

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Large advertisements for the drug Vivitrol decorate the walls of Grand Central Station on June 15, 2017 in New York City. (Photo: Andrew Lichtenstein via Getty)

FDA slaps down Alk­er­mes for mis­lead­ing Viv­it­rol ads — don't for­get vul­ner­a­bil­i­ty to opi­oid over­dose

The ads piqued interest as soon as they started appearing in 2016: at Grand Central Station, on the Red Line in Cambridge, and on a billboard off the New Jersey Turnpike. All showed a young person, generally with his or her arms crossed, and the question, “what is Vivitrol?”

Vivitrol’s maker, Alkermes, was in the midst of a marketing and lobbying campaign to promote the anti-opioid addiction drug — a campaign that would face significant backlash for tarnishing competitors despite little evidence for Vivitrol’s superiority.

FDA in-house re­view spot­lights an is­sue with one of Hori­zon's end­points but notes ef­fi­ca­cy for lead drug

The FDA in-house review highlights a disagreement of investigators’ use of a key endpoint by Horizon Pharma in the late-stage trial for the top drug in its pipeline, but largely agreed that the antibody was effective.

Horizon submitted a BLA for thyroid eye disease (TED) drug teprotumumab in March, less than two years after they bought the drug (and the rest of a division) from Narrow River for $145 million upfront. With breakthrough status, priority review, orphan designation and in-house sales projections of up to $750 million, the one-time Roche reject became the marquee pipeline asset for a company that’s developed some of the world’s most expensive drugs.

Seat­tle Ge­net­ics de­tails pos­i­tive OS and PFS da­ta for tu­ca­tinib in breast can­cer

Seattle Genetics $SGEN is showing off more positive data around tucatinib, its pivotal-stage drug for HER2 positive breast cancer.

A month after hearing about solidly upbeat hazard ratios, we learned today that the estimated progression-free survival rate at one year was 33% in the tucatinib arm compared to 12% for patients taking trastuzumab and capecitabine alone.

Median PFS was 7.8 months (95% CI: 7.5, 9.6) in the tucatinib arm, compared to 5.6 months (95% CI: 4.2, 7.1) in the control arm.

Bat­tered, cash hun­gry In­tec feels the burn of No­var­tis re­jec­tion

It’s a case of some bad timing for Intec.

Just when a key trial testing the company’s Accordion drug delivery tech imploded in Parkinson’s disease, they handed Novartis data from a successful PK study of a custom Accordion pill engineered to deliver a Novartis compound to entice the Swiss drugmaker into signing a licensing agreement.

Novartis said thanks, but no thanks.

For the cash-strapped Israeli drug developer, the failure to clinch the deal marks a big blow. As of the third quarter, the company has $15.7 million in cash and equivalents, which HC Wainwright analysts estimate will keep the lights on into mid-2020.

Bris­tol-My­ers shows off a low-pro­file AML con­tender it gained from Cel­gene buy­out — and they’re tak­ing it straight to the FDA

Bristol-Myers Squibb reaped an enormous pipeline with its much-criticized $64 billion megadeal to buy Celgene. And it got a few hidden gems in the deal.

One of those gems was brought out for display on Tuesday, with a late-breaker at ASH on CC-486, which is now being prepped for regulatory filings at the FDA and elsewhere.

Celgene top-lined the positive results in a maintenance setting for acute myeloid leukemia a few months ago, but at ASH investigators pulled back the curtains on the all-important data they believe will give them an advantage in the commercial wars to come.

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De­sert­ed by Astel­las and Mer­ck, lit­tle Cor­re­vio still can't win over FDA pan­el con­cerned with its AFib drug's safe­ty

When the FDA spurned Astellas’ pitch for atrial fibrillation drug vernakalant in 2008, regulators made it abundantly clear that it wasn’t the efficacy they had a problem with — two Phase III trials had shown the drug successfully restored 52% of patients’ heartbeat from irregular to normal — but the cardio safety issues for a drug that was to compete with well established, low-risk options. One licensing deal, one clinical hold and several studies later, the chances of approval aren’t looking any better.