Yale spin­out re-en­gi­neers an im­munother­a­py GSK, oth­ers once aban­doned

Be­gin­ning in 2004, Glax­o­SmithK­line ran 5 dif­fer­ent tri­als to see if giv­ing pa­tients a mol­e­cule called IL-18 could treat their can­cers. An ear­ly form of im­munother­a­py, it was sup­posed to boost the body’s nat­ur­al abil­i­ty to fight tu­mors.

It didn’t. The largest of the stud­ies was ter­mi­nat­ed ear­ly; the tu­mors pro­gressed af­ter around 7 months no mat­ter how much IL-18 you gave them. The field even­tu­al­ly moved on both from IL-18 and, to a de­gree, from the class of im­mune mod­u­la­tors, called cy­tokines, in gen­er­al.

Fail­ure is par the course in can­cer re­search. Still, this par­tic­u­lar fail­ure both­ered Yale im­mu­nol­o­gist Aaron Ring. Sim­i­lar mol­e­cules, IL-2 and IL-15, had been ap­proved as drugs, and when he searched a cou­ple years ago for path­ways that may have been over­looked in drug de­vel­op­ment, the search turned up IL-18; T cells and nat­ur­al killer cells around the tu­mor were cov­ered in re­cep­tors for it. In the­o­ry, you should’ve been able to send IL-18 and stim­u­late them.

Aaron Ring

“It looked like this open port we could tap in­to and send this pow­er­ful pro-in­flam­ma­to­ry mes­sage,” Ring told End­points News. “So we were re­al­ly in­trigued by this para­dox that IL-18 had been tried in the clin­ic and failed and not due to safe­ty con­cerns but for lack of ef­fi­ca­cy.”

The an­swer, Ring learned, was that de­coy re­cep­tors around the tu­mor were soak­ing up that IL-18, ef­fec­tive­ly neu­ter­ing it. Al­though the de­coy re­cep­tor is ex­pressed through­out the body, Ring found it was par­tic­u­lar­ly present around can­cers. So he and his team de­vel­oped a de­coy for the de­coy, a pro­tein that would bind on­ly to IL-18 re­cep­tors and not the vari­ant. Ring pub­lished the re­sults yes­ter­day in Na­ture, and with it, an­nounced the launch of a new biotech that, with $25 mil­lion in back­ing, will try to put their new pro­tein in­to the clin­ic by next year.

If it holds up, the new pro­tein, called DR-18, could be giv­en with oth­er im­munother­a­pies such as PD-1 in­hibitors or CAR-T to en­hance their ef­fec­tive­ness. DR-18 could ef­fec­tive­ly act as a check­point ther­a­py for the in­nate im­mune sys­tem, amp­ing up both nat­ur­al killer cells and T cells’ abil­i­ty to at­tack a tu­mor. In a re­view pub­lished the same day, Mark Smyth of the QIMR Berghofer Med­ical Re­search In­sti­tute, said the study had “broad trans­la­tion­al im­pli­ca­tions.”

So­nia Shar­ma

So­nia Shar­ma, as­sis­tant pro­fes­sor at the La Jol­la In­sti­tute for Im­munol­o­gy, called the Na­ture pa­per “el­e­gant” and “clever” and a “re­al­ly nice proof of con­cept” for bring­ing cy­tokines back in­to can­cer re­search. Still, she cau­tioned there could be se­ri­ous dif­fi­cul­ties mov­ing it from mice to hu­mans.

Can­cer treat­ments that af­fect the adap­tive im­mune sys­tem, such as check­point ther­a­pies and CAR-T, can cause that sys­tem to go in­to over­drive, some­times killing tu­mors but al­so oc­ca­sion­al­ly lead­ing to dan­ger­ous hy­per-in­flam­ma­tion. Over­stim­u­lat­ing the in­nate im­mune sys­tem can be even more harm­ful, she said, be­cause a sig­nal like IL-18 af­fects a broad­er range of cells and path­ways.

The body makes the de­coy mol­e­cule — known tech­ni­cal­ly as IL-18BP or IL-18 bind­ing pro­tein — pre­cise­ly be­cause too much IL-18 can lead to hy­per­in­flam­ma­tion au­toim­mune dis­or­ders. Se­vere ad­verse events have been seen with oth­er in­ter­leukins and oth­er drugs that change the in­nate im­mune sys­tems, such as STING in­hibitors.

“The body’s turn­ing up IL-18BP for a rea­son,” Shar­ma told End­points. “This is go­ing to hinge on how they de­liv­er this, be­cause in­fus­ing a pa­tient with a com­bi­na­tion of IL-18 that isn’t sen­si­tive to its nat­ur­al in­hibitor and then com­bin­ing that with an an­ti PD-1 might in­duce se­ri­ous side ef­fects.”

Ring’s team built DR-18 us­ing a No­bel Prize-win­ning process called “di­rect­ed evo­lu­tion.” Es­sen­tial­ly, they made 250 mil­lion ran­dom ge­net­ic vari­a­tions of IL-18, search­ing for one that would bind to IL-18 and not IL-18BP. Be­cause the de­coy mol­e­cule is much bet­ter at bind­ing to IL-18 than the ac­tu­al re­cep­tor, they found on­ly 11 dif­fer­ent vari­ants that fit the cri­te­ria. They whit­tled those to two, and then, af­ter look­ing at how each stim­u­lat­ed test-tube nat­ur­al killer cells, one.

In mice tu­mors, they found, IL-18 had lit­tle ef­fect but DR-18 worked at a “com­men­su­rate or su­pe­ri­or” rate to PD-1 ther­a­py. When they com­bined DR-18 and a PD-1 in­hibitor, the tu­mors dis­ap­peared in most of the mice. Fur­ther analy­sis showed this hap­pened be­cause of the mol­e­cule chang­ing the make­up of T cells around the tu­mor and re-ac­ti­vat­ing NK cells.

The pa­per ac­knowl­edged the po­ten­tial for tox­i­c­i­ties but said pre­clin­i­cal da­ta found the drug would be well-tol­er­at­ed.

The new com­pa­ny, called Sim­cha Ther­a­peu­tics, will try to ad­vance the drug in­to the clin­ic by the first half of 2021. So far, it’s just been Ring and a se­ries of con­sul­tants and board mem­bers —  no em­ploy­ees — but with the new fi­nanc­ing, they will now look to fill out a team. In­vestors in­clud­ed WuXi AppTec’s Cor­po­rate Ven­ture Fund, Se­quoia Cap­i­tal Chi­na, and Con­necti­cut In­no­va­tions.

Al­though it’s Ring’s first com­pa­ny, it won’t be his first li­censed com­pound. In 2012, as a grad­u­ate stu­dent, he co-in­vent­ed an IL-2 drug that’s now in pre­clin­i­cal stud­ies at Medicen­na Ther­a­peu­tics. A year lat­er, he pub­lished a CD-47 drug in Sci­ence that’s now the lead drug for ALX On­col­o­gy.

DR-18 is Sim­cha’s on­ly as­set for now, but Ring said the same tech­niques could be used to re­vive a range of oth­er cy­tokines and im­munother­a­pies that drug com­pa­nies aban­doned be­cause of ear­ly bi­o­log­i­cal lim­i­ta­tions.

“It’s re­al­ly an ar­che­type,” he said. “It’s a tem­plate for how we would ap­proach oth­er types of cy­tokines and mol­e­cules. Es­sen­tial­ly, the idea is we don’t want to ac­cept na­ture’s so­lu­tion.”

Patrick Soon-Shiong at the JP Morgan Healthcare Conference, Jan. 13, 2020 (David Paul Morris/Bloomberg via Getty Images)

Af­ter falling be­hind the lead­ers, dissed by some ex­perts, biotech show­man Patrick Soon-Sh­iong fi­nal­ly gets his Covid-19 vac­cine ready for a tri­al. But can it live up to the hype?

In January, when dozens of scientists rushed to start making a vaccine for the then-novel coronavirus, they were joined by an unlikely compatriot: Patrick Soon-Shiong, the billionaire doctor most famous for making big, controversial promises on cancer research.

Soon-Shiong had spent the last 4 years on his “Cancer Moonshot,” but part of his project meant buying a small Seattle biotech that specialized in making common-cold vectors, called adenoviruses, to train the immune system. The billionaire had been using those vectors for oncology, but the company had also developed vaccine candidates for H1N1, Lassa fever and other viruses. When the outbreak began, he pivoted.

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Jude Samulski, Marianne De Backer

Bay­er buys a biotech ‘race horse’ with a $4B deal — $2B in cash — aimed at go­ing big in­to gene ther­a­py

In the latest sign that Big Pharma wants a leading place in the push to develop a new generation of cell and gene therapies, Bayer is stepping up today with a $2 billion cash deal to buy out one of the fast-moving pioneers in the field, while adding up to $2 billion more in milestones if the new pharma subsidiary can deliver the goods.

As part of a continuing series of deals engineered by Bayer BD chief Marianne De Backer, the pharma player has snapped up Asklepios, more commonly referred to in more casual fashion as AskBio. And they are paying top dollar for a Research Triangle Park-based company that raised $225 million a little more than a year ago to back the brainchild of Jude Samulski, the gene therapy pioneer out of the University of North Carolina Gene Therapy Center.

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No­var­tis CEO Vas Narasimhan signs off on a $231M deal to try some­thing new in the R&D fight against SARS-CoV-2

Patrick Amstutz was baptized by pandemic fire early on.

He and colleagues attended the notorious Cowen conference in early March that included some of the top Biogen execs who helped trigger a superspreader event in Boston. Heading back to his post as CEO of Molecular Partners in Switzerland, the outbreak was sweeping through Italy, triggering near panic in some quarters and creeping into the voices of people he knew, including one friend on the Italian side of the country.

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Covid-19 roundup: Sanofi and GSK pledge 200 mil­lion vac­cine dos­es for a glob­al dis­tri­b­u­tion cam­paign

Sanofi and GSK have agreed to give 200 million doses of their vaccine candidate to the COVAX Facility, which is part of a program set up by CEPI, the WHO and Gavi to equitably distribute vaccines around the world.

The idea behind COVAX is to give all participating countries equal access to vaccines, regardless of income level. As of Oct 14, more than 180 countries had signed agreements to the COVAX Facility, including France and the UK. China joined earlier this month, pledging to make its vaccines a “global public good.” One country notably off the list is the United States.

Cedric Francois, Apellis CEO (Optum via YouTube)

UP­DAT­ED: So­bi bets $250M cash, about $1B in mile­stones for rights to a C3 ther­a­py be­ing pushed through 5 piv­otal tri­als

A couple years after licensing Novimmune’s emapalumab and turning around a quick FDA OK, Stockholm-based Sobi is betting up to $1.2 billion for rights to another rare disease drug.

The company is shelling out $250 million upfront and adding up to $915 million in milestones for rights to develop and commercialize Apellis Pharmaceuticals’ drug pegcetacoplan outside the US. Together, the companies will see the systemic C3 therapy through five registrational trials in hematology, nephrology and neurology.

Christian Rommel (via Roche)

Bay­er fol­lows R&D deal spree by raid­ing Roche's can­cer group for its new re­search chief

The day after Bayer signed off on a $4 billion deal designed to put the company among the leaders in gene therapy development, the pharma giant has recruited a new chief for its R&D division. And they opted for an expert in the cancer field.

Christian Rommel, Roche’s head of discovery and early-stage oncology development, has been tapped to take over the job. Joerg Moeller, who got the top research post after early and late-stage development roles were combined 2 years ago, is hitting the exit “to pursue other career opportunities.”

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Albert Bourla, AP

UP­DAT­ED: Where's the Pfiz­er ef­fi­ca­cy read­out? CEO Bourla says 'soon,' but you're go­ing to have to wait for it

Pfizer CEO Albert Bourla had promised repeatedly that the pharma giant would know if its leading Covid-19 vaccine is effective by the end of this month — now just a few days away.

Instead, the company reported early Tuesday that it has yet to conduct any interim efficacy analyses. And it won’t now until sometime next month.

The news was included in a slide for their Q3 report.

In the morning Q3 call with analysts, Bourla says that they expect efficacy data “soon,” but noted that they wouldn’t be able to say anything until all the administrative work was done on the interim, which would take about a week. And he added that Pfizer isn’t going to say anything else about that hot topic until they have the data in hand.

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Charles Baum, Mirati CEO

UP­DAT­ED: Mi­rati plots a march to the FDA for its KRAS G12C drug, breath­ing down Am­gen’s neck with bet­ter da­ta

Mirati Therapeutics $MRTX took another closely-watched step toward a now clearly defined goal to file for an approval for its KRAS G12C cancer drug adagrasib (MRTX849), scoring a higher response rate than the last readout from the class-leading rival at Amgen but still leaving open a raft of important questions about its future.

Following a snapshot of the first handful of responses, where the drug scored a tumor response in 3 of 5 patients with non-small cell lung cancer, the response rate has now slid to 45% among a pooled group of 51 early-stage and Phase II patients, 43% — 6 of 14 — when looking solely at the Phase I/Ib. Those 14 patients had a median treatment duration of 8.2 months, with half still on therapy and 5 of 6 responders still in response.

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Yung Chyung, Scholar Rock CMO (Business Wire)

A dark horse en­trant in­to the spinal mus­cu­lar at­ro­phy field dou­bles its val­ue on some PhII da­ta

The last four years have seen a sudden explosion in treatments for spinal muscular atrophy, a neurodegenerative condition that once led patients — often young ones — with a grim prognosis and no options. The prognosis still isn’t rosy, but now there are three FDA-approved options, enough to make the choice of one difficult.

Now a fourth potential option has entered the mix. Today, Scholar Rock announced the results from a proof-of-concept testing their SMA drug by itself and in combination with Ionis’ Spinraza, showing that all patient cohorts improved on standard scales used for measuring motor function in people with SMA.