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.”

Regeneron CEO Leonard Schleifer speaks at a meeting with President Donald Trump, members of the Coronavirus Task Force, and pharmaceutical executives in the Cabinet Room of the White House (AP Photo/Andrew Harnik)

OWS shifts spot­light to drugs to fight Covid-19, hand­ing Re­gen­eron $450M to be­gin large scale man­u­fac­tur­ing in the US

The US government is on a spending spree. And after committing billions to vaccines defense operations are now doling out more of the big bucks through Operation Warp Speed to back a rapid flip of a drug into the market to stop Covid-19 from ravaging patients — possibly inside of 2 months.

The beneficiary this morning is Regeneron, the big biotech engaged in a frenzied race to develop an antibody cocktail called REGN-COV2 that just started a late-stage program to prove its worth in fighting the virus. BARDA and the Department of Defense are awarding Regeneron a $450 million contract to cover bulk delivery of the cocktail starting as early as late summer, with money added for fill/finish and storage activities.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 84,800+ biopharma pros reading Endpoints daily — and it's free.

UP­DAT­ED: Bio­gen shares spike as ex­ecs com­plete a de­layed pitch for their con­tro­ver­sial Alzheimer's drug — the next move be­longs to the FDA

Biogen is stepping out onto the high wire today, reporting that the team working on the controversial Alzheimer’s drug aducanumab has now completed their submission to the FDA. And they want the agency to bless it with a priority review that would cut the agency’s decision-making time to a mere 6 months.

The news drove a 10% spike in Biogen’s stock $BIIB ahead of the bell.

Part of that spike can be attributed to a relief rally. Biogen execs rattled backers and a host of analysts earlier in the year when they unexpectedly delayed their filing to the third quarter. That delay provoked all manner of speculation after CEO Michel Vounatsos and R&D chief Al Sandrock failed to persuade influential observers that the pandemic and other factors had slowed the timeline for filing. Actually making the pitch at least satisfies skeptics that the FDA was not likely pushing back as Biogen was pushing in. From the start, Biogen execs claimed that they were doing everything in cooperation with the FDA, saying that regulators had signaled their interest in reviewing the submission.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 84,800+ biopharma pros reading Endpoints daily — and it's free.

Daniel O'Day, Gilead CEO (Kevin Dietsch/UPI/Bloomberg via Getty Images)

A new study points to $6.5B in pub­lic sup­port build­ing the sci­en­tif­ic foun­da­tion of Gilead­'s remde­sivir. Should that be re­flect­ed in the price?

By drug R&D standards, Gilead’s move to repurpose remdesivir for Covid-19 and grab an emergency use authorization was a remarkably easy, low-cost layup that required modest efficacy and a clean safety profile from just a small group of patients.

The drug OK also arrived after Gilead had paid much of the freight on getting it positioned to move fast.

In a study by Fred Ledley, director of the Center for Integration of Science and Industry at Bentley University in Waltham, MA, researchers concluded that the NIH had invested only $46.5 million in the research devoted to the drug ahead of the pandemic, a small sum compared to the more than $1 billion Gilead expected to spend getting it out this year, all on top of what it had already cost in R&D expenses.

Endpoints Premium

Premium subscription required

Unlock this article along with other benefits by subscribing to one of our paid plans.

Sin­gu­lar fo­cus on ROR1 earns Velos­Bio $137M to fund PhI ADC and oth­er pro­grams

Years after selling Acerta to AstraZeneca for $7 billion, largely on the promise of its BTK inhibitor, Dave Johnson has once again gathered hefty financial support behind a new cancer target.

Matrix Capital Management and Surveyor Capital are leading a $137 million round for VelosBio, which has recently begun a Phase I study for its lead antibody-drug conjugate targeted against ROR1. Johnson took up the CEO post in October 2018.

Alexander Vos, VarmX CEO

'Fun­da­men­tal­ly dif­fer­en­t' from Por­to­la, Dutch biotech lands €32M to steer an­ti-an­ti­co­ag­u­lant through the clin­ic

Portola may not have had much success proving the commercial value of an anti-anticoagulant, but that’s not stopping European investors from pouring $36.2 million (€32 million) into what they see as a superior approach put forth by a Dutch biotech.

VarmX’s blood thinner reversal agent stems from research done by founder and CSO Pieter Reitsma at Leiden University Medical Center. A modified recombinant form of factor X, VMX-C001 “has an insertion of 16 amino acids that replaces a stretch of 7 amino acids in the so-called serine protease domain” compared to the native coagulation factor, CEO Alexander Vos told Endpoints News.

FDA bars the door — for now — against Mer­ck’s star can­cer drug af­ter Roche beat them to the punch

Merck has been handed a rare setback at the FDA.

After filing for the accelerated approval of a combination of their star PD-1 drug Keytruda with Eisai’s Lenvima as a first-line treatment for unresectable hepatocellular carcinoma, the FDA nixed the move, handing out a CRL because Roche beat them to the punch on the same indication by a matter of weeks.

According to Merck:

Ahead of the Prescription Drug User Fee Act action dates of Merck’s and Eisai’s applications, another combination therapy was approved based on a randomized, controlled trial that demonstrated overall survival. Consequently, the CRL stated that Merck’s and Eisai’s applications do not provide evidence that Keytruda in combination with Lenvima represents a meaningful advantage over available therapies for the treatment of unresectable or metastatic HCC with no prior systemic therapy for advanced disease. Since the applications for KEYNOTE-524/Study 116 no longer meet the criteria for accelerated approval, both companies plan to work with the FDA to take appropriate next steps, which include conducting a well-controlled clinical trial that demonstrates substantial evidence of effectiveness and the clinical benefit of the combination.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 84,800+ biopharma pros reading Endpoints daily — and it's free.

Covid-19 roundup: Mod­er­na sticks to Ju­ly for its Phase III as ru­mors swirl; Fol­low­ing US lead, EU buys up Covid-19 treat­ments

The Phase III might be delayed from its original early July goal, but Moderna says it will still kick off the pivotal study for what could ultimately be the first Covid-19 vaccine before the end of the month.

A day after Reuters reported that squabbling between the Cambridge biotech and government regulators had held up the trial by about two weeks, Moderna released a statement saying that they had completed enrollment of their 650-person Phase II trial and were on track to begin Phase III by the end of the month. The protocol for that study, which is meant to prove whether or not the vaccine can prevent people from becoming sick, has been finalized, they said.

Noubar Afeyan, Flagship CEO and Tessera chairman (Victor Boyko/Getty Images)

Flag­ship ex­ecs take a les­son from na­ture to mas­ter ‘gene writ­ing,’ launch­ing a star-stud­ded biotech with big am­bi­tions to cure dis­ease

Flagship Pioneering has opened up its deep pockets to fund a biotech upstart out to revolutionize the whole gene therapy/gene editing field — before gene editing has even made it to the market. And they’ve surrounded themselves with some marquee scientists and execs who have crowded around to help shepherd the technology ahead.

The lead player here is Flagship general partner Geoff von Maltzahn, an MIT-trained synthetic biologist who set out in 2018 to do CRISPR — a widely used gene editing tool — and other rival technologies one or two better. Von Maltzahn has been working with Sana co-founder Jake Rubens, another synthetic biology player out of MIT who he describes as his “superstar,” who’s taken the CSO role.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 84,800+ biopharma pros reading Endpoints daily — and it's free.

Stephen Hahn, AP

Trump and Navar­ro press again for hy­drox­y­chloro­quine. Can the FDA stay in­de­pen­dent?

Tuesday morning, economist and Trump advisor Peter Navarro walked onto the White House driveway and promptly brought a political cloud back onto the FDA.

Speaking to a White House pool reporter, Navarro said that four Detroit doctors were, based on a single disputed study, filing for the FDA to again issue an emergency authorization for hydroxychloroquine, the anti-malarial pill that President Trump hyped for months as a Covid-19 treatment over the objections of his own scientists. Then, while avoiding directly calling for the FDA to OK the drug, blasted the agency. He said its decision to pull an earlier authorization “was based on bad science” and “had a tremendously negative effect” on doctors and patients.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 84,800+ biopharma pros reading Endpoints daily — and it's free.