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.”

Im­ple­ment­ing re­silience in the clin­i­cal tri­al sup­ply chain

Since January 2020, the clinical trials ecosystem has quickly evolved to manage roadblocks impeding clinical trial integrity, and patient care and safety amid a global pandemic. Closed borders, reduced air traffic and delayed or canceled flights disrupted global distribution, revealing how flexible logistics and supply chains can secure the timely delivery of clinical drug products and therapies to sites and patients.

Pascal Soriot (AP Images)

UP­DAT­ED: As­traZeneca, Ox­ford on the de­fen­sive as skep­tics dis­miss 70% av­er­age ef­fi­ca­cy for Covid-19 vac­cine

On the third straight Monday that the world wakes up to positive vaccine news, AstraZeneca and Oxford are declaring a new Phase III milestone in the fight against the pandemic. Not everyone is convinced they will play a big part, though.

With an average efficacy of 70%, the headline number struck analysts as less impressive than the 95% and 94.5% protection that Pfizer/BioNTech and Moderna have boasted in the past two weeks, respectively. But the British partners say they have several other bright spots going for their candidate. One of the two dosing regimens tested in Phase III showed a better profile, bringing efficacy up to 90%; the adenovirus vector-based vaccine requires minimal refrigeration, which may mean easier distribution; and AstraZeneca has pledged to sell it at a fraction of the price that the other two vaccine developers are charging.

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Vas Narasimhan, Novartis CEO (Jason Alden/Bloomberg via Getty Images)

Vas Narasimhan's 'Wild Card' drugs: No­var­tis CEO high­lights po­ten­tial jack­pots, as well as late-stage stars, in R&D pre­sen­ta­tion

Novartis is always one of the industry’s biggest R&D spenders. As they often do toward the end of each year, company execs are highlighting the drugs they expect will most likely be winners in 2021.

And they’re also dreaming about some potential big-time lottery tickets.

As part of its annual investor presentation Tuesday, where the company allows investors and analysts to virtually schmooze with the bigwigs, Novartis CEO Vas Narasimhan will outline what he thinks are the pharma’s “Wild Cards.” The slate of five experimental drugs are those that Novartis hopes can be high-risk, high-reward entrants into the market over the next half-decade or so, and cover a wide range of indications.

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Feng Tian, Ambrx CEO (Ambrx)

Af­ter 5 qui­et years, a for­mer Scripps spin­out rais­es $200M and an­nounces plans to try again at an IPO

The first time San Diego biotech Ambrx tried to go public in 2014, they failed and the company’s board switched to a radically different strategy: They sold themselves for an undisclosed amount to a syndicate of Chinese investors and pharma companies.

Now, after 5 quiet years, that syndicate has raised a mountain of cash and indicated they’ll soon make another bid to go public.

Earlier this month, Ambrx raised $200 million in what they billed as a crossover round financed by Fidelity, BlackRock, Cormorant Asset Management, HBM Healthcare Investments, Invus, Adage Capital Partners and Suvretta Capital Management. It’s the largest amount they’ve ever raised and, according to Crunchbase figures, more than doubles the total amount of VC capital collected since their launch 17 years ago.

Bob Nelsen (Photo by Michael Kovac/Getty Images)

Bob Nelsen rais­es $800M and re­cruits a star-stud­ded board to build the 'Fox­con­n' of biotech

Bob Nelsen spent his pandemic spring in his Seattle home, talking on the phone with Luciana Borio, the scientist who used to run pandemic preparedness on the National Security Council, and fuming with her about the dire state of American manufacturing.

Companies were rushing to develop vaccines and antibodies for the new virus, but even if they succeeded, there was no immediate supply chain or infrastructure to mass-produce them in a way that could make a dent in the outbreak.

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Michelle Longmire, Medable CEO (Jeff Rumans)

Med­able gets $91M for vir­tu­al clin­i­cal tri­als, bring­ing to­tal raise to $136M

As biotechs look to get clinical studies back on track amid the pandemic, Medable returned to the venture well for the second time this year, bagging a $91 million Series C to build out its virtual trial platform.

The software provider recently launched three new apps for decentralizing clinical trials, and saw a 500% revenue spike this year. And it isn’t alone. Back in August, Science 37 secured a $40 million round for its virtual trial tech, with support from Novartis, Sanofi Ventures and Amgen. Patients and researchers are taking a liking to the online approach, suggesting regulators could allow it to become a new normal even after the pandemic is over.

The ad­u­canum­ab co­nun­drum: The PhI­II failed a clear reg­u­la­to­ry stan­dard, but no one is cer­tain what that means any­more at the FDA

Eighteen days ago, virtually all of the outside experts on an FDA adcomm got together to mug the agency’s Billy Dunn and the Biogen team when they presented their upbeat assessment on aducanumab. But here we are, more than 2 weeks later, and the ongoing debate over that Alzheimer’s drug’s fate continues unabated.

Instead of simply ruling out any chance of an approval, the logical conclusion based on what we heard during that session, a series of questionable approvals that preceded the controversy over the agency’s recent EUA decisions has come back to haunt the FDA, where the power of precedent is leaving an opening some experts believe can still be exploited by the big biotech.

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Pur­due Phar­ma pleads guilty in fed­er­al Oxy­Con­tin probe, for­mal­ly rec­og­niz­ing it played a part in the opi­oid cri­sis

Purdue Pharma, the producer of the prescription painkiller OxyContin, admitted Tuesday that, yes, it did contribute to America’s opioid epidemic.

The drugmaker formally pleaded guilty to three criminal charges, the AP reported, including getting in the way of the DEA’s efforts to combat the crisis, failing to prevent the painkillers from ending up on the black market and encouraging doctors to write more painkiller prescriptions through two methods: paying them in a speakers program and directing a medical records company to send them certain patient information. Purdue’s plea deal calls for $8.3 billion in criminal fines and penalties, but the company is only liable for a fraction of that total — $225 million.

John Maraganore, Alnylam CEO (Scott Eisen/Bloomberg via Getty Images)

UP­DAT­ED: Al­ny­lam gets the green light from the FDA for drug #3 — and CEO John Maraganore is ready to roll

Score another early win at the FDA for Alnylam.

The FDA put out word today that the agency has approved its third drug, lumasiran, for primary hyperoxaluria type 1, better known as PH1. The news comes just 4 days after the European Commission took the lead in offering a green light.

An ultra rare genetic condition, Alnylam CEO John Maraganore says there are only some 1,000 to 1,700 patients in the US and Europe at any particular point. The patients, mostly kids, suffer from an overproduction of oxalate in the liver that spurs the development of kidney stones, right through to end stage kidney disease.

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