As safe­ty looms larg­er in CAR-T re­search, study high­lights how small tweaks can make it eas­i­er to use

For all the promis­es of CAR-T ther­a­py, sig­nif­i­cant side ef­fects — no­tably life-threat­en­ing episodes of cy­tokine re­lease syn­drome and neu­ro­tox­i­c­i­ty — have lim­it­ed its use in close­ly mon­i­tored set­tings. As re­searchers seek new ap­proach­es to tamp down safe­ty con­cerns, a small clin­i­cal tri­al pub­lished in Na­ture Med­i­cine has of­fered the first glimpse of hope that small tweaks on ex­ist­ing mol­e­cules can make CAR-T safer while main­tain­ing its can­cer killing abil­i­ty.

Si-Yi Chen

The hy­poth­e­sis here, Uni­ver­si­ty of South­ern Cal­i­for­nia pro­fes­sor and lead study au­thor Si-Yi Chen tells me, is that CAR-T doesn’t need to ex­crete so much cy­tokines to work. So they took No­var­tis’ FDA-ap­proved Kym­ri­ah and made a vari­ant with slow­er cy­tokine pro­duc­tion, ob­serv­ing sig­nif­i­cant dif­fer­ence in how the ther­a­py be­haved.

Among 25 pa­tients en­rolled in the Phase I study — which took place in Chi­na in col­lab­o­ra­tion with Mari­no Biotech­nol­o­gy — none of them ex­pe­ri­enced cy­tokine re­lease syn­drome or neu­ro­tox­i­c­i­ty. That com­pares to a 57% CRS rate and 39% neu­ro­tox­i­c­i­ty rate in No­var­tis’ Phase I tri­al for its prod­uct by Chen’s count.

“All the pa­tients don’t need sup­port­ing care, ba­si­cal­ly,” he said, hint­ing at the po­ten­tial for CAR-T ad­min­is­tra­tion as an out­pa­tient pro­ce­dure.

Mean­while, the tweaked con­struct ap­peared to “achieve ef­fi­ca­cy com­pa­ra­ble to oth­er clin­i­cal tri­als” of es­tab­lished CAR-Ts, Chen told me, with the longest re­sponse tracked for about two years. At the high­est dose (2–4×10^8), 6 of 11 pa­tients saw com­plete re­mis­sion.

Source: Si-Yi Chen, USC.

Click on the im­age to see the full-sized ver­sion

The im­prove­ments can all be at­trib­uted to a switch up in amino acid se­quence, Chen said. Struc­tural­ly, chimeric anti­gen re­cep­tors (the CAR that gets en­gi­neered in­to T cells) con­sist of an ex­tra­cel­lu­lar anti­gen recog­ni­tion do­main, an in­tra­cel­lu­lar ac­ti­va­tion do­main, and a hinge and trans­mem­brane re­gion that con­nects the two. By adding a few amino acids in the hinge re­gion, Chen’s team was able to cre­ate a CAR-T that pro­lif­er­at­ed more slow­ly, giv­ing the pa­tient’s body more time to clear cy­tokines in the blood.

Whether the re­mis­sions in­duced by this sup­pos­ed­ly safer CAR-T will hold up in the long term will be cru­cial. And Chen wants to pur­sue a glob­al, mul­ti­cen­ter Phase II with 80 to 100 pa­tients to prove that the ef­fects were not by chance.

Hav­ing be­gun the project six years ago — at a time when the fo­cus was square­ly on prov­ing ef­fi­ca­cy — Chen counts him­self an ear­ly la­bor­er on a top­ic that Fred Hutchin­son and the Na­tion­al Can­cer In­sti­tute are now work­ing on. Ear­li­er this year at ASH, a team of NCI sci­en­tists re­port­ed “strik­ing­ly” low­er neu­ro­tox­i­c­i­ty rate us­ing a CAR con­struct sim­i­lar­ly com­pris­ing a hinge re­gion from a CD8α mol­e­cule.

“Al­ter­ing CAR hinge and TM do­mains can af­fect CAR T‐cell func­tion and is a promis­ing ap­proach to im­prove the ef­fi­ca­cy to tox­i­c­i­ty ra­tio of CAR T‐cells,” they wrote in an ab­stract.

Chen ad­mits that he has yet to raise the funds need­ed for the Phase II, or sort through the patent is­sues sur­round­ing the tweaked com­pound, but he’s open to any op­tions that will move the work for­ward. “Sci­en­tif­i­cal­ly I feel it’s jus­ti­fied to take a look,” he said.

Novotech CRO Ex­pands Chi­na Team as Biotech De­mand for Clin­i­cal Tri­als In­creas­es up to 79%

An increase in demand of up to 79% for clinical trials in China has prompted Novotech the Asia-Pacific CRO to rapidly expand the China team, appointing expert local clinical executives to their Shanghai and Hong Kong offices. The company is planning to expand their team by 30% over the next quarter.

Novotech China has seen considerable demand recently which is borne out by research from GlobalData:
A global migration of clinical research is occurring from high-income countries to low and middle-income countries with emerging economies. Over the period 2017 to 2018, for example, the number of clinical trial sites opened by biotech companies in Asia-Pacific increased by 35% compared to 8% in the rest of the world, with growth as high as 79% in China.
Novotech CEO Dr John Moller said China offers the largest population in the world, rapid economic growth, and an increasing willingness by government to invest in research and development.
Novotech’s 23 years of experience working in the region means we are the ideal CRO partner for USA biotechs wanting to tap the research expertise and opportunities that China offers.
There are over 22,000 active investigators in Greater China, with about 5,000 investigators with experience on at least 3 studies (source GlobalData).

Daniel O'Day [via AP Images]

UP­DAT­ED: Gilead un­leash­es a $5B late-stage cash al­liance with Gala­pa­gos — lay­ing out O'­Day's R&D strat­e­gy

Daniel O’Day is executing his first major development deal since taking over as CEO of Gilead $GILD. And he’s going in deep to ally himself with a longstanding partner.

O’Day announced today that he is spending $5 billion in cash to add new late-stage drugs to Gilead’s pipeline, picking up rights to Galapagos’ $GLPG Phase III IPF drug GLPG1690 alongside adoption of the biotech’s Phase IIb drug GLPG1972 for osteoarthritis. And Gilead is also putting billions more on the table for milestones, gaining options for everything else in Galapagos’ pipeline, with a shot at all rights outside of Europe.

Altogether, Gilead is gaining rights to 6 clinical-stage assets, 20 preclinical programs and everything else being hatched in translation.

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Alk­er­mes adds bipo­lar de­pres­sion to its FDA wish list; Con­go con­firms first Ebo­la case in large city

→ An ever-ambitious Alkermes $ALKS team plans to add bipolar depression to its list of conditions for ALKS-3831, which it plans to pitch to the FDA in Q4. Alkermes says they were persuaded to add bipolar depression after a pre-NDA meeting with the agency, which came about 7 months after the biotech reported positive data for schizophrenia. The drug is a combo using olanzapine/samidorphan, which they hope will be shown to be as effective as olanzapine without the substantial increase in the risk of weight gain.

Pe­ter Kolchin­sky and Raj Shah raise a $300M fund de­vot­ed to biotech star­tups

Peter Kolchinsky and Raj Shah have another $300 million-plus to play with on the biotech venture side of their investment business. 

The two announced Monday morning that they’ve put together their first pure-play venture fund at RA Capital Management, which has been known to bet on just about every angle in healthcare investing — from rounds to follow-on investments at public companies. This new fund of theirs arrives well into a go-go era of new startup financing, with a particular focus on building new biotechs.

Boehringer buys Swiss biotech in its lat­est M&A deal, go­ing the next-gen can­cer vac­cine route

Boehringer Ingelheim has snapped up a Swiss biotech startup and added their group as a new platform for the oncology pipeline. 

The German biopharma company has bagged Geneva-based AMAL Therapeutics, paying out an unspecified upfront in a $358 million deal — cash, milestones and everything else, all in. Plus there’s 100 million euros on the line for commercial milestones.

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Ab­b­Vie beefs up the on­col­o­gy pipeline, bag­ging an up­start STING play­er with its own unique ap­proach

AbbVie isn’t letting its $63 billion buyout of Allergan stop its M&A/deals team from continuing their work.

Monday morning we learned that the pharma giant is snapping up tiny Mavupharma out of Seattle, a Frazier-backed startup that has its own unique take on STING — which is on the threshold of their first clinical trial.

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Hal Barron [File photo]

Hal Bar­ron's team at GSK scores a win with pos­i­tive Ze­ju­la PhI­II front­line study — now comes the hard part

Score one for Hal Barron and the new R&D team steering GlaxoSmithKline’s pipeline.

The pharma giant reported this morning that its recently acquired PARP, Zejula (niraparib), hit the primary endpoint on progression-free survival in a frontline maintenance setting for women suffering ovarian cancer — following chemo and regardless of their BRCA status.

GSK bet $5 billion on the Tesaro buyout primarily to get this drug, drawing the shaking heads of biopharma. Why pay a big premium for a drug like this when AstraZeneca was going from strength to strength with Lynparza, ran the argument, having won a hugely important accelerated approval to jump out ahead — way ahead — of the rest of the PARP players? Lynparza — now co-owned by a powerhouse cancer team at Merck — won the first approval in frontline maintenance in ovarian cancer.

Billing it­self as the first AI biotech to launch hu­man tri­als, Re­cur­sion adds $121M C round

Billing itself as the first AI biotech with programs in the clinic, Salt Lake City-based Recursion now has a $121 million bankroll to start gathering human data to see if it’s on the right track. 

“We’re trying to build this discovery engine,” Recursion CEO Chris Gibson tells me ahead of the C round news. “We now have the first two programs in the clinic.” And that, he adds, qualifies as a first for any AI establishment “that actually have something in the clinic.”

FDA bats back As­traZeneca's SGLT di­a­betes drug for Type 1 di­a­betes — block­ing a class on safe­ty fears

The FDA has just fired its latest salvo at the SGLT class of diabetes drugs, blowing up some commercial opportunity at AstraZeneca as part of the collateral damage.

The pharma giant reported early Monday that the FDA has rejected its blockbuster drug Farxiga for Type 1 diabetes that can’t be controlled by insulin. And while the pharma giant maintained its usual grim silence in the face of a setback, this one should be easy to interpret.