Just how con­fi­dent is Arie Bellde­grun about Kite's po­si­tion in the tur­bu­lent CAR-T race? He's glad you asked.

Ear­ly on in his ca­reer, Arie Bellde­grun did re­search un­der Steven Rosen­berg at the NCI. Now, look­ing back over the in­ter­ven­ing decades, he still mar­vels at the first ground­break­ing lab ex­per­i­ments that would even­tu­al­ly point to the late-stage CAR-T ther­a­pies at a hand­ful of com­pa­nies like Kite Phar­ma, where he’s the CEO now and Rosen­berg is the em­i­nent sci­en­tist in his cor­ner of the ring.

“We were so im­pressed that T cells were killing can­cer cells in vi­vo, in 1985,” Bellde­grun tells me. “That’s where it start­ed. Since then we’ve con­tin­ued to work.”

Lat­er, much lat­er, en­gi­neer­ing T cells with the right anti­gen would pro­duce dra­mat­ic re­sults in pa­tients who had run out of op­tions.  “That is 10 years old,” Bellde­grun says, “you can’t take it out of con­text.”

But you might be for­giv­en for it if you just tuned in over the last two years. The field has ex­plod­ed, at­tract­ing hun­dreds of mil­lions of dol­lars and the fixed at­ten­tion of some of the most in­ter­est­ing com­pa­nies in biotech.

Over just the last few months, the com­pet­i­tive line­up on CAR-T has changed dra­mat­i­cal­ly as the three lead­ing com­pa­nies turned in­to the fi­nal stretch in the race to see who will be the first on the mar­ket. Juno Ther­a­peu­tics was tripped by a brief clin­i­cal hold in Ju­ly fol­low­ing the death of four pa­tients, which pushed back its first po­ten­tial ap­proval to 2018. Then, just days ago, No­var­tis made the stun­ning an­nounce­ment that it is dis­band­ing its 400-mem­ber cell ther­a­py unit, lay­ing off 120 and ab­sorb­ing the sur­vivors in­to its on­col­o­gy di­vi­sion — a clear re­treat that left the phar­ma gi­ant look­ing frag­ile on the CAR-T front as it protest­ed that noth­ing had changed.

On­ly Kite has re­mained un­dam­aged and on track, still plug­ging away at long-stand­ing plans to launch mar­ket­ing in a loom­ing 2017. If any­thing, it picked up the pace, sur­pris­ing an­a­lysts with its re­cent­ly an­nounced de­ci­sion to piv­ot to the FDA in just a few weeks with the first round of da­ta from its first piv­otal study. And the com­pa­ny, which now has 350 staffers, plans to see that num­ber swell to 500 by the end of this year as it marks a big tran­si­tion in­to mar­ket­ing.

For Bellde­grun, though, this sprint to the fin­ish — as well as prep­ping for every­thing still ahead — is be­ing pro­pelled by the mo­men­tum of those decades of re­search work. In an in­ter­view with End­points News this week, he ad­mits to be­ing sur­prised by some re­cent events, and not so star­tled by oth­ers.

“I have the high­est re­spect for No­var­tis,” he adds, cit­ing David Ep­stein, the phar­ma chief who re­cent­ly was un­ex­pect­ed­ly bounced from the phar­ma gi­ant and who helped shep­herd the pro­gram, and CEO Joe Jimenez, who adopt­ed cell ther­a­pies as the next big thing in on­col­o­gy. “I wish them luck. I know what we are do­ing at Kite. It has ab­solute­ly no ef­fect on what we are do­ing.”

He does won­der, though, how you can man­age a op­er­a­tion like CAR-T re­quires in the midst of a ma­jor phar­ma R&D di­vi­sion, as No­var­tis is now plan­ning.

“This is where biotech­nol­o­gy is bet­ter than large phar­ma,” he says. CAR-T, he adds, isn’t about de­vel­op­ing a treat­ment in a vial or a pill, it’s a 24/7 process in­volv­ing mul­ti­ple peo­ple.

“How can No­var­tis be suc­cess­ful in­clud­ing cell ther­a­py in­to a phar­ma­co­log­i­cal group?” asks the Kite CEO. “I don’t know.”

One no­table sur­prise came from Juno, which had to drop flu­dara­bine from its piv­otal study of JCAR015 fol­low­ing a se­ries of deaths. As Juno would care­ful­ly ex­plain at AS­CO, it’s the mix­ture of flu­dara­bine and cy­clophos­phamide — the cy/flu com­bo — that con­di­tions pa­tients for the best re­sponse, clear­ing the path for the cell ther­a­py to work. But they would drop flu­dara­bine from the key tri­al in or­der to per­suade the FDA that it was safe to con­tin­ue.

“We came to the con­clu­sion that a low-dose com­bi­na­tion of flu­dara­bine and cy­clophos­phamide, plus the num­ber of cells we test­ed,” was the right way to go, ex­plains Bellde­grun. “Since then we have not changed it and we are not plan­ning to.”

“We found the right dose, in­ter­me­di­ate.” Too much, he adds, and you get huge tox­i­c­i­ty. Too lit­tle, and there’s no ef­fect. “Now we know the num­ber of cells to give, what is the best chemo ab­la­tion need­ed to get the best ef­fect” and al­low cells to pro­lif­er­ate.

Juno it­self is like­ly to agree with that as­sess­ment. As I re­port­ed ear­li­er to­day, the com­pa­ny has been work­ing on its own recipe, hop­ing to achieve the kind of con­fi­dence that Bellde­grun has in Kite’s work.

“It def­i­nite­ly changed the com­pet­i­tive scene,” Bellde­grun says about events at Juno, “and I can­not say it made it hard­er.”

The CEO cites oth­er ad­van­tages as well. Kite won their break­through drug des­ig­na­tion at the FDA as a com­pa­ny, says the CEO, while No­var­tis (tied to the Uni­ver­si­ty of Penn­syl­va­nia) and Juno (al­lied with Memo­r­i­al Sloan Ket­ter­ing) would re­ly on their aca­d­e­m­ic li­aisons. He’s con­vinced that di­rect ex­po­sure gave his com­pa­ny valu­able ex­pe­ri­ence in de­ci­pher­ing the agency’s ex­pec­ta­tions for their work.

He al­so is bull­ish about Kite’s ini­tial work across all CD19-pos­i­tive cells, see­ing Juno and No­var­tis’ ini­tial ap­proach to ALL as too lim­it­ing. And he ex­pects the field to con­tin­ue to make dra­mat­ic leaps that will con­tin­ue to dis­rupt the com­pet­i­tive land­scape.

“This is just the be­gin­ning of a rev­o­lu­tion­ary tech­nol­o­gy,” he says. Syn­thet­ic bi­ol­o­gy will help give birth to su­per T cells that can go far be­yond where Kite or any­one else can ap­proach now. With gene edit­ing, he says, you can ed­it in a PD-L1 check­point in­hibitor, not give it to pa­tients sep­a­rate­ly.

Those fu­ture tech­nol­o­gy waves will give oth­er com­pa­nies a chance to step in, just as No­var­tis or some oth­er big play­ers may choose to buy in at the right time.

“Whether they push it now or not is ir­rel­e­vant,” says Bellde­grun, “they [No­var­tis] can come back lat­er, find an­oth­er com­pa­ny.”

In the mean­time, he’s al­so been work­ing with GE to make big im­prove­ments in the man­u­fac­tur­ing process, look­ing to trans­form what has been a very com­plex, time-con­sum­ing process in­to a quick, sim­ple turn­around that will be need­ed to help make this a com­mer­cial suc­cess.

Says Bellde­grun: “GE will rev­o­lu­tion­ize every­thing.”

And just as Kite was in on the be­gin­ning of the CAR-T rev­o­lu­tion, he ex­pects it to be a leader in what’s com­ing.

So far, he’s been right in a field where wrong turns have been plen­ti­ful. Steer­ing the com­pa­ny through the next phase will re­quire all the ex­pe­ri­ence that Bellde­grun likes to cite. It will al­so like­ly take some luck. The CEO doesn’t seem to lack for ei­ther right now.

What Will it Take to Re­al­ize the Promise and Po­ten­tial of Im­mune Cell Ther­a­pies?

What does it take to get to the finish line with a new cancer therapy – fast? With approvals in place and hundreds of immune cell therapy candidates in the pipeline, the global industry is poised to create a fundamental shift in cancer treatments towards precision medicine. At the same time, unique challenges associated with cell and process complexity present manufacturing bottlenecks that delay speed to market and heighten cost of goods sold (COGS) — these hurdles must be overcome to make precision treatments an option for every cancer patient. This series of articles highlights some of the key manufacturing challenges associated with the production of cell-based cancer therapies as well as the solutions needed to transcend them. Automation, process knowledge, scalability, and assured supply of high-quality starting material and reagents are all critical to realizing the full potential of CAR-based therapies and sustaining the momentum achieved in recent years. The articles will highlight leading-edge technologies that incorporate these features to integrate across workflows, accelerate timelines and reduce COGS – along with how these approaches are enabling the biopharmaceutical industry to cross the finish line faster with new treatment options for patients in need.

The biggest ques­tions fac­ing gene ther­a­py, the XLMTM com­mu­ni­ty, and Astel­las af­ter fourth pa­tient death

After three patients died last year in an Astellas gene therapy trial, the company halted the study and began figuring out how to safely get the program back on track. They would, executives eventually explained, cut the dose by more than half and institute a battery of other measures to try to prevent the same thing from happening again.

Then tragically, Astellas announced this week that the first patient to receive the new regimen had died, just weeks after administration.

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As­traZeneca touts Imfinzi im­munother­a­py com­bos for lung can­cer in push to dri­ve PD-L1 drug up­take

Facing the big dogs in the PD-(L)1 space, AstraZeneca has taken its own contender Imfinzi into blockbuster territory in its four years on the market but sees even bigger things for the drug. Combinations could be the key, and early results from a mid-stage test are adding some fuel to that strategy.

Imfinzi combined with one of two investigational immunotherapies — a CD73 antibody dubbed oleclumab or an anti-NGK2a named monalizumab — topped Imfinzi alone in terms of overall response and progression-free survival in patients with stage III non-small cell lung cancer whose tumors had not worsened during concurrent chemoradiation, according to interim data from the Phase II COAST trial set to be presented at #ESMO21.

Amgen VP of R&D David Reese

Am­gen rolls out da­ta for KRAS in­hibitor com­bo study in col­orec­tal can­cer, hop­ing to move on from ug­ly ear­ly re­sults

With the first win for its KRAS inhibitor sotorasib in hand, Amgen is pushing ahead with an aggressive clinical plan to capitalize on its first-to-market standing. The drugmaker thinks combinations — in-house or otherwise — could offer a path forward, and one early readout from that strategy is bearing fruit.

A combination of Amgen’s sotorasib and its EGFR inhibitor Vectibix posted an overall response rate of 27% in 26 patients with advanced colorectal cancer (CRC) with the KRAS-G12C mutation, according to data from the larger Phase Ib/II CODEBREAK 101 study set to present at this weekend’s virtual ESMO Congress.

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Gri­fols drops $1B on Ger­man hold­ing com­pa­ny in con­tin­ued plas­ma push

One Spanish biotech is beefing up its plasma therapy operations, and on Friday, it announced that it’s doing so in a billion-dollar deal.

Grifols is now the largest shareholder of Biotest, a company valued at more than $1.8 billion. By teaming up, the two will try to increase the number of plasma therapies available and increase patient access around the world, Grifols said in a press release.

The company did so by acquiring holding company Tiancheng Pharmaceutical, the Germany-based owner of nearly 90% of Biotest shares, for nearly $1.27 billion. Grifols now owns nearly 90% of Biotest voting rights and almost 45% of the total share capital of Biotest.

Dan O'Day, Gilead CEO (Jim Watson/AFP via Getty Images)

Eu­ro­pean study finds that Gilead­'s Covid-19 an­tivi­ral remde­sivir shows no clin­i­cal ben­e­fit

Gilead’s remdesivir — or Veklury, as it’s marketed in the US — raked in around $2.8 billion last year as the only FDA-approved antiviral to treat Covid-19. But new data from a European study suggest the drug, which has been given to about half of hospitalized Covid patients in the country, has no actual benefit.

The open-label DisCoVeRy trial enrolled Covid-19 patients across 48 sites in Europe to test a handful of treatments, including remdesivir, lopinavir–ritonavir, lopinavir–ritonavir and interferon beta-1a, and hydroxychloroquine. To participate, patients had to show symptoms for seven days and require oxygen support. A total of 429 patients were randomized to receive remdesivir plus standard of care, while 428 were assigned to standard of care alone.

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Covid-19 roundup: FDA re­veals boost­er ad­comm ques­tion; Eli Lil­ly's an­ti­body cock­tail cleared for pre­ven­tion

The FDA released briefing documents this week from the agency and Pfizer each outlining their arguments for today’s Covid-19 booster shot adcomm, but one thing conspicuously missing was the question on which panel members would be voting. But late Thursday night, regulators published that question.

Adcomm members will be asked whether or not the safety and efficacy data from Pfizer/BioNTech’s original Phase III study “support approval” of a booster shot at least six months after the second dose in individuals older than 16. The question notably excludes the real-world data from Israel and other analyses that Pfizer and the Biden administration had said would be a centerpiece of their arguments for boosters.

A Pfiz­er part­ner wel­comes ex-ADC Ther­a­peu­tics CMO Jay Fein­gold to the team; Amid tough sled­ding, Im­muno­vant choos­es Eli Lil­ly alum as CFO

→ Last week we told you about the CMO revolving door at ADC Therapeutics, as Joseph Camardo replaced the departing Jay Feingold. The next opportunity for Feingold in the CMO slot has opened up at antibody-drug conjugate and mAb developer Pyxis Oncology, which has added several new execs and scientific advisory board members in recent months, including ex-Immunovant CFO Pamela Yanchik Connealy. Before his tenure at ADC, Feingold was Daiichi Sankyo’s VP of US medical affairs and chairman of the Global Medical Affairs Oversight Committee. Within weeks in March, Pyxis struck a licensing deal with Pfizer for two of its ADCs and raked in $152 million from a Series B round.

Ali Tehrani, Zymeworks CEO

Zymeworks squares up with Her­ceptin af­ter HER2 bis­pe­cif­ic aces mid-stage test in esophageal can­cer

Roche’s Herceptin has long stood as standard of care across multiple advanced cancers, but a suite of next-gen players are looking to beat the aging giant at its own game. In HER2-expressing esophageal cancer, BeiGene partner Zymeworks thinks its bispecific antibody could have the juice to get it done.

Zymeworks’ bispecific antibody zanidatamab, combined with one of two chemotherapy regimens, posted an overall response rate of 75% in patients with advanced gastroesophageal adenocarcinoma (GEA) who had not previously received a HER2-targeted cancer therapy, the Vancouver-based biotech said Thursday.