No­var­tis posts land­mark CAR-T da­ta as head-to-head ri­val­ry with Kite Phar­ma looms

Vas­ant Narasimhan, chief med­ical of­fi­cer of No­var­tis AG, looks on dur­ing a Jan­u­ary 2017 news con­fer­ence in Basel  Michele Lim­i­na/Bloomberg


No­var­tis’ pi­o­neer­ing CAR-T drug CTL019 (ti­s­agen­le­cleu­cel) scored high in treat­ing dif­fuse large B-cell lym­phoma (DL­B­CL), spot­light­ing num­bers that will like­ly al­low the phar­ma gi­ant to plunge head-to-head in the mar­ket against its main ini­tial ri­val, Kite Phar­ma. But No­var­tis al­so found it­self de­fend­ing its man­u­fac­tur­ing op­er­a­tions Wednes­day morn­ing, as an­a­lysts ze­roed in on a num­ber of pa­tients who couldn’t be treat­ed in the study.

The fig­ures — drawn from its ea­ger­ly an­tic­i­pat­ed Phase II JULI­ET study — that will at­tract every­one’s at­ten­tion first: At three months the over­all re­sponse rate hit 45% among 23 of 51 pa­tients eval­u­at­ed with an im­pres­sive 37% achiev­ing a com­plete re­sponse and 8% achiev­ing a par­tial re­sponse. And those CRs con­tin­ued be­yond the three months to the da­ta cut­off in prep­ping for the an­nounce­ment, of­fer­ing a glimpse of dura­bil­i­ty that will help make No­var­tis’ case.

“For us as a med­ical com­pa­ny and from my or­ga­ni­za­tion’s stand­point, we want to have a dra­mat­ic im­pact,” No­var­tis $NVS chief med­ical of­fi­cer Vas Narasimhan tells me. “This is, of course, trans­for­ma­tive… It gives us the con­vic­tion to move ahead.”

Narasimhan in par­tic­u­lar high­light­ed ear­ly ev­i­dence of per­sis­tence for this ther­a­py, which will be cru­cial to dif­fer­en­ti­at­ing their drug from all the CAR-T ther­a­pies to come, from any an­gle.

The best rea­son to sug­gest why CTL019 could be a stand­out, he says, points to their drug’s use of the 4-1BB cos­tim­u­la­to­ry do­main, dis­tin­guished from the CD28 do­main used by Kite’s ri­val drug and Juno’s ini­tial lead ther­a­py, now scrapped in fa­vor of a drug that us­es 4-1BB. That 4-1BB do­main may ex­plain why the ini­tial ramp up of T cell ex­pres­sion is slight­ly slow­er, adding to longterm per­sis­tence. And it may al­so ex­plain No­var­tis’ rel­a­tive­ly clean safe­ty pro­file, with no ma­jor is­sues (so far) re­lat­ed to neu­ro­tox­i­c­i­ty, which will like­ly be giv­en care­ful scruti­ny at the FDA.

All that, though, has yet to be de­ter­mined.

Purists hate cross-tri­al com­par­isons, not­ing hard-to-score com­par­isons in the pa­tients stud­ied. But Wall Street’s first re­sponse will be to line up the da­ta from the phar­ma gi­ant against the num­bers for Kite’s KTE-C19 (axi­cab­ta­gene ciloleu­cel) at 3 months. Their drug hit an ORR of 39% among 51 pa­tients, with 33% achiev­ing a com­plete re­sponse — com­pa­ra­ble, though, mar­gin­al­ly less sig­nif­i­cant re­sults that will leave these two com­pa­nies bat­tling it out.

Narasimhan de­clined to touch my ques­tion about com­par­ing num­bers in the piv­otal stud­ies, which was to be ex­pect­ed. But Twit­ter was abuzz this morn­ing.

As ex­pect­ed, cy­tokine re­lease syn­drome was com­mon, with 57% ex­pe­ri­enc­ing CRS — al­though no one died from it. No deaths were at­trib­uted to the drug.

Kite’s num­bers have ma­tured be­yond that to the 6-month mark, slip­ping slight­ly but re­main­ing strong­ly com­pet­i­tive, as Kite CEO Arie Bellde­grun pre­dict­ed it would. And af­ter the JULI­ET da­ta were ini­tial­ly re­leased in an ab­stract ear­ly Wednes­day, cir­cu­lat­ing on Twit­ter, Kite’s shares jumped 6% af­ter in­vestors got a chance to eval­u­ate how the two drugs stacked up.

No­var­tis will get the first crack at an ap­proval for chil­dren with acute lym­phoblas­tic leukemia, with an FDA ex­pert pan­el slat­ed for Ju­ly 12. And with a pri­or­i­ty re­view, the agency is com­mit­ted to a quick re­sponse with a de­ci­sion due lat­er this year. Kite is about two months be­hind with a PDU­FA date of No­vem­ber 29.

An­oth­er area that No­var­tis, Kite and any fu­ture ri­vals will com­pete on is man­u­fac­tur­ing time.

Says Narasimhan: “Vein-to-vein time (the stretch from ex­tract­ing cells to get­ting them back in as a ther­a­py) we ex­pect to have in the range of 20 days. We were slow­er in the clin­i­cal tri­als,” with the man­u­fac­tur­ing arm bring­ing that down from 29 days.

Cowen got the dis­cus­sion about man­u­fac­tur­ing start­ed Wednes­day morn­ing by not­ing the ab­stract’s fig­ures on pa­tients in the study who nev­er made it to the in­fu­sion point. No­var­tis re­spond­ed with a state­ment, not­ing that they had fac­tored in a high dropout rate due to the very ad­vanced stage of an ag­gres­sive dis­ease and the rapid de­te­ri­o­ra­tion you would ex­pect in their sta­tus.

An­a­lysts al­so not­ed that a num­ber of pa­tients nev­er were treat­ed be­cause of man­u­fac­tur­ing prob­lems — a po­ten­tial­ly se­ri­ous sna­fu. But No­var­tis says it is get­ting a bet­ter han­dle on that and down­played the is­sue, adding:

 On­ly 6% (9 of 141) of en­rolled pa­tients were dis­con­tin­ued due to in­abil­i­ty to man­u­fac­ture an ad­e­quate dose of CART cells. Over the course of JULI­ET, with con­tin­u­ous process im­prove­ments, man­u­fac­tur­ing suc­cess rate im­proved to 97% for the last 30 pa­tients.

In JULI­ET, pa­tients could re­ceive bridg­ing chemother­a­py, re­flect­ing the ag­gres­sive na­ture of dis­ease in pa­tients with r/r DL­B­CL, so even pa­tients in poor con­di­tion could be en­rolled and in­fused. The cry­op­re­served leuka­phere­sis used in JULI­ET gives physi­cians the flex­i­bil­i­ty to sched­ule aphere­sis at a time that is in the best in­ter­est of their pa­tients, in­clud­ing times far in ad­vance of man­u­fac­tur­ing. The tri­al de­sign and pop­u­la­tion in­fused re­flects the re­al world chal­lenges in treat­ing pa­tients with an ag­gres­sive can­cer such as r/r DL­B­CL.

As for man­u­fac­tur­ing, we are con­fi­dent we will be able to meet the re­quired man­u­fac­tur­ing de­mands mov­ing for­ward.

The ac­tu­al cell pro­cess­ing time is 10-12 days. We an­tic­i­pate that the time from man­u­fac­ture start to prod­uct re­lease (in­clud­ing Qual­i­ty as­sess­ments) will be 22 days at the time of com­mer­cial launch. We have a rig­or­ous qual­i­ty as­sess­ment process to en­sure a GMP com­pli­ant prod­uct is re­leased to pa­tients.

Sig­nif­i­cant­ly, Kite CMO David Chang told me at AS­CO that they have vein-to-vein down to about 17 days, and would still like to shave a few days off that.

No­tably, No­var­tis’ man­u­fac­tur­ing chief for CAR-T re­cent­ly re­signed to take a sim­i­lar job at Seat­tle Ge­net­ics, rais­ing con­cerns with­in the phar­ma gi­ant’s R&D op­er­a­tions that the con­tin­u­ing ex­o­dus of ex­ecs out of No­var­tis — par­tic­u­lar­ly fol­low­ing last sum­mer’s re­or­ga­ni­za­tion — could ham­per its per­for­mance.

No­var­tis ex­ecs, though, have in­sist­ed that the multi­na­tion­al com­pa­ny is com­plete­ly com­mit­ted to mak­ing this all work com­mer­cial­ly, not­ing their lead role in the field.

An­a­lysts have been de­bat­ing for months now how the com­pe­ti­tion will shake out. The lead CAR-T at Juno im­plod­ed last year af­ter it killed five pa­tients due to cere­bral ede­ma. Then Kite rat­tled the mar­ket re­cent­ly with the news that one of its pa­tients al­so died from cere­bral ede­ma. Some have the­o­rized that the added safe­ty threat could be due to the dif­fer­ent cos­tim­u­la­to­ry do­mains used in the drug, with Kite and Juno’s first lead us­ing CD28 and No­var­tis fo­cused on 4-1BB. It’s nev­er been es­tab­lished, though, as re­searchers con­tin­ue to gain new in­sights on the best way to de­sign these CAR-Ts.

No­var­tis has made CTL019 one of its top on­col­o­gy pro­grams, push­ing hard to gain first-mar­ket ad­van­tage for a new kind of can­cer treat­ment that reengi­neers pa­tients cells in­to a ther­a­py. Its best ear­ly promise lies in liq­uid tu­mors with in­ves­ti­ga­tors work­ing to tack­le a broad slate of these can­cers. Next stop: find­ing bet­ter ways to go af­ter sol­id tu­mors with this tech­nol­o­gy. Be­hind that, Cel­lec­tis and oth­ers will try to de­vel­op off-the-shelf ther­a­pies that can be di­rect­ly ad­min­is­tered to pa­tients.

Narasimhan al­so men­tioned that the phar­ma gi­ant has been work­ing on freez­ing cells for lat­er use, per­haps prepar­ing ther­a­pies that can be used at a lat­er stage, if a pa­tient needs them to bat­tle drug re­sis­tance. How that sort of op­er­a­tion could be squared with pay­ers, though, he freely ad­mits will be a com­plex chal­lenge.

This first round of da­ta marks the cut­ting edge of the com­pe­ti­tion. There’s much, much more to come.

UP­DAT­ED: In sur­prise switch, Bris­tol-My­ers is sell­ing off block­buster Ote­zla, promis­ing to com­plete Cel­gene ac­qui­si­tion — just lat­er

Apart from revealing its checkpoint inhibitor Opdivo blew a big liver cancer study on Monday, Bristol-Myers Squibb said its plans to swallow Celgene will require the sale of blockbuster psoriasis treatment Otezla to keep the Federal Trade Commission (FTC) at bay.

The announcement — which has potentially delayed the completion of the takeover to early 2020 — irked investors, triggering the New York-based drugmaker’s shares to tumble Monday morning in premarket trading.

Celgene’s Otezla, approved in 2014 for psoriasis and psoriatic arthritis, is a rising star. It generated global sales of $1.6 billion last year, up from the nearly $1.3 billion in 2017. Apart from the partial overlap of Bristol-Myers injectable Orencia, the company’s rival oral TYK2 psoriasis drug is in late-stage development, after the firm posted encouraging mid-stage data on the drug, BMS-986165, last fall. With Monday’s decision, it appears Bristol-Myers is favoring its experimental drug, and discounting Otezla’s future.

The move blindsided some analysts. Credit Suisse’s Vamil Divan noted just days ago:

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Novotech CEO Dr. John Moller

Novotech CRO Award­ed Frost & Sul­li­van Best Biotech CRO Asia-Pa­cif­ic 2019

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More than 2 years af­ter No­var­tis sur­prised the biotech in­vest­ment com­mu­ni­ty with its $50 mil­lion up­front and promise of R&D sup­port to part­ner with the lit­tle biotech on NASH — ig­nit­ing a light­ning strike for the share price — Cona­tus $CNAT is back with the lat­est bit­ter tale to tell about em­ri­c­as­an, which once in­spired con­fi­dence at the phar­ma gi­ant.

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Gene ther­a­py biotech sees its stock rock­et high­er on promis­ing re­sults for rare cas­es of but­ter­fly dis­ease

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Ab­b­Vie gets a green light to re­sume re­cruit­ing pa­tients for one myelo­ma study — but Ven­clex­ta re­mains un­der a cloud

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Bris­tol-My­ers star Op­di­vo fails sur­vival test in a matchup with Nex­avar aimed at shak­ing up the big HCC mar­ket

Bris­tol-My­ers Squibb has suf­fered an­oth­er painful set­back in its years-long quest to ex­pand the reach of Op­di­vo. The phar­ma gi­ant this morn­ing not­ed that their Check­mate-459 study com­par­ing Op­di­vo with Bay­er’s Nex­avar in front­line cas­es of he­pa­to­cel­lu­lar car­ci­no­ma — the most com­mon form of liv­er can­cer — failed to hit the pri­ma­ry end­point on over­all sur­vival.

This was a sig­nif­i­cant mile­stone in Bris­tol-My­ers’ tal­ly of PD-1 cat­a­lysts this year. Nex­avar (so­rafenib) has been the stan­dard of care in front­line HCC for the past decade, though Op­di­vo has been mak­ing head­way in sec­ond-line HCC cas­es, where it’s go­ing toe-to-toe with Bay­er’s Sti­var­ga (re­go­rafenib) af­ter re­cent ap­provals shook up the mar­ket.

Dean Hum. Nasdaq via YouTube

Gen­fit goes to Chi­na with a deal worth up to $228M for NASH drug

Fresh off the high of its Nas­daq IPO de­but, and the low of com­par­isons to Cymabay — whose NASH drug re­cent­ly stum­bled — Gen­fit on Mon­day un­veiled an up to $228 mil­lion deal with transpa­cif­ic biotech Terns Phar­ma­ceu­ti­cals to de­vel­op its flag­ship ex­per­i­men­tal liv­er drug — elafi­bra­nor — in Greater Chi­na.

The deal comes more than a week af­ter Gen­fit $GN­FT is­sued a fiery de­fense of its dual PPAR ag­o­nist elafi­bra­nor, when com­peti­tor Cymabay’s PPARδ ag­o­nist, se­ladel­par, fiz­zled in a snap­shot of da­ta from an on­go­ing mid-stage tri­al. The main goal at the end of 12 weeks was for se­ladel­par to in­duce a sta­tis­ti­cal­ly sig­nif­i­cant im­prove­ment in liv­er fat con­tent, but da­ta showed that pa­tients on the place­bo ac­tu­al­ly per­formed bet­ter.