First ap­proved in 2013 for re­lapsed/re­frac­to­ry man­tle cell lym­phoma (MCL), J&J’s Im­bru­vi­ca is now be­ing used as the first line of de­fense for the rare, ag­gres­sive, in­cur­able form of non-Hodgkin lym­phoma. How­ev­er, some pa­tients do not re­spond to the treat­ment — which sci­en­tists at­tribute to un­der­ly­ing in­trin­sic or ac­quired drug re­sis­tance. Now, re­searchers at the Uni­ver­si­ty of Texas MD An­der­son Can­cer Cen­ter may have de­vel­oped a drug that could help Im­bru­vi­ca-re­sis­tant pa­tients.

J&J’s $JNJ Im­bru­vi­ca, known chem­i­cal­ly as ibru­ti­nib, has demon­strat­ed an­ti-tu­mor ac­tiv­i­ty with an over­all re­sponse rate of 68% and me­di­an sur­vival du­ra­tion of 18 months in MCL — but the one-year sur­vival rate is 22% af­ter re­lapse on Im­bru­vi­ca.

Af­ter iso­lat­ing tu­mor cells from the cere­brospinal flu­id from a pa­tient who did not re­spond to mul­ti­ple ther­a­pies in­clud­ing Im­bru­vi­ca, MD An­der­son Can­cer Cen­ter sci­en­tists de­vel­oped an Im­bru­vi­ca-re­sis­tant B-cell lym­phoma mouse mod­el to test the ther­a­peu­tic po­ten­tial of their drug, IACS-10759.

In the study, the re­searchers found that in­hibit­ing key meta­bol­ic process­es that can­cer cells de­pend on for growth and sur­vival — in par­tic­u­lar, ox­ida­tive phos­pho­ry­la­tion (OX­PHOS) and glu­t­a­minol­y­sis — was as­so­ci­at­ed with ther­a­peu­tic re­sis­tance to Im­bru­vi­ca in MCL and poor clin­i­cal out­comes. The da­ta was pub­lished in the jour­nal Sci­ence Trans­la­tion­al Med­i­cine on Wednes­day.

Luhua (Michael) Wang

“In­hi­bi­tion of OX­PHOS with IACS-10759 re­sults in marked growth in­hi­bi­tion in vi­vo and in vit­ro in ibru­ti­nib-re­sis­tant, pa­tient-de­rived can­cer mod­els,” said, Michael Wang, the tri­al’s lead in­ves­ti­ga­tor, in a state­ment. Ox­ida­tive phos­pho­ry­la­tion is an ef­fi­cient method of pro­duc­ing large amounts of ATP, the ba­sic unit of en­er­gy for meta­bol­ic process­es.

Oth­er tri­als have fo­cused on the PI3K/AKT/mTOR path­way in re­lapsed and/or re­frac­to­ry lym­phoma, but clin­i­cal suc­cess thus far has been lim­it­ed. Ev­i­dence from this on­go­ing study sug­gests glu­t­a­minol­y­sis and OX­PHOS path­way ac­tiv­i­ty are promi­nent sources of en­er­gy that sup­port pro­lif­er­a­tion in Im­bru­vi­ca-re­sis­tant MCL cells.

This pre­clin­i­cal da­ta “war­rants the ex­ploita­tion of ac­tive can­cer meta­bol­ic path­ways, es­pe­cial­ly OX­PHOS and glu­t­a­minol­y­sis, to im­prove clin­i­cal out­comes for man­tle cell lym­phoma and oth­er lym­phomas,” the re­searchers said.

A Phase I lym­phoma tri­al, which will in­clude an Im­bru­vi­ca-re­sis­tant co­hort, will fur­ther in­ves­ti­gate the po­ten­tial of the IACS-10759, they added.

The BTK in­hibitor Im­bru­vi­ca — which is ap­proved for four forms of can­cer and graft-ver­sus-host dis­ease — gen­er­at­ed 2018 sales of about $2.6 bil­lion glob­al­ly.

Blue­bird bio $BLUE has un­veiled its price for the new­ly ap­proved gene ther­a­py Zyn­te­glo (Lenti­Glo­bin), which came as a big sur­prise. And it wasn’t the on­ly un­ex­pect­ed twist in to­day’s sto­ry.

With some an­a­lysts bet­ting on a $900,000 price for the β-tha­lassemia treat­ment in Eu­rope, where reg­u­la­tors pro­vid­ed a con­di­tion­al ear­ly OK, blue­bird CEO Nick Leschly said Fri­day morn­ing that the pa­tients who are suc­cess­ful­ly treat­ed with their drug over 5 years will be charged twice that — $1.8 mil­lion — on the con­ti­nent. That makes this drug the sec­ond most ex­pen­sive ther­a­py on the plan­et, just be­hind No­var­tis’ new­ly ap­proved Zol­gens­ma at $2.1 mil­lion, with an­a­lysts still wait­ing to see what kind of pre­mi­um can be had in the US.

Re­gen­eron’s close­ly-watched bis­pe­cif­ic con­tin­ues to ring up high re­sponse rates

Re­gen­eron’s high-pro­file bis­pe­cif­ic REGN1979 is back in the spot­light at the Eu­ro­pean Hema­tol­ogy As­so­ci­a­tion sci­en­tif­ic con­fab. And while the stel­lar num­bers we saw at ASH have erod­ed some­what as more blood can­cer pa­tients are eval­u­at­ed, the re­sponse rates for this CD3/CD20 drug re­main high.

A to­tal of 13 out of 14 fol­lic­u­lar lym­phomas re­spond­ed to the drug, a 93% ORR, down from 100% at the last read­out. In 10 out of 14, there was a com­plete re­sponse. In dif­fuse large B-cell lym­phoma the re­sponse rate was 57% among pa­tients treat­ed at the 80 mg to 160 mg dose range. They were all com­plete re­spons­es. And 2 of these Cars were for pa­tients who had failed CAR-T ther­a­py.

In­vestors are in no mood to hear biotechs tout the suc­cess of a “key” sec­ondary end­point when the piv­otal Phase III flunks the pri­ma­ry goal. Just ask Savara. 

The Texas biotech $SVRA went look­ing for a sil­ver lin­ing as com­pa­ny ex­ecs blunt­ly con­ced­ed that Mol­gradex, an in­haled for­mu­la­tion of re­com­bi­nant hu­man gran­u­lo­cyte-macrophage colony-stim­u­lat­ing fac­tor (GM-CSF), failed to spur sig­nif­i­cant­ly im­proved treat­ment out­comes for pa­tients with a rare res­pi­ra­to­ry dis­ease called au­toim­mune pul­monary alve­o­lar pro­teinosis, or aPAP.

Late-stage da­ta pre­sent­ed at the Amer­i­can Di­a­betes As­so­ci­a­tion an­nu­al meet­ing in 2010 pushed Eli Lil­ly to put a crimp on teplizum­ab as the phar­ma gi­ant found it un­able to re­set the clock on new­ly di­ag­nosed type 1 di­a­betes. At the same con­fer­ence but in dif­fer­ent hands nine years lat­er, the drug is mak­ing a crit­i­cal come­back by scor­ing suc­cess in an­oth­er niche: de­lay­ing the on­set of the dis­ease.

In a Phase II tri­al with 76 high-risk in­di­vid­u­als — rel­a­tives of pa­tients with type 1 di­a­betes who have di­a­betes-re­lat­ed au­toan­ti­bod­ies in their bod­ies — teplizum­ab al­most dou­bled the me­di­an time of di­ag­no­sis com­pared to place­bo (48.4 months ver­sus 24.4 months). The haz­ard ra­tio for di­ag­no­sis was 0.41 (p=0.006).