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.

As more and more biopharmas develop artificial intelligence platforms, the drug discovery process is being reshaped to fit new goals on cutting down the prodigious amount of time, energy and money that go into a drug program. Now one of the most ambitious players in the drive to improve on ROI, AstraZeneca, is marking a milestone on that front by adding the first target generated by AI to its portfolio.