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.

Vertex has clinched a priority review for the all-important cystic fibrosis triple that will blaze the trail for treating a large group of patients unhelped by its current drugs.

FDA regulators have set a PDUFA date of March 19, 2020, just a year after the Boston biotech posted positive Phase III results showing that people with two F508del mutations experienced statistically significant improvements in lung function after a 4-week regimen of VX-445, tezacaftor and ivacaftor. After reviewing 24-week data among patients with one F508del mutation and one minimal function mutation — and thoroughly comparing the VX-445 triple with another combo featuring VX-659 on scores like safety, drug-drug interactions, and photosensitivity — Vertex ultimately went with VX-445.

Just a few weeks after bagging $80 million in a deal to collaborate with Gingko Bioworks on its special blend of engineered bacteria used for “living therapeutics,” little Synlogic in Boston $SYBX is tossing one of its two clinical programs after watching an early-stage study go down in defeat.

Their Phase Ib/IIa study for SYNB1020 to counter the accumulation of ammonia in the body, a condition called hyperammonemia or urea cycle disorder, floundered at the interim readout, forcing the biotech to kill it and reserve its cash for pipeline therapies with greater potential.

Last week, Elanco explicitly dodged answering questions about its rumored interest in Bayer’s animal health business in its post-earnings call. On Tuesday, the Eli Lilly spinoff disclosed it was purchasing the German drug maker’s veterinary unit in a cash-and-stock deal worth $7.6 billion. 

Elanco $ELAN has been busy on the deal-making front. In April, it laid out plans to swallow its partner, Kansas-based pet therapeutics company Aratana $PETX. A July report by Reuters suggested a potential Bayer deal was being explored, and Bloomberg last week said the deal was imminent, citing sources. 

Months ago, data on J&J’s $JNJ Invokana indicated the diabetes drug conferred cardiovascular (CV) benefit in patients who do and do not have preexisting CV disease. On Tuesday, AstraZeneca’s $AZN rival treatment, Farxiga, was shown to cut the risk of CV death or the worsening of heart failure in patients with heart disease, in a landmark trial.

The treatments, in addition to Jardiance from Eli Lilly $LLY, belong to a class of diabetes drugs called sodium-glucose co-transporter 2 (SGLT2) inhibitors, which work by curbing the absorption of glucose via the kidneys so that surplus glucose is excreted through urination.