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.

In a bewildering twist to the long-suffering market for antibiotics — there has actually been a bidding war for an antibiotic company: Tetraphase.

It all started back in March, when the maker of Xerava (an FDA approved therapy for complicated intra-abdominal infections) said it had received an offer from AcelRx for an all-stock deal valued at $14.4 million.

The offer was well-timed. Xerava was approved in 2018, four years after Tetraphase posted its first batch of pivotal trial data, and sales were nowhere near where they needed to be in order for the company to keep its head above water.

Lonza chairman Albert Baehny took his time headhunting a new CEO for the company, making it absolutely clear he wanted a Big Pharma or biotech CEO with a good long track record in the business for the top spot. In the end, he went with the gold standard, turning to Roche’s ranks to recruit Pierre-Alain Ruffieux for the job.

Ruffieux, a member of the pharma leadership team at Roche, spent close to 5 years at the company. But like a small army of manufacturing execs, he gained much of his experience at the other Big Pharma in Basel, remaining at Novartis for 12 years before expanding his horizons.

Another Big Pharma is entering the Covid-19 antibody hunt.

AbbVie has announced a collaboration with the Netherlands’ Utrecht University and Erasmus Medical Center and the Chinese-Dutch biotech Harbour Biomed to develop a neutralizing antibody that can treat Covid-19. The antibody, called 47D11, was discovered by AbbVie’s three partners, and AbbVie will support early preclinical work, while preparing for later preclinical and clinical development. Researchers described the antibody in Nature Communications last month.

There haven’t been a lot of big venture rounds for biotech companies looking to run a Phase II study in Alzheimer’s.

The field has been a disaster over the past decade. Amyloid didn’t pan out as a target — going down in a litany of Phase III failures — and is now making its last stand at Biogen. Tau is a comer, but when you look around and all you see is destruction, the idea of backing a startup trying to find complex cocktails to swing the course of this devilishly complicated memory-wasting disease would daunt the pluckiest investors.

In 2011, GlaxoSmithKline’s Benlysta became the first biologic to win approval for lupus patients. Nine years on, the British drugmaker has unveiled detailed positive results from a study testing the drug in lupus patients with associated kidney disease — a post-marketing requirement from the initial FDA approval.

Lupus is a drug developer’s nightmare. In the last six decades, there has been just one FDA approval (Benlysta), with the field resembling a graveyard in recent years with a string of failures including UCB and Biogen’s late-stage flop, as well as defeats in Xencor and Sanofi’s programs. One of the main reasons the success has eluded researchers is because lupus, akin to cancer, is not just one disease — it really is a disease of many diseases, noted Al Roy, executive director of Lupus Clinical Investigators Network, an initiative of New York-based Lupus Research Alliance that claims it is the world’s leading private funder of lupus research, in an interview.