Jennifer Pietenpol (Joe Howell for Vanderbilt)

Back to the draw­ing board for triple-neg­a­tive breast can­cer tar­gets, re­searchers pro­pose new com­bo ap­proach

The rea­son why triple-neg­a­tive breast can­cer is such a tough dis­ease to treat is large­ly giv­en away in its name. Such tu­mors can’t be de­fined by tra­di­tion­al bio­mark­ers — nei­ther es­tro­gen re­cep­tors, prog­es­terone re­cep­tors, nor ex­cess HER2 pro­tein — forc­ing drug hunters down un­chart­ed new path­ways.

Re­searchers at Van­der­bilt-In­gram Can­cer Cen­ter ex­plored one of them, and turned up with some new sug­ges­tions.

Jo­han­na Schafer

In a new pa­per, the sci­en­tists be­gan with the ob­ser­va­tion that dereg­u­lat­ed MY­CN — a mem­ber of the tran­scrip­tion fac­tor fam­i­ly that ac­ti­vates ex­pres­sion of some onco­genes — has been im­pli­cat­ed in a sub­set of breast can­cers with un­fa­vor­able prog­nos­tic fea­tures and clin­i­cal out­comes. They end­ed by putting forth a new drug reg­i­men that could spark new hope.

“Giv­en that pa­tients with TNBC pri­mar­i­ly re­ceive sys­temic cy­to­tox­ic chemother­a­pies that fre­quent­ly re­sult in un­fa­vor­able out­comes,” they wrote in Sci­ence Trans­la­tion­al Med­i­cine, “we pro­pose the clin­i­cal de­vel­op­ment of com­bi­na­tion BETi and ME­Ki for pa­tients with ad­vanced TNBC, with par­al­lel eval­u­a­tion of MY­CN as a po­ten­tial mark­er for pa­tient se­lec­tion.”

Jo­han­na Schafer, a grad­u­ate stu­dent work­ing in Jen­nifer Pieten­pol’s lab, is the first au­thor, while the pro­fes­sor is the se­nior au­thor.

The MY­CN pro­tein, some­times dubbed N-Myc, has long been stud­ied as a tar­get in neu­ronal or neu­roen­docrine tu­mors, but its role in breast can­cer is less clear. It’s dis­tinct from MYC (c-Myc), though the two are be­lieved to af­fect each oth­er.

Their in­tri­cate re­la­tion­ship would prove cru­cial in ther­a­peu­tic de­vel­op­ment. But the first ques­tion is just how com­mon they are, and ac­cord­ing to the study, the two fam­i­ly mem­bers are “het­ero­ge­neous­ly ex­pressed in sep­a­rate cell nu­clei with­in a giv­en tu­mor in at least 40% of TNBC tu­mors.” In fact, the ex­pres­sion of MY­CN ap­peared to in­crease af­ter neoad­ju­vant chemother­a­py, part of the cur­rent stan­dard of care.

The preva­lence gave them enough rea­son to think about how to tar­get it. When the team se­lect­ed a cell line mod­el, they had an­oth­er find­ing that MY­CN-ex­press­ing cells were es­sen­tial­ly more prone to re­sis­tance to PI3K in­hibitors, which block an al­ter­na­tive path­way for tu­mor growth.

Be­cause the MYC fam­i­ly lack cat­alyt­ic do­mains, the team re­sort­ed to epi­ge­net­ic reg­u­la­tors, screen­ing 158 com­pounds against the cell lines. BET drugs, which block the bro­mod­omain (BRD)-con­tain­ing fam­i­ly of tran­scrip­tion­al reg­u­la­tors, emerged as the win­ner.

It echoes an ear­li­er study, done at Michi­gan State Uni­ver­si­ty, show­ing that the ex­per­i­men­tal class of mol­e­cules can pre­vent the growth of breast and lung can­cers.

But that’s not it — and here’s where the MEK in­hibitors come in.

Most of the MYNC-ex­press­ing TNBCs al­so con­tain MYC-ex­press­ing cells, the re­searchers not­ed, which can still dri­ve can­cer growth. In fact, sin­gle-agent treat­ment with a BETi seemed to have in­creased MYC ex­pres­sion. Adding tram­e­tinib (Mekin­ist) to the cells, how­ev­er, de­creased the amount of both pro­teins. The re­sults were fur­ther test­ed and con­firmed in mouse mod­els.

“As a next step, our re­search team is propos­ing the fur­ther de­vel­op­ment and clin­i­cal tri­als of this com­bi­na­tion ther­a­py,” Pieten­pol, the di­rec­tor of Van­der­bilt-In­gram and EVP for re­search at Van­der­bilt Uni­ver­si­ty Med­ical Cen­ter, said in a state­ment.

In­cyte, which has a pact in place to fund Van­der­bilt re­search such as this study, has a BET in­hibitor in ear­ly de­vel­op­ment.

Nick Galakatos, Blackstone global head of life sciences

Nick Galakatos and the Black­stone team now have a record $4.6B to in­vest in bio­phar­ma, with a big fo­cus on push­ing com­pa­nies over the top

Nick Galakatos and his team at Blackstone Life Sciences have seen their biggest opportunities swell up in mostly established players who don’t have all the money they need to accomplish everything on the to-do list. And right now, with the industry booming, that’s a long list with some hefty needs.

The Blackstone team has neatly tied up the largest private fund ever raised in life sciences for making big dreams come true in biopharma. Late Thursday, Blackstone put out word that they had closed their highly anticipated fund with the projected $4.6 billion all in.

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UP­DAT­ED: Bio­gen shares spike as ex­ecs com­plete a de­layed pitch for their con­tro­ver­sial Alzheimer's drug — the next move be­longs to the FDA

Biogen is stepping out onto the high wire today, reporting that the team working on the controversial Alzheimer’s drug aducanumab has now completed their submission to the FDA. And they want the agency to bless it with a priority review that would cut the agency’s decision-making time to a mere 6 months.

The news drove a 10% spike in Biogen’s stock $BIIB ahead of the bell.

Part of that spike can be attributed to a relief rally. Biogen execs rattled backers and a host of analysts earlier in the year when they unexpectedly delayed their filing to the third quarter. That delay provoked all manner of speculation after CEO Michel Vounatsos and R&D chief Al Sandrock failed to persuade influential observers that the pandemic and other factors had slowed the timeline for filing. Actually making the pitch at least satisfies skeptics that the FDA was not likely pushing back as Biogen was pushing in. From the start, Biogen execs claimed that they were doing everything in cooperation with the FDA, saying that regulators had signaled their interest in reviewing the submission.

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Gilead boasts of pos­i­tive remde­sivir da­ta on mor­tal­i­ty — but their analy­sis pro­vokes the skep­tics

Gilead is surging again off data that suggest its antiviral remdesivir might improve survival.

The new data come from an analysis Gilead conducted comparing the death rate and recovery time of patients in one of its remdesivir trials to a group of 800 patients “with similar baseline characteristics and disease severity” who received only standard-of-care around the same time. The result, they said, suggested that patients who received remdesivir had a 62% better chance at surviving than those who did not.

Hal Barron, GSK

Win or lose on the mar­ket­ing OK, the FDA just gunned down GSK’s bright hopes for their BC­MA ther­a­py

The FDA’s ODAC — the Oncologic Drugs Advisory Committee — has a well-known bias in favor of adding new cancer drugs to the market, even if efficacy is at best marginal and serious safety issues demand careful management.

Doctors want as many arrows in their quiver as they can get. And when patients are dying after failing multiple drugs, why not give it a go one more time?

GlaxoSmithKline, though, is about to test out how their new BCMA antibody drug conjugate belantamab mafodotin can do after being mauled in an in-house FDA review, ahead of the Tuesday expert panel discussion. Even if the agency goes ahead with an expected green light, this drug will likely be constrained to a small niche — icing any plans they may have for making waves in oncology anytime soon.

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Covid-19 roundup: BioN­Tech go­ing head-to-head with Mod­er­na as PhI­II mR­NA launch looms; Tri­al on Shin­zo Abe’s once-fa­vorite an­tivi­ral is in­con­clu­sive

It’s a race to the Phase III finish line now for the 2 leading mRNA vaccines in the pipeline for Covid-19.

BioNTech chief Ugur Sahin told the Wall Street Journal that his company will start Phase III testing of their vaccine later this month, setting them up to lateral the data to regulators before the end of this year.

That puts them essentially on the exact same schedule as Moderna is dedicated to. The Massachusetts rival to BioNTech also expects to launch Phase III this month. Lots of rumors have circulated about delays and conflict among the scientists advancing the Moderna jab, but the biotech has consistently stuck to its plan to start a late-stage pivotal this month.

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Regeneron CEO Leonard Schleifer speaks at a meeting with President Donald Trump, members of the Coronavirus Task Force, and pharmaceutical executives in the Cabinet Room of the White House (AP Photo/Andrew Harnik)

OWS shifts spot­light to drugs to fight Covid-19, hand­ing Re­gen­eron $450M to be­gin large scale man­u­fac­tur­ing in the US

The US government is on a spending spree. And after committing billions to vaccines defense operations are now doling out more of the big bucks through Operation Warp Speed to back a rapid flip of a drug into the market to stop Covid-19 from ravaging patients — possibly inside of 2 months.

The beneficiary this morning is Regeneron, the big biotech engaged in a frenzied race to develop an antibody cocktail called REGN-COV2 that just started a late-stage program to prove its worth in fighting the virus. BARDA and the Department of Defense are awarding Regeneron a $450 million contract to cover bulk delivery of the cocktail starting as early as late summer, with money added for fill/finish and storage activities.

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An­oth­er four biotechs scratch out the first num­ber and ask for more as IPO boom con­tin­ues

Four more biotechs are raising their offers in an already record year for biotech IPOs.

Softbank-backed Relay Therapeutics scratched out its original $200 million filing and proposed a $250 million raise that would make them a $1.5 billion company. CAR-T developer Poseida Therapeutics bumped itself up $74 million to $224 million. Off-the-shelf cell therapy startup Nkarta upped from $150 million to $215 million — and then priced even higher, at $252 million. France’s Inventiva did its own modest reset, raising its bar from $102 million to $108 million.

Top biotech an­a­lyst projects a gloomy out­look for Pfiz­er's JAK port­fo­lio

Many in the pharma world are hoping — better yet, expecting — JAK inhibitors to provide one of the next big boons for the industry. Few have invested as heavily in this area as Pfizer, which boasts a portfolio including Xeljanz and at least five mid-to-late stage candidates in the pipeline.

But a top Wall Street analyst is pumping the brakes on just how much good fortune is in store for the Big Pharma.

Oph­thalmic drugs, can­cer cell ther­a­pies at­tract $340M+ on two HKEX biotech de­buts

Nasdaq may be running the main biotech IPO show, but the Hong Kong stock exchange has some stellar performance on display even as the city confronts a third wave of Covid-19.

Ocumension Therapeutics and Immunotech Biopharm both traded up after making their public debuts on the HKEX’s busiest IPO day of the year so far, with seven stocks getting listed. The former raised close to $200 million while the latter took home $141 million.