Sci­en­tists find un­ex­pect­ed an­ti-can­cer ac­tiv­i­ty in range of non-on­col­o­gy drugs — study

As the sec­ond lead­ing cause of mor­tal­i­ty glob­al­ly, the lu­cra­tive field of can­cer treat­ment has elicit­ed a fren­zy of drug de­vel­op­ment and bil­lions in ven­ture fund­ing. But a new study sug­gests that can­cer-killing com­pounds may be lurk­ing in the ex­ist­ing ar­se­nal of non-on­col­o­gy med­i­cines.

By an­a­lyz­ing thou­sands of FDA-ap­proved drugs and com­pounds that have been proven safe in clin­i­cal tri­als, sci­en­tists at the Broad In­sti­tute of MIT and Har­vard and Dana-Far­ber Can­cer In­sti­tute found near­ly 50 com­pounds — in­clud­ing drugs for di­a­betes, in­flam­ma­tion, al­co­holism and even a treat­ment for arthri­tis in dogs — with pre­vi­ous­ly un­de­tect­ed an­ti-can­cer ac­tiv­i­ty.

Todd Gol­ub

“We thought we’d be lucky if we found even a sin­gle com­pound with an­ti-can­cer prop­er­ties, but we were sur­prised to find so many,” said Todd Gol­ub, chief sci­en­tif­ic of­fi­cer and di­rec­tor of the Can­cer Pro­gram at the Broad, Charles A. Dana In­ves­ti­ga­tor in Hu­man Can­cer Ge­net­ics at Dana-Far­ber, and pro­fes­sor of pe­di­atrics at Har­vard Med­ical School, in a state­ment.

The study, pub­lished in the jour­nal Na­ture Can­cer, em­ployed the Broad’s Drug Re­pur­pos­ing Hub, an­a­lyz­ing 4,518 drugs against 578 hu­man can­cer cell lines from the Broad’s Can­cer Cell Line En­cy­clo­pe­dia. Af­ter tag­ging each cell line with a DNA bar­code, the re­searchers ex­posed each pool of bar­cod­ed cells to a sin­gle com­pound from the re­pur­pos­ing li­brary and mea­sured the sur­vival rate of can­cer cells.

Some of the can­cer-slay­ing com­pounds kill in un­fore­seen ways, study lead au­thor Steven Corsel­lo said. Corsel­lo is an on­col­o­gist at Dana-Far­ber and founder of the Drug Re­pur­pos­ing Hub.

Most ex­ist­ing can­cer drugs work by sti­fling pro­teins — but some of the can­cer-killing com­pounds Corsel­lo et al came across ap­peared to work by ac­ti­vat­ing a pro­tein or sta­bi­liz­ing a pro­tein-pro­tein in­ter­ac­tion. For ex­am­ple, the team found that near­ly a dozen non-on­col­o­gy drugs killed can­cer cells that ex­press a pro­tein called PDE3A by sta­bi­liz­ing the in­ter­ac­tion be­tween PDE3A and an­oth­er pro­tein called SLFN12.

Steven Corsel­lo

The re­sults of the analy­sis — which scoured near­ly half of all drugs ever test­ed in hu­mans — sug­gests that some non-on­col­o­gy drugs could be tak­en straight in­to clin­i­cal test­ing in can­cer pa­tients, al­though sci­en­tists will need to en­sure the can­cer culling ac­tiv­i­ty of these drugs is ob­served at con­cen­tra­tions that are tol­er­a­ble in hu­mans. It is al­so im­per­a­tive to con­firm that the pre­dic­tive bio­mark­ers iden­ti­fied in cell lines rep­re­sent dis­tinct pop­u­la­tions of hu­man tu­mors, the re­searchers cau­tioned.

“In con­trast to the repo­si­tion­ing of ex­ist­ing drugs for new in­di­ca­tions, the…re­sults re­port­ed here al­so rep­re­sent start­ing points for new drug de­vel­op­ment. In par­tic­u­lar, when the an­ti-can­cer ac­tiv­i­ty of a drug oc­curs via an off-tar­get mech­a­nism, it is like­ly that fur­ther op­ti­miza­tion for this new tar­get will re­sult in more po­tent and se­lec­tive drug can­di­dates,” the re­searchers wrote.

Re­pur­pos­ing drugs on pur­pose (or by ac­ci­dent) has yield­ed some suc­cess — that the process in­volves large­ly de-risked com­pounds, low­er de­vel­op­men­tal costs, and briefer time­lines don’t hurt ei­ther.

Aside from as­pirin’s car­dio­vas­cu­lar ben­e­fits, Vi­a­gra is an­oth­er heav­i­ly cit­ed ex­am­ple. The drug was orig­i­nal­ly be­ing test­ed as a treat­ment for coro­nary hy­per­ten­sion — but a pesky side ef­fect felt by pa­tients in tri­als cul­mi­nat­ed in its even­tu­al ap­proval as an erec­tile dys­func­tion drug.

Then there’s the seda­tive thalido­mide — which gained no­to­ri­ety af­ter its link to se­vere skele­tal birth de­fects trig­gered its with­draw­al in 1957. How­ev­er, years lat­er it was deemed ef­fec­tive as a can­cer treat­ment, even breed­ing the de­vel­op­ment and ap­proval of even more suc­cess­ful de­riv­a­tives, such as Cel­gene’s block­buster Revlim­id.

Mean­while, Mer­ck’s Vioxx — which was un­cer­e­mo­ni­ous­ly tak­en off shelves af­ter its link to dou­bling pa­tients’ risk of heart at­tack and stroke emerged — could resur­face as a gener­ic treat­ment for a side ef­fect ex­pe­ri­enced by he­mo­phil­ia pa­tients.

But akin to tra­di­tion­al drug de­vel­op­ment, drug re­pur­pos­ing has al­so seen its share of set­backs. Two ex­am­ples of late-stage fail­ures in­clude a bid to use the an­ti­his­t­a­mine, la­trepir­dine, as a treat­ment for Hunt­ing­ton’s dis­ease, as well as the pur­suit of re­pur­pos­ing the an­tibi­ot­ic, cef­tri­ax­one, as a med­i­cine for ALS.

Michel Younatsos, Biogen CEO (via YouTube)

UP­DAT­ED: Bio­gen scores a pri­or­i­ty re­view for its Alzheimer's drug ad­u­canum­ab, mov­ing one gi­ant leap for­ward in its con­tro­ver­sial quest

Biogen scored a big win at the FDA today as regulators accepted their application for the controversial Alzheimer’s drug aducanumab and gave it a priority review.

The PDUFA date is March 7, 2021.

Significantly, Biogen says it did not use its priority review voucher to win special treatment at the FDA. The agency handed that out gratis.

That’s the ideal scenario Biogen was looking for as disappointed analysts wondered aloud about the delayed application earlier in the year.

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Ryan Watts, Denali CEO

Bio­gen hands De­nali $1B-plus in cash, $1B-plus in mile­stones to part­ner on late-stage Parkin­son’s drug

Biogen is handing over more than a billion dollars cash to partner with the up-and-coming neurosciences crew at Denali on a new therapy for Parkinson’s. And the big biotech is ready to pile on more than a billion dollars more in milestones — if the alliance is a success.

For Biogen $BIIB, the move on Denali’s small molecule inhibitors of LRRK2 puts them in line to collaborate on a late-stage program for DNL151, which is scheduled to start next year.

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Covid-19 roundup: No­vavax inks vac­cine deals with Japan and In­dia; As­traZeneca near­ing agree­ments with Japan and Brazil

Following the release this week of promising early data for their Covid-19 vaccine candidate, Novavax has announced collaborations to supply it to two countries — Japan and India.

The Maryland-based biotech announced a deal Friday morning with Takeda to develop and manufacture up to 250 million doses per year of its adjuvanted vaccine. And late Thursday afternoon, Novavax entered into an agreement with the Serum Institute of India to provide up to 1 billion doses to India and low- and middle-income countries.

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In sur­pris­ing set­back, com­bo of Roche’s Tecen­triq and chemo fails to help pa­tients with triple-neg­a­tive breast can­cer

Roche broke ground last year when they secured the first FDA approval for a checkpoint therapy in triple-negative breast cancer, a notoriously difficult-to-treat indication that has been passed over by the wave of targeted therapies.

Now, though, doctors are puzzling over why a combination of drugs meant to make that therapy more potent instead appeared to make it less effective.

Roche said Thursday that in a Phase III trial, combining their PD-1/L1 checkpoint therapy Tecentriq with the chemotherapy paclitaxel, did not significantly improve progression-free survival for patients with locally advanced or metastatic triple-negative breast cancer over giving those patients chemotherapy alone. In fact, patients on the Tecentriq-chemo arm had lower overall survival than patients on chemo, although the drugmaker cautioned that the trial was not powered for that endpoint and the data were immature.

President Trump (AP Images)

FDA takes the lead on defin­ing es­sen­tial un­der Trump's 'Buy Amer­i­can' ex­ec­u­tive or­der — as in­dus­try warns of sup­ply chain dis­rup­tion

President Donald Trump has signed an executive order detailing how the federal government should help on-shore drug manufacturing — and the FDA will play a central role.

The agency now has three months to draw up the list of “essential medicines, medical countermeasures, and their critical inputs” that the US must have available at all times. Various departments and agencies are then directed to buy these drugs and their ingredients from American manufacturers.

Jan Hatzius (Photographer: Christopher Goodney/Bloomberg via Getty Images)

When will it end? Gold­man econ­o­mist gives late-stage vac­cines a good shot at tar­get­ing 'large shares' of the US by mid-2021 — but the down­side is daunt­ing

It took decades for hepatitis B research to deliver a slate of late-stage candidates capable of reining the disease in.

With Covid-19, the same timeline has devoured all of 5 months. And the outcome will influence the lives of billions of people and a multitrillion-dollar world economy.

Count the economists at Goldman Sachs as optimistic that at least one of these leading vaccines will stay on this furiously accelerated pace and get over the regulatory goal line before the end of this year, with a shot at several more near-term OKs. That in turn should lead to the production of billions of doses of vaccines that can create herd immunity in the US by the middle of next year, with Europe following a few months later.

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J&J gets a fresh OK for es­ke­t­a­mine, but is it re­al­ly the game-chang­er for de­pres­sion Trump keeps tweet­ing about?

Backed by an enthusiastic set of tweets from President Trump and a landmark OK for depression, J&J scooped up a new approval from the FDA for Spravato today. But this latest advance will likely bring fresh scrutiny to a drug that’s spurred some serious questions about the data, as well as the price.

First, the approval.

Regulators stamped their OK on the use of Spravato — developed as esketamine, a nasal spray version of the party drug Special K or ketamine — for patients suffering from major depressive disorder with acute suicidal ideation or behavior.

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Douglas Fambrough, Dicerna CEO (Boehringer Ingelheim via YouTube)

Roche-backed Dicer­na push­es in­to the pack rac­ing to­ward the block­buster hep B goal line, armed with PhI da­ta

Dicerna has lined up a set of proof-of-concept data from a small cohort of hepatitis B patients in a match-up against some heavyweight rivals which got out in front of this race. And right in the front row you’ll find a team from Roche, which paid $200 million in cash and offered another $1.5 billion in milestones to partner with Dicerna $DRNA on their RNAi program for hep B.

Right now it’s looking competitive, with lots of big challenges ahead.

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Lund­beck sounds taps on an­oth­er CNS drug, re­treat­ing from a mine field still oc­cu­pied by a Mer­ck team

Lundbeck has snipped another clinical-stage branch of its CNS research, dumping a schizophrenia program after determining that their therapy would have no positive influence on the disease.

Designed originally as a 240-patient study, researchers set out in early 2019 to see if a homegrown drug dubbed Lu AF11167 could make it through a proof-of-concept study. The drug is a PDE10Ai inhibitor, targeting an enzyme which it said at the time offered a new pathway to retuning the body’s neurotransmitter dopamine. The big idea was that by hitting their target, the drug would modulate “dopamine D1 and D2 receptor-mediated intraneuronal signaling without binding to these receptors,” influencing negative symptoms of schizophrenia.

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