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 Vounatsos, Biogen CEO (via YouTube)

UP­DAT­ED: Bio­gen spot­lights a pair of painful pipeline set­backs as ad­u­canum­ab show­down looms at the FDA

Biogen has flagged a pair of setbacks in the pipeline, spotlighting the final failure for a one-time top MS prospect while scrapping a gene therapy for SMA after the IND was put on hold due to toxicity.

Both failures will raise the stakes even higher on aducanumab, the Alzheimer’s drug that Biogen is betting the ranch on, determined to pursue an FDA OK despite significant skepticism they can make it with mixed results and a reliance on post hoc data mining. And the failures are being reported as Biogen was forced to cut its profit forecast for 2020 as a generic rival started to erode their big franchise drug.

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Stephen Hahn, FDA commissioner (AP Images)

As FDA sets the stage for the first Covid-19 vac­cine EUAs, some big play­ers are ask­ing for a tweak of the guide­lines

Setting the stage for an extraordinary one-day meeting of the Vaccines and Related Biological Products Advisory Committee this Thursday, the FDA has cleared 2 experts of financial conflicts to help beef up the committee. And regulators went on to specify the safety, efficacy and CMC input they’re looking for on EUAs, before they move on to the full BLA approval process.

All of this has already been spelled out to the developers. But the devil is in the details, and it’s clear from the first round of posted responses that some of the top players — including J&J and Pfizer — would like some adjustments and added feedback. And on Thursday, the experts can offer their own thoughts on shaping the first OKs.

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A new chap­ter in the de­cen­tral­ized clin­i­cal tri­al ap­proach

Despite the promised decentralized trial revolution, we haven’t yet moved the needle in a significant way, although we are seeing far bolder commitments to this as we continue to experience the pandemic restrictions for some time to come. The vision of grandeur is one thing, but operationalizing and execution are another and recognising that change, particularly mid-flight on studies, is worthy of thorough evaluation and consideration in order to achieve success. Here we will discuss one of the critical building blocks of a Decentralized and Remote Trial strategy: TeleConsent; more than paper under glass, it is a paradigm change and key digital enabler.

UP­DAT­ED: CRISPR Ther­a­peu­tics gets a snap­shot of off-the-shelf CAR-T suc­cess in B-cell ma­lig­nan­cies — marred by the death of a pa­tient

Just days after scientific founder Emmanuelle Charpentier shared the Nobel prize for her work on CRISPR/Cas9, CRISPR Therapeutics $CRSP is showing off a snapshot of success in their early-stage study for an off-the-shelf CAR-T approach to CD19+ B cell malignancies — a snapshot marred by the death of a patient who had been given a high dose of the treatment.

Using their gene editing tech, researchers for CRISPR engineered cells from healthy donors into an attack vehicle aimed at cancer, something that has been achieved with great success using patients’ own cells — the autologous approach. But autologous CAR-T is hampered by the more complex vein-to-vein requirement that delays treatment, and now CRISPR Therapeutics along with other players like Allogene are determined to replace the pioneers with CAR-T 2.0.

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RBC's Bri­an Abra­hams holds a mock ad­comm on Bio­gen's iffy ad­u­canum­ab da­ta — and most of these ex­perts don't see a path to an ap­proval

As catalysts go, few loom larger than the aducanumab adcomm slated for Nov. 6.

With its big franchise under assault, Biogen is betting the ranch that its mixed late-stage Alzheimer’s data can squeak past the experts and regulators and get onto the market. And the topic — after a decade of Alzheimer’s R&D disasters in what still represents the El Dorado of drug markets — remains in the center ring of discussions around late-stage pipeline prospects.

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David Hung (file photo)

Mas­ter deal­mak­er David Hung re­tools a SPAC sedan in­to a fi­nanc­ing mus­cle ve­hi­cle that leaves his can­cer start­up with $850M and a place on Wall Street

It’s only right that one of the industry’s top dealmakers just completed one of the biggest SPAC-related deals in the pipeline.

David Hung, of Medivation fame, has completed a back flip into the market, merging with EcoR1 Capital’s SPAC Panacea and landing neatly on Wall Street with an $NUVB stock ticker after filling out the blank check in his name. In addition to the $144 million held in the SPAC — provided none of the investors opt out — Hung is getting ahold of $500 million more being chipped in by a slate of institutional investors who feel that Hung could have the keys to another Medivation-style success.

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Years af­ter a ma­jor tri­al set­back, No­var­tis switch­es gears with SMA drug. This time they're try­ing it for Hunt­ing­ton's

Four years after a Phase I/II setback in spinal muscular atrophy (SMA), Novartis is hoping its drug branaplam will find more success in a new neurological indication: Huntington’s disease.

The decision was announced a year after the head of research, Jay Bradner, said he did not see a “big opportunity” in SMA, according to Reuters. Novartis says it has preclinical data showing that branaplam reduces levels of mutant huntingtin protein, and SMA data showing patients on the drug had reductions in huntingtin mRNA. The FDA gave branaplam their orphan drug designation, and Novartis plans to move forth with a Phase IIb trial next year.

Glax­o­SmithK­line's vac­cines group aims for a first as it kicks off PhI­II RSV stud­ies

One of GlaxoSmithKline’s big projects at its global vaccine R&D center in Rockville, MD is set to enter Phase III after passing early-stage tests with flying colors.

Eyeing the wide-open respiratory syncytial virus (RSV) space, GSK is pushing two different vaccine candidates: GSK3888550A is designed to confer protection to infants via maternal immunization, while GSK3844766A is meant for the elderly.

Pur­due Phar­ma signs guilty plea, preps $8B+ set­tle­ment on Oxy con­tro­ver­sy — re­port; Flag­ship brings in a comms chief

Purdue Pharma may soon be signing off on a guilty plea and an $8 billion-plus settlement to wrap up its controversial role distributing OxyContin.

The AP has the breaking story this morning.

Purdue filed for bankruptcy last year, along with Insys and followed by Mallinckrodt, as it navigated its way through a blizzard of litigation surrounding Oxy, which triggered an epidemic of abuse around the country.