#ES­MO20: Out to beat Tagris­so, J&J touts 100% ORR for EGFR bis­pe­cif­ic/TKI com­bo — fu­el­ing a quick leap to PhI­II

J&J’s one-two punch on EGFR-mu­tant non-small cell lung can­cer has turned up some promis­ing — al­though de­cid­ed­ly ear­ly — re­sults, fu­el­ing the idea that there’s yet room to one up on third-gen­er­a­tion ty­ro­sine ki­nase in­hibitors.

Mark Wild­gust

Twen­ty out of 20 ad­vanced NSCLC pa­tients had a re­sponse af­ter tak­ing a com­bi­na­tion of an in-house TKI dubbed laz­er­tinib and ami­van­tam­ab, a bis­pe­cif­ic an­ti­body tar­get­ing both EGFR and cMET en­gi­neered on part­ner Gen­mab’s plat­form, J&J re­port­ed at ES­MO. All were treat­ment-naïve, and none has seen their can­cer progress at a me­di­an fol­low-up of sev­en months.

Armed with the Phase Ib da­ta, J&J is tak­ing the com­bo straight to Phase III , where it’s go­ing head to head with As­traZeneca’s dom­i­nant TKI, Tagris­so, for pre­vi­ous­ly un­treat­ed pa­tients.

“So while it’s 20 pa­tients and it’s quite ear­ly still, you can’t get bet­ter than a 100% re­sponse rate. You just can’t,” Mark Wild­gust, the VP of glob­al med­ical af­fairs, on­col­o­gy at J&J’s Janssen sub­sidiary, told End­points News. “We know that os­imer­tinib it­self gets you in the mid-80% range for re­sponse rate, so it’s hard to say that ami­van­tam­ab or laz­er­tinib is bet­ter, I would nev­er say that, but cer­tain­ly as I was say­ing you can’t get bet­ter than 100%.”

While laz­er­tinib binds to EGFR in­tra­cel­lu­lar­ly like the oth­er drugs in the class, ami­van­tam­ab tar­gets the re­cep­tor ex­tra­cel­lu­lar­ly, he ex­plained. The bis­pe­cif­ic is thus un­af­fect­ed by co-mu­ta­tions with­in bind­ing pock­ets that can blunt the ef­fi­ca­cy of TKIs, while al­so pro­mot­ing macrophage dri­ven an­ti­body de­pen­dent tro­go­cy­to­sis and block­ing oth­er re­sis­tance path­ways dri­ven by MET am­pli­fi­ca­tions.

At the same time, Wild­gust not­ed that laz­er­tinib stands out among TKIs with low rates of rash and di­ar­rhea as well as low car­diac tox­i­c­i­ty — a key rea­son J&J chose to li­cense the drug from Ko­rea’s Yuhan for $50 mil­lion up­front al­most two years ago. In se­lect­ing a drug for the com­bo, over­lap­ping tox­i­c­i­ty was a key con­cern.

“We re­al­ly want­ed to find a third gen­er­a­tion EGFR TKI that has a re­al­ly good safe­ty pro­file,” he said, “and we found that with laz­er­tinib.”

The soon-to-be­gin Phase III MARI­POSA tri­al will have three arms, de­signed to suss out the con­tri­bu­tions of each J&J drug in ad­di­tion to pit­ting them against Tagriso: laz­er­tinib alone, laz­er­tinib plus ami­van­tam­ab, and Tagris­so.

The front­line use of the com­bo reg­i­men, though, is on­ly one of three paths where the Janssen team is steer­ing ami­van­tam­ab.

In the Phase Ib CHRYSALIS study pre­sent­ed at ES­MO, fol­low­ing the dose es­ca­la­tion por­tion in­ves­ti­ga­tors al­so en­rolled a group of 45 pa­tients who have re­lapsed af­ter tak­ing Tagris­so. There, the ami­van­tam­ab/laz­er­tinib com­bo re­sults in a 36% ORR, with one com­plete re­sponse and 15 par­tial re­spons­es.

No­tably, all were tak­ing both ami­van­tam­ab and laz­er­tinib at their re­spec­tive full dos­es.

“To­day in fact there are no ap­proved agents post a third gen­er­a­tion EGFR TKI,” Wild­gust said. “So to­day many pa­tients are get­ting os­imer­tinib, and re­al­ly the next ther­a­py for those pa­tients af­ter­wards is chemother­a­py.”

The next step here will be a Phase II tri­al test­ing the com­bi­na­tion in pa­tients who have pro­gressed af­ter re­ceiv­ing both Tagris­so and chemother­a­py.

The fi­nal play is push­ing ami­van­tam­ab as a monother­a­py to treat pa­tients with rare EGFR Ex­on 20 in­ser­tion mu­ta­tions, an in­di­ca­tion that’s earned the drug a break­through ther­a­py des­ig­na­tion.

Both ami­van­tam­ab — which is de­signed with Gen­mab’s Duo­body tech — and laz­er­tinib are fea­tured on J&J’s lat­est list of late-stage block­buster can­di­dates, al­though Wild­gust hint­ed that pitch­ing the two to­geth­er re­mains the pri­ma­ry goal.

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.

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.

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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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 million-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.

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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Lit­tle Zosano takes an­oth­er beat­ing as the FDA slaps down their ap­pli­ca­tion for a mi­graine patch

Zosano $ZSAN has officially come up short in its bid to develop a migraine patch.

The FDA rejected the company’s application to repurpose the triptan zolmitriptan in a new delivery system as Qtrypta, Zosano said Wednesday morning, issuing a CRL for the microneedle patch. Regulators cited inconsistent exposure levels across multiple clinical trials as the main reason for the thumbs down.

Investors did not take too kindly to the news, with Zosano shares plunking down around 25%. The company is requesting a Type A meeting to “provide clarity on the next steps for the program,” CEO Steven Lo said in a statement.