As­traZeneca, Dai­ichi Sankyo un­cork new TNBC da­ta for 2nd part­nered ADC — and it's adding more heat un­der Gilead­'s Trodelvy

Af­ter the ap­proval of their part­nered an­ti-HER2 an­ti­body-drug con­ju­gate ear­li­er this year, As­traZeneca and Dai­ichi Sankyo are rid­ing high on the promise of their bloom­ing part­ner­ship. Now a sec­ond ADC is show­ing promise in hard-to-treat breast can­cer, and the com­pa­nies have their eyes set on their on­ly ap­proved com­peti­tor in the space.

As­traZeneca and Dai­ichi Sankyo’s next-gen ADC datopotam­ab derux­te­can post­ed a 43% re­sponse rate and five con­firmed com­plete or par­tial re­spons­es among 21 pa­tients with triple-neg­a­tive breast can­cer, ac­cord­ing to co­hort da­ta from the TRO­PI­ON-Pan­Tu­mor01 Phase I study pre­sent­ed Sat­ur­day at the vir­tu­al ES­MO Breast an­nu­al meet­ing.

The vast ma­jor­i­ty of those pa­tients were treat­ed with 6-mg dos­es of the drug while two re­ceived an 8-mg high dose. On top of the five con­firmed re­spons­es, the part­ners were await­ing con­fir­ma­tion on four ad­di­tion­al re­spons­es at the Jan. 8 cut­off date. Datopotam­ab post­ed a dis­ease con­trol rate of 95%.

It’s ear­ly days, but the da­ta stack up well in terms of ORR against Gilead and im­munomedics’ Trodelvy, the first TROP2-tar­get­ed ADC ap­proved for TNBC in April. As­traZeneca opt­ed in June to shell out $1 bil­lion up­front for co-de­vel­op­ment rights to datopotam­ab, a fol­low-up on its win­ning part­ner­ship with Dai­ichi on an­ti-HER2 drug En­her­tu.

The part­ners added the TNBC co­hort af­ter un­cork­ing ear­ly da­ta at last year’s AS­CO show­ing datopotam­ab post­ed a 38% ORR in 34 ad­vanced non-small cell lung can­cer pa­tients at an 8-mg high dose. Among all test­ed dos­es, the drug hit a 25% ORR. As of a Sept. 4 up­date, datopotam­ab post­ed an ORR rang­ing from 21% to 25%, as as­sessed by an in­de­pen­dent cen­tral re­view, among 159 pa­tients in that study.

TNBC is a tough-to-treat in­di­ca­tion with a par­tic­u­lar­ly poor prog­no­sis, with pa­tients in the As­traZeneca study hav­ing un­der­gone a me­di­an four pri­or lines of treat­ment and up to nine lines of treat­ment. Thir­ty-three per­cent of pa­tients post­ed a Grade 3 side ef­fect or high­er with stom­ati­tis, fa­tigue and ane­mia re­port­ed as the most com­mon. Mean­while, none of those se­ri­ous events were di­ar­rhea or neu­trope­nia — a con­cern giv­en both Trodelvy and En­her­tu’s la­bels.

Cris­t­ian Mas­sace­si

Mean­while, the TNBC co­hort re­port­ed ze­ro cas­es of in­ter­sti­tial lung dis­ease, a big safe­ty red flag that cropped up in the NSCLC arm of the dat­apotam­ab study and is list­ed a black box warn­ing on En­her­tu’s la­bel. Both TROP2 and HER2 are ex­pressed on a range of tu­mor types, but al­so on healthy cells in the lungs, which can lead to off-tar­get tox­i­c­i­ties.

Eight cas­es of ILD were re­port­ed in the NSCLC arm of TRO­PI­ON-Pan­Tu­mor01, with six re­ports and one death in the 8-mil­ligram arm. All but one of those cas­es were deemed to be treat­ment re­lat­ed.

Dai­ichi and now As­traZeneca have ar­gued that datopotam­ab could have best-in-class ef­fi­ca­cy and safe­ty with a low­er drug-to-an­ti­body ra­tio and a more sta­ble link­er. Tox­i­c­i­ty is a big con­cern for the ADC class on the whole, with Pfiz­er aban­don­ing its own an­ti-TROP2 drug, PF-06664178, back in 2016.

“What we be­lieve at As­traZeneca and through our re­la­tion­ship Daichii Sankyo is we can be a pre­mier com­pa­ny in the ADC space,” Cris­t­ian Mas­sace­si, As­traZeneca’s se­nior VP and head of late stage de­vel­op­ment on­col­o­gy, told End­points News. “En­her­tu and (datopotam­ab) I be­lieve are best-in-class agents. Even though there’s a back­bone of chemother­a­py in breast can­cer, this is a much bet­ter way to de­liv­er chemother­a­py. The key ques­tion is, how good is your drug?”

Un­pack­ing the Aduhelm de­ci­sion, Ver­tex's half full glass, a $525M J&J breakup, and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

By now you have surely read about the FDA’s controversial approval of Biogen’s Alzheimer’s drug and all its reverberations. But I’d still recommend checking out the meaty recap below to make sure you didn’t miss all the angles that the Endpoints team has covered. If you’d rather look ahead, look no further than our three-day virtual panels next week at BIO, where we will discuss what the new normal means for every part of the industry.

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What does a clear ma­jor­i­ty of the bio­phar­ma in­dus­try think of the FDA ap­proval of ad­u­canum­ab? 'Hor­ri­fy­ing' 'Dan­ger­ous' 'Con­fus­ing' 'Dis­as­ter'

Over the years, we’ve become used to seeing a consensus emerge early in our industry polls at Endpoints News. And when we took the pulse of drug hunters on the heels of a controversial FDA approval for aducanumab this week, it became immediately apparent that the vast majority of our readers — heavily concentrated among biopharma staffers and execs — were incensed by what they had just witnessed.

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Aaron Kesselheim (Scott Eisen/AP Images for AIDS Healthcare Foundation)

Har­vard’s Aaron Kessel­heim re­signs from ex­pert pan­el in wake of ad­u­canum­ab OK, blast­ing FDA for ‘worst drug ap­proval de­ci­sion in re­cent U.S. his­to­ry'

A third member of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee has resigned in the wake of Biogen’s controversial Aduhelm approval, slamming the agency as he left and further deepening the controversy surrounding the decision.

Harvard University professor Aaron Kesselheim quit in protest Thursday afternoon, calling the Aduhelm OK “probably the worst drug approval decision in recent U.S. history.” Kesselheim follows both Joel Perlmutter, a neurologist from Washington University in St. Louis, and David Knopman, a neurologist from the Mayo Clinic, out the door.

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David Knopman (Mayo Clinic via YouTube)

A sec­ond ad­comm mem­ber aban­dons his post in af­ter­math of con­tro­ver­sial ad­u­canum­ab de­ci­sion

As the fallout from the FDA’s approval of Alzheimer’s med aducanumab grows, a second member of the adcomm overseeing that drug’s review has walked away. But even with two experts now having resigned from that committee in protest, is there enough broad-level outrage to prevent another aducanumab from getting approved?

The FDA on Wednesday lost another member of its Peripheral and Central Nervous System Drugs Advisory Committee as Mayo Clinic neurologist David Knopman hit the exit over the agency’s decision to approve Biogen’s Alzheimer’s drug Aduhelm despite the committee’s near-unanimous vote against it.

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Reshma Kewalramani, Vertex CEO (BIO via YouTube)

UP­DAT­ED: Ver­tex strikes out on its lat­est big shot at a rare ge­net­ic dis­ease. But they're go­ing to keep on swing­ing

It’s been several months since Vertex culled one of its small molecules for alpha-1 antitrypsin deficiency (AATD), taking a big hit after evidence of liver damage surfaced in a key Phase II trial. Now we learned that the company has whiffed on its second shot, and there’s nothing left in the clinic to treat the rare genetic disease — but that won’t stop it from trying.

Despite avoiding the safety issues that plagued the last candidate, Vertex $VRTX is taking the axe to VX-864 after Phase II results revealed the magnitude of the drug’s response is “unlikely to translate into substantial clinical benefit.” As a result of the news, the company’s stock fell 12.5% after hours.

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FDA au­tho­rizes about 10M J&J vac­cine dos­es, trash­es 60M more from trou­bled Emer­gent plant

The FDA on Friday released about 10 million doses of J&J’s vaccine for use, and disposed of another 60 million doses that were manufactured at the now-shuttered Emergent BioSolutions facility in Baltimore where cross-contamination occurred.

The agency said it’s not yet ready to allow the Emergent plant to be included in the J&J EUA, but that may occur soon. FDA came to the decision to authorize some of the doses after reviewing facility records and quality testing results.

Paul Hudson, Sanofi CEO (Eric Piermont/AFP via Getty Images)

Months af­ter FDA re­jec­tion, Sanofi touts piv­otal win for rare dis­ease drug su­tim­limab as it preps to re­file

One of the pillar drugs of Sanofi’s $11.6 billion pickup of Bioverativ hit a big setback late last year when the FDA sent its application for approval back. Now, as Sanofi gears up to resubmit the drug for review, the drugmaker is touting pivotal data it hopes will help take it over the finish line.

Sanofi’s sutimlimab nailed all three of its primary endpoints in its Phase III CADENZA study for patients with cold agglutinin disease, a rare disorder that can cause severe anemia, without a recent history of blood transfusion, the French drugmaker said Friday. The topline results will be presented at this weekend’s virtual EHA meeting.

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Ver­tex and CRISPR Ther­a­peu­tics un­veil more pos­i­tive gene ther­a­py da­ta, but busul­fan again casts a shad­ow over the field

Less than 12 hours after revealing a flop on its second shot for alpha-1 antitrypsin deficiency, Vertex plowed ahead with another data drop from its partnership with CRISPR Therapeutics. And though the topline proved positive, concerns over conditioning agents continue to linger over the collaboration, as well as the entire gene therapy space.

Presenting data from two trials at the European Hematology Association annual meeting, the pair announced that follow-up data of at least three months for 22 patients with genetic blood disorders indicated a “consistent and sustained” response to the experimental drug CTX001. All 15 patients with transfusion-dependent beta thalassemia did not need further blood transfusions and all seven with severe sickle cell disease were pain free, the biotechs announced.

Janet Woodcock, acting FDA commissioner, at Thursday's Senate Appropriations hearing (Bill Clark/CQ Roll Call via AP Images)

Sen­a­tors lam­bast new Alzheimer’s drug’s price but give Janet Wood­cock a free pass on the ap­proval de­ci­sion

Senate Finance Democrats took aim at Biogen’s pricey new Alzheimer’s drug on Thursday, but members on both sides of the aisle at a separate appropriations hearing didn’t question acting FDA commissioner Janet Woodcock on the approval.

“I was appalled that Biogen priced their Alzheimer’s drug approved by the FDA at $56,000 per year — I’m not going to debate whether this is effective or not, but it’s double the household median income for Michiganders over the age of 65,” Sen. Debbie Stabenow (D-MI) said at the finance hearing.