Jonathan Mow, PhaseBio CEO

Eye­ing an ac­cel­er­at­ed BLA, Phase­Bio says its mon­o­clon­al an­ti­body re­versed the dan­ger­ous ef­fects of As­traZeneca's blood thin­ner

A class of blood thin­ners called P2Y12 in­hibitors has been used for the last cou­ple decades to treat and pre­vent a range of car­dio­vas­cu­lar con­di­tions, in­clud­ing stroke and heart at­tack. But the an­tiplatelet drugs come with a risk of in­creased bleed­ing, which can prove fa­tal — es­pe­cial­ly for those who need ur­gent surgery and don’t have time to wean off their med­ica­tion.

Phase­Bio is work­ing on a so­lu­tion for that. And on Mon­day, the com­pa­ny pre­sent­ed pos­i­tive Phase III da­ta that could pave the way for a mid-2022 BLA sub­mis­sion.

The com­pa­ny’s lead drug ben­tracimab was shown to re­verse the ef­fects of As­traZeneca’s blood thin­ner Bril­in­ta in an in­ter­im analy­sis of more than 100 pa­tients who need­ed ur­gent surgery or an in­va­sive pro­ce­dure, Phase­Bio an­nounced at this year’s Amer­i­can Heart As­so­ci­a­tion con­fer­ence.

Pa­tients who took ben­tracimab in the piv­otal RE­VERSE-IT tri­al saw a 135% re­duc­tion in platelet in­hi­bi­tion with­in 5 to 10 min­utes of in­fu­sion (p<0.001) and saw those ef­fects last over 24 hours, ac­cord­ing to Phase­Bio. The drug al­so met its co-pri­ma­ry end­point, de­fined as good or ex­cel­lent he­mo­sta­sis with­in 24 hours of ad­min­is­tra­tion.

Reg­u­la­tors pre­vi­ous­ly told Phase­Bio that an in­ter­im analy­sis from the first 100 pa­tients in RE­VERSE-IT would be suf­fi­cient for an ac­cel­er­at­ed BLA sub­mis­sion, CEO Jonathan Mow told End­points News.

“When we then looked at the Phase III da­ta and saw that not on­ly did we hit the Ver­i­fyNow, platelet bio­mark­er end­point, we al­so hit the clin­i­cal end­point — al­beit with a slight­ly larg­er num­ber of pa­tients, you know, 150 in to­tal — but still, that’s a fan­tas­tic achieve­ment for us. One that was not ex­pect­ed at this point in time,” he said.

Ben­tracimab ap­peared safe, ac­cord­ing to Phase­Bio. And though 91% of pa­tients re­port­ed a treat­ment-emer­gent side ef­fect, the most com­mon was pain as­so­ci­at­ed with the sur­gi­cal pro­ce­dure. Eight ex­pe­ri­enced throm­bot­ic events, though none of the cas­es were tied to ben­tracimab.

“With no ap­proved re­ver­sal agents for oral P2Y12 in­hibitors, pa­tients who are pre­scribed these med­ica­tions to re­duce the risk of car­diac events are at in­creased risk for spon­ta­neous ma­jor bleed­ing events, and physi­cians are faced with a com­plex dilem­ma of bal­anc­ing bleed­ing risk and throm­bot­ic risk, should these pa­tients re­quire ur­gent surgery,” said Deep­ak Bhatt, ex­ec­u­tive di­rec­tor of in­ter­ven­tion­al car­dio­vas­cu­lar pro­grams at Boston’s Brigham and Women’s Hos­pi­tal, who pre­sent­ed the study at AHA.

Doc­tors typ­i­cal­ly rec­om­mend pa­tients stop tak­ing P2Y12 in­hibitors five to sev­en days be­fore any type of sur­gi­cal pro­ce­dure. But while oth­er P2Y12 in­hibitors like Sanofi’s Plav­ix and Eli Lil­ly’s Effient aren’t re­versible, Bril­in­ta is. That’s be­cause Plav­ix and Effient bind to the P2Y12 re­cep­tor per­ma­nent­ly, so to re­gain func­tion­al­i­ty, you need to wait for platelet turnover. Bril­in­ta, on the oth­er hand, binds tran­sient­ly and on­ly has about a 15-minute res­i­dence time on the re­cep­tor.

Ben­tracimab is a mon­o­clon­al an­ti­body frag­ment that binds to Bril­in­ta when it’s in that off state, and re­moves it from the platelet en­vi­ron­ment.

John Lee

“Es­sen­tial­ly it just se­questers tica­grelor [Bril­in­ta] from the platelet,” CMO John Lee told End­points.

The Phase III read­out comes just a cou­ple weeks af­ter Phase­Bio re­port­ed pos­i­tive topline re­sults for a Phase IIb study eval­u­at­ing ben­tracimab in healthy, old­er vol­un­teers on Bril­in­ta. Ear­li­er re­sults have al­so shown promise in treat­ing younger vol­un­teers.

The news al­so bodes well for the Ital­ian biotech Al­fasig­ma, which back in June put down up to $245 mil­lion for the Eu­ro­pean rights to ben­tracimab.

Phase­Bio orig­i­nal­ly li­censed the drug from Med­Im­mune, the bi­o­log­ics arm of As­traZeneca, in 2017 for an up­front fee of $100,000, with $68 mil­lion in po­ten­tial mile­stones. A lit­tle over a year lat­er, the biotech rode that deal to an IPO with Med­Im­mune own­ing 5% of the stock. And in 2019, ben­tracimab re­ceived break­through ther­a­py des­ig­na­tion from the FDA.

While ben­tracimab would be the first an­tiplatelet re­ver­sal ther­a­py for a P2Y12 in­hibitor, it would not be the first to ad­dress the risk of bleed­ing in pa­tients on blood thin­ners. Back in 2018, the FDA ap­proved Por­to­la Phar­ma­ceu­ti­cals’ An­dexxa as the first re­ver­sal agent for Fac­tor Xa in­hibitors, such as Janssen’s Xarel­to and Bris­tol My­ers Squibb and Pfiz­er’s Eliquis.

Phase­Bio is still re­cruit­ing pa­tients with un­con­trolled ma­jor or life-threat­en­ing bleed­ing for the RE­VERSE-IT tri­al, and aims to be ful­ly-en­rolled as soon as pos­si­ble.

ZS Per­spec­tive: 3 Pre­dic­tions on the Fu­ture of Cell & Gene Ther­a­pies

The field of cell and gene therapies (C&GTs) has seen a renaissance, with first generation commercial therapies such as Kymriah, Yescarta, and Luxturna laying the groundwork for an incoming wave of potentially transformative C&GTs that aim to address diverse disease areas. With this renaissance comes several potential opportunities, of which we discuss three predictions below.

Allogenic Natural Killer (NK) Cells have the potential to displace current Cell Therapies in oncology if proven durable.

Despite being early in development, Allogenic NKs are proving to be an attractive new treatment paradigm in oncology. The question of durability of response with allogenic therapies is still an unknown. Fate Therapeutics’ recent phase 1 data for FT516 showed relatively quicker relapses vs already approved autologous CAR-Ts. However, other manufacturers, like Allogene for their allogenic CAR-T therapy ALLO-501A, are exploring novel lymphodepletion approaches to improve persistence of allogenic cells. Nevertheless, allogenic NKs demonstrate a strong value proposition relative to their T cell counterparts due to comparable response rates (so far) combined with the added advantage of a significantly safer AE profile. Specifically, little to no risk of graft versus host disease (GvHD), cytotoxic release syndrome (CRS), and neurotoxicity (NT) have been seen so far with allogenic NK cells (Fig. 1). In addition, being able to harness an allogenic cell source gives way to operational advantages as “off-the-shelf” products provide improved turnaround time (TAT), scalability, and potentially reduced cost. NKs are currently in development for a variety of overlapping hematological indications with chimeric antigen receptor T cells (CAR-Ts) today, and the question remains to what extent they will disrupt the current cell therapy landscape. Click for more details.

Graphic: Kathy Wong for Endpoints News

What kind of biotech start­up wins a $3B syn­di­cate, woos a gallery of mar­quee sci­en­tists and re­cruits GSK's Hal Bar­ron as CEO in a stun­ner? Let Rick Klaus­ner ex­plain

It started with a question about a lifetime’s dream on a walk with tech investor Yuri Milner.

At the beginning of the great pandemic, former NCI chief and inveterate biotech entrepreneur Rick Klausner and the Facebook billionaire would traipse Los Altos Hills in Silicon Valley Saturday mornings and talk about ideas.

Milner’s question on one of those mornings on foot: “What do you want to do?”

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FDA+ roundup: FDA's neu­ro­science deputy de­parts amid on­go­ing Aduhelm in­ves­ti­ga­tions; Califf on the ropes?

Amid increased scrutiny into the close ties between FDA and Biogen prior to the controversial accelerated approval of Aduhelm, the deputy director of the FDA’s office of neuroscience has called it quits after more than two decades at the agency.

Eric Bastings will now take over as VP of development strategy at Ionis Pharmaceuticals, the company said Wednesday, where he will provide senior clinical and regulatory leadership in support of Ionis’ pipeline.

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CBO: Medicare ne­go­ti­a­tions will ham­per drug de­vel­op­ment more than pre­vi­ous­ly thought

As President Biden’s Build Back Better Act — and, with it, potentially the Democrats’ last shot at major drug pricing reforms in the foreseeable future — remains on life support, the Congressional Budget Office isn’t helping their case.

The CBO last week released a new slide deck, outlining an update to its model on how Medicare negotiations might take a bite out of new drugs making it to market. The new model estimates a 10% long-term reduction in the number of new drugs, whereas a previous CBO report from August estimated that 8% fewer new drugs will enter the market over 30 years.

Joshua Brumm, Dyne Therapeutics CEO

FDA or­ders DMD tri­al halt, rais­ing ques­tions about a whole class of promis­ing drugs

Dyne Therapeutics’ stock took a nasty hit this morning after the biotech put out word that the FDA had slapped a clinical hold on their top program for Duchenne muscular dystrophy. And now speculation is bouncing around Biotwitter that there could be a class effect at work here that would implicate other drug developers in the freeze.

Dyne execs didn’t have a whole lot to say about why the FDA sidelined their IND for DYNE-251 in DMD while “requesting additional clinical and non-clinical information for” the drug.

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Sec­ondary patents prove to be key in biosim­i­lar block­ing strate­gies, re­searchers find

While the US biosimilars industry has generally been a disappointment since its inception, with FDA approving 33 biosimilars since 2015, just a fraction of those have immediately followed their approvals with launches. And more than a handful of biosimilars for two of the biggest blockbusters of all time — AbbVie’s Humira and Amgen’s Enbrel — remain approved by FDA but still have not launched because of legal settlements.

Hal Barron (GSK via YouTube)

GSK R&D chief Hal Bar­ron jumps ship to run a $3B biotech start­up, Tony Wood tapped to re­place him

In a stunning switch, GlaxoSmithKline put out word early Wednesday that R&D chief Hal Barron is exiting the company after 4 years — a relatively brief run for the man chosen by CEO Emma Walmsley in late 2017 to turn around the slow-footed pharma giant.

Barron is being replaced by Tony Wood, a close associate of Barron’s who’s taking one of the top jobs in Big Pharma R&D. He’ll be closer to home, though, for GSK. Barron has been running a UK and Philadelphia-based research organization from his perch in San Francisco.

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Chamath Palihapitiya and Pablo Legorreta

Bil­lion­aires Chamath Pal­i­hapi­tiya and Pablo Legor­re­ta hatch an $825M SPAC for cell ther­a­py biotech

Three years after Royalty Pharma chief Pablo Legorreta led a group of investors to buy up a pair of biotechs and create a new startup called ProKidney, the biotech is jumping straight into an $825 million public shell created by SPAC king and tech billionaire Chamath Palihapitiya.

ProKidney was founded 6 years ago but really got going at the beginning of 2019 with the $62 million acquisition of inRegen, which was working on an autologous — from the patient — cell therapy for kidney disease. After extracting kidney cells from patients, researchers expand the cells in the lab and then inject them back into patients, aiming to restore the kidneys of patients suffering from CKD.

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Michel Vounatsos, Biogen CEO (Credit: World Economic Forum/Ciaran McCrickard)

An un­ortho­dox pro­pos­al for Bio­gen's Medicare-man­dat­ed Aduhelm tri­al

Biogen has gone full blitz since Medicare announced it would only cover its new Alzheimer’s drug when used in clinical trials, accusing the agency of discriminating against Alzheimer’s patients and trying to get physicians to change regulators’ minds.  Critics, meanwhile, cheered what they see as a necessary wall protecting payers and patients from an unproven and unsafe drug.

Far less attention, though, has gone to what a Medicare-funded clinical trial would actually look like. Biogen has operated as if it would be a standard late-stage Alzheimer’s trial, enrolling a couple thousand patients and giving half placebo.

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