#AS­CO21: As­traZeneca takes a swing at J&J and Ab­b­Vie's Im­bru­vi­ca with long-term da­ta from head-to-head tri­al

A year and a half af­ter get­ting its next-gen BTK in­hibitor ap­proved in chron­ic lym­pho­cyt­ic leukemia (CLL), As­traZeneca is back with long-term da­ta that sug­gest the drug stands a fight­ing chance against J&J and Ab­b­Vie’s first gen­er­a­tion block­buster Im­bru­vi­ca.

At a me­di­an fol­low-up of 40.9 months, Calquence matched Im­bru­vi­ca for a me­di­an pro­gres­sion-free sur­vival of 38.4 months in pa­tients who had pre­vi­ous­ly been treat­ed for CLL, As­traZeneca an­nounced at AS­CO. But when it came to car­diac events, Calquence best­ed its long­stand­ing ri­val, with a 9.4% in­ci­dence of all-grade atri­al fib­ril­la­tion, com­pared to a 16% rate in the Im­bru­vi­ca arm (p= 0.02). Atri­al fib­ril­la­tion is an ir­reg­u­lar heart­beat that can lead to stroke or heart fail­ure.

The news — which comes as As­traZeneca strug­gles in vac­cines — rep­re­sents an­oth­er win in Pas­cal So­ri­ot’s ef­fort to es­tab­lish the com­pa­ny as a leader in on­col­o­gy.

“Car­diac ad­verse events are an im­por­tant con­sid­er­a­tion for treat­ing chron­ic lym­pho­cyt­ic leukemia pa­tients with Bru­ton’s ty­ro­sine ki­nase in­hibitors be­cause they can pro­duce sig­nif­i­cant mor­bid­i­ty in some cas­es and al­so lead pa­tients to dis­con­tin­ue treat­ment,” John Byrd, lead in­ves­ti­ga­tor of As­traZeneca’s EL­E­VATE-RR tri­al, said in a state­ment.

CLL is the most com­mon type of leukemia in adults, with more than 21,000 new cas­es re­port­ed in the US so far this year. In pa­tients with the dis­ease, too many blood stem cells in the bone mar­row be­come ab­nor­mal lym­pho­cytes, which have dif­fi­cul­ty fight­ing in­fec­tions. As the num­ber of ab­nor­mal cells grows, there’s less room for healthy white and red blood cells and platelets, As­traZeneca said.

Calquence was ap­proved for CLL back in No­vem­ber 2019, both as a monother­a­py in sec­ond-line pa­tients and as a com­bi­na­tion treat­ment with Roche’s Gazy­va in front­line pa­tients. But the El­e­vate-RR tri­al is the first to com­pare the two BTK in­hibitors head-to-head in CLL, and should help As­traZeneca carve out a space in the mar­ket.

Calquence bagged $522 mil­lion in sales last year, com­pared to Im­bru­vi­ca’s glob­al sales of $5.3 bil­lion.

El­e­vate-RR en­rolled 533 pa­tients with a form of CLL that doesn’t re­spond to treat­ments like chemother­a­py. In ad­di­tion to low­er in­ci­dence of atri­al fib­ril­la­tion, As­traZeneca says those in the Calquence arm al­so saw a less­er fre­quen­cy of oth­er side ef­fects, in­clud­ing bleed­ing events, hy­per­ten­sion and in­fec­tions.

“The safe­ty and tol­er­a­bil­i­ty of Calquence in El­e­vate-RR was con­sis­tent with the known pro­file of Calquence,” the com­pa­ny said in a state­ment.

In the Calquence arm, ad­verse events led 14.7% of pa­tients to dis­con­tin­ue the treat­ment, ver­sus 21.3% of pa­tients in the Im­bru­vi­ca arm. All-grade car­diac events were seen in 24.1% of Calquence pa­tients and 30% of Im­bru­vi­ca pa­tients. All-grade bleed­ing events were record­ed in 38% of Calquence pa­tients ver­sus 51.3% of Im­bru­vi­ca pa­tients. Hy­per­ten­sion was seen in 9.4% and 23.2% of pa­tients in the re­spec­tive arms. And all-grade in­fec­tions were seen in 78.2% ver­sus 81.4% of the pa­tients.

How­ev­er, a greater num­ber of pa­tients in the Calquence arm ex­pe­ri­enced sec­ond pri­ma­ry ma­lig­nan­cies ex­clud­ing non-melanoma skin can­cer (9% ver­sus 7.6% in the Im­bru­vi­ca arm).

As­traZeneca al­so read out four-year da­ta from its Phase III El­e­vate-TN tri­al, in which Calquence “con­tin­ued to show a strong PFS ben­e­fit” as a com­bi­na­tion ther­a­py or monother­a­py in pre­vi­ous­ly un­treat­ed CLL pa­tients, the com­pa­ny said.

Af­ter a me­di­an fol­low-up of 46.9 months, Calquence and Gazy­va re­duced pa­tients’ risk of dis­ease pro­gres­sion or death by 90% com­pared to Gazvya and the chemother­a­py chlo­ram­bu­cil, As­traZeneca said. As a monother­a­py, Calquence re­duced the risk of dis­ease pro­gres­sion or death by 81%, ac­cord­ing to the da­ta. Me­di­an pro­gres­sion-free sur­vival wasn’t met in ei­ther arm at the four-year fol­low-up.

Ac­cord­ing to As­traZeneca, es­ti­mat­ed PFS rates for the com­bi­na­tion ther­a­py and monother­a­py are 87% and 78%, re­spec­tive­ly, com­pared to 25% for chlo­ram­bu­cil plus Gazy­va.

“Tol­er­a­bil­i­ty is a crit­i­cal fac­tor in treat­ing pa­tients with chron­ic lym­pho­cyt­ic leukemia who of­ten re­main on med­i­cines for many years and ex­pe­ri­ence mul­ti­ple co­mor­bidi­ties,” Dave Fredrick­son, ex­ec­u­tive VP of As­traZeneca’s on­col­o­gy busi­ness unit, said in a state­ment.

Calquence and Im­bru­vi­ca could soon have some new com­peti­tors, in­clud­ing BeiGene’s Brukin­sa, which demon­strat­ed a “sta­tis­ti­cal­ly sig­nif­i­cant low­er risk of atri­al fib­ril­la­tion or flut­ter” in a head-to-head tri­al with Im­bru­vi­ca back in April. And back in De­cem­ber, Eli Lil­ly said it would but its own BTK in­hibitor LOXO-305 against Im­bru­vi­ca in two head-to-head stud­ies.

In­side Track: Be­hind the Scenes of a Ma­jor Biotech SPAC

Dr. David Hung and Michelle Doig are no strangers to the SPAC phenomenon. As Founder and CEO of Nuvation Bio, a biotech company tackling some of the greatest unmet needs in oncology, Dr. Hung recently took the company public in one of this year’s biggest SPAC related deals. And as Partner at Omega Funds, Doig not only led and syndicated Nuvation Bio’s Series A, but is now also President of the newly formed, Omega-sponsored, Omega Alpha SPAC (Nasdaq: OMEG; oversubscribed $138m IPO priced January 6, 2021).

Barry Greene, Sage CEO

UP­DAT­ED: Sage's sec­ond chance at de­pres­sion hits the PhI­II pri­ma­ry, but ques­tions re­main over dura­bil­i­ty, side ef­fects

Looking to make a comeback after a big Phase III flop, Sage Therapeutics revealed data they believe could change the entire depression treatment landscape, given the vast array of failures in the field. But some results are spooking investors, sending Sage $SAGE shares down early Tuesday.

First, the primary: Sage and Biogen reported Phase III data for once-daily zuranolone Tuesday morning, saying the experimental drug hit its primary endpoint by spurring a statistically significant change from baseline in the 17-item Hamilton Rating Scale for Depression total score. After 15 days, patients in the drug arm saw an average change of -14.1 points, compared to -12.3 on placebo.

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Bio­gen sig­nals a big PhI­II fail­ure as the lead gene ther­a­py in their $800M Night­star buy­out goes down in flames

That $800 million buyout of Nightstar has turned into a bust for Biogen as the lead therapy in the deal failed a pivotal study, signaling a severe setback for the biotech’s ambitions in gene therapies.

The big biotech put out the word after the market closed on Monday that the gene therapy they picked up in the deal for a degenerative blindness called choroideremia failed the Phase III study, just a month after their #2 drug in the deal also flopped in a mid-stage study.

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CEO Harith Rajagopalan (Fractyl)

Af­ter a decade in the type 2 di­a­betes game, Fractyl Lab­o­ra­to­ries recharges with a fresh $100M and a new name

Harith Rajagopalan compared the way type 2 diabetes is managed to sticking your fingers in a dam that’s leaking from a number of places.

You can take drugs to lower your blood sugar, cholesterol, or blood pressure, but you’re not addressing what he says is the core issue — the metabolic abnormality that causes the disease.

“We’re so busy plugging the holes in the dam, we don’t have time to see that the whole infrastructure is at risk,” he said. “That infrastructure is a full-body systemic metabolic abnormality called metabolic syndrome, that we’re ignoring while we’re so busy trying to treat all of the individual symptoms of the condition.”

Hal Barron, GSK R&D chief (Endpoints News)

Hal Bar­ron gam­bles $625M cash on high-wire TIG­IT act, throw­ing Glax­o­SmithK­line in­to heat­ed race and com­plet­ing next-gen I/O trin­i­ty

Count Hal Barron and GlaxoSmithKline in for the TIGIT fight.

The stakes are as high as the risks: While a growing pack of Big Pharma rivals is lending credence to the hypothesis that TIGIT will be the next big immune checkpoint and cancer drug target, the first clinical trials have shown response rates that can be described as modest at best. But Barron’s bet is on the whole “axis” that the receptor sits on, with an eye on testing its new anti-TIGIT antibody not just in combo with PD-1 but also in triplets.

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Michel Sade­lain puts his name and new cell en­gi­neer­ing tech be­hind 'ag­nos­tic' CAR-T start­up chas­ing epi­ge­net­ic anti­gens

It felt natural for Alain Maiore and Sebastian Amigorena to bring in Michel Sadelain as a co-founder of Mnemo Therapeutics. A CAR-T pioneer, Sadelain had been involved as an advisor since the early days — enthusiastic about Amigorena’s work in a genetic knockout that could enhance T cell memory and a new class of potential targets he’s discovered — and could introduce some well-known technologies to the toolbox. So they got the initial cash from Sofinnova Partners to plant roots in Paris and New York in early 2019; within a few months, they began to see more clearly just what the antigen discovery platform might unlock.

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Geoffrey Porges, SVB Leerink

Top an­a­lyst maps a rocky road for Ver­tex — un­less they adopt a $10B M&A cam­paign to save the pipeline

After repeatedly poking Vertex $VRTX execs with pointed criticism of their R&D strategy, top SVB Leerink analyst Geoffrey Porges is now turning up the heat to a full-scale roasting.

In a note out early Monday morning, Porges spotlights the impact of Vertex’s recent follow-up failure on AATD — their treatment hit the endpoint but missed on commercial prospects — rewriting his recommended scenario for CEO Reshma Kewalramani as she grapples with the setback.

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Lynn Fitch, Mississippi Attorney General (Rogelio V. Solis/AP Images)

Mis­sis­sip­pi sues Eli Lil­ly, Sanofi and No­vo over in­sulin prices as in­ter­change­able biosim­i­lars may ar­rive soon

Mississippi Attorney General Lynn Fitch last week sued the top three insulin manufacturers, which collectively cover almost the entire US insulin market, alleging that they’ve colluded to raise their prices in lockstep, and in some cases by more than 1,000% for drugs that are decades old.

“Because of Manufacturer Defendants’ collusive price increases, nearly a century after the discovery of insulin, diabetes medications have become unaffordable for many diabetics,” the lawsuit says.

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Andrew Hopkins, Exscientia CEO

Ex­sci­en­tia spends Soft­Bank's cash in bid to edge out AI ri­vals

Exscientia is sprinting to win the great AI biotech race.

The UK company, having long labored on small discovery deals with large pharmas, raised up to $525 million in a Series D led by the infamous Japanese conglomerate SoftBank in April and followed it up less than a month later with a Bristol Myers Squibb deal that paid $50 million cash and $1.2 billion in milestones.

Now, the Oxford spinout is splurging on a shiny new tool. On Monday they announced they purchased the three-year-old molecule-screening biotech Allcyte, a longtime collaborator, for $60.6 million in cash and stock.

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