BeiGene CEO John Oyler (Image: Endpoints News)

BeiGene's BTK in­hibitor fails to beat mar­ket leader Im­bru­vi­ca in key head-to-head study

BeiGene’s quest to de­vel­op a su­pe­ri­or BTK in­hibitor hit a ma­jor road­block on Mon­day as the com­pa­ny con­ced­ed that the drug failed a keen­ly an­tic­i­pat­ed head-to-head tri­al test­ing its re­cent­ly ap­proved drug, Brukin­sa, against the mar­ket-lead­ing Im­bru­vi­ca.

The re­sults amount to a se­ri­ous set­back for Chi­na’s BeiGene that is hop­ing to po­si­tion Brukin­sa, known chem­i­cal­ly as zanubru­ti­nib, as the best-in-class ther­a­py.

The tri­al, dubbed AS­PEN, test­ed the two ther­a­pies in 229 pa­tients with Walden­ström’s macroglob­u­line­mia (WMG), a rare form of lym­phoma. Brukin­sa failed the pri­ma­ry end­point of su­pe­ri­or­i­ty in com­plete re­sponse rates and “very good” par­tial re­sponse (VG­PR) rates ver­sus Im­bru­vi­ca, the com­pa­ny said.

Over­all, the VG­PR rate was 28.4% in the zanubru­ti­nib arm and 19.2% in the ibru­ti­nib arm (no pa­tients achieved a com­plete re­sponse in ei­ther arm). But since the dif­fer­ence was not sta­tis­ti­cal­ly sig­nif­i­cant, zanubru­ti­nib missed the main goal of the study.

BeiGene’s shares $BGNE tum­bled near­ly 11% to $157 in pre­mar­ket trad­ing on Mon­day.

On the safe­ty side how­ev­er, Brukin­sa emerged bet­ter off. Se­ri­ous ad­verse events were seen in 58.4% pa­tients on the Brukin­sa arm, while 63.3% pa­tients suf­fered such side-ef­fects on the Im­bru­vi­ca arm. There was one death in the Brukin­sa group, and four in the Im­bru­vi­ca group.

Er­ic Hedrick BeiGene

Er­ic Hedrick — who is chief ad­vi­sor to BeiGene and for­mer­ly was re­spon­si­ble for the de­vel­op­ment of Im­bru­vi­ca in his ca­pac­i­ty as in­ter­im chief med­ical of­fi­cer at Phar­ma­cyclics — in­sist­ed the to­tal­i­ty of da­ta was still sup­port­ive of Brukin­sa’s po­ten­tial.

“Ob­vi­ous­ly, the hope was for the pri­ma­ry end­point to be met,” he not­ed in an in­ter­view with End­points News.

“But I think, the pic­ture here…in terms of ef­fi­ca­cy is some­what in­com­plete, you know the changes we do see a high­er VG­PR rate with zanubru­ti­nib and ear­ly PFS re­sults are sort of go­ing in the same di­rec­tion. So, I think this par­tic­u­lar re­sult is more in­com­plete rather than go­ing against our hy­poth­e­sis.”

BeiGene is al­so test­ing Brukin­sa against Im­bru­vi­ca in the head-to-head ALPINE study, which in­volves the larg­er pa­tient pop­u­la­tion of chron­ic lym­pho­cyt­ic leukemia (CLL) pa­tients.

There are some dif­fer­ences in the way that the tri­al is de­signed (for ex­am­ple, it first looks at non-in­fe­ri­or­i­ty and then su­pe­ri­or­i­ty) as well as the fact that it has more pa­tients, which gives BeiGene con­fi­dence that there still could be a pos­i­tive read­out, Hedrick added.

Both Brukin­sa (zanubru­ti­nib) and Im­bru­vi­ca in­hib­it Bru­ton’s ty­ro­sine ki­nase (BTK), an en­zyme that plays a cru­cial role in onco­genic sig­nal­ing that is key for the pro­lif­er­a­tion and sur­vival of leukemic cells in many B-cell ma­lig­nan­cies. J&J and Ab­b­Vie’s block­buster Im­bru­vi­ca was first ap­proved in 2013, but safe­ty and tol­er­a­bil­i­ty is­sues with the drug soon emerged. Since then, sec­ond-gen­er­a­tion BTK in­hibitors, such as As­traZeneca’s Calquence, have been po­si­tioned as safer but equal­ly ef­fi­ca­cious al­ter­na­tives.

“Our hy­poth­e­sis wasn’t to make a safer drug, it was to make a more ef­fi­ca­cious drug by be­ing able to shut down BTK any­where in your body 24 hours a day, sev­en days a week,” BeiGene chief John Oyler told End­points News ear­li­er this year.

But by kick­ing off the head-to-head tri­al long be­fore scor­ing its first FDA ap­proval, BeiGene had sig­naled its con­fi­dence in Brukin­sa.

Weeks af­ter Am­gen took a $2.7 bil­lion stake in BeiGene, the Bei­jing-based biotech se­cured its first-ever FDA ap­proval for Brukin­sa in No­vem­ber — months ahead of sched­ule — for pre­vi­ous­ly treat­ed pa­tients with man­tle cell lym­phoma (MCL), a typ­i­cal­ly ag­gres­sive, rare, form of blood can­cer. In a first, the ap­proval was based on da­ta from pa­tients that were large­ly based out­side of the Unit­ed States.

Co-found­ed by Oyler and Xi­aodong Wang, BeiGene has close ties with the Unit­ed States, the world’s largest phar­ma­ceu­ti­cals mar­ket. In ad­di­tion to a cadre of part­ner­ships with small and mid-sized US drug de­vel­op­ers, the com­pa­ny sells a raft of Cel­gene drugs in Chi­na, while Am­gen has tak­en a hefty  20.5% stake in the drug­mak­er.

Beigene is a promi­nent mem­ber of a pack of Chi­nese biotech firms that have mush­roomed to cater to the sky­rock­et­ing rates of can­cer in the re­gion, with an eye on the lu­cra­tive US drug mar­ket, and have lured mil­lions in ven­ture fund­ing and pub­lic list­ings.

In­vestors and an­a­lysts have been ea­ger­ly fo­cused on the AS­PEN study. “The safe­ty and tol­er­a­bil­i­ty pro­file (for zanubru­ti­nib) are as im­por­tant as the ef­fi­ca­cy da­ta, in our opin­ion, as the Achilles heel for Im­bru­vi­ca is not the lack of ef­fi­ca­cy, but the rel­a­tive­ly high rates of atri­al fib­ril­la­tion and ma­jor he­m­or­rhage,” SVB Leerink an­a­lysts wrote in a note in Oc­to­ber pre­view­ing AS­PEN re­sults.

“(T)his will be the first ran­dom­ized piv­otal tri­al com­par­ing zanu head-to-head vs. the mar­ket lead­ing BTK in­hibitor, and is like­ly to shape in­vestor per­cep­tions of how com­mer­cial­ly com­pet­i­tive zanu could be in larg­er op­por­tu­ni­ties such as CLL. Zanu com­pris­es ~60% of our to­tal BGNE fun­da­men­tal val­ue, so sen­ti­ment ex­it­ing this event is para­mount.”

Ear­li­er this month, at the an­nu­al Amer­i­can So­ci­ety of Hema­tol­ogy (ASH) meet­ing, BeiGene broke out en­cour­ag­ing da­ta on 109 pa­tients from the SE­QUOIA tri­al eval­u­at­ing Brukin­sa against a com­bi­na­tion of Roche’s Rit­ux­an and the chemother­a­py ben­damus­tine in pa­tients with treat­ment-naive chron­ic lym­pho­cyt­ic leukemia/small lym­pho­cyt­ic lym­phoma (CLL/SLL).

The over­all re­sponse rate was 92.7% (101/109), with a par­tial re­sponse rate of 78.9% (86/109), and a com­plete re­sponse rate of 1.9% (2/109), BeiGene said, not­ing that there were four cas­es of dis­ease pro­gres­sion. “Over­all, the safe­ty pro­file for zanu ap­peared large­ly con­sis­tent with pre­vi­ous­ly re­port­ed da­ta. The clin­i­cal ac­tiv­i­ty and safe­ty/tol­er­a­bil­i­ty con­tin­ue to look com­pet­i­tive vs. Im­bru­vi­ca in this dif­fi­cult-to-treat pop­u­la­tion,” SVB Leerink’s An­drew Berens wrote in a note last week.

Mean­while, the FDA last month ex­pand­ed the use of As­traZeneca’s Calquence in pa­tients with CLL.

Scoop: Boehringer qui­et­ly shut­ters a PhII for one of its top drugs — now un­der re­view

Boehringer Ingelheim has quietly shut down a small Phase II study for one of its lead drugs.

The private pharma player confirmed to Endpoints News that it had shuttered a study testing spesolimab as a therapy for Crohn’s patients suffering from bowel obstructions.

A spokesperson for the company tells Endpoints:

Taking into consideration the current therapeutic landscape and ongoing clinical development programs, Boehringer Ingelheim decided to discontinue our program in Crohn’s disease. It is important to note that this decision is not based on any safety findings in the clinical trials.

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Ireland has been on a roll in 2022, with several large pharma companies announcing multimillion-euro projects. Now AstraZeneca’s rare disease outfit Alexion is looking to get in on the action.

Alexion on Friday announced a €65 million ($68.8 million) investment in new and enhanced capabilities across two sites in the country, including at College Park in the Dublin suburb of Blanchardstown and the Monksland Industrial Park in the central Irish town of Athlone, according to the Industrial Development Agency of Ireland.

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Since Friday’s SCOTUS opinion to overturn Americans’ constitutional right to an abortion after almost 50 years, reproductive rights lawyers at Planned Parenthood and other organizations have already challenged these trigger laws in Utah and Louisiana. According to the Guttmacher Institute, other states with trigger laws that could take effect include Arkansas, Idaho, Kentucky, Mississippi, Missouri, North Dakota, Oklahoma, South Dakota, Tennessee, Texas, and Wyoming.

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Merck partner 4D Pharma has reported that a key lender, Oxford Finance, shoved the UK company into administration after calling in a $14 million loan they couldn’t immediately make good on. Trading in their stock was halted with a market cap that had fallen to a mere £30 million.

“Despite the very difficult prevailing market conditions,” 4D reported on Friday, the biotech had been making progress on finding some new financing and turned to Oxford with an alternative late on Thursday and then again Friday morning.

Members of the G7 from left to right: Prime Minister of Italy Mario Draghi, European Commission President Ursula von der Leyen, President Joe Biden, German Chancellor Olaf Scholz, British Prime Minister Boris Johnson, Canadian Prime Minister Justin Trudeau, Prime Minister of Japan Fumio Kishida, French President Emmanuel Macron and European Council President Charles Michel (AP Photo/Susan Walsh)

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Some Celgene shareholders aren’t happy with how Bristol Myers Squibb’s takeover went down.

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When Bristol Myers put down $74 billion to scoop up Celgene back in 2019, liso-cel — the CAR-T lymphoma treatment now marketed as Breyanzi — was supposedly one of the centerpieces of the deal. After going back and forth on negotiations for about six months, BMS put $6.4 billion into a CVR agreement that required an FDA approval for Zeposia, Breyanzi and Abecma, each by an established date.