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 best-in-class 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.

2019 Trin­i­ty Drug In­dex Eval­u­ates Ac­tu­al Com­mer­cial Per­for­mance of Nov­el Drugs Ap­proved in 2016

Fewer Approvals, but Neurology Rivals Oncology and Sees Major Innovations

This report, the fourth in our Trinity Drug Index series, outlines key themes and emerging trends in the industry as we progress towards a new world of targeted and innovative products. It provides a comprehensive evaluation of the performance of novel drugs approved by the FDA in 2016, scoring each on its commercial performance, therapeutic value, and R&D investment (Table 1: Drug ranking – Ratings on a 1-5 scale).

How to cap­i­talise on a lean launch

For start-up biotechnology companies and resource stretched pharmaceutical organisations, launching a novel product can be challenging. Lean teams can make setting a launch strategy and achieving your commercial goals seem like a colossal undertaking, but can these barriers be transformed into opportunities that work to your brand’s advantage?
We spoke to Managing Consultant Frances Hendry to find out how Blue Latitude Health partnered with a fledgling subsidiary of a pharmaceutical organisation to launch an innovative product in a
complex market.
What does the launch environment look like for this product?
FH: We started working on the product at Phase II and now we’re going into Phase III trials. There is a significant unmet need in this disease area, and everyone is excited about the launch. However, the organisation is still evolving and the team is quite small – naturally this causes a little turbulence.

UP­DAT­ED: Eli Lil­ly’s $1.6B can­cer drug failed to spark even the slight­est pos­i­tive gain for pa­tients in its 1st PhI­II

Eli Lilly had high hopes for its pegylated IL-10 drug pegilodecakin when it bought Armo last year for $1.6 billion in cash. But after reporting a few months ago that it had failed a Phase III in pancreatic cancer, without the data, its likely value has plunged. And now we’re getting some exact data that underscore just how little positive effect it had.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 70,500+ biopharma pros reading Endpoints daily — and it's free.

Aymeric Le Chatelier, Ipsen

A $1B-plus drug stum­bles in­to an­oth­er big PhI­II set­back -- this time flunk­ing fu­til­i­ty test -- as FDA hold re­mains in ef­fect for Ipsen

David Meek

At the time Ipsen stepped up last year with more than a billion dollars in cash to buy Clementia and a late-stage program for a rare bone disease that afflicts children, then CEO David Meek was confident that he had put the French biotech on a short path to a mid-2020 launch.

Instead of prepping a launch, though, the company was hit with a hold on the FDA’s concerns that a therapy designed to prevent overgrowth of bone for cases of fibrodysplasia ossificans progressiva might actually stunt children’s growth. So they ordered a halt to any treatments for kids 14 and under. Meek left soon after to run a startup in Boston. And today the Paris-based biotech is grappling with the independent monitoring committee’s decision that their Phase III had failed a futility test.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 70,500+ biopharma pros reading Endpoints daily — and it's free.

Roche's check­point play­er Tecen­triq flops in an­oth­er blad­der can­cer sub­set

Just weeks after Merck’s star checkpoint inhibitor Keytruda secured FDA approval for a subset of bladder cancer patients, Swiss competitor Roche’s Tecentriq has failed in a pivotal bladder cancer study.

The 809-patient trial — IMvigor010 — tested the PD-L1 drug in patients with muscle-invasive urothelial cancer (MIUC) who had undergone surgery, and were at high risk for recurrence.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 70,500+ biopharma pros reading Endpoints daily — and it's free.

UP­DAT­ED: FDA’s golodirsen CRL: Sarep­ta’s Duchenne drugs are dan­ger­ous to pa­tients, of­fer­ing on­ly a small ben­e­fit. And where's that con­fir­ma­to­ry tri­al?

Back last summer, Sarepta CEO Doug Ingram told Duchenne MD families and investors that the FDA’s shock rejection of their second Duchenne MD drug golodirsen was due to some concerns regulators raised about the risk of infection and the possibility of kidney toxicity. But when pressed to release the letter for all to see, he declined, according to a report from BioPharmaDive, saying that kind of move “might not look like we’re being as respectful as we’d like to be.”

He went on to assure everyone that he hadn’t misrepresented the CRL.

But Ingram’s public remarks didn’t include everything in the letter, which — following the FDA’s surprise about-face and unexplained approval — has now been posted on the FDA’s website and broadly circulated on Twitter early Wednesday.

The CRL raises plenty of fresh questions about why the FDA abruptly decided to reverse itself and hand out an OK for a drug a senior regulator at the FDA believed — 5 months ago, when he wrote the letter — is dangerous to patients. It also puts the spotlight back on Sarepta $SRPT, which failed to launch a confirmatory study of eteplirsen, which was only approved after a heated internal controversy at the FDA. Ellis Unger, director of CDER’s Office of Drug Evaluation I, notes that study could have clarified quite a lot about the benefit and risks associated with their drugs — which can cost as much as a million dollars per patient per year, depending on weight.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 70,500+ biopharma pros reading Endpoints daily — and it's free.

Gilead claims Tru­va­da patents in HHS’ com­plaint are in­valid

Back in November, the Department of Health and Human Services took the rare step of filing a complaint against Gilead for infringing on government-owned patents related to the HIV drug Truvada (emtricitabine/tenofovir disoproxil fumarate) for pre-exposure prophylaxis (PrEP).

But on Thursday, Gilead filed its own retort, making clear that it does not believe it has infringed on the Centers for Disease Control and Prevention’s (CDC) Truvada patents because they are invalid.

Gilead dusts off a failed Ebo­la drug as coro­n­avirus spreads; Ex­elix­is boasts pos­i­tive Ph I/II da­ta

→ Less than a year ago Gilead’s antiviral remdesivir failed to make the cut as investigators considered a raft of potential drugs that could be used against an Ebola outbreak. But it may gain a new mission with the outbreak of the coronavirus in China, which is popping up now around the world.

Gilead put out a statement saying that they’re now in discussions with health officials in the US and China about testing their NUC against the virus. It’s the latest in a growing lineup of biopharma companies that are marshaling R&D forces to see if they can come up with a vaccine or therapy to blunt the spread of the virus, which has now sickened hundreds, killed at least 17 people and led the Chinese government to start quarantining cities.

Alex Karnal (Deerfield)

Deer­field vaults to the top of cell and gene ther­a­py CD­MO game with $1.1B fa­cil­i­ty at Philadel­phi­a's newest bio­phar­ma hub

Back at the beginning of 2015, Deerfield Management co-led a $10 million Series C for a private gene therapy startup, reshaping the company and bringing in new leaders to pave way for an IPO just a year later.

Fast forward four more years and the startup, AveXis, is now a subsidiary of Novartis marketing the second-ever gene therapy to be approved in the US.

For its part, Deerfield has also grown more comfortable and ambitious about the nascent field. And the investment firm is now putting down its biggest bet yet: a $1.1 billion contract development and manufacturing facility to produce everything one needs for cell and gene therapy — faster and better than how it’s currently done.