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.

Spe­cial re­port: Meet 20 ex­tra­or­di­nary women who are su­per­charg­ing bio­phar­ma R&D

Even though many biopharma leaders have come together in recent years to address its gender gap, the consensus is clear: We still have a long way to go.

Companies this year were 2.5 times more likely than last year to have a diversity and inclusion program in place, according to a recent BIO survey, but women are still largely absent from executive roles. Getting women to enter the industry isn’t the problem — studies show that they represent just under half of all biotech employees around the world. But climbing through the ranks can be challenging, as women still report facing stereotypes, and, unfortunately, harassment.

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Op­ti­miz­ing Oral Drug De­liv­ery us­ing Zy­dis® Oral­ly Dis­in­te­grat­ing Tablet Tech­nol­o­gy to Ad­dress Pa­tient Chal­lenges

KEY POINTS

Patients prefer oral dosing, but swallowing tablets can be a challenge for many patients.
The Zydis® orally disintegrating tablet (ODT) platform addresses challenges associated with oral dosing, expanding benefits for patients and options for healthcare providers.
A strong growth trajectory is expected for ODTs given therapeutic innovation and continued technology development.

Many patients prefer conventional tablets for the administration of medications, but some geriatric and pediatric patients and those with altered mental status and physical impairments find swallowing tablets to be difficult. Orally disintegrating tablets (ODTs), which dissolve completely without chewing or sucking, offer a patient-friendly dosage form for the administration of small-molecule drugs, peptides and proteins. With the potential for multiple sites of drug absorption, often faster onset action for the active pharmaceutical ingredient (API), and potentially greater bioavailability, ODTs are an attractive option for drug developers considering first-to-market formulations or product line extensions of existing drugs with compatible API. In this report, we look at how innovation in the industry-leading Zydis ODT platform is expanding oral formulation options and bringing benefits to patients.

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Geoffrey Porges (SVB Leerink)

The 2022 wave com­ing? Top an­a­lyst says Big Phar­ma will have more than $1T avail­able to sat­is­fy its grow­ing ap­petite for biotech M&A

All through this year you could practically feel the frustration of the biotech investor class as M&A activity continued to drag behind expectations — or desires. Buyouts of public companies provide the essential juice for keeping stocks lively, and there’s been a notable lack of juice in 2021.

So is all that about to change, big time?

SVB Leerink’s Geoffrey Porges, a longtime student of biotech M&A, thinks so. In a lengthy analysis he put out last week, Porges totted up the cash flow of the major pharmas and determined that there was a good long list of industry buyers who would have around a half trillion dollars of cash to play with in 2022. Leverage that up with added debt and you could get that deal cache to $1.6 trillion.

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Mer­ck pumps the brakes on two more PhI­II tri­als for its lead an­ti-HIV drug

After trial investigators flagged a drop in immune cell counts that an external committee determined was related to treatment last month, Merck has been pausing HIV-related Phase II and III trials ever since.

On Monday, the biopharma company announced it’s pausing enrollment in two of its Phase III trials evaluating its leading anti-HIV drug candidate, which is the once-monthly, oral islatravir.

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Bolt Bio CEO Randy Schatzman

Bolt Bio goes bust as in­vestors boo sin­gle re­sponse in ear­ly test against HER2-ex­press­ing tu­mors

Bolt Bio’s BDC-1001, an antibody conjugate drug designed to amp up the body’s innate immune system response to tumors, posted a single partial response in a Phase I/II study in patients with HER2-expressing solid tumors after a year of dosing. Just 13 of 40 evaluable patients showed any signs of “clinical activity,” the biotech said Monday.

BDC-1001 links a HER2-targeting biosimilar of Herceptin with a TLR7/8 agonist, which is designed to activate myeloid cells in the innate immune system and drive tumor cytotoxicity, Bolt said. But the early results paint the picture of a drug with little effect on HER2 tumors, one of the most highly validated tumor targets in drug development.

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Biohaven CEO Vlad Coric (Photo Credit_ Andrew Venditti)

Bio­haven shakes up lead­er­ship team as it feels the heat from mi­graine com­peti­tors

As Biohaven Pharma comes off a rollercoaster pipeline year, its CEO will take on more responsibility in a full C-suite makeover.

Vlad Coric was unanimously elected to the role of chairman of the board of directors, after Declan Doogan’s retirement. Matthew Buten will take over the role of CFO after James Engelhart’s retirement, and director Michael Heffernan has been appointed lead independent director. All of the appointments are effective immediately, a company press release said.

Chen Schor, Adicet CEO

Adicet un­veils ear­ly re­spons­es for off-the-shelf drug lever­ag­ing rare T cells. Will dura­bil­i­ty hold up?

On the hunt for the next generation of “off-the-shelf” cell therapies, biotech players like Adicet Bio have looked to leverage some of the less-obvious members of the immune system as potent cancer fighters. In Adicet’s case, scarce gamma delta T cells are on the menu, and an early cut of data is showing some promise.

Adicet’s AD-001, an off-the-shelf cell therapy developed by engineering a CD20-targeting chimeric antigen receptor (CAR) onto a donor’s gamma delta T cells, posted two complete responses across four patients in an early Phase I study testing the drug in patients with heavily pretreated B cell non-Hodgkin’s lymphoma, the biotech said Monday.

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Mar­ket­ingRx Matchup: How Ab­b­Vie and Bio­haven ads rank in head-to-head mi­graine chal­lenge

Are you ready to rumble? DTC brands that is. MarketingRx is launching a new monthly feature today called MarketingRx Matchup. We’re pitting two pharma brands’ DTC advertising in the same therapeutic category against each other to find out what consumers and patients really think.

Market research company Leger is handling the polling and analysis each month, and I’ll be writing up the results — along with my own take — inside MRx on the first Tuesday of the month.

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Wendy Lund, Organon chief communications officer

Q&A: Organon chief com­mu­ni­ca­tions of­fi­cer Wendy Lund talks about the Mer­ck spin­off, women’s health and why it mat­ters

One of Wendy Lund’s earliest jobs was head of marketing at Planned Parenthood. As the youngest person on its management team, she introduced them to emerging new technologies, and in return, she learned the importance of fighting for what you believe in.

Now as chief communications officer at Organon, the women’s health company recently spun off by Merck, Lund is keeping that point top of mind. That’s in part because women’s health hasn’t been a spotlight therapy area for Big Pharma in years. Several companies have spun off, sold or at least considered selling women’s health assets to focus on “core” products.

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