As the third player to enter the BTK realm, BeiGene has had its eyes fixated on AbbVie and Johnson & Johnson’s market leader Imbruvica. After clinical wins in smaller indications, the Chinese-American biotech has once again posted competitive data for Brukinsa—this time in the all-important newly diagnosed leukemia.
In previously untreated patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), Brukinsa significantly slashed the risk of disease progression or death by 58% over a combo of the chemotherapy bendamustine and Roche’s Rituxan, or BR, BeiGene unveiled ahead of the American Society of Hematology (ASH) annual meeting. The number was the same between independent review committee and investigator analyses.
Combining the latest frontline phase 3 data with a recent head-to-head win against Imbruvica in relapsed or refractory disease, BeiGene is talking with multiple health authorities about filings in CLL/SLL and will provide an update when it has an accepted filing, Jane Huang, M.D., BeiGene’s chief medical officer of hematology, said in an interview.
With consistent efficacy and safety data across multiple cancer types, the latest success from the phase 3 SEQUOIA trial “adds to the body of evidence that we think we have a potentially best-in-class molecule,” Huang said.
Imbruvica got its front-line CLL nod from the FDA more than five years ago with data showing superior progression-free survival over a weak chemo, chlorambucil. Imbruvica later registered its own phase 3 against BR. Brukinsa’s showing looks at least on par with the first-to-market BTK inhibitor’s trial data and is even better on some markers.
In the investigator-initiated ALLIANCE A041202 trial, Imbruvica cut the risk of disease progression or death by 62% over BR. But that trial included some patients carrying the del(17p) aberration, a resistance risk factor that lowers how well BR works. Without del(17p) or del(11q) patients, Imbruvica’s efficacy edge over BR dropped to 56%. Brukinsa’s 58% result covers del(11q) but not del(17q).
In a separate arm of the SEQUOIA trial, BeiGene paired Brukinsa with AbbVie and Roche’s Bcl-2 inhibitor Venclexta in del(17q) patients. Early data from that arm showed a good tolerability profile, BeiGene will detail at ASH 2021, which starts Dec. 11.
If it’s hard to distinguish a winner between the two BTK drugs from an efficacy standpoint, Brukinsa did clearly show a better safety profile. The rates of atrial fibrillation, or irregular heartbeat, were 3.3% for Brukinsa in the SEQUOIA trial and 17% for Imbruvica in the ALLIANCE study.
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In the past, Brukinsa has outperformed Imbruvica in terms of atrial fibrillation rates in the phase 3 ALPINE trial in relapsed or refractory CLL/SLL and the phase 3 ASPEN study in Waldenström macroglobulinemia. In those head-to-head trials, Brukinsa also showed better tumor shrinkage data, though not all differences meet the statistical significance bar.
The atrial fibrillation incidents are important, because the CLL population is generally older with more underlying diseases such as cardiovascular risks, Huang explained. In SEQUOIA, the median patient was 70 years.
Huang recently had a personal experience with atrial fibrillation where her father passed away after his disease developed into a stroke.
“I point this out not only because it just hit home but because … we have a statistically significant difference when you’re looking at our head-to-head trials, that is meaningful … and it will be meaningful if you’re that patient that doesn’t get atrial fibrillation; your risk of stroke and other complications goes down,” she said. Huang stressed the importance of safety in addition to showing efficacy benefits.
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In September, the FDA handed Brukinsa approvals in Waldenström’s and relapsed or refractory marginal zone lymphoma. Although the Waldenström’s ASPEN trial missed its primary goal—as the BeiGene drug only showed a numerical tumor response improvement over Imbruvica—the approval indicates “the FDA views [Brukinsa’s] profile favorably based on a detailed review of the data, something that we believe will resonate commercially with clinicians as the drug enters larger opportunities,” SVB Leerink analyst Andrew Berens wrote in a note in September.
Front-line CLL is a key battleground for BTK inhibitors, which also include AstraZeneca’s Calquence. Without it, Brukinsa is having a hard time catching up with Imbruvica. In the second quarter, Brukinsa brought in sales of only $42.4 million, mainly driven by uptake in China, where the drug enjoys national reimbursement, including a label in second-line CLL/SLL. By contrast, AbbVie recorded $1.1 billion sales for Imbruvica during the same three months in the U.S. alone, thanks to a 4.3% year-over-year growth.