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 — 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.