FDA Accepts sNDA for Zanubrutinib for Treatment of Waldenström Macroglobulinemia

A supplemental new drug application submission was primarily based on safety and efficacy data from the global phase 3 ASPEN trial of zanubrutinib compared with ibrutinib for the treatment of Waldenström macroglobulinemia.

The FDA has accepted a supplemental new drug application (sNDA) for the Bruton tyrosine kinase (BTK) inhibitor zanubrutinib (Brukinsa) for the treatment of adult patients with Waldenström macroglobulinemia (WM), according to the drug’s developer, BeiGene.1

A prescription drug user fee act (PDUFA) target action date has been set by the FDA for October 18, 2021.

The sNDA submission was primarily based on safety and efficacy data from the global phase 3 ASPEN trial (NCT03053440) of zanubrutinib compared with ibrutinib (Imbruvica) for the treatment of WM, with supportive data from a pivotal phase 2 trial (NCT03332173) of zanubrutinib in relapsed or refractory WM conducted in China and a global phase 1/2 trial (NCT02343120) in patients with B-cell malignancies. Overall, the culmination of these trials included data from 351 patients with WM.

Additionally, safety data from 779 patients across 6 clinical trials of zanubrutinib were also included in the submission.

In the ASPEN study, patients with MYD88 L265P–mutated disease were randomly assigned 1:1 to receive either ibrutinib or zanubrutinib.2 The primary end point was the proportion of patients achieving a complete response (CR) or a very good partial response (VGPR) by independent review and secondary end points included major response rate (MRR), progression-free survival (PFS), duration of response (DOR), disease burden, and safety.

A total of 201 patients were randomized, and 199 received at least 1 dose of study treatment. Importantly though, no patient achieved a CR.

Overall, 29 patients treated with zanubrutinib (28%) and 19 treated with ibrutinib (19%) achieved a VGPR; however, this difference was a not statistically significant (P =.09). Moreover, MRRs were 77% and 78%, respectively. The median DOR and PFS were not reached; however, 84% and 85% of patients receiving ibrutinib and zanubrutinib, respectively, were progression free at 18 months.

Regarding safety, atrial fibrillation, contusion, diarrhea, peripheral edema, hemorrhage, muscle spasms, and pneumonia, as well as adverse events leading to treatment discontinuation, were less common among those who received zanubrutinib. The incidence of neutropenia was higher with zanubrutinib, although grade 3 or higher infection rates were similar in both arms, at 1.2 and 1.1 events per 100 person-months.

“We are pleased that the FDA has accepted the sNDA for [zanubrutinib] in WM, a rare disease with significant morbidity. BTK inhibitors have transformed the treatment of WM in recent years, but discrepancies in response exist in patients with different subtypes, and toxicity can remain an issue,” Jane Huang, MD, chief medical officer of Hematology at BeiGene, said in a press release. “We look forward to continuing our communications with the FDA in the coming months and hope that [zanubrutinib] will become a new treatment option for patients with WM in the United States.”

In addition to the United States, zanubrutinib is also under regulatory review as a treatment for patients with WM in the European Union, Canada, Australia, China, Taiwan, and South Korea.

Zanubrutinib received accelerated approval in the United States in November 2019 as a treatment for mantle cell lymphoma (MCL) in adult patients who have received at least 1 prior therapy. This indication was approved based on overall response rate, however continued approval for this indication may be dependent upon verification and description of clinical benefit in a confirmatory trial.

In June 2020, the BTK inhibitor also received conditional approval in China as a treatment for adult patients with chronic lymphocytic leukemia/small lymphocytic lymphoma who have received at least 1 prior therapy, and as a treatment for adult patients with MCL who have received at least 1 prior therapy. Importantly, complete approval for these indications may be dependent upon results from ongoing randomized, controlled confirmatory clinical trials.

Moreover, a marketing authorization application has been accepted for review by the European Medicines Agency (EMA) for zanubrutinib for the treatment of patients with WM who have received at least 1 prior therapy or as first-line treatment for patients unsuitable for chemo-immunotherapy. Twenty marketing applications for zanubrutinib have also been submitted in 16 countries and regions.


1. BeiGene announces U.S. FDA acceptance of supplemental new drug application for Brukinsa (zanubrutinib) in Waldenström’s macroglobulinemia. News release. BeiGene. Published February 17, 2021. Accessed February 17, 2021. https://ir.beigene.com/news-releases/news-release-details/beigene-announces-us-fda-acceptance-supplemental-new-drug?loc=us

2. Tam CS, Opat S, D’Sa S, et al. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study. Blood. 2020;136(18):2038-2050. doi: 10.1182/blood.2020006844