BeiGene Receives Positive CHMP Opinion for BRUKINSA® (Zanubrutinib) for the Treatment of Adults with Waldenström’s Macroglobulinemia
Sep 17, 2021 8:00 AM
BeiGene’s European commercial team is preparing to launch BRUKINSA, the company’s first medicine submitted for marketing authorization in the EU, upon approval
The CHMP recommendation is based on results from the Phase 3 ASPEN trial, in which BRUKINSA demonstrated a numerically higher very good partial response rate (VGPR) and a favorable safety profile compared to ibrutinib
“Bruton’s tyrosine kinase (BTK) inhibitors have emerged as a promising treatment for WM, yet treatment discontinuation due to lack of response or side effects remains a concern,” said Prof.
The positive CHMP opinion is based on results from the randomized, Phase 3 ASPEN clinical trial, evaluating BRUKINSA compared to ibrutinib in patients with relapsed or refractory (R/R) or treatment-naïve (TN) WM who are unsuitable for chemo-immunotherapy. Based on the modified
BRUKINSA demonstrated a more favorable safety profile compared to ibrutinib with lower frequency of certain adverse events, including atrial fibrillation or flutter (2.0% vs. 15.3%) minor bleeding (48.5% vs 59.2%) and major hemorrhage (5.9% vs 9.2%).1 Of the 101 patients with WM treated with BRUKINSA, four percent of patients discontinued due to adverse events, and adverse events leading to dose reduction occurred in 14% of patients.
“The positive CHMP opinion reflects BRUKINSA’s potential role in the WM therapeutic landscape as a selective inhibitor designed to deliver sustained and continuous inhibition of BTK, offering patients the potential for reduced frequency of certain cardiovascular events like atrial fibrillation compared to ibrutinib, and underscores our bold approach to R&D,” said
“We have a strong team in
Following the CHMP positive opinion, the
About Waldenström’s Macroglobulinemia
WM is a rare lymphoma representing approximately one percent of all non-Hodgkin’s lymphomas and typically progresses slowly after diagnosis.2 The disease usually affects older adults and is primarily found in the bone marrow, although lymph nodes and the spleen may be involved.3 Throughout
About the
The Phase 3 randomized, open-label, multicenter
The study includes two cohorts, a randomized cohort (cohort 1) consisting of 201 patients with a MYD88 mutation (MYD88MUT) and a non-randomized cohort (cohort 2) in which 28 patients with MYD88 wild-type (MYD88WT) received zanubrutinib because they have historically responded poorly to ibrutinib therapy.
The randomized cohort 1 enrolled 102 patients (including 83 relapsed or refractory (R/R) patients and 19 TN (patients) in the zanubrutinib arm and 99 patients (including 81 R/R patients and 18 TN patients) in the ibrutinib arm. Patients in the zanubrutinib arm were assigned to receive zanubrutinib 160 mg twice daily (BID) and patients in the ibrutinib arm received 420 mg of ibrutinib once daily (QD).
Results of cohort 2 were previously presented at the 24th
About BRUKINSA
BRUKINSA is a small molecule inhibitor of Bruton’s tyrosine kinase (BTK) discovered by
BRUKINSA is approved in the following indications and regions:
-
For the treatment of mantle cell lymphoma (MCL) in adult patients who have received at least one prior therapy (
United States ,November 2019 )*; -
For the treatment of MCL in adult patients who have received at least one prior therapy (
China ,June 2020 )**; -
For the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in adult patients who have received at least one prior therapy (
China ,June 2020 )**; -
For the treatment of relapsed or refractory MCL (
United Arab Emirates ,February 2021 ); -
For the treatment of Waldenström’s macroglobulinemia (WM) in adult patients (
Canada ,March 2021 ); -
Registered and reimbursed for the treatment of MCL in patients who have received at least one prior therapy (
Israel ,April 2021 ); -
For the treatment of adult patients with WM who have received at least one prior therapy (
China ,June 2021 )**; -
For the treatment of MCL in adult patients who have received at least one prior therapy (
Canada ,July 2021 ); -
For the treatment of MCL in adult patients who have received at least one prior therapy (
Chile ,July 2021 ); -
For the treatment of adult patients with MCL who have received at least one previous therapy (
Brazil ,August 2021 ); -
For the treatment of adult patients with WM (
United States ,August 2021 ); and -
For the treatment of adult patients with marginal zone lymphoma (MZL) who have received at least one anti-CD20-based regimen (
United States ,September 2021 )*.
To date, more than 30 marketing authorization applications in multiple indications have been submitted in
* This indication was approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
** This indication was approved under conditional approval. Complete approval for this indication may be contingent upon results from ongoing randomized, controlled confirmatory clinical trials.
IMPORTANT
Warnings and Precautions
Hemorrhage
Fatal and serious hemorrhagic events have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher hemorrhage including intracranial and gastrointestinal hemorrhage, hematuria and hemothorax have been reported in 3.4% of patients treated with BRUKINSA monotherapy. Hemorrhage events of any grade occurred in 35% of patients treated with BRUKINSA monotherapy.
Bleeding events have occurred in patients with and without concomitant antiplatelet or anticoagulation therapy. Co-administration of BRUKINSA with antiplatelet or anticoagulant medications may further increase the risk of hemorrhage.
Monitor for signs and symptoms of bleeding. Discontinue BRUKINSA if intracranial hemorrhage of any grade occurs. Consider the benefit-risk of withholding BRUKINSA for 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.
Infections
Fatal and serious infections (including bacterial, viral, or fungal) and opportunistic infections have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher infections occurred in 27% of patients, most commonly pneumonia. Infections due to hepatitis B virus (HBV) reactivation have occurred.
Consider prophylaxis for herpes simplex virus, pneumocystis jiroveci pneumonia and other infections according to standard of care in patients who are at increased risk for infections. Monitor and evaluate patients for fever or other signs and symptoms of infection and treat appropriately.
Cytopenias
Grade 3 or 4 cytopenias, including neutropenia (26%), thrombocytopenia (11%) and anemia (8%) based on laboratory measurements, developed in patients treated with BRUKINSA monotherapy. Grade 4 neutropenia occurred in 13% of patients, and Grade 4 thrombocytopenia occurred in 3.6% of patients.
Monitor complete blood counts regularly during treatment and interrupt treatment, reduce the dose, or discontinue treatment as warranted. Treat using growth factor or transfusions, as needed.
Second Primary Malignancies
Second primary malignancies, including non-skin carcinoma, have occurred in 14% of patients treated with BRUKINSA monotherapy. The most frequent second primary malignancy was non-melanoma skin cancer, reported in 8% of patients. Other second primary malignancies included malignant solid tumors (4.0%), melanoma (1.7%) and hematologic malignancies (1.2%). Advise patients to use sun protection and monitor patients for the development of second primary malignancies.
Cardiac Arrhythmias
Atrial fibrillation and atrial flutter were reported in 3.2% of patients treated with BRUKINSA monotherapy. Patients with cardiac risk factors, hypertension, and acute infections may be at increased risk. Grade 3 or higher events were reported in 1.1% of patients treated with BRUKINSA monotherapy. Monitor signs and symptoms for atrial fibrillation and atrial flutter and manage as appropriate.
Embryo-Fetal Toxicity
Based on findings in animals, BRUKINSA can cause fetal harm when administered to a pregnant woman. Administration of zanubrutinib to pregnant rats during the period of organogenesis caused embryo-fetal toxicity including malformations at exposures that were 5 times higher than those reported in patients at the recommended dose of 160 mg twice daily. Advise women to avoid becoming pregnant while taking BRUKINSA and for 1 week after the last dose. Advise men to avoid fathering a child during treatment and for 1 week after the last dose.
If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
Adverse reactions
The most common adverse reactions, including laboratory abnormalities, in ≥ 30% of patients who received BRUKINSA (N = 847) included decreased neutrophil count (54%), upper respiratory tract infection (47%), decreased platelet count (41%), hemorrhage (35%), decreased lymphocyte count (31%), rash (31%) and musculoskeletal pain (30%).
Drug Interactions
CYP3A Inhibitors: When BRUKINSA is co-administered with a strong CYP3A inhibitor, reduce BRUKINSA dose to 80 mg once daily. For coadministration with a moderate CYP3A inhibitor, reduce BRUKINSA dose to 80 mg twice daily.
CYP3A Inducers: Avoid coadministration with moderate or strong CYP3A inducers.
Specific Populations
Hepatic Impairment: The recommended dose of BRUKINSA for patients with severe hepatic impairment is 80 mg orally twice daily.
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About
Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 and other federal securities laws, including statements regarding future development and potential commercialization of BRUKINSA in the
References:
1. Tam, et al. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the
2.
3.
4. Buske, C, et al. Treatment and outcome patterns in European patients with Waldenström’s macroglobulinaemia: a large, observational, retrospective chart review. The Lancet Haematology 2018; 5: e0299-309.
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