On September 17, 2021 BeiGene (NASDAQ: BGNE; HKEX: 06160) reported the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion, recommending approval of BRUKINSA (zanubrutinib) for the treatment of adult patients with Waldenström’s macroglobulinemia (WM) who have received at least one prior therapy or first-line treatment for patients unsuitable for chemo-immunotherapy (Press release, BeiGene, SEP 17, 2021, View Source [SID1234587906]).
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"The ASPEN trial demonstrated that BRUKINSA provided deep and durable responses and offered substantial improvements in safety and tolerability over standard therapy. Patients in Europe with WM may soon have a new treatment option that can offer improved outcomes."
"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. Christian Buske, Medical Director at the University Hospital Ulm, Germany, and a trial investigator of the ASPEN study. "The ASPEN trial demonstrated that BRUKINSA provided deep and durable responses and offered substantial improvements in safety and tolerability over standard therapy. Patients in Europe with WM may soon have a new treatment option that can offer improved outcomes."
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 Sixth International Workshop on Waldenström’s Macroglobulinemia (IWWM-6) response criteria (Treon 2015), the combined complete response (CR) +VGPR rate in the overall intention-to-treat (ITT) population was 28.4% with BRUKINSA (95% CI: 20, 38), compared to 19.2% with ibrutinib (95% CI: 12, 28). While this difference was not statistically significant, BRUKINSA did achieve numerically higher VGPR rates and trends towards increased response quality.1
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 Jane Huang, M.D., Chief Medical Officer, Hematology, at BeiGene. "We are committed to advancing the global registration of BRUKINSA and, if approved, believe it will become the preferred BTK inhibitor for patients with WM."
"We have a strong team in Europe who are excited for the opportunity to further work with the many investigators who have participated in BRUKINSA trials conducted in Europe to-date. Looking to the future, we have built a team in Europe and they are poised to help patients access BRUKINSA following its expected approval," said Gerwin Winter, Senior Vice President, Head of Commercial, Europe, at BeiGene. "We look forward to continuing our work with the European health authorities to bring BRUKINSA to patients living with this rare, incurable blood cancer."
Following the CHMP positive opinion, the European Commission will consider BeiGene’s marketing application, with a final decision expected within 67 days of receipt of the CHMP opinion. The decision will be applicable to all 27 member states of the EU plus Iceland and Norway.
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 Europe, the estimated incidence rate of WM is approximately seven for every one million men and four for every one million women.4
About the ASPEN trial
The Phase 3 randomized, open-label, multicenter ASPEN clinical trial (NCT03053440) evaluated zanubrutinib versus ibrutinib in people with relapsed or refractory (R/R) or treatment-naïve (TN) WM. The primary objective was to establish superiority of zanubrutinib compared to ibrutinib as demonstrated by the proportion of people achieving complete response (CR) or very good partial response (VGPR). Secondary endpoints included major response rate, duration of response and progression-free survival, and safety, measured by incidence, timing and severity of treatment-emergent adverse events. The pre-specified analysis populations for the trial included the overall population (n=201) and R/R patients (n=164). Exploratory endpoints included quality of life measures.
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 Congress of European Hematology Association (EHA) (Free EHA Whitepaper) and showed an overall response rate (ORR) of 80.8%, a major response rate (MRR; partial response or better) of 53.8% and a VGPR rate of 23.1%.
About BRUKINSA
BRUKINSA is a small molecule inhibitor of Bruton’s tyrosine kinase (BTK) discovered by BeiGene scientists that is currently being evaluated globally in a broad clinical program as a monotherapy and in combination with other therapies to treat various B-cell malignancies. Because new BTK is continuously synthesized, BRUKINSA was specifically designed to deliver complete and sustained inhibition of the BTK protein by optimizing bioavailability, half-life, and selectivity. With differentiated pharmacokinetics compared to other approved BTK inhibitors, BRUKINSA has been demonstrated to inhibit the proliferation of malignant B cells within a number of disease relevant tissues.
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 the United States, China, the European Union, and more than 20 other countries or regions.
* 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 U.S. SAFETY INFORMATION FOR BRUKINSA (ZANUBRUTINIB)
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.