BeiGene Announces FDA Acceptance of sNDA for Fifth BRUKINSA® Indication

- Submission seeks approval for BRUKINSA in combination with obinutuzumab as a treatment for relapsed or refractory follicular lymphoma

BeiGene (NASDAQ: BGNE; HKEX: 06160; SSE: 688235), a global biotechnology company, today announced the U.S. Food and Drug Administration (FDA) has accepted for review the Company’s supplemental new drug application (sNDA) for BRUKINSA^® (zanubrutinib) in combination with obinutuzumab for the treatment of adult patients with relapsed or refractory (R/R) follicular lymphoma (FL) after at least two prior lines of therapy. BRUKINSA was previously granted Fast Track and Orphan designation for this indication. The FDA has assigned a target action date in the first quarter of 2024, under the Prescription Drug User Fee Act.

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Mehrdad Mobasher, M.D., M.P.H., Chief Medical Officer, Hematology at BeiGene commented that BRUKINSA is the first Bruton's tyrosine kinase inhibitor to demonstrate efficacy in follicular lymphoma and BeiGene plans to continue worldwide regulatory submissions based on the ROSEWOOD results (Photo: Business Wire)

“Follicular lymphoma is the most common slow-growing non-Hodgkin lymphoma, but there are limited treatment options for patients whose condition has progressed after two lines of therapy. We are therefore pleased that BRUKINSA is the first Bruton's tyrosine kinase inhibitor to demonstrate efficacy in follicular lymphoma and plan to continue worldwide regulatory submissions based on the ROSEWOOD results,” said Mehrdad Mobasher, M.D., M.P.H., Chief Medical Officer, Hematology. “Importantly, we are grateful to the people living with relapsed or refractory follicular lymphoma who chose to participate in the ROSEWOOD study.”

The sNDA filing in FL is based on results from the Phase 2 ROSEWOOD study (NCT03332017) that included 217 patients with pre-treated R/R non-Hodgkin FL (145 receiving BRUKINSA plus obinutuzumab and 72 patients receiving obinutuzumab monotherapy). In the primary ROSEWOOD analysis at a median follow-up of 12.5 months, BRUKINSA plus obinutuzumab demonstrated superior efficacy to obinutuzumab monotherapy with a 68.3% overall response rate (ORR) versus 45.8% respectively (p = 0.0017). Responses were durable with 18-month landmark duration of response (DOR) of 69.3%.

Safety results from the ROSEWOOD study were consistent with previous studies of both medicines. The most common treatment emergent adverse events reported in the primary analysis for the combination arm compared with the obinutuzumab alone arm were diarrhea (18.2% vs 16.9%), fatigue (15.4% vs 14.1%), and pyrexia (13.3% vs 19.7%).ⁱ

Longer-term data included in the sNDA demonstrated the efficacy benefit for BRUKINSA plus obinutuzumab persisted at a median follow-up of 20.2 months, with an ORR of 69.0% versus 45.8% for obinutuzumab monotherapy (p = 0.0012). Additionally, the combination of BRUKINSA and obinutuzumab reduced the risk of disease progression or death by 50% compared with obinutuzumab alone (HR 0.50; 95% CI 0.33-0.75).ⁱⁱ

BeiGene currently has submissions for BRUKINSA in R/R FL under review by regulatory authorities in the European Union and China. BeiGene’s submission for BRUKINSA in R/R FL is under review by regulatory authorities in Canada, Switzerland, and the United Kingdom as part of the Access Consortium New Active Substance Work-sharing Initiative.

BRUKINSA is approved in more than 65 markets including the U.S., China, European Union, Great Britain, Canada, Australia, South Korea, and Switzerland in selected indications and under development for additional approvals globally. The product information may differ from country to country. Prescribers should consult the product information approved in their respective country. The global BRUKINSA development program includes more than 4,900 subjects enrolled to-date in 29 countries and regions.

About ROSEWOOD

ROSEWOOD is a randomized, open-label, Phase 2 study comparing BRUKINSA plus obinutuzumab to obinutuzumab alone in patients with R/R FL who have received two or more lines of therapy. The primary endpoint was ORR assessed by independent central review (ICR) according to the Lugano classification. Select secondary endpoints include investigator-assessed ORR, ICR-reviewed and investigator-assessed DOR and progression-free survival, overall survival, and analysis of safety.

About BRUKINSA^® (zanubrutinib)

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.

IMPORTANT U.S. INDICATIONS AND SAFETY INFORMATION FOR BRUKINSA (ZANUBRUTINIB)

Indications

BRUKINSA is a kinase inhibitor indicated for the treatment of adult patients with:

• Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)
• Waldenström’s macroglobulinemia (WM)
• Mantle cell lymphoma (MCL) who have received at least one prior therapy
• Relapsed or refractory marginal zone lymphoma (MZL) who have received at least one anti-CD20-based regimen

The MCL and MZL indications are approved under accelerated approval based on overall response rate. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

Warnings and Precautions

Hemorrhage

Fatal and serious hemorrhage has 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 3.6% of patients treated with BRUKINSA monotherapy in clinical trials, with fatalities occurring in 0.3% of patients. Bleeding of any grade, excluding purpura and petechiae, occurred in 30% of patients.

Bleeding has occurred in patients with and without concomitant antiplatelet or anticoagulation therapy. Coadministration 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 infections) and opportunistic infections have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher infections occurred in 24% of patients, most commonly pneumonia (11%), with fatal infections occurring in 2.9% of patients. Infections due to hepatitis B virus (HBV) reactivation have occurred.

Consider prophylaxis for herpes simplex virus, pneumocystis jirovecii 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 (22%), thrombocytopenia (8%) and anemia (7%) based on laboratory measurements, developed in patients treated with BRUKINSA monotherapy. Grade 4 neutropenia occurred in 11% of patients, and Grade 4 thrombocytopenia occurred in 2.8% 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 13% of patients treated with BRUKINSA monotherapy. The most frequent second primary malignancy was non-melanoma skin cancer reported in 7% of patients. Other second primary malignancies included malignant solid tumors (5%), melanoma (1.2%), and hematologic malignancies (0.5%). Advise patients to use sun protection and monitor patients for the development of second primary malignancies.

Cardiac Arrhythmias

Serious cardiac arrhythmias have occurred in patients treated with BRUKINSA. Atrial fibrillation and atrial flutter were reported in 3.7% of 1550 patients treated with BRUKINSA monotherapy, including Grade 3 or higher cases in 1.7% of patients. Patients with cardiac risk factors, hypertension, and acute infections may be at increased risk. Grade 3 or higher ventricular arrhythmias were reported in 0.2% of patients.

Monitor for signs and symptoms of cardiac arrhythmias (e.g., palpitations, dizziness, syncope, dyspnea, chest discomfort), manage appropriately, and consider the risks and benefits of continued BRUKINSA treatment.

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

In this pooled safety population, the most common adverse reactions, including laboratory abnormalities, in ≥30% of patients who received BRUKINSA (N=1550) included decreased neutrophil count (42%), upper respiratory tract infection (39%), decreased platelet count (34%), hemorrhage (30%), 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 strong or moderate CYP3A inducers. Dose adjustment may be recommended with moderate CYP3A inducers.

Specific Populations

Hepatic Impairment: The recommended dose of BRUKINSA for patients with severe hepatic impairment is 80 mg orally twice daily.

Please see full U.S. Prescribing Information at www.beigene.com/PDF/BRUKINSAUSPI.pdf and Patient Information at www.beigene.com/PDF/BRUKINSAUSPPI.pdf

About BeiGene

BeiGene is a global biotechnology company that is discovering and developing innovative oncology treatments that are more affordable and accessible to cancer patients worldwide. With a broad portfolio, we are expediting development of our diverse pipeline of novel therapeutics through our internal capabilities and collaborations. We are committed to radically improving access to medicines for far more patients who need them. Our growing global team of more than 9,400 colleagues spans five continents, with administrative offices in Beijing, China; Cambridge, U.S.; and Basel, Switzerland. To learn more about BeiGene, please visit www.beigene.com and follow us on Twitter at @BeiGeneGlobal.

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 BeiGene’s advancement, anticipated clinical development, regulatory submissions and commercialization of zanubrutinib, particularly as a treatment for R/R FL; and BeiGene’s plans, commitments, aspirations, and goals under the heading “About BeiGene.” Actual results may differ materially from those indicated in the forward-looking statements as a result of various important factors, including BeiGene's ability to demonstrate the efficacy and safety of its drug candidates; the clinical results for its drug candidates, which may not support further development or marketing approval; actions of regulatory agencies, which may affect the initiation, timing, and progress of clinical trials and marketing approval; BeiGene's ability to achieve commercial success for its marketed medicines and drug candidates, if approved; BeiGene's ability to obtain and maintain protection of intellectual property for its medicines and technology; BeiGene's reliance on third parties to conduct drug development, manufacturing, and other services; BeiGene’s limited experience in obtaining regulatory approvals and commercializing pharmaceutical products and its ability to obtain additional funding for operations and to complete the development and commercialization of its drug candidates and achieve and maintain profitability; and the impact of the COVID-19 pandemic on BeiGene’s clinical development, regulatory, commercial, manufacturing, and other operations, as well as those risks more fully discussed in the section entitled “Risk Factors” in BeiGene’s most recent quarterly report on Form 10-Q, as well as discussions of potential risks, uncertainties, and other important factors in BeiGene's subsequent filings with the U.S. Securities and Exchange Commission. All information in this press release is as of the date of this press release, and BeiGene undertakes no duty to update such information unless required by law.

ⁱ Zinzani, P. L., Mayer, J., Auer, R., Bijou, F., De Oliveira, A. C., Flowers, C., ... & Trotman, J. (2022). Zanubrutinib plus obinutuzumab (ZO) versus obinutuzumab (O) monotherapy in patients (pts) with relapsed or refractory (R/R) follicular lymphoma (FL): Primary analysis of the phase 2 randomized ROSEWOOD trial. DOI: 10.1200/JCO.2022.40.16_suppl.7510 Journal of Clinical Oncology 40, no. 16_suppl (June 01, 2022) 7510-7510.

ⁱⁱ Nastoupil, L. J., Song, Y., Sehn, L. H., Sarkozy, C., Zinzani, P. L., Salar, A., ... & Trotman, J. (2023). MAHOGANY: A Phase 3 Trial of Zanubrutinib Plus Anti-CD20 Antibodies vs Lenalidomide Plus Rituximab in Patients With Relapsed or Refractory Follicular or Marginal Zone Lymphoma. DOI: 10.1200/JCO.2023.41.16_suppl.TPS7590 Journal of Clinical Oncology 41, no. 16_suppl (June 01, 2023) TPS7590-TPS7590.

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