On June 10, 2022 BeiGene (NASDAQ: BGNE; HKEX: 06160; SSE: 688235), a global, science-driven biotechnology company focused on developing innovative and affordable medicines to improve treatment outcomes and access for patients worldwide, reported that the China National Medical Products Administration (NMPA) has approved BeiGene’s anti-PD-1 antibody, tislelizumab, in combination with chemotherapy as a first-line treatment for patients with recurrent or metastatic nasopharyngeal cancer (NPC) (Press release, BeiGene, JUN 10, 2022, View Source [SID1234615888]).

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"The NMPA’s approval of tislelizumab in NPC is welcoming news to these many patients with the disease."

"NPC is one of the most common head and neck cancers in China and many parts of Asia. Treatment options have been limited, with chemotherapy primarily provided for front-line care. On behalf of these patients, today’s approval of tislelizumab, a potentially differentiated checkpoint inhibitor, for patients with recurrent or metastatic NPC could provide new hope," commented Mark Lanasa, M.D., Ph.D., Chief Medical Officer, Solid Tumors at BeiGene. "We look forward to bringing this important immunotherapy to the underserved patient community in China."

"With nine approved indications in China, our 3,100+ science-based commercial team is working to make tislelizumab more broadly available to those who may benefit from this important immunotherapy," commented Xiaobin Wu, Ph.D., President, Chief Operating Officer, and General Manager of China, at BeiGene. "Today’s approval is a great step for patients in China with NPC."

"In the pivotal Phase 3 RATIONALE-309 trial, comparing two arms of patients receiving either tislelizumab in combination with standard chemotherapy, or a placebo with standard chemotherapy, we observed statistical and clinically meaningful improvement in progression-free survival in the tislelizumab arm as assessed by both independent review committee and clinical investigators, and a positive trend in overall survival. These results were consistent with the updated survival data with a follow up time of 15 months, and tislelizumab was generally well tolerated," said Li Zhang, M.D., professor at the Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China and Sun Yat-sen University Cancer, and the principal investigator of the trial. "The NMPA’s approval of tislelizumab in NPC is welcoming news to these many patients with the disease."

This approval was supported by clinical results from the randomized, double-blind, Phase 3 clinical trial RATIONALE 309 (NCT03924986) to evaluate the efficacy and safety of tislelizumab combined with gemcitabine and cisplatin versus placebo combined with gemcitabine and cisplatin as a first-line treatment for patients with recurrent or metastatic NPC.

As announced in May 2021, RATIONALE 309 met the primary endpoint of PFS at the planned interim analysis. Updated efficacy analyses at a median follow-up of 15.5 months, tislelizumab in combination with chemotherapy continued to demonstrate a clinically significant progression-free survival (PFS) benefit over chemotherapy and placebo for patients with RM-NPC. Meanwhile, the tislelizumab arm continued to demonstrate a positive trend in overall survival (OS) and improvement in time to disease progression or death after next-line therapy (PFS2). The safety profile of the tislelizumab and chemotherapy combination was generally manageable and consistent with safety profiles of each treatment agent. These data were presented at an ASCO (Free ASCO Whitepaper) Virtual Plenary session in April and at the ASCO (Free ASCO Whitepaper) Annual Meeting in June 2022.

About Nasopharyngeal Cancer (NPC)

Nasopharyngeal cancer (NPC) is a malignant, squamous cell carcinoma which arises from the epithelial cells of the nasopharynx, most commonly originating in the pharyngeal recess (the fossa of Rosenmüller).i There were an estimated 62,555 new cases of NPC in China in 2020, accounting for 46.8 percent of the worldwide incidence.ii Despite the heavy public health burden of NPC in southern China and other endemic areas, relatively little is known about the etiology and prevention of NPC.iii The major risk factors for NPC are genetic predisposition, Epstein-Barr virus (EBV) infection, and consumption of salt-preserved food.iv The median overall survival rate is about 20 months in advanced NPC;v with progressively worsening prognoses falling to a three-year survival of 7-40% reported in patients with recurrent or metastatic NPC, indicating a high medical unmet need with more effective treatment urgently needed.vi,vii,viii

About RATIONALE-309

RATIONALE-309 is a multicenter, randomized, double-blind, placebo-controlled Phase 3 clinical trial (NCT03924986) designed to evaluate the efficacy and safety of tislelizumab combined with gemcitabine and cisplatin (Arm A) versus placebo combined with gemcitabine and cisplatin (Arm B) as a first-line treatment for patients with RM-NPC.

The primary endpoint of the trial is progression-free survival (PFS) in the intent-to-treat (ITT) population as assessed by an independent review committee (IRC) per RECIST v1.1 criteria; secondary endpoints include IRC-assessed overall response rate (ORR), IRC-assessed duration of response (DoR), overall survival (OS), investigator-assessed PFS, time to second objective disease progression (PFS2), and safety.

A total of 263 patients were enrolled in the trial, with 131 and 132 randomized to Arm A and Arm B, respectively, with balanced baseline characteristics between both arms. Interim results from the trial were presented in December at the European Society for Medical Oncology Immuno-Oncology (ESMO I-O) Congress. Those data showed that at a media follow-up time of 10 months, tislelizumab demonstrated a statistically significant improvement in terms of extending progression-free survival (PFS) as well as clinically meaningful benefit on other survival endpoints compared with chemotherapy and placebo and a generally manageable safety profile.

About Tislelizumab

Tislelizumab is an anti-programmed death receptor-1 (PD-1) inhibitor designed to help aid the body’s immune cells to detect and fight tumors. Tislelizumab, a humanized monoclonal antibody, is specifically designed to minimize binding to FcγR on macrophages. In pre-clinical studies, binding to FcγR on macrophages has been shown to compromise the anti-tumor activity of PD-1 antibodies through activation of antibody-dependent macrophage-mediated killing of T effector cells.

Tislelizumab is the first drug from BeiGene’s immuno-oncology biologics program and is being developed internationally as a monotherapy and in combination with other therapies for the treatment of a broad array of both solid tumor and hematologic cancers. BeiGene has initiated or completed more than 20 potentially registration-enabling clinical trials in 35 countries and regions, including 17 Phase 3 trials and four pivotal Phase 2 trials.

Tislelizumab is approved by the China National Medical Products Administration (NMPA) as a treatment for nine indications, including multiple approvals in non-small cell lung cancer (NSCLC). Tislelizumab has been submitted for regulatory review as a potential treatment for unresectable recurrent locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) after prior systemic therapy in the U.S., and in NSCLC and second-line ESCC in Europe. In January 2021, BeiGene partnered with Novartis to accelerate the clinical development and marketing of tislelizumab in North America, Europe and Japan.

BeiGene Oncology

BeiGene is committed to advancing best- and first-in-class clinical candidates internally or with like-minded partners to develop impactful and affordable medicines for patients across the globe. We have a growing R&D and medical affairs team of approximately 2,900 colleagues dedicated to advancing more than 100 clinical trials that have involved more than 16,000 subjects. Our expansive portfolio is directed predominantly by our internal colleagues supporting clinical trials in more than 45 countries and regions. Hematology-oncology and solid tumor targeted therapies and immuno-oncology are key focus areas for the Company, with both mono- and combination therapies prioritized in our research and development. BeiGene currently has three approved medicines discovered and developed in our own labs: BTK inhibitor BRUKINSA in the United States, China, the EU and U.K., Canada, Australia and additional international markets; and the non-FC-gamma receptor binding anti-PD-1 antibody tislelizumab as well as the PARP inhibitor pamiparib in China.

BeiGene also partners with innovative companies who share our goal of developing therapies to address global health needs. We commercialize a range of oncology medicines in China licensed from Amgen, Bristol Myers Squibb, EUSA Pharma and Bio-Thera. We also plan to address greater areas of unmet need globally through our other collaborations including with Mirati Therapeutics, Seagen, and Zymeworks.

In January 2021 BeiGene and Novartis announced a collaboration granting Novartis rights to co-develop, manufacture, and commercialize BeiGene’s anti-PD1 antibody tislelizumab in North America, Europe, and Japan. Building upon this productive collaboration, including a biologics license application (BLA) under FDA review, BeiGene and Novartis announced an option, collaboration and license agreement in December 2021 for BeiGene’s TIGIT inhibitor, ociperlimab, that is in Phase 3 development. Novartis and BeiGene also entered into a strategic commercial agreement through which BeiGene is promoting five approved Novartis Oncology products across designated regions of China.

On June 10, 2022 MorphoSys AG (FSE: MOR; NASDAQ: MOR) reported that data from multiple analyses of the ongoing MANIFEST study, an open-label Phase 2 clinical trial of pelabresib, an investigational BET inhibitor, in patients with myelofibrosis, a rare bone marrow cancer for which only limited treatment options are available (Press release, MorphoSys, JUN 10, 2022, View Source [SID1234615872]). The latest findings suggest pelabresib may have disease-modifying properties and confirm previous data supporting the potential of pelabresib as a treatment for patients with myelofibrosis. The data are being presented during oral and poster sessions at the European Hematology Association (EHA) (Free EHA Whitepaper) 2022 (EHA 2022) Hybrid Congress being held in Vienna.
"The standard for evaluating disease response in myelofibrosis focuses on symptom relief rather than true disease modification, which remains an unmet need for these patients," said John Mascarenhas, M.D., Director of the Adult Leukemia Program at The Tisch Cancer Institute at Mount Sinai, New York. "The body of data being presented at EHA (Free EHA Whitepaper) 2022 – including new findings that pelabresib may address cellular defects seen in myelofibrosis, thereby getting at the root cause of the disease – with correlated clinical improvements, suggests pelabresib may have the potential to enhance the current standard of care in the first-line treatment of myelofibrosis."

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A study that will be presented in an oral session on June 11 analyzed cells derived from blood of patients who enrolled in the MANIFEST trial and from healthy volunteers. The findings indicate that pelabresib alone or in combination with the JAK inhibitor ruxolitinib may have the potential to improve the typical imbalance in the two white blood cell populations, the myeloid and lymphoid cells, and help restore normal blood cell development. These improvements also correlated with decreases in spleen volume, a key clinical measure of treatment success. Additionally, pelabresib alone or in combination decreased pro-inflammatory and pro-fibrotic signaling in monocytes, suggesting a potential attenuation of disease processes.
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"The latest findings from the MANIFEST trial at EHA (Free EHA Whitepaper) 2022 highlight the potential of pelabresib to offer patients and their physicians benefits over monotherapy with JAK inhibitors, if approved," said Malte Peters, M.D., MorphoSys Chief Research and Development Officer. "The full complement of MANIFEST data being presented this week suggests pelabresib may help improve outcomes for patients with myelofibrosis and reaffirms our confidence in the Phase 3 MANIFEST-2 study. We are committed to these patients, who need better options in first-line treatment and beyond."
A second oral presentation on June 11 highlights positive interim data from the MANIFEST trial on the safety and efficacy of pelabresib in combination with ruxolitinib in patients who were not previously treated with a JAK inhibitor and in those with suboptimal response to ruxolitinib. The findings show that the combination was generally well tolerated and offered reductions in spleen volume and symptom burden, with disease-modifying activity as measured by reduced levels of pro-inflammatory cytokines and improved bone marrow morphology. Over two-thirds (68%; n=57) of JAK inhibitor-naïve patients treated with the combination achieved at least a 35% reduction in spleen volume (SVR35) from baseline at week 24. Notably, 80% of patients achieved SVR35 at any time on study. Most patients also saw their symptoms reduced, with 56% (n=46) achieving at least a 50% reduction in total symptom score (TSS50) from baseline at week 24. No new safety signals were identified in the study. The most common hematologic adverse events were thrombocytopenia (12%, grade 3/4) and anemia (34%, grade 3/4). Non-hematological events included dyspnea (5%, grade 3) and respiratory tract infections (8%, grade 3/4).
In a poster presentation at EHA (Free EHA Whitepaper) 2022, matching-adjusted indirect comparisons were used to compare findings for the combination of pelabresib plus ruxolitinib in treatment-naïve patients with intermediate- or high-risk disease in one arm of the MANIFEST trial with findings from historical clinical trials examining the use of JAK inhibitor monotherapy in myelofibrosis. Adjusting for cross-trial differences, the estimated response rate ratios favored the pelabresib combination over ruxolitinib, fedratinib or momelotinib monotherapy for SVR35 and for TSS50, suggesting improved efficacy versus the JAK inhibitors alone.
A second poster presentation includes trial design information for the Phase 3 MANIFEST-2 study. MANIFEST-2, which is currently enrolling, will compare pelabresib in combination with ruxolitinib versus placebo plus ruxolitinib in approximately 400 patients with myelofibrosis who are naïve to JAK inhibitor therapy. MorphoSys is expected to report topline data from the MANIFEST-2 trial in the first half of 2024.
About Pelabresib
Pelabresib (CPI-0610) is an investigational selective small molecule designed to promote anti-tumor activity by inhibiting the function of bromodomain and extra-terminal domain (BET) proteins to decrease the expression of abnormally expressed genes in cancer. Pelabresib is being investigated as a treatment for myelofibrosis and has not yet been evaluated or approved by any regulatory authorities.

About Myelofibrosis
Myelofibrosis is a type of chronic leukemia that causes extensive scarring in the bone marrow, which disrupts the body’s normal production of healthy blood cells. The result is a reduction in red blood cells, which can cause weakness and fatigue, and in platelets, which increases the risk of bleeding due to deficient clotting. Myelofibrosis
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often causes an enlarged spleen. It is most often diagnosed in people older than 50 and can occur on its own (called primary myelofibrosis) or because of another bone marrow disorder.

About MANIFEST
MANIFEST (NCT02158858) is an open-label Phase 2 clinical trial of pelabresib in patients with myelofibrosis.

The MANIFEST trial is evaluating pelabresib in combination with ruxolitinib in JAK-inhibitor-naïve myelofibrosis patients (Arm 3), with a primary endpoint of the proportion of patients with a ≥35% spleen volume reduction from baseline (SVR35) after 24 weeks of treatment. The trial is also evaluating pelabresib either as a monotherapy in patients who are resistant to, intolerant of, or ineligible for ruxolitinib and no longer on the drug (Arm 1) or as add-on therapy in combination with ruxolitinib in patients with a suboptimal response to ruxolitinib or myelofibrosis progression (Arm 2). Patients in Arms 1 and 2 are being stratified based on transfusion-dependent (TD) status. The primary endpoint for the patients in cohorts 1A and 2A, who were TD at baseline, is conversion to transfusion independence for 12 consecutive weeks. The primary endpoint for patients in cohorts 1B and 2B, who were not TD at baseline, is the proportion of patients with a ≥35% spleen volume reduction from baseline after 24 weeks of treatment.

Constellation Pharmaceuticals, Inc., a MorphoSys company, is the MANIFEST trial sponsor.

About MANIFEST-2
MANIFEST-2 (NCT04603495) is a global, double-blind, randomized Phase 3 clinical trial with pelabresib in combination with ruxolitinib versus placebo plus ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis. The primary endpoint of the study is a 35% or greater reduction in spleen volume (SVR35) from baseline at 24 weeks. A key secondary endpoint of the study is a 50% or greater improvement in total symptom score (TSS50) from baseline at 24 weeks.

Constellation Pharmaceuticals, Inc., a MorphoSys company, is the MANIFEST-2 trial sponsor.

On June 10, 2022 BeiGene (NASDAQ: BGNE; HKEX: 06160; SSE: 688235), a global, science-driven biotechnology company focused on developing innovative and affordable medicines to improve treatment outcomes and access for patients worldwide, reported that data from its hematology portfolio at the European Hematology Association (EHA) (Free EHA Whitepaper) 2022 Hybrid Congress being held June 9-12, 2022, in Vienna, Austria (Press release, BeiGene, JUN 10, 2022, View Source [SID1234615889]).

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"Our data presentations at EHA (Free EHA Whitepaper) build a more complete picture of the potential for our BTK inhibitor zanubrutinib across a number of hematologic malignancies, with positive clinical results from ROSEWOOD in follicular lymphoma, long-term efficacy and safety results from ASPEN, as well as patient-reported outcomes from ALPINE and SEQUIOA." said Lai Wang, Ph.D., Global Head of R&D at BeiGene. "We are seeing our promising early pipeline beginning to mature as a result of our deep expertise in developing treatments for hematologic malignancies, and we’re pleased to present positive proof-of-concept data from two studies with our BCL2 inhibitor, BGB-11417, at this important hematology meeting."

Highlights from the broad clinical program for zanubrutinib (BRUKINSA) presented at EHA (Free EHA Whitepaper) include:

ASPEN: Long-term safety and efficacy results from the Phase 3 ASPEN trial of zanubrutinib versus ibrutinib in patients with Waldenström macroglobulinemia (WM) showed that, at a median follow up of 43 months, zanubrutinib continued to demonstrate clinically meaningful efficacy and a tolerable safety profile in patients with WM.
ROSEWOOD: The Phase 2 ROSEWOOD trial of zanubrutinib plus obinutuzumab versus (vs.) obinutuzumab monotherapy in patients with relapsed/refractory (R/R) follicular lymphoma met its primary endpoint of overall response rate (ORR) and was generally well-tolerated, with safety results consistent with previous studies of both medicines.
ALPINE: In the head-to-head ALPINE trial of zanubrutinib versus ibrutinib in patients with R/R chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), those who received zanubrutinib monotherapy reported improvements in key health-related quality of life (HRQoL) endpoints compared with patients who received ibrutinib monotherapy.
SEQUOIA: In the SEQUOIA trial of zanubrutinib vs. bendamustine plus rituximab (BR), zanubrutinib was associated with significant improvements in HRQoL in patients with treatment-naïve (TN) CLL/SLL without del(17p), as indicated by patient reported outcome (PRO) endpoints.
The ROSEWOOD and ASPEN study findings were presented at the American Society of Cancer Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in June 2022.

BeiGene also presented two posters from proof-of-concept studies of BGB-11417, a highly selective investigational BCL2 inhibitor in CLL, non-Hodgkin’s lymphoma and acute myeloid leukemia (AML).

Preliminary data from an ongoing Phase 1/1b dose-escalation and expansion study evaluating the safety, tolerability, maximum tolerated dose (MTD), and recommended Phase 2 dose of oral BGB-11417 as monotherapy or in combination with zanubrutinib, in patients with B-cell malignancies, showed promising efficacy potential for BGB-11417 and an improved safety profile, particularly in combination cohorts.
Preliminary data from an ongoing Phase 1b/2 global, multi-center dose escalation and expansion study evaluating BGB-11417 plus azacytidine in patients with AML demonstrated the combination to be generally well-tolerated with the majority of complete responses observed by the end of Cycle 1.
Zanubrutinib Plus Obinutuzumab Versus Obinutuzumab Monotherapy in Patients with Relapsed or Refractory Follicular Lymphoma: Primary Analysis of the Phase 2 Randomized ROSEWOOD Trial
Abstract Number: S205

The ROSEWOOD trial met its primary endpoint, with a 68.3% ORR in the zanubrutinib plus obinutuzumab arm versus 45.8% in the obinutuzumab arm (p = 0.0017) and median follow-up of 12.5 months. Zanubrutinib plus obinutuzumab was generally well-tolerated, with safety results consistent with previous studies of both medicines.

Zanubrutinib plus obinutuzumab was associated with a deep and durable response, with a complete response (CR) rate of 37.2% compared to 19.4% for obinutuzumab alone; 18-month duration of response rate was 70.9% in the zanubrutinib plus obinutuzumab arm versus 54.6% in the obinutuzumab arm.
Time to next anti-lymphoma treatment was significantly prolonged in the zanubrutinib plus obinutuzumab arm (HR 0.37 [95% CI, 0.23, 0.60].
Median progression-free survival was 27.4 months in the zanubrutinib plus obinutuzumab arm compared to 11.2 months in the obinutuzumab arm (HR: 0.51 [95% CI, 0.32, -0.81]).
The most common adverse events in the zanubrutinib plus obinutuzumab arm were thrombocytopenia or platelet count decreased (34.3% any grade; 14% grade ≥ 3) and neutrophil count decreased or neutropenia (27.3% any grade; 22.4% grade ≥ 3); other adverse events were similar between the two arms.
Infusion-related reactions were more frequent in the obinutuzumab monotherapy arm.
ASPEN: Long-term Follow-up Results of a Phase 3 Randomized Trial of Zanubrutinib vs. Versus Ibrutinib in Patients with Waldenström Macroglobulinemia (WM)
Abstract Number: P1161

With a median follow-up of 43 months, zanubrutinib continued to demonstrate a clinically meaningful efficacy and tolerable safety profile in patients with WM.

Exploratory analyses showed a consistent trend of deeper, earlier, and more durable responses (CR+VGPR) compared with ibrutinib over time.
Median time to CR+VGPR was shorter for zanubrutinib: 6.7 months (range, 1.9-42.0) vs ibrutinib: 16.6 months (range, 2.0-49.9).
Over the follow-up period, patients receiving zanubrutinib had fewer adverse events leading to death, treatment discontinuation, and dose reduction as compared with ibrutinib.
The prevalence of atrial fibrillation, hypertension, and bleeding were lower in the zanubrutinib arm at all time intervals; neutropenia occurred early, and prevalence decreased over time for patients receiving zanubrutinib.
Health-related Quality of Life Outcomes Associated with Zanubrutinib vs Ibrutinib Monotherapy in Patients with Relapsed/Refractory (R/R) CLL/SLL: Results from The Randomized Phase 3 ALPINE Trial
Abstract Number: P663

In the Phase 3 open-label ALPINE trial, HRQoL was examined at key cycles (7 and 13; corresponding to 6 and 12 months of treatment, respectively). PRO endpoints included global health status (GHS), physical and role functions, and fatigue, pain, diarrhea, and nausea/vomiting.

Adjusted completion rates for PROs were high (>85%) in both arms at Cycles 7 and 13.
Estimated mean treatment differences and 95% CI in key PRO endpoints demonstrated treatment differences, in favor of zanubrutinib, in GHS, physical functioning, and fatigue in Cycle 7, and diarrhea in Cycle 13.
Mean change from baseline showed greater improvement with zanubrutinib compared with ibrutinib at both Cycle 7 and Cycle 13.
Patient-Reported Outcomes from a Phase 3 Randomized Study of Zanubrutinib Versus Bendamustine Plus Rituximab (BR) in Patients with Treatment-naïve (TN) CLL/SLL
Abstract Number: P662

PROs were secondary endpoints in the Phase 3, open-label,SEQUOIA trial of zanubrutinib (n=241) versus bendamustine plus BR (n=238) in adult patients with TN CLL/SLL without del(17p) and were assessed using the EORTC QLQ-C30, and EQ-5D-5L VAS. The PRO endpoints included GHS, physical and role functions, and symptoms of fatigue, pain, diarrhea, and nausea/vomiting measured at critical clinical cycles of Weeks 12 and 24.

Across all patients, adjusted completion rates for PROs were high (80%) at Weeks 12 and 24.
Patients treated with zanubrutinib experienced greater improvements in HRQoL at Weeks 12 and 24 compared with patients who received BR.
By Week 24, improvements were observed with zanubrutinib vs. BR in GHS, physical functioning, role functioning as well as greater reductions in diarrhea, fatigue, and nausea/vomiting.
Comparable improvements from baseline between zanubrutinib and BR in the health status were observed at Weeks 12 and 24, respectively.
A Phase 1 Study with the Novel B-Cell Lymphoma 2 Inhibitor BGB-11417 as Monotherapy or in Combination with Zanubrutinib in Patients with B-cell Malignancies: Preliminary Data
Abstract Number: P687

This ongoing first-in-human Phase 1/1b dose-escalation and expansion study evaluated the safety, tolerability, maximum tolerated dose (MTD), and recommended Phase 2 dose of oral BGB-11417, a highly selective investigational inhibitor of BCL2, as monotherapy (n=34) or in combination with zanubrutinib (n=44), in patients with B-cell malignancies.

Early phase 1 results suggested that BGB-11417 monotherapy and combination with zanubrutinib is generally well-tolerated in patients with CLL or NHL at the dose levels tested:

Dose escalation concluded for monotherapy patients with NHL, with 1 dose limiting toxicity (DLT) seen and no MTD reached at doses as high as 640mg; 1 DLT was seen in monotherapy patients with CLL.
Transient neutropenia was the most frequent grade ≥3 AE; risk of TLS appears limited and manageable.
Dose escalation was completed for Cohort 1A, with no MTD reached through 640mg and only 1 DLT of grade 3 febrile neutropenia was seen at 160 mg Although dose escalation has not yet been completed for the other cohorts and the follow up is limited, responses were observed at the preliminary dose levels:

A reduction in ALC was noted among all patients with CLL during ramp-up, with reduction in lymphocytes noted at dose levels as low as 1 mg. Four of six R/R CLL/SLL patients receiving BGB-11417 and zanubrutinib achieved PR-L or better across dose levels ranging from 40 – 320 mg.
Preliminary Safety and Efficacy of BGB-11417, a Potent and Selective B-Cell Lymphoma 2 (BCL2) Inhibitor, in Patients with Acute Myeloid Leukemia
Abstract Number: P590

This ongoing Phase 1b/2, global, multi-center, dose-escalation and expansion study evaluated the combination of BGB-11417 and azacitidine in patients (n=31) with acute myeloid leukemia (TN unfit for intensive chemotherapy or R/R). Preliminary results showed that the 10-day regimen of BGB-11417 in 28-day cycle plus 7-day azacytidine was generally well-tolerated and active across the three dose levels tested (40, 80, 160 mg):

58% TN and 55% R/R patients with AML met CR+CRh criteria.
Most CRs (7 of 11) were achieved by the end of cycle 1.
Five of 13 evaluable CR/CRi achieved minimal residual disease negativity.
Neutropenia was the most common grade ≥3 AE (54.8%) and was manageable with growth factor support and dose modification.
DLTs of grade 4 neutropenia/thrombocytopenia occurred in two patients; safety stopping criteria were not met.
Higher dose and different dosing scheduling are being explored.
About ASPEN

ASPEN is a randomized, open-label, multi-center Phase 3 study comparing BRUKINSA to ibrutinib in patients with relapsed or refractory (R/R) or treatment-naïve WM. The primary endpoint was proportion of patients achieving complete response or very good partial response (CR+VGPR). Patients with MYD88 mutations were assigned to cohort 1 and randomized 1:1 to receive BRUKINSA 160 mg twice daily or ibrutinib 420 mg once daily. Patients without MYD88 mutations were assigned to cohort 2 and received BRUKINSA160 mg twice daily. A total of 229 patients were enrolled in the trial, with 130 patients receiving BRUKINSA and 99 patients receiving ibrutinib.

As assessed by an independent review committee (IRC) based on the modified Sixth International Workshop on Waldenström Macroglobulinemia (IWWM-6) response criteria (Treon 2015), the combined rate of complete response (CR) and very good partial response (VGPR) in the overall intention-to-treat (ITT) population was 28% with BRUKINSA (95% CI: 20, 38), compared to 19% with ibrutinib (95% CI: 12, 28). While this difference was not statistically significant (p=0.09), BRUKINSA did achieve numerically higher VGPR rates and trends towards increased response quality.

In the ASPEN trial, BRUKINSA demonstrated a more favorable safety profile compared to ibrutinib with lower frequency of certain adverse events, including atrial fibrillation or flutter (2% vs. 15%) and major hemorrhage (6% vs. 9%). Of the 101 patients with WM treated with BRUKINSA, 4% of patients discontinued due to adverse events, and adverse events leading to dose reduction occurred in 14% of patients.

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 overall response rate (ORR) assessed by independent central review (ICR) according to Lugano classification. Select secondary endpoints include investigator-assessed ORR, ICR-reviewed and investigator-assessed duration of response (DOR) and progression-free survival (PFS), overall survival (OS), ICR- and investigator-assessed CR and complete metabolic response (CMR) rate. A total of 217 patients were enrolled in the trial, with 145 patients receiving BRUKINSA plus obinutuzumab and 72 patients receiving obinutuzumab.

About BRUKINSA (zanubrutinib)

BRUKINSA (zanubrutinib) 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 supported by a broad clinical program which includes more than 3,900 subjects in 35 trials across 28 markets. To date, BRUKINSA has received more than 20 approvals covering nearly 50 countries and regions, including the United States, China, the EU, Great Britain, Canada, Australia, and additional international markets. Currently, more than 40 additional regulatory submissions are in review around the world.

U.S. INDICATIONS and IMPORTANT SAFETY INFORMATION

INDICATIONS

BRUKINSA is a kinase inhibitor indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.
This indication is 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.

BRUKINSA is indicated for the treatment of adult patients with Waldenström’s macroglobulinemia (WM).
BRUKINSA is indicated for the treatment of adult patients with relapsed or refractory marginal zone lymphoma (MZL) who have received at least one anti-CD20-based regimen.
This indication is 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.

Please see full Prescribing Information including Patient Information.

IMPORTANT SAFETY INFORMATION

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 events 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, were reported 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.

BeiGene Oncology

BeiGene is committed to advancing best- and first-in-class clinical candidates internally or with like-minded partners to develop impactful and affordable medicines for patients across the globe. We have a growing R&D and medical affairs team of approximately 2,900 colleagues dedicated to advancing more than 100 clinical trials that have involved more than 16,000 subjects. Our expansive portfolio is directed predominantly by our internal colleagues supporting clinical trials in more than 45 countries and regions. Hematology-oncology and solid tumor targeted therapies and immuno-oncology are key focus areas for the Company, with both mono- and combination therapies prioritized in our research and development. BeiGene currently has three approved medicines discovered and developed in our own labs: BTK inhibitor BRUKINSA in the U.S., China, the European Union, Great Britain, Canada, Australia, and additional international markets; and the non-FC-gamma receptor binding anti-PD-1 antibody tislelizumab as well as the PARP inhibitor pamiparib in China.

On June 10, 2022 NuCana plc (NASDAQ: NCNA) reported that data to be presented at the European Hematology Association (EHA) (Free EHA Whitepaper) 2022 Hybrid Congress highlighting the activity of NUC-7738, a phosphoramidate transformation of 3’-deoxyadenosine (3’-dA), in a broad range of Acute Myeloid Leukemia (AML) cell lines. NUC-7738 has already shown promise as monotherapy in patients with solid tumors in a Phase 1/2 study (NuTide:701) and will also be combined with a PD-1 checkpoint inhibitor (Press release, Nucana BioPharmaceuticals, JUN 10, 2022, View Source [SID1234615873]).

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The data at EHA (Free EHA Whitepaper) 2022 show that NUC-7738 can suppress the expansion and survival of AML cells by reducing β-catenin signaling, a key pathway in AML. NUC-7738’s effect was observed in multiple different AML cell lines suggesting broad therapeutic potential. Furthermore, it was observed that NUC-7738 resulted in a reduction of the cells that are resistant to standard chemotherapy drugs and thought to be responsible for disease relapse.

These findings, combined with the anti-cancer activity and favorable safety profile of NUC-7738 observed in the NuTide:701 study provide a strong rationale for the evaluation of NUC-7738 in patients with leukemia.

The details of NuCana’s poster presentation at EHA (Free EHA Whitepaper) are as follows:

Title: NUC-7738 regulates β-catenin signaling resulting in reduced proliferation and self-renewal of AML cells
Abstract Number: P459
Presentation Date & Time: Friday June 10, 2022 from 16:30-17:45 CEST (e-poster online at 9:00 CEST)
Presenting Author: Akbar M. Shahid

Hugh S. Griffith, NuCana’s Founder and Chief Executive Officer said: "NUC-7738 has entered Phase 2 development in patients with solid tumors and we have been encouraged by the clinical activity and favorable safety profile we have observed. The data presented at EHA (Free EHA Whitepaper) indicate that NUC-7738 may have applications beyond solid tumors and we are currently evaluating the optimal pathway for NUC-7738’s development for the treatment of hematologic malignancies."

About NUC-7738
NUC-7738 is a ProTide transformation of 3′-deoxyadenosine (3′-dA), also known as cordycepin. 3’-dA has demonstrated potent anti-cancer activity in non-clinical studies, but has not been successfully developed as an anti-cancer agent due to its rapid breakdown by adenosine deaminase (ADA). NUC-7738 is designed to generate the active anti-cancer metabolite of 3’-dA directly inside cancer cells, thus overcoming 3’-dA’s key limitations of breakdown, transportation and activation. The cytotoxic effect of NUC-7738 is largely attributed to the generation of the main active anti-cancer metabolite, 3′-dATP. Primarily, 3′-dATP interferes with RNA polyadenylation, causing changes in the expression of genes involved in metabolism, differentiation, and apoptosis, ultimately leading to metabolic stress, cessation of cancer-cell growth and cell death.

On June 10, 2022 The Janssen Pharmaceutical Companies of Johnson & Johnson reported that updated efficacy and safety results from the teclistamab cohort of the Phase 1b TriMM-2 study (NCT04108195) (Press release, Johnson & Johnson, JUN 10, 2022, View Source [SID1234615890]).1 Teclistamab, an investigational, off-the-shelf, T-cell redirecting bispecific antibody targeting B-cell maturation antigen (BCMA) and CD3 on T-cells, is being studied in combination with the anti-CD38 monoclonal antibody, DARZALEX (daratumumab) subcutaneous (SC) formulation, in patients with relapsed or refractory multiple myeloma (RRMM) who have received three or more prior lines of therapy.1 Patients in the study, including a high proportion with prior anti-CD38 monoclonal antibody exposure, achieved encouraging overall response rates (ORR) with this combination treatment.1 These data will be presented at the 2022 European Hematology Association (EHA) (Free EHA Whitepaper) Annual Congress as an oral presentation on Sunday, 12 June (Abstract S188).

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At a median follow-up of 8.6 months (range, 0.3-19.6), 76.5 percent (39/51) of response-evaluable patients enrolled in the study achieved a response, including 36 patients (70.6 percent) who achieved a very good partial response (VGPR) or better.1 In patients with prior anti-CD38 exposure, an ORR of 73.7 percent was achieved.1 The median time to first confirmed response was one month, and responses remained durable and deepened over time.1 At the analysis cut-off, 66.7 percent of patients who achieved a response (26/39) were alive and continuing on therapy.1

"Responders to the combination of teclistamab plus subcutaneous daratumumab included patients with prior exposure to BCMA or anti-CD38 targeted agents, which is encouraging," said Paula Rodríguez-Otero†, M.D., Ph.D., Department of Hematology, Clínica Universidad de Navarra, Pamplona, Spain and principal study investigator. "These data also suggest this steroid-sparing regimen may lead to a clinically efficacious regimen in highly refractory patients."

The open-label, multicentre, multicohort Phase 1b TriMM-2 study is investigating the safety and efficacy of teclistamab in combination with daratumumab SC for patients with RRMM.1 Enrolled patients received a median of five prior lines of therapy, 58.5 percent were triple-class refractory, 30.8 percent were penta-drug refractory, and 63.1 percent were refractory to anti-CD38 treatment.1 Eighty percent of patients were refractory to their last line of therapy.1

As of April 6, 2022, 65 patients received daratumumab SC 1,800mg at the approved schedule plus teclistamab 1.5mg/kg weekly (QW) or 3mg/kg every other week (Q2W) subcutaneously.1 Pre-medications, including steroids, were limited to the two step-up doses and the first full dose of teclistamab.1 Treatment with the combination regimen were tolerable and no unexpected or overlapping toxicities were observed.1 The most common adverse events (AEs) were cytokine release syndrome (CRS) (67.7 percent, all Grade 1 or 2); neutropenia (49.2 percent, 41.5 percent Grade 3 or 4); and anaemia (41.5 percent, 27.7 percent Grade 3 or 4).1 One patient (two percent) had Grade 1 immune effector cell–associated neurotoxicity syndrome (ICANS) which fully resolved.1 Infections were experienced by 67.7 percent of patients (27.7 percent Grade 3 or 4).1 Four patients died from AEs, all unrelated to teclistamab or daratumumab SC treatment.1

"For nearly 20 years, we have been committed to overcoming multiple myeloma and an important part of our strategy is to continue to invest and develop complementary and combinable regimens that improve outcomes for patients and their caregivers," said Edmond Chan MBChB M.D. (Res), EMEA Therapeutic Area Lead Haematology, Janssen-Cilag Limited. "Daratumumab has become a foundational therapy for multiple myeloma, and it is exciting to see how we can continue to grow its potential through combinations with novel treatments."

Pharmacodynamic analyses demonstrate that the combination upregulates CD38+/CD8+ T-cells and proinflammatory cytokines, suggesting the potential for complementary activity.1 Additional studies are needed to fully understand the potential clinical benefit of this biological activity.

The efficacy and pharmacodynamic profile of teclistamab in combination with daratumumab SC in patients refractory to anti-CD38 therapy suggest that higher response rates may be observed in patients with anti-CD38 naïve or sensitive disease who are enrolling in the MajesTEC-3 study (NCT05083169).1,2 The ongoing Phase 3 MajesTEC-3 study compares the efficacy of the teclistamab-daratumumab combination with daratumumab SC in combination with pomalidomide and dexamethasone (DPd) or daratumumab SC in combination with bortezomib and dexamethasone (DVd).2 Patients in the trial must have received one to three prior lines of therapy including a proteasome inhibitor (PI) and lenalidomide; patients who have received only one prior line of therapy must be refractory to lenalidomide.2 Patients who have progressed on or within 60 days of the last dose of lenalidomide given as maintenance therapy are also included.2

"These data suggest the potential of a fully immune-based regimen for patients with heavily pretreated multiple myeloma," said Yusri Elsayed, M.D., M.HSc., Ph.D., Vice President, Disease Area Leader, Hematologic Malignancies, Janssen Research & Development, LLC. "We are committed to the ongoing development of this combination and other treatments for patients who remain in need of new options."

#ENDS#

About Teclistamab
Teclistamab is an investigational, fully humanised, T-cell redirecting, IgG4 bispecific antibody targeting both BCMA (B-cell maturation antigen) and CD3, on T-cells.1 BCMA is expressed at high levels on multiple myeloma cells.3,4,5,6,7 Teclistamab redirects CD3-positive T-cells to BCMA-expressing myeloma cells to induce killing of tumor cells.8

Teclistamab is currently being evaluated in several monotherapy and combination studies.9,10,11,12,13 In 2020, the European Commission (EC) and the United Stated (U.S.) Food and Drug Administration (FDA) both granted teclistamab Orphan Drug Designation for the treatment of multiple myeloma. In January 2021 and June 2021, teclistamab received a PRIority MEdicines (PRIME) designation by the European Medicines Agency (EMA) and Breakthrough Therapy Designation (BTD) by the U.S. FDA, respectively. PRIME offers enhanced interaction and early dialogue to optimise drug development plans and speed up evaluation of cutting-edge, scientific advances that target a high unmet medical need.14 The FDA grants BTD to expedite the development and regulatory review of an investigational medicine that is intended to treat a serious or life-threatening condition based on preliminary clinical evidence that demonstrates the drug may have substantial improvement in at least one clinically significant endpoint over available therapy.15 In December 2021, Janssen submitted a Biologics License Application (BLA) to the FDA seeking approval of teclistamab for the treatment of patients with RRMM; a marketing authorisation application (MAA) was submitted to the EMA for teclistamab approval in January 2022.

About daratumumab and daratumumab SC
Janssen is committed to exploring the potential of daratumumab for patients with multiple myeloma across the spectrum of the disease. Daratumumab has been approved in eight indications for multiple myeloma, three of which are in the frontline setting, including newly diagnosed patients who are transplant eligible and ineligible.16

In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement, which granted Janssen an exclusive license to develop, manufacture and commercialise daratumumab. Since launch, daratumumab has become a foundational therapy in the treatment of multiple myeloma, having been used in the treatment of more than 274,000 patients worldwide.17 Daratumumab is the only CD38-directed antibody approved to be given subcutaneously to treat patients with multiple myeloma. Daratumumab SC is co-formulated with recombinant human hyaluronidase PH20 (rHuPH20), Halozyme’s ENHANZE drug delivery technology.18

CD38 is a surface protein that is present in high numbers on multiple myeloma cells, regardless of the stage of disease.16 Daratumumab binds to CD38 and inhibits tumour cell growth causing myeloma cell death.16 Daratumumab may also have an effect on normal cells.16 Data across eight Phase 3 clinical trials, in both the frontline and relapsed settings, have shown that daratumumab based regimens resulted in significant improvement in PFS and/or OS.19,20,21,22,23,24,25,26

For further information on daratumumab, please see the Summary of Product Characteristics at: View Source

About Multiple Myeloma
Multiple myeloma is an incurable blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow.27 In multiple myeloma, cancerous plasma cells change and grow out of control.27 In Europe, more than 50,900 people were diagnosed with multiple myeloma in 2020, and more than 32,500 patients died.28 While some patients with multiple myeloma initially have no symptoms, most patients are diagnosed due to symptoms, which can include bone fracture or pain, low red blood cell counts, tiredness, high calcium levels or kidney failure.29