On December 11, 2021 BeiGene (NASDAQ: BGNE; HKEX: 06160), a global, science-driven biotechnology company focused on developing innovative and affordable medicines to improve treatment outcomes and access for patients worldwide, reported results from a planned interim analysis of the Phase 3 SEQUOIA trial in patients with treatment-naïve (TN) chronic lymphocytic leukemia (CLL), including the randomized Cohort 1 comparing BRUKINSA to bendamustine plus rituximab (B+R) and Cohort 3 (Arm D) of BRUKINSA in combination with venetoclax in patients with deletion of chromosome 17p (del[17p]) and/or pathogenic TP53 variants (Press release, BeiGene, DEC 11, 2021, View Source [SID1234596858]). These data were reported in two oral presentations at the 63rd American Society for Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

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"In the positive SEQUOIA trial, BRUKINSA delivered the therapeutic promise of a selective BTK inhibitor as a frontline treatment for CLL patients, with demonstrated superiority over chemoimmunotherapy. These robust data, along with the results from our previously reported Phase 3 ALPINE trial, strengthen our belief that BRUKINSA could become an important new treatment option for patients with CLL," remarked Jane Huang, M.D., Chief Medical Officer of Hematology at BeiGene. "In addition, BRUKINSA achieved favorable safety advantages in both trials such as lower rates of atrial fibrillation."

"Compared to chemoimmunotherapy, BRUKINSA demonstrated superior PFS benefit for CLL patients receiving frontline treatment, including those harboring high-risk characteristics, such as unmutated IGHV status and del(11q)," said Constantine Tam, MBBS, M.D., Peter MacCallum Cancer Center, and a principal investigator of the study. "Safety findings in SEQUOIA were similar to what has been reported in other BRUKINSA clinical trials, with consistently low rates of atrial fibrillation. Based on these results, BRUKINSA, as a highly selective BTK inhibitor, can potentially provide a chemo-free treatment option for CLL patients."

For more information on BeiGene’s clinical program and company updates, please visit BeiGene’s virtual booth at this year’s ASH (Free ASH Whitepaper) Annual Meeting at View Source

SEQUOIA Cohort 1: BRUKINSA vs. B+R in TN CLL Patients Without del (17p)

Oral Presentation; Abstract #396; Plain language summary available at View Source

A total of 479 patients with TN CLL whose tumor did not exhibit del(17p) were enrolled in Cohort 1 of the SEQUOIA trial, with 241 patients randomized to receive BRUKINSA (Arm A) and 238 patients randomized to receive B+R (Arm B). Patient characteristics were balanced between the two arms, with more than 50% with unmutated IGHV gene and 18% with del(11q) in each. Patients with del(17p) typically have poor response to chemoimmunotherapy and were assigned to receive BRUKINSA treatment in Cohort 2. Results from Cohort 2 were previously presented at the 2020 ASH (Free ASH Whitepaper) Annual Meeting.

The primary endpoint of the SEQUOIA trial is progression-free survival (PFS) per independent review committee (IRC) assessment in the randomized Cohort 1.

At the interim analysis, with a median follow-up of 26.15 months, BRUKINSA demonstrated superiority in PFS over B+R, as assessed by IRC. Results included:

The 24-month PFS rate was 85.5% (95% CI: 80.1, 89.6) in Arm A, compared to 69.5% (95% CI: 62.4, 75.5) in Arm B, with a hazard ratio (HR) of 0.42 (95% CI: 0.27, 0.63), p < 0.0001;
PFS benefit was consistently observed across key patient subgroups, including patients with del(11q), unmutated IGHV status, Binet stage C, and bulky disease; and
Overall survival (OS) results were early, and at 24 months, OS probability was similar between two arms, with 94.3% (95% CI: 90.4, 96.7) in Arm A and 94.6% (95% CI: 90.6, 96.9) in Arm B.
Safety analysis was based on 240 patients in Arm A and 227 patients in Arm B who received at least one dose of respective treatment. BRUKINSA was generally well tolerated with a safety profile consistent with its broad clinical program, including a low rate of atrial fibrillation. Results included:

224 patients (93.3%) in Arm A experienced at least one adverse event (AE) of any grade, with the most common (≥12%) being contusion (19.2%), upper respiratory tract infection (17.1%), neutropenia (15.4%), diarrhea (13.8%), and arthralgia (13.3%);
In comparison, 218 patients (96.0%) in Arm B experienced at least one AE of any grade, with the most common (≥12%) being neutropenia (56.8%), nausea (32.6%), pyrexia (26.4%), rash (19.4%), anemia (18.9%), constipation (18.9%), infusion-related reaction (18.9%), fatigue (15.9%), vomiting (14.5%), thrombocytopenia (13.7%), and diarrhea (13.2%);
126 patients (52.5%) in Arm A experienced at least one Grade ≥3 AE, compared to 181 patients (79.7%) in Arm B, with the most common in both arms being neutropenia (11.3% in Arm A vs. 51.1% in Arm B) and thrombocytopenia (1.7% in Arm A vs. 7.0% in Arm B);
88 patients (36.7%) in Arm A experienced at least one serious AE, compared to 113 patients (49.8%) in Arm B;
AEs leading to dose reduction, interruption or delay, and discontinuation occurred in 18 patients (7.5%), 111 patients (46.3%), and 20 patients (8.3%), respectively, in Arm A, compared to 84 patients (37.4%), 154 patients (67.8%), and 31 patients (13.7%), respectively, in Arm B;
Fatal AEs were reported in 11 patients (4.6%) in Arm A, compared to 11 patients (4.8%) in Arm B;
AEs of interest of any grade included anemia (Arm A vs. Arm B: 4.6% vs. 19.4%), arthralgia (13.3% vs. 8.8%), atrial fibrillation (3.3% vs. 2.6%), bleeding (45.0% vs. 11.0%), diarrhea (13.8% vs. 13.7%), hypertension (14.2% vs. 10.6%), infections (62.1% vs. 55.9%), myalgia (3.8% vs. 1.3%), neutropenia (15.8% vs. 56.8%), other cancers (12.9% vs. 8.8%), and thrombocytopenia (4.6% vs. 17.6%).
In addition, efficacy results with an extended follow-up from Cohort 2 (Arm C) of BRUKINSA as a monotherapy in patients with del(17p) were reported at ASH (Free ASH Whitepaper). With a median follow-up of 30.5 months, the 24-month PFS rate was 88.9% (95% CI: 81.3, 93.6).

Summary of SEQUOIA Cohort 1 Interim Analysis

SEQUOIA Cohort 1

Summary

BRUKINSA

(n=241)

Bendamustine + Rituximab

(n=238)

Efficacy Results

IRC-Assessed

24-month PFS (Primary Endpoint)

85.5%

(95% CI: 80.1, 89.6)

69.5%

(95% CI: 62.4, 75.5)

Hazard Ratio=0.42 (95%CI: 0.27, 0.63)

2-sided p <0.0001

Overall Safety Results

AEs of any grade

93.3%

96.0%

Grade ≥3 AEs

52.5%

79.7%

Serious AEs

36.7%

49.8%

AEs leading to dose reduction

7.5%

37.4%

AEs leading to dose interruption or delay

46.3%

67.8%

AEs leading to treatment discontinuation

8.3%

13.7%

Fatal AEs

4.6%

4.8%

Adverse Events of Interest (Any Grade)

Anemia

4.6%

19.4%

Neutropenia

15.8%

56.8%

Thrombocytopenia

4.6%

17.6%

Arthralgia

13.3%

8.8%

Atrial fibrillation

3.3%

2.6%

Bleeding

45.0%

11.0%

Diarrhea

13.8%

13.7%

Hypertension

14.2%

10.6%

Infections

62.1%

55.9%

Myalgia

3.8%

1.3%

Other cancers

12.9%

8.8%

SEQUOIA Cohort 3 (Arm D): BRUKINSA + Venetoclax in TN CLL Patients with del(17p) and/or TP53 Mutations

Oral Presentation; Abstract #67

Cohort 3 of SEQUOIA was designed to examine the hypothesis that the addition of venetoclax to BRUKINSA can drive tumors into deeper remission. Building on the demonstrated efficacy and safety of BRUKINSA in Cohort 2, Cohort 3 is planned to enroll approximately 80 patients with TN CLL whose tumor exhibits del(17p) or TP53 mutations, with key endpoints being safety, overall response rate (ORR), PFS, and duration of response (DoR). These patients will receive BRUKINSA treatment at 160 mg twice daily for three months, followed by combination treatment of BRUKINSA at the same dosing and venetoclax with a ramp-up dosing to 400 mg once daily for 12 to 24 cycles until progressive disease, unacceptable toxicity, or confirmed undetectable measurable residual disease (uMRD).

"Unfavorable prognosis is often seen in CLL patients with del(17p) or pathogenic TP53 variants, even in the front-line setting. While the follow-up in Cohort 3 was relatively short, the high response rate and the deepened responses observed among those treated for longer periods suggested the potential of BRUKINSA in combination with venetoclax in these high-risk CLL patients. The combination treatment also appeared generally well tolerated," commented Alessandra Tedeschi, M.D., Grande Ospedale Metropolitano Niguarda in Italy, a principal investigator on the study. "We look forward to the continued evaluation of BRUKINSA in combination with venetoclax in untreated CLL patients with del(17p) or TP53 mutations."

At the data cutoff on September 7, 2021, 49 patients were enrolled in Cohort 3, including 46 patients (93.9%) with centrally confirmed positive del(17p) status and three patients (6.1%) with a pathogenic TP53 variant alone. Patients enrolled in Cohort 3 also exhibited other markers of high risk, including 87.8% with unmutated IGHV, 91.9% with concurrent TP53 mutation, and 83.3% with complex karyotype (at least three abnormalities).

With a short median follow-up of 12.0 months, a high ORR was observed in the 36 patients who had at least one post-baseline response evaluation by the data cutoff date. Preliminary efficacy results per investigator assessment included:

Of the 14 patients who received combination treatment for more than 12 months, five patients (36%) achieved a confirmed complete response (CR) or CR with incomplete bone marrow recovery (CRi) in a bone marrow assessment and four additional patients met the criteria for CR or CRi but not confirmed in bone marrow assessment due to COVID-19 restrictions; and
In all 36 patients evaluable for efficacy, the ORR was 97.2% (95% CI: 85.5, 99.9) and the CR/CRi rate was 13.9% (all CRs or CRis were in patients who received combination treatment for more than 12 months).
With a median follow-up of 7.9 months, safety results in all 49 enrolled patients included:

40 patients (81.6%) experienced at least one AE of any grade, with the most common (≥12%) being infections (16.3%), neutropenia (14.3%), bruising (12.2%), diarrhea (12.2%), minor bleeding (12.2%), and nausea (12.2%);
16 patients (32.7%) experienced at least one Grade ≥3 AE and four patients (8.2%) experienced at least one serious AE;
AEs leading to dose interruption, dose reduction, and treatment discontinuation occurred in 10 patients (20.4%), no patients (0.0%), and one patient (2.0%), respectively; and
One patient (2.0%) experienced a fatal AE.
With a median follow-up of 13.5 months, safety results in the 34 patients who received combination treatment included:

29 patients (85.3%) experienced at least one AE of any grade, with the most common (≥12%) being infections (23.5%), neutropenia (20.6%), diarrhea (14.7%), fatigue (14.7%), nausea (14.7%), and bruising (11.8%);
13 patients (38.2%) experienced at least one Grade ≥3 AE and three patients (8.8%) experienced at least one serious AE; and
AEs leading to dose interruption occurred in 10 patients (29.4%), with no AEs leading to dose reduction or treatment discontinuation.
About SEQUOIA

SEQUOIA is a randomized, multicenter, global Phase 3 trial (NCT03336333) designed to evaluate the efficacy and safety of BRUKINSA compared to B+R in patients with TN CLL or SLL. The trial consists of three cohorts:

Cohort 1 (n=479): randomized 1:1 to receive BRUKINSA (n=241) or B+R (n=238) until disease progression or unacceptable toxicity, in patients not harboring del(17p); data from this group comprise the primary endpoint;
Cohort 2 (n=110): patients with del(17p) receiving BRUKINSA as a monotherapy; and
Cohort 3 (enrollment ongoing): patients with del(17p) or pathogenic TP53 variant receiving BRUKINSA in combination with venetoclax.
Patients with del(17p) were not randomized to B+R, as they experience poor clinical outcomes and poor response to chemoimmunotherapy. The primary endpoint of the trial is IRC-assessed PFS. Secondary endpoints include investigator-assessed PFS, IRC- and investigator-assessed overall response rate (ORR), overall survival (OS), PFS and ORR in patients with del(17p), and safety.

Cohort 2 (Arm C), representing high-risk patients treated with BRUKINSA monotherapy, was previously presented at the American Society for Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in December 2020. This cohort of patients with del(17p) achieved significant efficacy with an 18-month PFS of 90.6%, as assessed by investigator.

About Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults, with a global incidence of approximately 114,000 new cases in 2017.1,2 CLL affects white blood cells or lymphocytes in the bone marrow.1 Proliferation of cancer cells (leukemia) in the marrow result in reduced ability to fight infection and spread into the blood, which affects other parts of the body including the lymph nodes, liver and spleen.1,3 The BTK pathway is a known route that signals malignant B cells and contributes to the onset of CLL.4 Small lymphocytic lymphoma (SLL) is a non-Hodgkin’s lymphoma affecting the B-lymphocytes of the immune system, which shares many similarities to CLL but with cancer cells found mostly in lymph nodes.5

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 has received 12 approvals covering 40 countries 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);
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);
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)*;
For the treatment of adult patients with MCL who have received at least one previous therapy (Singapore, October 2021);
For the treatment of MCL in patients who have received at least one prior therapy (Israel, October 2021);
For the treatment of adult patients with WM who have received at least one prior therapy, or in first line treatment for patients unsuitable for chemo-immunotherapy (Australia, October 2021);
For the treatment of adult patients with MCL who have received at least one prior therapy (Australia, October 2021);
For the treatment of adult patients with MCL who have received at least one previous therapy (Russia, October 2021);
For the treatment of adult patients with MCL who have received at least one previous therapy (Saudi Arabia, November 2021); and
For the treatment of adult patients with WM who have received at least one prior therapy or first-line treatment of patients unsuitable for chemo-immunotherapy (European Union plus Iceland and Norway, November 2021).
To date, more than 20 marketing authorization applications have been submitted for BRUKINSA for various indications.

* 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.

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

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 team of approximately 2,750 colleagues dedicated to advancing more than 90 ongoing or planned clinical trials that have involved more than 14,000 patients and healthy volunteers. 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, 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 and Bristol Myers Squibb. We also plan to address greater areas of unmet need globally through our collaborations including with Amgen, Bio-Thera, EUSA Pharma, Mirati Therapeutics, Seagen, and Zymeworks. BeiGene has also entered into a collaboration with Novartis granting Novartis rights to develop, manufacture, and commercialize tislelizumab in North America, Europe, and Japan.

On December 11, 2021 The Janssen Pharmaceutical Companies of Johnson & Johnson reported longer-term results from the Phase 1b/2 CARTITUDE-1 study evaluating the efficacy and safety of ciltacabtagene autoleucel (cilta-cel), an investigational B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell (CAR-T) therapy administered as a single infusion, in the treatment of patients with relapsed and/or refractory multiple myeloma (Press release, Johnson & Johnson, DEC 11, 2021, View Source [SID1234596856]).1 The data, featured as an oral presentation at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2021 Annual Meeting (Abstract #549) and selected as part of the Highlights of ASH (Free ASH Whitepaper) programme, show that patients receiving cilta-cel demonstrate deep and durable responses, with a very high overall response rate (ORR) of 98 percent.1

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Responses in the 97 patients treated with cilta-cel deepened over time, with 83 percent of patients achieving a stringent complete response (sCR) at median 22-month follow-up, an increase from 80 percent at the 18-month median follow-up data presented at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, and from 67 percent at the 12.4-month median follow-up data presented at ASH (Free ASH Whitepaper) 2020.1,2,3 At median follow-up of 22 months, median progression-free survival (PFS) and median overall survival (OS) were not reached, suggesting long-term durability of responses and survival for patients.1 Two-year PFS and OS rates were 61 percent (95 percent Confidence Interval [CI], 48.5–70.4) and 74 percent (95 percent CI, 61.9–82.7), respectively.1 Among 61 minimal residual disease (MRD) evaluable patients, 92 percent of patients achieved MRD negativity (at 10-5).1 The two-year PFS rates in patients who achieved MRD negativity for ≥six and ≥12 months were 91 percent (95 percent CI, 67.1–97.8) and 100 percent, respectively.1

"Unfortunately, patients with multiple myeloma for whom at least three treatment regimens have stopped working, face a median survival of less than a year with currently available treatments," said Thomas Martin, M.D.,* Director of Clinical Research, Clinical Professor of Medicine, Adult Leukemia and Bone Marrow Transplantation Program, Associate Director, Myeloma Program and Co-Leader, Hematopoietic Malignancies Program, at UCSF Helen Diller Family Comprehensive Cancer Center, and principal study investigator. "The CARTITUDE-1 data presented at ASH (Free ASH Whitepaper) 2021 builds upon previous results that show that a single infusion of cilta-cel resulted in durable responses and survival across the study population, further supporting the potential of cilta-cel in offering patients and physicians a valuable new treatment option."

Median time to first response was one month (range, 0.9–10.7), with responses deepening over time.1 Additionally, median time to best response was 2.6 months (range, 0.9–17.8) and median time to complete response or better was 2.9 months (range, 0.9–17.8).1 Twelve percent of patients achieved a very good partial response and three percent achieved a partial response.1 The study included patients who received a median of six prior treatment regimens (range, 3–18).1 All patients were triple-class [immunomodulatory agent (IMiD), proteasome inhibitor (PI) and an anti-CD38 antibody] exposed, while 42 percent of patients were penta-drug refractory and 99 percent of patients were refractory to the last line of therapy.1

"These data add to the growing body of evidence supporting the potential clinical benefit of cilta-cel in the treatment of patients with relapsed and/or refractory multiple myeloma, a population in need of new options," said Sen Zhuang, M.D., Ph.D., Vice President, Clinical Research and Development, Janssen Research & Development, LLC. "We look forward to further evaluation of cilta-cel as part of our comprehensive CARTITUDE clinical development programme that includes studying cilta-cel in patients with newly diagnosed multiple myeloma."

The data demonstrated a consistent safety profile for cilta-cel and no new safety signals were observed with longer follow-up.1 In 18-month follow-up data presented at ASCO (Free ASCO Whitepaper) 2021, the most common haematologic adverse events (AEs) observed were neutropenia (96 percent); anaemia (81 percent); thrombocytopenia (79 percent); leukopenia (62 percent); and lymphopenia (53 percent).2 At 18 months, cytokine release syndrome (CRS) of any grade was observed in 95 percent of patients with a median duration of four days (range, 1–97), and 99 percent of which resolved within 14 days of onset.2 Of the 92 patients with CRS at 18-month follow-up, 95 percent experienced grade 1/2 events.2 Neurotoxicity of any grade was observed in 21 percent (n=20) of patients at 18 months, with grade 3 or higher neurotoxicity observed in 10 percent (n=10) of patients.2 There were no new events of cilta-cel–related neurotoxicity or movement and neurocognitive treatment (MNT) emergent adverse events reported in CARTITUDE-1 since the median 12.4-month follow-up data were presented at ASH (Free ASH Whitepaper) 2020.1,3 At the 22-month data cut-off, more than 200 patients have been dosed with cilta-cel across the CARTITUDE clinical development programme and MNT incidence has decreased to less than one percent since the implementation of MNT mitigation measures.1

"We are pleased that we are again able to present longer-term follow-up data, this time at nearly two years, for this innovative potential treatment for people living with relapsed/refractory multiple myeloma." said Edmond Chan MBChB M.D. (Res), EMEA Therapeutic Area Lead Haematology, Janssen-Cilag Limited. "The sustained efficacy and consistent safety profile build on the strong results seen to date and may bring us one step closer to changing the expectations of what a multiple myeloma diagnosis means for patients."

Subgroup Analysis of the Phase 1b/2 CARTITUDE-1 Study
In the abstract accepted for presentation at ASH (Free ASH Whitepaper) 2021, data demonstrated that cilta-cel resulted in deep, durable responses in all evaluated subgroups in CARTITUDE-1 at median follow-up of 18 months.4 An ORR range of 95 to 100 percent was observed in patients across all subgroups, including those with high-risk cytogenetics, International Staging System (ISS) stage III multiple myeloma, baseline bone marrow cells ≥60 percent, and presence of baseline plasmacytomas.4 In patients with ISS stage III, high risk cytogenetics and with baseline plasmacytomas, median duration of response appeared shorter and 18-month PFS and OS rates lower.4 The cilta-cel safety profile across the subgroups was consistent with the overall population, with no new safety signals.4 The latest data from this analysis will be presented in a poster presentation (Abstract #3938) at ASH (Free ASH Whitepaper) 2021 on Monday, December 13.4

# ENDS #

About CARTITUDE-1
CARTITUDE-1 (NCT03548207)5 is an ongoing Phase 1b/2, open-label, multicentre study evaluating the safety and efficacy of cilta-cel in adults with relapsed and/or refractory multiple myeloma, 99 percent of whom were refractory to the last line of treatment; 88 percent of whom were triple-class refractory, meaning their cancer did not respond, or no longer responds, to an immunomodulatory agent (IMiD), a proteasome inhibitor (PI) and an anti-CD38 antibody.1

The primary objective of the Phase 1b portion of the study, involving 29 patients, was to characterise the safety and confirm the dose of cilta-cel, informed by the first-in-human study with LCAR-B38M CAR-T cells (LEGEND-2).1,5,6 Based on the safety profile observed in this portion of the study, outpatient dosing is being evaluated in additional CARTITUDE studies. The Phase 2 portion of the study, involving 68 additional patients, is evaluating the efficacy of cilta-cel with overall response as the primary endpoint.1,5

About Ciltacabtagene Autoleucel (cilta-cel)
Cilta-cel is an investigational chimeric antigen receptor T-cell (CAR-T) therapy that is being studied in a comprehensive clinical development programme for the treatment of patients with relapsed or refractory multiple myeloma and in earlier lines of treatment.1 The design consists of a structurally differentiated CAR-T with two BCMA-targeting single domain antibodies.1 In December 2017, Janssen Biotech, Inc. (Janssen) entered into an exclusive worldwide license and collaboration agreement with Legend Biotech to develop and commercialise cilta-cel.7

In April 2021, Janssen announced its submission of a Marketing Authorisation Application (MAA) to the European Medicines Agency seeking approval of cilta-cel for the treatment of patients with relapsed and/or refractory multiple myeloma.8 In December 2020, Janssen announced initiation of a rolling submission of its Biologics License Application (BLA) to the United States (U.S.) Food and Drug Administration (FDA) for cilta-cel.9 In addition to U.S. Breakthrough Therapy Designation in December 2019, cilta-cel received a PRIority MEdicines (PRiME) designation from the European Commission in April 2019, and a Breakthrough Therapy Designation in China in August 2020.10,11 Janssen also received Orphan Drug Designation for cilta-cel from the European Commission in February 2020.12

About Multiple Myeloma
Multiple myeloma is currently an incurable blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow.13 When damaged, these plasma cells rapidly spread and replace normal cells with tumors in the bone marrow.13 In Europe, more than 50,900 people were diagnosed with multiple myeloma in 2020, and more than 32,500 patients died.14 While some patients with multiple myeloma 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, kidney problems or infections.15

On December 11, 2021 Epizyme, Inc. (Nasdaq: EPZM), a fully integrated, commercial-stage biopharmaceutical company developing and delivering transformative therapies against novel epigenetic targets, reported that preclinical data and the Phase 1/1b trial design for EZM0414, the Company’s novel, first-in-class, oral SETD2 inhibitor, an investigational agent being developed for the treatment of adult patients with relapsed or refractory multiple myeloma (MM) or with diffuse large B-cell lymphoma (DLBCL) (Press release, Epizyme, DEC 11, 2021, View Source [SID1234596855]). The data and the design were presented today at the 2021 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

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The data presented from both in vitro and in vivo preclinical studies (Abstract #1142), demonstrated that targeting SETD2 with EZM0414 resulted in significantly reduced growth of t(4;14) MM cell lines, as well as non-t(4;14) MM and DLBCL cell lines. Additionally, in in vitro studies, EZM0414 showed synergy with MM and DLBCL standard of care and emerging therapies, which supports the potential for the study of EZM0414 in combination with current MM and DLBCL treatments.

"We are excited to share our preclinical data on EZM0414 with the research community at ASH (Free ASH Whitepaper), which highlights its anti-tumor activity in multiple myeloma and DLBCL xenograft models, as well as its in vitro combination activity," said Dr. Jeffery Kutok, MD, PhD, Chief Scientific Officer at Epizyme. "This work has increased our understanding of the potential for EZM0414 in B cell malignancies and formed the basis for our first-in-human studies, beginning with our SET-101 Phase 1/1b trial."

Epigenetic mutations and dependencies have been identified in B cell malignancies, including MM and DLBCL, providing therapeutic rationale for epigenetic inhibitors in these tumor types. Previous data demonstrated that there is broad sensitivity of MM cell lines to SETD2 inhibition, and in particular, t(4;14) MM cell lines, which are dependent on SETD2 due to overexpression of MMSET by the high-risk t(4;14) translocation.

These preclinical data form the basis for SET-101, the Company’s Phase 1/1b clinical study (Abstract #1679), which is designed to evaluate the safety and determine the optimal dose of EZM0414. Under the trial protocol, following the Phase 1 dose ranging portion of the trial, the study will be expanded to evaluate EZM0414 in three patient cohorts: t(4;14) MM, non-t(4;14) MM, and DLBCL.

In the Phase 1 portion of the study, adult patients with relapsed or refractory MM and DLBCL will be enrolled and treated in a Bayesian optimal interval design to evaluate the safety, tolerability, and pharmacokinetics of EZM0414 at six dose levels. Up to 36 patients will be enrolled, and at least nine patients will be evaluated for maximum tolerated dose. At least eight patients, each with t(4;14) MM, non-t(4;14) MM, or DLBCL will be included. The primary endpoints include the safety and tolerability of EZM0414 and the maximum tolerated dose.

The Phase 1b dose expansion portion of the study will include three cohorts, t(4;14) MM, non-t(4;14) MM, and DLBCL, of up to 20 patients each. There will be two interim assessments when clinical data from the first 10 and 15 patients enrolled in each expansion cohort are available. Futility assessments will also be conducted at that time. The final analysis will be performed when all data from the 20 patients in each expansion cohort are available. Primary endpoints include the recommended Phase 2 dose, and secondary endpoints include efficacy and response rates. The trial is currently enrolling patients in the United States and has been screening patients for enrollment.

"There is a significant unmet need for new therapeutic options for patients living with multiple myeloma and DLBCL, which are both very aggressive and difficult-to-treat malignancies," said Dr. Shefali Agarwal, Executive Vice President and Chief Medical and Development Officer at Epizyme. "We are thrilled to bring the first SETD2 inhibitor into the clinic to learn more about its potential in the treatment of these diseases, which is an important milestone for our oncology portfolio. The SET-101 study is open, we’re actively screening patients and we look forward to dosing our first patient and sharing more about EZM0414 as trial data become available."

About EZM0414

EZM0414 is a potent, selective, oral, small molecule, investigational drug agent that inhibits the histone methyltransferase, SETD2, which plays a role in oncogenesis. SETD2 methylates histone as well as non-histone proteins, and this activity is involved in several key biological processes including transcriptional regulation, RNA splicing, and DNA damage repair. Based on the preclinical data on SETD2 inhibition by EZM0414 in multiple settings, including high risk t(4;14) multiple myeloma (MM) and in other B-cell malignancies such as diffuse large B-cell lymphoma (DLBCL), the Company is conducting SET-101, a Phase 1/1b study of EZM0414, for the treatment of adult patients with relapsed or refractory MM and DLBCL.

On December 11, 2021 Aleta Biotherapeutics, a privately held immuno-oncology company focused on transforming cellular therapeutics to allow a broad spectrum of cancer indications to be targeted, reported a summary of ALETA-001 preclinical results from a poster being presented at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, held in Atlanta, Georgia and in a virtual platform on December 11-14, 2021 (Press release, Aleta Biotherapeutics, DEC 11, 2021, View Source [SID1234596854]).

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The presentation featured preclinical data that support the upcoming Phase 1/2 clinical trial of ALETA-001 being run in collaboration with Cancer Research UK. ALETA-001 is a multifunctional biologic for injection that contains an anti-CD20 llama VHH linked to an optimized CD19 protein and further linked to an anti-albumin llama VHH. Extensive preclinical in vitro modeling demonstrated that ALETA-001 specifically binds to CD20-positive/CD19 negative lymphoma cells with high affinity, thereby densely coating these cancer cells with the CD19 protein. In the presence of anti-CD19 CAR T cells, ALETA-001 mediated cytotoxicity against CD19 negative lymphoma cells at sub-nM concentrations. The administration of ALETA-001 and anti-CD19 CAR T cells in vivo eliminated systemic CD19 negative lymphoma that otherwise produced lethal disease at doses of ALETA-001 as low as 0.5mg/kg. Further, upon stopping dosing in the in vivo lymphoma model, 40% of ALETA-001-treated animals did not relapse through day 43, more than 2 weeks after the last dose, suggesting apparent cures. Additionally, excess ALETA-001 did not interfere with cytotoxicity. ALETA-001 is designed to be administered to patients who have received CAR19 T cell therapy and who fail to achieve a complete response at the time of their first clinical evaluation, or who relapse from a complete response thereafter. Clinical trial development is underway in collaboration with Cancer Research UK.

On December 11, 2021 Schrödinger, Inc. (Nasdaq: SDGR), whose physics-based software platform is transforming the way therapeutics and materials are discovered, reported that new preclinical data from its mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) inhibitor program in B-cell lymphomas in a poster session at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition in Atlanta, Georgia (Press release, Schrodinger, DEC 11, 2021, View Source [SID1234596853]). MALT1 is considered a potential therapeutic target for several non-Hodgkin’s B-cell lymphomas as well as chronic lymphocytic leukemia. Schrödinger has identified novel MALT1 inhibitors that demonstrate strong anti-tumor activity across multiple tumor models, including cell- and patient-derived xenograft models, and combination potential with other agents, including standards of care such as ibrutinib.

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"We are pleased that our data strongly underscore the therapeutic potential of our MALT1 inhibitors and present an opportunity to advance a potential best-in-class MALT1 inhibitor into the clinic," said Karen Akinsanya, Ph.D., executive vice president, chief biomedical scientist and head of discovery R&D at Schrödinger. "We are on track to submit the IND for our MALT1 development candidate to the FDA in the first half of 2022."

The data presented suggest that targeting MALT1 may expand therapeutic options for patients with selected B-cell lymphomas, such as activated B-cell (ABC) subtype of diffuse large B cell lymphoma (DLBCL), with the possibility of expanding into other B-cell lymphomas such as mantle cell lymphoma (MCL). Furthermore, these small molecule MALT1 inhibitors demonstrate potential in combination with Bruton’s tyrosine kinase (BTK) inhibitors to overcome drug-induced resistance in patients with relapsed/refractory B-cell lymphomas.

Additional Details About the Study

The presentation, "Characterization of Potent Paracaspase MALT1 Inhibitors for Hematological Malignancies," highlighted preclinical data with multiple lead molecules discovered using Schrodinger’s proprietary physics-based free energy perturbation (FEP+) modeling technology. These molecules demonstrate potent inhibition of MALT1 enzymatic activity and anti-proliferative activity in the ABC-DLBCL cell lines, such as OCI-LY3 and OCI-LY10. In combination with approved agents, these inhibitors demonstrate strong combination potential with Bruton’s tyrosine kinase (BTK) inhibitors such as ibrutinib in ABC-DLBCL cell lines. In ABC-DLBCL cell line-derived xenograft (CDX) models, the company’s representative MALT1 inhibitor induces tumor regression as a single agent and complete tumor regression in combination with ibrutinib. The representative MALT1 inhibitor, when tested in LY2298 patient-derived xenograft (PDX) models, demonstrates similar results. In addition, the representative MALT1 inhibitor was explored in a CDX model derived from a mantle cell lymphoma REC-1 cell line, and demonstrates strong anti-tumor activity of ~78% tumor growth inhibition as a single agent. Taken together, these data strongly underscore the therapeutic potential of Schrödinger’s MALT1 inhibitors and support further evaluation of a potential best-in-class MALT1 inhibitor in clinical trials.