On December 7, 2020 Bristol Myers Squibb (NYSE: BMY) reported data from multiple studies evaluating lisocabtagene maraleucel (liso-cel), an investigational CD19-directed chimeric antigen receptor (CAR) T cell therapy, in relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), in relapsed or refractory mantle cell lymphoma (MCL), and in relapsed or refractory large B-cell lymphoma (LBCL) were presented at the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (Press release, Bristol-Myers Squibb, DEC 7, 2020, View Source [SID1234573350]). The data include longer-term follow-up from the Phase 1 TRANSCEND CLL 004 study in a cohort of patients with relapsed or refractory CLL and SLL treated with liso-cel as monotherapy and initial results from the combination cohort with ibrutinib, and safety and preliminary efficacy results from TRANSCEND NHL 001 in the cohort of patients with relapsed or refractory MCL treated with liso-cel. Additionally, initial results from the OUTREACH study evaluating outcomes of treatment with liso-cel for patients with relapsed or refractory LBCL across inpatient and outpatient settings were presented.

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"In our mission to transform patients’ lives through science, we have established a diverse and comprehensive development program to understand the potential of liso-cel across both aggressive and indolent hematologic malignancies and sites of care," said Noah Berkowitz, M.D., Ph.D., senior vice president, Global Clinical Development, Hematology, Bristol Myers Squibb. "In addition, we continue to advance our cell therapy research to inform potential combination strategies with our CAR T cell therapies to optimize treatment outcomes for patients in need."

Liso-cel in Combination with Ibrutinib and as Monotherapy in CLL/SLL: TRANSCEND CLL 004

In the Phase 1/2 TRANSCEND CLL 004 study, patients with relapsed or refractory CLL and SLL were enrolled in a cohort receiving liso-cel in combination with ibrutinib (Presentation #544). Nineteen patients started or continued ibrutinib treatment for >90 days at enrollment and were evaluated for safety and efficacy following liso-cel treatment.

Seventy-four percent of patients experienced any grade cytokine release syndrome (CRS) with one Grade 3 event. Median time to onset of CRS was 6.5 days (1-13) and median duration of CRS was 6 days (3-13). Any grade neurologic events (NEs) occurred in 32% of patients with three Grade 3 events. Median time to onset of NEs was 8 days (5-12) and median duration of NEs was 6.5 days (1-8).1

With median follow-up of 10 months, liso-cel in combination with ibrutinib demonstrated high rates of response with 18 patients (95%) deriving an overall response, and 12 (63%) achieving a complete response. All responses were achieved by Day 30 following liso-cel treatment and among 18 patients with >6 months of follow-up, 89% maintained or improved their response from Day 30. Of 19 patients evaluable for minimal residual disease (MRD), 17 (89%) achieved undetectable MRD (uMRD) in blood by flow cytometry and 15 (79%) in bone marrow by next-generation sequencing (both with sensitivity 104).1

In a separate cohort of the Phase 1/2 TRANSCEND CLL 004 study, patients with relapsed or refractory CLL, including 83% of patients with high-risk disease, and patients who had progressed on prior therapy with ibrutinib, were enrolled to receive liso-cel as a monotherapy (Presentation #546). At median follow-up of 24 months, 23 patients were evaluable for safety and 22 patients were evaluable for efficacy.

In the 23 patients evaluated for safety, the safety profile for liso-cel was consistent with the known safety profile of liso-cel with no new late or delayed adverse events of concern emerging with longer follow-up. Seventy-four percent of patients experienced any grade CRS, with Grade >3 CRS occurring in 9% of patients. Median time to onset of CRS was three days (1-10) and median duration of CRS was 12 days (2-50). Any grade NEs occurred in 39% of patients, with 22% of patients experiencing Grade >3 NEs. Median time to onset of NEs was four days (2-21) and median duration of NEs was 20.5 days (6-50).2

Among the 22 patients evaluable for efficacy, the overall response rate was 82% (18/22). Complete responses were seen in 46% (10/22) of patients. By Day 30, 68% of patients (n=15) responded to therapy, and 27% had a deepening of response. At 12 months, 50% of patients remained in response and all seven patients who completed the 24-month follow-up maintained their response. The median duration of response was not reached (95% CI: 4.8 – NR) at median follow-up of 24 months and median progression-free survival was 18 months (95% CI: 3.0 – NR).2

"Patients with relapsed or refractory chronic lymphocytic leukemia and small lymphocytic lymphoma are often faced with a difficult treatment journey and many changes in therapy due to relapse," said William G. Wierda, M.D., Ph.D., executive medical director and professor, Department of Leukemia, Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center. "Results from TRANSCEND CLL 004 underscore the potential of liso-cel to deliver rapid, deep and durable responses as a monotherapy in heavily pretreated patients with difficult-to-treat disease and the potential of using liso-cel in combination with ibrutinib to provide high rates of overall response with a very manageable safety profile to address a significant unmet need for this disease."

Safety and Efficacy of Liso-cel in Relapsed or Refractory MCL: TRANSCEND NHL 001

In the TRANSCEND NHL 001 study cohort of patients with relapsed or refractory MCL, including many with highly proliferative disease, 32 patients received liso-cel across dose levels of 50 x 106 CAR positive T cells and 100 x 106 CAR positive T cells (Presentation #118).

Sixteen patients (50%) experienced any grade CRS, including one Grade >3 event. Median time to CRS onset and resolution was six days (2‒10) and four days (2-9), respectively. Eleven patients (34%) experienced any grade NEs, all of which occurred in those who received the higher dose level, including four Grade >3 NEs. Median time to NE onset and resolution was eight days (2-25) and four days (1-27), respectively.3

Preliminary efficacy results showed that treatment with liso-cel resulted in high response rates with 84% of patients responding to treatment and 66% of patients achieving a complete response (CR). Overall, the median time to first complete or partial response was less than one month (0.95; range 0.9-2.0). Median duration of response was not reached with a median follow-up of 3.9 months (0.0-21.3).3

"Mantle cell lymphoma is an aggressive type of non-Hodgkin lymphoma and many patients relapse after initial therapies with limited remaining treatment options," said M. Lia Palomba, M.D., Lymphoma Service and Center for Cellular Therapeutics, Memorial Sloan Kettering Cancer Center. "Initial results of liso-cel in MCL from TRANSCEND NHL 001 demonstrate the potential of this CAR T cell therapy to provide patients with high rates of response, representing a potentially important treatment option for these patients."

Initial Results from the OUTREACH Study of Liso-cel in Relapsed or Refractory Large B-Cell Lymphoma (LBCL) Across Sites of Care

In the Phase 2 OUTREACH study, adults with relapsed or refractory LBCL were treated with liso-cel in the inpatient and outpatient settings at nonuniversity centers (Presentation #1196). The primary endpoint was incidence of Grade >3 CRS based on the Lee grading system, NEs, prolonged cytopenias through day 29 and infections. Secondary endpoints included safety and overall response rate (ORR).

Based on initial results from 46 patients treated with liso-cel (inpatient n=16; outpatient n=30) at data cutoff, patients were successfully treated and monitored in the inpatient and outpatient settings. Any grade CRS was reported in six (37.5%) patients treated in the inpatient setting and 13 (43%) patients treated in the outpatient setting, with no Grade >3 events reported. NEs were reported in five (31%) inpatients and nine (30%) outpatients, with one Grade >3 event in the inpatient group and two in the outpatient group. Median time to onset of CRS and NEs, respectively, was 2.5 (1–3) and 10 (3–16) days for inpatients and five (2–9) and nine (6–14) days for outpatients.4

Among efficacy-evaluable patients (n=44), 75% of inpatients achieved an overall response with 50% of patients achieving a complete response (CR), and 79% of outpatients achieved an overall response with 61% achieving a CR.4

Bristol Myers Squibb: Creating a Better Future for People with Cancer

Bristol Myers Squibb is inspired by a single vision—transforming people’s lives through science. The goal of the company’s cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine, and through innovative digital platforms, are turning data into insights that sharpen their focus. Deep scientific expertise, cutting-edge capabilities and discovery platforms enable the company to look at cancer from every angle. Cancer can have a relentless grasp on many parts of a patient’s life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. Because as a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future.

On December 7, 2020 Incyte (Nasdaq:INCY) reported data from three ongoing Phase 2 studies evaluating parsaclisib, a potent, highly selective, next-generation oral inhibitor of phosphatidylinositol 3-kinase delta (PI3Kδ), for the treatment of patients with relapsed or refractory follicular (CITADEL-203), marginal zone (CITADEL-204) and mantle cell (CITADEL-205) lymphomas (Press release, Incyte, DEC 7, 2020, View Source [SID1234572326]). These data were accepted for presentation at the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (ASH 2020), held virtually from December 5–8, 2020.

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The primary endpoint for the CITADEL-203, -204 and -205 studies is objective response rate (ORR); duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety and tolerability are among the secondary endpoints. All radiology-based endpoints are based on independent review committee (IRC) assessment.

Eligible patients received parsaclisib 20 mg once daily for eight weeks followed by either 20 mg once weekly (weekly-dosing group [WG]) or 2.5 mg once daily (daily-dosing group [DG]). Subsequently, daily dosing was selected as the preferred regimen and patients initially enrolled in the WG were allowed to switch to DG. Data are presented for the DG and all patients.

Key results from the CITADEL studies include:

ORR (95% CI), %

mDOR (95% CI),

months

mPFS (95% CI),

months

mOS (95% CI),

months

CITADEL-203: R/R Follicular Lymphoma

DG (N=95)

75 (65-83)

14.7 (12.0-17.5)

15.8 (13.8-19.1)

–

All (N=118)

73 (64-81)

15.9 (12.0-NE)

15.8 (13.2-19.3)

–

CITADEL-204: R/R Marginal Zone Lymphoma

DG (N=72)

56.9 (44.7-68.6)

NR (8.1-NE)

NR (11.0-NE)

–

All (N=100)

57.0 (46.7-66.9)

12.0 (9.3-NE)

19.4 (13.7-NE)

–

CITADEL-205: R/R Mantle Cell Lymphoma (BTK Inhibitor Treatment Naive)

DG (N=77)

71 (60-81)

9.0 (6.7-14.7)

11.1 (8.3-NE)

NR (NE-NE)

All (N=108)

70 (61-79)

14.7 (7.7-NE)

11.1 (8.3-19.2)

NR (NE-NE)

CITADEL-205: R/R Mantle Cell Lymphoma (Previously Treated with Ibrutinib)

DG (N=41)

29 (16-46)

3.7 (1.9-NE)

3.7 (1.8-4.1)

11.2 (7.9-NE)

All (N=53)

25 (14-38)

3.7 (1.9-NE)

3.7 (1.8-3.9)

11.2 (7.9-17.1)

R/R: relapsed or refractory; ORR: objective response rate; mDOR: median duration of response (reported for responders); mPFS: median progression-free survival; mOS: median overall survival; DG: daily dosing group; BTK: Bruton’s tyrosine kinase.

Parsaclisib was generally well tolerated in all studies with a manageable safety profile.

"Data from the CITADEL studies presented at ASH (Free ASH Whitepaper) 2020 are very promising and they highlight the potential of parsaclisib to become a meaningful treatment for patients with relapsed or refractory follicular, marginal zone or mantle cell lymphomas," said Peter Langmuir, M.D., Group Vice President, Oncology Targeted Therapies, Incyte. "We look forward to continuing our work as we seek to bring this medicine to patients."

Presentations are available on the ASH (Free ASH Whitepaper) website at View Source; #338 (Oral presentation, CITADEL-204), #2935 (Poster, CITADEL-203), #1121 (Poster, CITADEL-205), #2044 (Poster, CITADEL-205).

About Follicular, Marginal Zone and Mantle Cell Lymphomas

Non-Hodgkin lymphoma (NHL) is a type of cancer that starts in the lymphocytes, a type of white blood cell. Follicular lymphoma (FL), marginal zone lymphoma (MZL) and mantle cell lymphoma (MCL) are forms of B-Cell NHLs. FL and MZL are indolent or slow growing lymphomas; MCL is an aggressive or rapidly developing form. There is an unmet medical need for treatment options for patients who are relapsed or refractory to initial therapies.

About CITADEL

The CITADEL (Clinical Investigation of TArgeted PI3K-DELta Inhibition in Lymphomas) clinical trial program is evaluating parsaclisib in several ongoing studies as a treatment for adult patients with lymphomas, including:

CITADEL-203 (NCT03126019) is evaluating patients with relapsed or refractory follicular lymphoma (FL) Grade 1, 2 or 3a who received at least two prior systemic therapies, had an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2, and were ineligible for hematopoietic stem cell transplantation (HSCT).
CITADEL-204 (NCT03144674) is evaluating patients with relapsed or refractory marginal zone lymphoma (MZL) who received at least one prior systemic therapy and were Bruton’s tyrosine kinase (BTK) inhibitor treatment naive. Patients with prior ibrutinib treatment were initially allowed to enroll; however, the cohort was terminated due to slow enrollment. Eligible patients had radiologically measurable lymphadenopathy or extranodal lymphoid malignancy (or histologically confirmed bone marrow infiltration in cases of splenic MZL), and an ECOG PS ≤2.
CITADEL-205 ( NCT03235544 ) is evaluating patients with relapsed or refractory mantle cell lymphoma (MCL), who received one to three prior systemic therapies and were either naive to or were previously treated with a BTK inhibitor. Eligible patients had an ECOG PS ≤2, and radiologically measurable lymphadenopathy or extranodal lymphoid malignancy.
Patients eligible for each trial were allocated to receive parsaclisib 20 mg once daily for eight weeks followed by either 20 mg once weekly (weekly-dosing group [WG]) or 2.5 mg once daily (daily-dosing group [DG]). Subsequently, daily dosing was selected as the preferred regimen and the WG patients were allowed to switch to DG. Prophylaxis for Pneumocystis jirovecii pneumonia (PJP) was required.

About Parsaclisib

Parsaclisib is a potent, highly selective, next-generation investigational novel oral inhibitor of phosphatidylinositol 3-kinase delta (PI3Kδ). It is currently under evaluation as a monotherapy in several ongoing Phase 2 trials as a treatment for non-Hodgkin lymphomas (follicular, marginal zone and mantle cell); and autoimmune hemolytic anemia. Pivotal trials of parsaclisib in combination with ruxolitinib for the treatment of patients with myelofibrosis are underway; and there are plans to initiate a trial to evaluate parsaclisib in combination with tafasitamab for B-cell malignancies.

In December 2018, Innovent and Incyte entered into a strategic collaboration for three clinical-stage product candidates, including parsaclisib. Under the terms of the agreement, Innovent has received the rights to develop and commercialize parsaclisib and two other assets in Mainland China, Hong Kong, Macau and Taiwan.

Conference Call Information

Incyte will host an investor conference call and webcast at 10:00 a.m. ET (7:00 a.m. PT) today, December 7, 2020—the call and webcast can be accessed via the Events and Presentations tab of the Investor section of Incyte.com and it will be available for replay for 90 days.

On December 7, 2020 Precigen, Inc., a biopharmaceutical company specializing in the development of innovative gene and cell therapies to improve the lives of patients, reported at the 62nd ASH (Free ASH Whitepaper) Annual Meeting and Exposition (Abstract 2864) clinical progress and new data from the ongoing Phase 1/1b clinical study of PRGN-3006 UltraCAR-T in patients with relapsed or refractory (r/r) acute myeloid leukemia (AML) and higher risk myelodysplastic syndrome (MDS) (clinical trial identifier: NCT03927261) (Press release, Precigen, DEC 7, 2020, View Source;prgn-3006-ultracar-t-at-the-62nd-ash-annual-meeting-and-exposition-301186957.html [SID1234572358]).

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AML is a rapidly progressing disease with poor prognosis and high unmet need. Precigen’s UltraCAR-T platform is designed to overcome limitations of currently available chimeric antigen receptor (CAR)-T therapies by utilizing an advanced overnight non-viral gene delivery manufacturing process at a medical center’s cGMP facility without the need for ex vivo expansion. Current CAR-T cell therapies are limited due to, inter alia, the prolonged interval between apheresis to product infusion and an exhausted phenotype of T cells resulting from lengthy ex vivo expansion. As announced in November 2020, UltraCAR-T cells for the PRGN-3006 study are now manufactured overnight using Precigen’s proprietary UltraPorator device. PRGN-3006 UltraCAR-T is a multigenic autologous CAR-T simultaneously expressing a CAR specifically targeting CD33; membrane bound IL-15 (mbIL15) for enhanced in vivo expansion and persistence; and a kill switch to conditionally eliminate CAR-T cells for an improved safety profile. CD33 is over-expressed on AML blasts with lesser expression on normal hematopoietic stem cells.

An investigator-initiated, non-randomized Phase 1/1b dose-escalation study to evaluate the safety and maximal tolerated dose of PRGN-3006 UltraCAR-T is currently ongoing in collaboration with the H. Lee Moffitt Cancer Center & Research Institute (Moffitt). The study population includes adult patients (≥ 18 years) with r/r AML and hypomethylating agent (HMA) failure, higher risk MDS or chronic myelomonocytic leukemia (CMML) patients with ≥ 5% blasts. To test the hypothesis that expression of mbIL15 on PRGN-3006 can promote UltraCAR-T cell expansion and persistence without the need for lymphodepletion and improve the overall safety profile, study subjects receive the PRGN-3006 infusion either without prior lymphodepletion (Cohort 1) or following lymphodepleting chemotherapy (Cohort 2). A multicenter expansion of the trial is planned.

Key findings:

At the data cutoff (November 10):
Six patients have been treated across the two lowest dose levels in Cohort 1 (no lymphodepletion):
N=3 at Dose Level 1 (3 x 104 – ≤ 1 x 105 UltraCAR-T cells/kg); Total 1.8 to 7 x 106 UltraCAR-T cells
N=3 at Dose Level 2 (1 x 105 – ≤ 3 x 105 UltraCAR-T cells/kg); Total 24 to 29 x 106 UltraCAR-T cells
Three patients have been treated at the lowest dose level in Cohort 2 (with lymphodepletion):
N=3 at Dose Level 1 (3 x 104 – ≤ 1 x 105 UltraCAR-T cells/kg); Total 4.9 x 106 to 1 x 107 UltraCAR-T cells
Encouraging expansion and persistence of PRGN-3006 UltraCAR-T was observed in both lymphodepletion and non-lymphodepletion cohorts and across all dose levels.
PRGN-3006 has been safe and well-tolerated with no dose limiting toxicities (DLTs), no neurotoxicity, and a low incidence of treatment-related adverse events (TRAEs) and serious adverse events (SAEs). A few treatment-related SAEs have been observed, including transient grade 1-3 cytokine release syndrome (CRS), which is more indicative of the biologic activity of the cells.
There has been a 100% manufacturing success rate using the UltraCAR-T manufacturing process.
A case study of the patient with the longest follow-up as of the data cutoff was also presented. This patient received, one day after gene transfer and without prior lymphodepletion, a very low dose, approximately three hundred thousand UltraCAR-T per kilogram (3 x 105 UltraCAR-T/kg) for a total of only 24 million UltraCAR-T. She is a 69 year old female with secondary AML (sAML) and four prior lines of therapy, including induction chemotherapy (IC), allogenic hematopoietic stem cell transplantation (allo-HSCT), HMA plus venetoclax (HMA+VEN), refractory to all therapy post allo-HSCT. The patient had approximately 40% peripheral blasts and 47% bone marrow blasts at baseline.

Case study findings:

After a very low dose infusion without prior lymphodepletion, PRGN-3006 UltraCAR-T cells demonstrated robust expansion and persistence in blood at seven months post-infusion at the time of the most recent sample collection (see FIGURE 1).
UltraCAR-T cells demonstrated trafficking to bone marrow and the ability to expand and persist in bone marrow.
The patient showed a decline in blast levels in blood and bone marrow concomitant with UltraCAR-T expansion and persistence (see FIGURE 1) and had stable disease. Patient follow-up is ongoing.
"There is an urgent need for novel therapies for relapsed or refractory AML patients as the median overall survival for this patient population is less than six months. Current CAR-T approaches for AML have faced challenges due to long manufacturing durations resulting in subsequent delays in treatment," said David A. Sallman, MD, of Moffitt and lead investigator for the PRGN-3006 clinical study. "We are encouraged by the initial data, including safety and manufacturing success from patients treated with autologous UltraCAR-T cells, which were manufactured on-site with almost instant turnaround. We are excited by the expansion and continued persistence of PRGN-3006 UltraCAR-T cells in the patient case study for over seven months post-infusion without prior lymphodepletion and are looking forward to higher doses in the lymphodepleted and non-lymphodepletion cohorts."

"Currently commercialized CAR-T therapies have not demonstrated the persistence needed to drive sustained, durable responses," said Helen Sabzevari, PhD, President and CEO of Precigen. "The results from Dr. Sallman’s patient case study are particularly encouraging as the patient received a very low dose of cells without any ex vivo expansion or activation and no lymphodepletion, which highlights the importance of membrane bound IL-15 in expansion and persistence of these cells and, we believe, differentiates the UltraCAR-T platform from other CAR-T’s. In particular, expansion and persistence of UltraCAR-T cells in the patient’s blood through seven months post-infusion show promise for the durability of PRGN-3006. We look forward to providing additional details for the PRGN-3006 study at our upcoming clinical update call this month."

About Acute Myeloid Leukemia (AML)
AML is a cancer that starts in the bone marrow, but most often moves into the blood.1 Though considered rare, AML is among the most common types of leukemia in adults.2 In 2019, it was estimated that 21,450 new cases of AML would be diagnosed in the US.2 AML is uncommon before the age of 45 and the average age of diagnosis is about 68.2 The prognosis for patients with AML is poor with an average 5–year survival rate of approximately 25 percent overall, and less than a 5 percent 5–year survival rate for patients older than 65.3 Amongst elderly AML patients (≥ 65 years of age), median survival is short, ranging from 3.5 months for patients 65 to 74 years of age to 1.4 months for patients ≥ 85 years of age.3

About Myelodysplastic Syndrome (MDS)
MDS are diseases of the bone marrow generally found in adults in their 70s.4 Incidence in the US is not known for sure, but estimates range from 10,000 each year and higher.4 Using International Prognostic Scoring System (IPSS-R), median survival for MDS patients can vary from less than one year for the "very high" IPSS-R risk group to more than eight years for the "very low" IPSS-R group.4

About PRGN-3006 UltraCAR-T
PRGN-3006 UltraCAR-T is a multigenic autologous CAR-T cell treatment utilizing Precigen’s non-viral Sleeping Beauty system to simultaneously express a CAR specifically targeting CD33, which is over expressed on acute myeloid leukemia blasts with lesser expression on normal hematopoietic stem cell populations and minimal non-hematopoietic expression; membrane bound IL-15 for enhanced in vivo expansion and persistence; and a kill switch to conditionally eliminate CAR-T cells for an improved safety profile. PRGN-3006 is being evaluated in collaboration with the Moffitt Cancer Center in a nonrandomized, investigator–initiated Phase 1/1b dose escalation study to evaluate the safety and maximal tolerated dose of PRGN–3006 UltraCAR-T (clinical trial identifier: NCT03927261). The study population includes patients with relapsed or refractory acute myeloid leukemia or higher risk myelodysplastic syndrome. The US Food and Drug Administration (FDA) has granted orphan drug designation (ODD) for PRGN-3006 UltraCAR-T in patients with AML.

On December 7, 2020 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160), a commercial-stage biotechnology company focused on developing and commercializing innovative medicines worldwide, reported that the China National Medical Products Administration (NMPA) has approved BLINCYTO (blinatumomab) for injection for the treatment of adult patients with relapsed or refractory (R/R) B-cell precursor acute lymphoblastic leukemia (ALL) (Press release, BeiGene, DEC 7, 2020, View Source [SID1234572376]). The biologics license application (BLA) had been submitted by Amgen and received priority review by the Center for Drug Evaluation (CDE) of the NMPA. Developed by Amgen and licensed to BeiGene in China under a strategic collaboration commenced earlier this year, this is the first approval for BLINCYTO in China and BeiGene’s first product licensed from Amgen to be newly approved. With this approval, BLINCYTO has become the first bispecific immunotherapy approved in China.

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"This approval of BLINCYTO provides us with an opportunity to offer adult patients in China with relapsed or refractory B-cell precursor ALL the first approved immunotherapy treatment for their disease. BLINCYTO is the first immunotherapy to demonstrate superior overall survival versus chemotherapy, more than doubling patients’ chances for survival, when used in first salvage R/R ALL in studies outside of China," commented Xiaobin Wu, Ph.D., General Manager of China and President of BeiGene. "We are working to ensure BLINCYTO is available to patients in China as soon as possible. Our commercial organization of more than 1,500 people in China is excited to add BLINCYTO to our product portfolio, which now includes six approved cancer treatments."

The approval of BLINCYTO was based on results from the Phase 3 trial (NCT03476239) in China evaluating the efficacy and safety of BLINCYTO in adult patients with Philadelphia-negative R/R B-cell precursor ALL. Results of the interim analysis of 67 patients showed that the efficacy results in Chinese subjects were generally consistent with those in the global and Japan studies in subjects with Philadelphia-negative R/R ALL. The complete response/complete response with partial recovery of blood cells (CR/CRh) rate within two cycles of BLINCYTO treatment (the primary endpoint) was 47.8% (32 of 67 subjects; 95% CI: 35.4, 60.3). The median overall survival time was 9.6 months (95% CI: 6.4, not estimable). The safety profile observed for Chinese subjects in this study was consistent with that observed in the global studies evaluating BLINCYTO in R/R ALL. No new safety risks were identified based on these interim analyses of adverse events in Chinese subjects.

"Our collaboration with BeiGene is advancing Amgen’s oncology pipeline for patients with significant unmet medical needs. We are confident the approval of BLINCYTO in China has the potential to make a meaningful difference to adult patients with R/R B-cell precursor acute lymphoblastic leukemia," said My Linh Kha, Vice President & General Manager, Amgen Japan Asia-Pacific (JAPAC). "We are deeply committed to continuing to bring therapeutic options to treat debilitating cancers for patients in China, while also actively supporting the Government’s focus on healthy aging through innovative products and initiatives designed to prevent chronic diseases, such as cardiovascular disease and fragility fracture."

About Acute Lymphoblastic Leukemia (ALL)

Acute lymphoblastic leukemia (ALL), also known as acute lymphocytic leukemia, is a rapidly progressing cancer of the blood and bone marrow that occurs in both adults and children1. ALL accounts for approximately 20% of all adult leukemia, and in China there were an estimated 82,607 new cases of leukemia in 20182,3. In children, the relapse rate of ALL is nearly 10%, while in adults the relapse rate is closer to 50%4.

About BLINCYTO (blinatumomab)

BLINCYTO is a bispecific CD19-directed CD3 T cell engager (BiTE) immuno-oncology molecule that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.

BiTE molecules are a type of immuno-oncology therapy being investigated for fighting cancer by helping the body’s immune system to detect and target malignant cells. The modified molecules are designed to engage two different targets simultaneously, thereby juxtaposing T cells (a type of white blood cell capable of killing other cells perceived as threats) to cancer cells. BiTE immuno-oncology molecules help place the T cells within reach of the targeted cell, with the intent of allowing T cells to inject toxins and trigger the cancer cell to die (apoptosis). BiTE immuno-oncology therapies are currently being investigated for their potential to treat a wide variety of cancers.

BLINCYTO was granted breakthrough therapy and priority review designations by the U.S. Food and Drug Administration and is approved in the U.S. for the treatment of:

relapsed or refractory B-cell precursor ALL in adults and children.
B-cell precursor ALL in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1% in adults and children. This indication is approved under accelerated approval based on MRD response rate and hematological relapse-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
In the European Union (EU), BLINCYTO is indicated as monotherapy for the treatment of:

adults with Philadelphia chromosome negative CD19-positive relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL).
adults with Philadelphia chromosome negative CD19-positive B-precursor ALL in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1%.
paediatric patients age 1 year or older with Philadelphia chromosome-negative CD19-positive B-precursor ALL which is refractory or in relapse after receiving at least two prior therapies or in relapse after receiving prior allogeneic hematopoietic stem cell transplantation.
In China, BLINCYTO is indicated for the treatment of adult patients with relapsed or refractory B-cell precursor ALL.

Important U.S. Safety Information

WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES

Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO and treat with corticosteroids as recommended.
Neurological toxicities, which may be severe, life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended.
Contraindications

BLINCYTO is contraindicated in patients with a known hypersensitivity to blinatumomab or to any component of the product formulation.

Warnings and Precautions

Cytokine Release Syndrome (CRS): CRS, which may be life-threatening or fatal, occurred in 15% of patients with R/R ALL and in 7% of patients with MRD-positive ALL. The median time to onset of CRS is 2 days after the start of infusion and the median time to resolution of CRS was 5 days among cases that resolved. Closely monitor and advise patients to contact their healthcare professional for signs and symptoms of serious adverse events such as fever, headache, nausea, asthenia, hypotension, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased total bilirubin (TBILI), and disseminated intravascular coagulation (DIC). The manifestations of CRS after treatment with BLINCYTO overlap with those of infusion reactions, capillary leak syndrome, and hemophagocytic histiocytosis/macrophage activation syndrome. If severe CRS occurs, interrupt BLINCYTO until CRS resolves. Discontinue BLINCYTO permanently if life-threatening CRS occurs. Administer corticosteroids for severe or life-threatening CRS.
Neurological Toxicities: Approximately 65% of patients receiving BLINCYTO in clinical trials experienced neurological toxicities. The median time to the first event was within the first 2 weeks of BLINCYTO treatment and the majority of events resolved. The most common (≥ 10%) manifestations of neurological toxicity were headache and tremor. Severe, life‐threatening, or fatal neurological toxicities occurred in approximately 13% of patients, including encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. Manifestations of neurological toxicity included cranial nerve disorders. Monitor patients for signs or symptoms and interrupt or discontinue BLINCYTO as outlined in the PI.
Infections: Approximately 25% of patients receiving BLINCYTO in clinical trials experienced serious infections such as sepsis, pneumonia, bacteremia, opportunistic infections, and catheter-site infections, some of which were life-threatening or fatal. Administer prophylactic antibiotics and employ surveillance testing as appropriate during treatment. Monitor patients for signs or symptoms of infection and treat appropriately, including interruption or discontinuation of BLINCYTO as needed.
Tumor Lysis Syndrome (TLS), which may be life-threatening or fatal, has been observed. Preventive measures, including pretreatment nontoxic cytoreduction and on-treatment hydration, should be used during BLINCYTO treatment. Monitor patients for signs and symptoms of TLS and interrupt or discontinue BLINCYTO as needed to manage these events.
Neutropenia and Febrile Neutropenia, including life-threatening cases, have been observed. Monitor appropriate laboratory parameters (including, but not limited to, white blood cell count and absolute neutrophil count) during BLINCYTO infusion and interrupt BLINCYTO if prolonged neutropenia occurs.
Effects on Ability to Drive and Use Machines: Due to the possibility of neurological events, including seizures, patients receiving BLINCYTO are at risk for loss of consciousness, and should be advised against driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered.
Elevated Liver Enzymes: Transient elevations in liver enzymes have been associated with BLINCYTO treatment with a median time to onset of 3 days. In patients receiving BLINCYTO, although the majority of these events were observed in the setting of CRS, some cases of elevated liver enzymes were observed outside the setting of CRS, with a median time to onset of 19 days. Grade 3 or greater elevations in liver enzymes occurred in approximately 7% of patients outside the setting of CRS and resulted in treatment discontinuation in less than 1% of patients. Monitor ALT, AST, gamma-glutamyl transferase, and TBILI prior to the start of and during BLINCYTO treatment. BLINCYTO treatment should be interrupted if transaminases rise to > 5 times the upper limit of normal (ULN) or if TBILI rises to > 3 times ULN.
Pancreatitis: Fatal pancreatitis has been reported in patients receiving BLINCYTO in combination with dexamethasone in clinical trials and the post-marketing setting. Evaluate patients who develop signs and symptoms of pancreatitis and interrupt or discontinue BLINCYTO and dexamethasone as needed.
Leukoencephalopathy: Although the clinical significance is unknown, cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving BLINCYTO, especially in patients previously treated with cranial irradiation and antileukemic chemotherapy.
Preparation and administration errors have occurred with BLINCYTO treatment. Follow instructions for preparation (including admixing) and administration in the PI strictly to minimize medication errors (including underdose and overdose).
Immunization: Vaccination with live virus vaccines is not recommended for at least 2 weeks prior to the start of BLINCYTO treatment, during treatment, and until immune recovery following last cycle of BLINCYTO.
Risk of Serious Adverse Reactions in Pediatric Patients due to Benzyl Alcohol Preservative: Serious and fatal adverse reactions including "gasping syndrome," which is characterized by central nervous system depression, metabolic acidosis, and gasping respirations, can occur in neonates and infants treated with benzyl alcohol-preserved drugs including BLINCYTO (with preservative). When prescribing BLINCYTO (with preservative) for pediatric patients, consider the combined daily metabolic load of benzyl alcohol from all sources including BLINCYTO (with preservative) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known. Due to the addition of bacteriostatic saline, 7-day bags of BLINCYTO solution for infusion with preservative contain benzyl alcohol and are not recommended for use in any patients weighing < 22 kg.
Adverse Reactions

The most common adverse reactions (≥ 20%) in clinical trial experience of patients with MRD-positive B-cell precursor ALL (BLAST Study) treated with BLINCYTO were pyrexia (91%), infusion-related reactions (77%), headache (39%), infections (pathogen unspecified [39%]), tremor (31%), and chills (28%). Serious adverse reactions were reported in 61% of patients. The most common serious adverse reactions (≥ 2%) included pyrexia, tremor, encephalopathy, aphasia, lymphopenia, neutropenia, overdose, device related infection, seizure, and staphylococcal infection.
The most common adverse reactions (≥ 20%) in clinical trial experience of patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL (TOWER Study) treated with BLINCYTO were infections (bacterial and pathogen unspecified), pyrexia, headache, infusion-related reactions, anemia, febrile neutropenia, thrombocytopenia, and neutropenia. Serious adverse reactions were reported in 62% of patients. The most common serious adverse reactions (≥ 2%) included febrile neutropenia, pyrexia, sepsis, pneumonia, overdose, septic shock, CRS, bacterial sepsis, device related infection, and bacteremia.
Adverse reactions that were observed more frequently (≥ 10%) in the pediatric population compared to the adults with relapsed or refractory B-cell precursor ALL were pyrexia (80% vs. 61%), hypertension (26% vs. 8%), anemia (41% vs. 24%), infusion-related reaction (49% vs. 34%), thrombocytopenia (34% vs. 21%), leukopenia (24% vs. 11%), and weight increased (17% vs. 6%).
In pediatric patients less than 2 years old (infants), the incidence of neurologic toxicities was not significantly different than for the other age groups, but its manifestations were different; the only event terms reported were agitation, headache, insomnia, somnolence, and irritability. Infants also had an increased incidence of hypokalemia (50%) compared to other pediatric age cohorts (15-20%) or adults (17%).
Dosage and Administration Guidelines

BLINCYTO is administered as a continuous intravenous infusion at a constant flow rate using an infusion pump which should be programmable, lockable, non-elastomeric, and have an alarm.
It is very important that the instructions for preparation (including admixing) and administration provided in the full Prescribing Information are strictly followed to minimize medication errors (including underdose and overdose).

On December 7, 2020 Theralase Technologies Inc. ("Theralase" or the "Company") (TSXV: TLT) (OTCQB: TLTFF), a clinical stage pharmaceutical company focused on the research and development of light activated Photo Dynamic Compounds ("PDC") and their associated drug formulations used to safely and effectively destroy various cancers, bacteria and viruses reported that the University of British Columbia ("UBC") Review Ethics Board ("REB") has approved the commencement of a Pivotal Phase II Non-Muscle Invasive Bladder Cancer ("NMIBC") Clinical Study to enroll and treat patients who present with Carcinoma In-Situ ("CIS") and who are considered Bacillus Calmette Guerin("BCG")-Unresponsive or are intolerant to BCG Therapy ("Study II") (Press release, Theralase, DEC 7, 2020, View Source [SID1234572397]).

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The University of British Columbia is a global center for teaching, learning and research, consistently ranked among the top 20 public universities in the world and recently recognized as North America’s most international university.

To date 14 patients have been treated in Study II. With the addition of UBC, the Company now has 5 sites open for patient enrollment and treatment in Canada. The Company is in advanced discussions to launch a number of U.S. based clinical study sites in 4Q2020, subject to the United States economy recovering from the COVID-19 pandemic. The U.S. based Trial Management Organization plans to launch 4 to 5 clinical study sites in 4Q2020 and commence Study II patient enrollment and treatment as early as 1Q2021.

Dr. Peter Black, MD, FRCSC, a Urologic Oncologist at Vancouver General Hospital, a Research Scientist at the Vancouver Prostate Centre, and a Professor in the Department of Urologic Sciences at the University of British Columbia stated "I think this is a great opportunity for patients to gain access to a promising new technology and treatment that is easy to deliver and very patient-friendly. We are delighted to be able to offer it to patients in British Columbia."

Shawn Shirazi PhD, Chief Executive Officer, Theralase, stated, "We are extremely pleased that the UBC, REB provided approval to proceed with Study II. We are excited that our recent FDA Fast Track Designation status for Study II could lead to the expedited development of this drug-device combination for NMIBC patients. The TLD-1433 technology represents a paradigm shift in medical technology and an advanced approach to treat NMIBC."

About Study II

Study II utilizes the Therapeutic Dose (0.70 mg/cm2) of TLD-1433 and is focused on the enrollment and treatment of approximately 100 BCG-Unresponsive NMIBC CIS patients in up to 20 clinical study sites located in Canada and the US.

Study II has a:

Primary endpoint of efficacy (defined by Complete Response ("CR") at any point in time
Secondary endpoint of duration of CR at 360 days post-initial CR (approximately 450 days post initial Study treatment, assuming CR is achieved at the 90 day assessment)
Tertiary endpoint of safety measured by incidence and severity of Adverse Events ("AEs") grade 4 or higher that do not resolve within 450 days post-initial treatment
The FDA, in its 2018 guidance to industry has stated that, "For single-arm trials of patients with BCG-unresponsive disease, the FDA defines a CR as at least one of the following:

Negative cystoscopy and negative (including atypical) urine cytology
Positive cystoscopy with biopsy-proven benign or low-grade NMIBC and negative cytology
For intravesical therapies without systemic toxicity, the FDA includes, in the definition of a CR, negative cystoscopy with malignant urine cytology, if cancer is found in the upper tract or prostatic urethra and random bladder biopsies are negative.
Intravesical instillation does not deliver the investigational drug to the upper tract or prostatic urethra; therefore, the development of disease in these areas cannot be attributed to a lack of activity of the investigational drug. Thus, sponsors can consider patients with new malignant lesions of the upper tract or prostatic urethra, who have received intravesical therapy to have achieved a CR in the primary analysis; however, sponsors should record these lesions and conduct sensitivity analyses in which these patients are not considered to have achieved a CR."1