On December 12, 2022 Kite, a Gilead Company, reported three-year follow-up data from the pivotal ZUMA-5 study for Yescarta (axicabtagene ciloleucel) in relapsed or refractory (r/r) indolent non-Hodgkin lymphoma (iNHL), showing continued response in 52% of all enrolled patients, and prolonged duration of progression-free survival (PFS) in the Phase 2 study, presented at the 2022 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition (Abstract #4660) (Press release, Kite Pharma, DEC 12, 2022, View Source;52-of-Patients-With-Indolent-Lymphomas-Continued-to-Have-Ongoing-Responses-at-a-Median-Follow-Up-of-40.5-Months [SID1234625176]). In addition, two-year follow-up data from the ZUMA-1 safety cohort (Cohort 6) evaluating use of prophylactic corticosteroids in patients with r/r large B-cell lymphoma (LBCL) (Abstract #4667) were also presented.

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"Multi-year follow-up continues to demonstrate the durable response achieved through a single treatment with Yescarta CAR T-cell therapy for difficult-to-treat types of lymphomas," said Frank Neumann, MD, PhD, SVP & Global Head of Clinical Development, Kite. "These longer-term results, coupled with additional Yescarta data previously presented, are building a consistent, remarkable story that is changing the standard of care and giving hope to thousands of blood cancer patients."

ZUMA-5 is a Phase 2, multi-center, single-arm study of Yescarta in patients with iNHL including follicular lymphoma (FL) and marginal zone lymphoma (MZL). Yescarta received accelerated approval from the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with r/r FL after two or more lines of systemic therapy in March 2021 and was approved in the European Union for the treatment of adult patients with r/r FL after three or more lines of therapy earlier this year. Yescarta is not approved anywhere in the world for MZL.

Abstract #4660
3-Year Follow-Up Analysis of ZUMA-5: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed/Refractory (R/R) Indolent Non-Hodgkin Lymphoma (iNHL)

In the ZUMA-5 study, Yescarta demonstrated continued durable responses in all patients (n=159) with a median follow-up of 40.5 months [range, 8.3-57.4; FL: 41.7, marginal zone lymphoma (MZL): 31.8]. At the time of data cut-off, the overall response rate (ORR) was 90% (95% CI, 84‒94) and the CR rate was 75% among all patients. Patients with FL had an ORR of 94% (79% CR rate) and patients with MZL had an ORR of 77% (65% CR rate). Among all patients, median duration of response (DoR) was 38.6 months (FL: 38.6, MZL: not reached), median DoR was not reached in patients with a CR, and median progression-free survival (PFS) was 40.2 months (FL: 40.2, MZL not reached). Compared to findings from the study’s two-year analysis, both ORR and CR rates were similar; medians for PFS had increased in MZL and remained unchanged in FL. Since the two-year analysis, no new safety signals were observed and 10 additional patients died due to the following reasons: progression (n=1), adverse events (n=3; none related to Yescarta) and other causes (n=6).

"We continue to see durable responses three years out in patients who were treated with axicabtagene ciloleucel, and in the last year of follow-up very few patients progressed," said Sattva S. Neelapu, MD, Professor, Department of Lymphoma-Myeloma, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center. "These results are particularly meaningful as patients with follicular lymphoma who have relapsed twice have historically only had a five-year progression free survival rate of 20 percent."

Abstract #4667
Prophylactic Corticosteroid Use with Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed/Refractory Large B-Cell Lymphoma (R/R LBCL): 2-Year Follow-Up of ZUMA-1 Cohort 6

A new analysis of the ZUMA-1 safety management cohort (Cohort 6) of patients with r/r LBCL (n=40) evaluating the longer-term impact of prophylactic use of corticosteroids and earlier treatment with corticosteroids and/or tocilizumab showed that the toxicity management strategy demonstrated improved long-term safety without compromising durability of response or survival in patients treated with Yescarta. Patients in the cohort received dexamethasone 10 mg orally on the day of Yescarta infusion and each of the two following days.

At the time of data cut-off, the median follow-up was 26.9 months (range, 24.0-30.1). The ORR was 95% (80% CR), which was consistent with results at the one-year analysis. Median DoR was 25.9 months (95% CI; 7.8-not estimable) and median PFS was 26.8 months (95% CI; 8.7-not estimable). No Grade ≥3 cytokine release syndrome (CRS) was observed. Grade ≥3 neurologic events increased to 18% at two years. The median time to onset of any grade CRS was five days with a median duration of four days. Two new neurologic events were observed (one Grade 2 dementia unrelated to Yescarta, one Yescarta-related leukoencephalopathy that was fatal). Median time to onset of any grade neurologic event was unchanged from the one-year analysis (6 days), and the median duration was similar (19.0 days vs 18.5 days, respectively). All patients in the cohort had treatment-emergent adverse events (TEAEs), including Grade ≥3 events. The most common Grade ≥3 TEAEs were neutropenia (80%), leukopenia (40%) and thrombocytopenia (28%).

"The two-year follow-up data of patients in ZUMA-1 Cohort 6 reinforce that prophylactic use of corticosteroids can improve the use of axicabtagene ciloleucel without compromising response durability or survival outcomes," said Olalekan O. Oluwole, MBBS, MD, MPH, ZUMA-1 Cohort 6 lead investigator and Associate Professor of Medicine, Vanderbilt University Medical Center. "As knowledge and experience with axicabtagene ciloleucel continue to grow, it’s critical that we continue to utilize this data as the basis for our safety management protocols so that our patients attain the best possible outcomes."

The Yescarta U.S. Prescribing Information has a BOXED WARNING for the risks of CRS and neurologic toxicities, and Yescarta is approved with a Risk Evaluation and Mitigation Strategy (REMS) due to these risks; see below for Important Safety Information.

About Indolent Non-Hodgkin Lymphoma

Follicular lymphoma and marginal zone lymphoma are both forms of indolent non-Hodgkin lymphoma (NHL) in which malignant tumors slowly grow but can become more aggressive over time.

Follicular lymphoma is the most common form of indolent lymphoma and the second most common type of lymphoma globally. It accounts for approximately 22 percent of all lymphomas diagnosed worldwide. Marginal zone lymphoma is the third most common lymphoma, accounting for 8 to 12 percent of all B-cell NHLs.

Despite advances in management and substantial improvements in long-term survival, patients living with follicular lymphoma have varied outcomes. Currently, there are no standard of care treatments for relapsed and refractory follicular lymphoma after two or more lines of therapy, and there are limited options for the treatment of relapsed or refractory marginal zone lymphoma.

About Large B-Cell Lymphoma

Globally, large B-cell lymphoma (LBCL) is the most common type of non-Hodgkin lymphoma (NHL). In the United States, more than 18,000 people are diagnosed with LBCL each year. About 30-40% of patients with LBCL will need second-line treatment, as their cancer will either relapse (return) or become refractory (not respond) to initial treatment.

About Yescarta

Please see full US Prescribing Information, including BOXED WARNING and Medication Guide.

YESCARTA is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of:

Adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy.
Adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.
Limitations of Use: YESCARTA is not indicated for the treatment of patients with primary central nervous system lymphoma.
Adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy. This indication is approved under accelerated approval based on the response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial(s).
U.S. IMPORTANT SAFETY INFORMATION

BOXED WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITIES

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving YESCARTA. Do not administer YESCARTA to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving YESCARTA, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with YESCARTA. Provide supportive care and/or corticosteroids as needed.
YESCARTA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the YESCARTA and TECARTUS REMS Program.
CYTOKINE RELEASE SYNDROME (CRS)

CRS, including fatal or life-threatening reactions, occurred. CRS occurred in 90% (379/422) of patients with non-Hodgkin lymphoma (NHL), including ≥ Grade 3 in 9%. CRS occurred in 93% (256/276) of patients with large B-cell lymphoma (LBCL), including ≥ Grade 3 in 9%. Among patients with LBCL who died after receiving YESCARTA, 4 had ongoing CRS events at the time of death. For patients with LBCL in ZUMA-1, the median time to onset of CRS was 2 days following infusion (range: 1-12 days) and the median duration was 7 days (range: 2-58 days). For patients with LBCL in ZUMA-7, the median time to onset of CRS was 3 days following infusion (range: 1-10 days) and the median duration was 7 days (range: 2-43 days). CRS occurred in 84% (123/146) of patients with indolent non-Hodgkin lymphoma (iNHL) in ZUMA-5, including ≥ Grade 3 in 8%. Among patients with iNHL who died after receiving YESCARTA, 1 patient had an ongoing CRS event at the time of death. The median time to onset of CRS was 4 days (range: 1-20 days) and the median duration was 6 days (range: 1-27 days) for patients with iNHL.

Key manifestations of CRS (≥ 10%) in all patients combined included fever (85%), hypotension (40%), tachycardia (32%), chills (22%), hypoxia (20%), headache (15%), and fatigue (12%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), renal insufficiency, cardiac failure, respiratory failure, cardiac arrest, capillary leak syndrome, multi-organ failure, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome.

The impact of tocilizumab and/or corticosteroids on the incidence and severity of CRS was assessed in 2 subsequent cohorts of LBCL patients in ZUMA-1. Among patients who received tocilizumab and/or corticosteroids for ongoing Grade 1 events, CRS occurred in 93% (38/41), including 2% (1/41) with Grade 3 CRS; no patients experienced a Grade 4 or 5 event. The median time to onset of CRS was 2 days (range: 1-8 days) and the median duration of CRS was 7 days (range: 2-16 days). Prophylactic treatment with corticosteroids was administered to a cohort of 39 patients for 3 days beginning on the day of infusion of YESCARTA. Thirty-one of the 39 patients (79%) developed CRS and were managed with tocilizumab and/or therapeutic doses of corticosteroids with no patients developing ≥ Grade 3 CRS. The median time to onset of CRS was 5 days (range: 1-15 days) and the median duration of CRS was 4 days (range: 1-10 days). Although there is no known mechanistic explanation, consider the risk and benefits of prophylactic corticosteroids in the context of pre-existing comorbidities for the individual patient and the potential for the risk of Grade 4 and prolonged neurologic toxicities.

Ensure that 2 doses of tocilizumab are available prior to YESCARTA infusion. Monitor patients for signs and symptoms of CRS at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated.

NEUROLOGIC TOXICITIES

Neurologic toxicities (including immune effector cell-associated neurotoxicity syndrome) that were fatal or life-threatening occurred. Neurologic toxicities occurred in 78% (330/422) of all patients with NHL receiving YESCARTA, including ≥ Grade 3 in 25%. Neurologic toxicities occurred in 87% (94/108) of patients with LBCL in ZUMA-1, including ≥ Grade 3 in 31% and in 74% (124/168) of patients in ZUMA-7 including ≥ Grade 3 in 25%. The median time to onset was 4 days (range: 1-43 days) and the median duration was 17 days for patients with LBCL in ZUMA-1. The median time to onset for neurologic toxicity was 5 days (range:1-133 days) and the median duration was 15 days in patients with LBCL in ZUMA-7. Neurologic toxicities occurred in 77% (112/146) of patients with iNHL, including ≥ Grade 3 in 21%. The median time to onset was 6 days (range: 1-79 days) and the median duration was 16 days. Ninety-eight percent of all neurologic toxicities in patients with LBCL and 99% of all neurologic toxicities in patients with iNHL occurred within the first 8 weeks of YESCARTA infusion. Neurologic toxicities occurred within the first 7 days of infusion for 87% of affected patients with LBCL and 74% of affected patients with iNHL.

The most common neurologic toxicities (≥ 10%) in all patients combined included encephalopathy (50%), headache (43%), tremor (29%), dizziness (21%), aphasia (17%), delirium (15%), and insomnia (10%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events, including aphasia, leukoencephalopathy, dysarthria, lethargy, and seizures occurred. Fatal and serious cases of cerebral edema and encephalopathy, including late-onset encephalopathy, have occurred.

The impact of tocilizumab and/or corticosteroids on the incidence and severity of neurologic toxicities was assessed in 2 subsequent cohorts of LBCL patients in ZUMA-1. Among patients who received corticosteroids at the onset of Grade 1 toxicities, neurologic toxicities occurred in 78% (32/41), and 20% (8/41) had Grade 3 neurologic toxicities; no patients experienced a Grade 4 or 5 event. The median time to onset of neurologic toxicities was 6 days (range: 1-93 days) with a median duration of 8 days (range: 1-144 days). Prophylactic treatment with corticosteroids was administered to a cohort of 39 patients for 3 days beginning on the day of infusion of YESCARTA. Of those patients, 85% (33/39) developed neurologic toxicities, 8% (3/39) developed Grade 3, and 5% (2/39) developed Grade 4 neurologic toxicities. The median time to onset of neurologic toxicities was 6 days (range: 1-274 days) with a median duration of 12 days (range: 1-107 days). Prophylactic corticosteroids for management of CRS and neurologic toxicities may result in a higher grade of neurologic toxicities or prolongation of neurologic toxicities, delay the onset of and decrease the duration of CRS.

Monitor patients for signs and symptoms of neurologic toxicities at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter, and treat promptly.

REMS

Because of the risk of CRS and neurologic toxicities, YESCARTA is available only through a restricted program called the YESCARTA and TECARTUS REMS Program which requires that: Healthcare facilities that dispense and administer YESCARTA must be enrolled and comply with the REMS requirements and must have on-site, immediate access to a minimum of 2 doses of tocilizumab for each patient for infusion within 2 hours after YESCARTA infusion, if needed for treatment of CRS. Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer YESCARTA are trained in the management of CRS and neurologic toxicities. Further information is available at www.YescartaTecartusREMS.com or 1-844-454-KITE (5483).

HYPERSENSITIVITY REACTIONS

Allergic reactions, including serious hypersensitivity reactions or anaphylaxis, may occur with the infusion of YESCARTA.

SERIOUS INFECTIONS

Severe or life-threatening infections occurred. Infections (all grades) occurred in 45% of patients with NHL; ≥ Grade 3 infections occurred in 17% of patients, including ≥ Grade 3 infections with an unspecified pathogen in 12%, bacterial infections in 5%, viral infections in 3%, and fungal infections in 1%. YESCARTA should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after infusion and treat appropriately. Administer prophylactic antimicrobials according to local guidelines.

Febrile neutropenia was observed in 36% of all patients with NHL and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as medically indicated.

In immunosuppressed patients, including those who have received YESCARTA, life-threatening and fatal opportunistic infections including disseminated fungal infections (e.g., candida sepsis and aspergillus infections) and viral reactivation (e.g., human herpes virus-6 [HHV-6] encephalitis and JC virus progressive multifocal leukoencephalopathy [PML]) have been reported. The possibility of HHV-6 encephalitis and PML should be considered in immunosuppressed patients with neurologic events and appropriate diagnostic evaluations should be performed.

Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells, including YESCARTA. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

PROLONGED CYTOPENIAS

Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and YESCARTA infusion. ≥ Grade 3 cytopenias not resolved by Day 30 following YESCARTA infusion occurred in 39% of all patients with NHL and included neutropenia (33%), thrombocytopenia (13%), and anemia (8%). Monitor blood counts after infusion.

HYPOGAMMAGLOBULINEMIA

B-cell aplasia and hypogammaglobulinemia can occur. Hypogammaglobulinemia was reported as an adverse reaction in 14% of all patients with NHL. Monitor immunoglobulin levels after treatment and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement. The safety of immunization with live viral vaccines during or following YESCARTA treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during YESCARTA treatment, and until immune recovery following treatment.

SECONDARY MALIGNANCIES

Secondary malignancies may develop. Monitor life-long for secondary malignancies. In the event that one occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

Due to the potential for neurologic events, including altered mental status or seizures, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following YESCARTA infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.

ADVERSE REACTIONS

The most common non-laboratory adverse reactions (incidence ≥ 20%) in patients with LBCL in ZUMA-7 included fever, CRS, fatigue, hypotension, encephalopathy, tachycardia, diarrhea, headache, musculoskeletal pain, nausea, febrile neutropenia, chills, cough, infection with an unspecified pathogen, dizziness, tremor, decreased appetite, edema, hypoxia, abdominal pain, aphasia, constipation, and vomiting.

The most common adverse reactions (incidence ≥ 20%) in patients with LBCL in ZUMA-1 included CRS, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections with an unspecified, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias.

The most common non-laboratory adverse reactions (incidence ≥ 20%) in patients with iNHL in ZUMA-5 included fever, CRS, hypotension, encephalopathy, fatigue, headache, infections with an unspecified, tachycardia, febrile neutropenia, musculoskeletal pain, nausea, tremor, chills, diarrhea, constipation, decreased appetite, cough, vomiting, hypoxia, arrhythmia, and dizziness.

On December 12, 2022 Schrödinger, Inc. (Nasdaq: SDGR), whose physics-based computational platform is transforming the way therapeutics and materials are discovered, reported new preclinical data on its potent and selective CDC7 inhibitor, SGR-2921, in a poster session at the American Society of Hematology (ASH) (Free ASH Whitepaper) 64th Annual Meeting taking place virtually and in New Orleans, Louisiana (Press release, Schrodinger, DEC 12, 2022, View Source [SID1234625174]). The data presented demonstrate that SGR-2921 exhibits strong anti-tumor activity in vivo across multiple acute myeloid leukemia (AML) models, including cell-derived xenograft models, as a monotherapy and in combination with standard of care agents. Moreover, SGR-2921 demonstrates anti-tumor activity in AML patient-derived samples resistant to standard of care agents.

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CDC7 is a cell cycle kinase involved in DNA replication and is an important activator of replication stress and DNA damage responses. CDC7 inhibition is considered a promising therapeutic approach for the treatment of cancers, including AML. Schrödinger is advancing SGR-2921 through investigational new drug (IND)-enabling studies with plans to submit an IND application to the U.S. Food and Drug Administration in the first half of 2023 and to initiate a Phase 1 clinical trial in patients with relapsed/refractory AML in the second half of 2023.

"The strength of our preclinical data presented today underscore the power of our computational platform to overcome drug design challenges that plague the industry, in this case designing a potent CDC7 inhibitor that could potentially be combined with other DNA damage repair therapies, such as PARP and BCL-2 inhibitors," said Karen Akinsanya, Ph.D., president of R&D, therapeutics, at Schrödinger. "We are pleased that our data show that SGR-2921-mediated CDC7 inhibition represents a promising novel therapeutic strategy for treating AML, with potential utility in patients with relapsed and refractory AML, and we look forward to advancing this potential best-in-class inhibitor into the clinic."

Additional Details About the Study
The presentation (Abstract #2653), "Inhibition of CDC7 with SGR-2921 in AML models results in enhanced DNA damage and anti-leukemic activity as monotherapy and in combination with standard of care agents," highlighted preclinical data for SGR-2921, which was discovered using Schrödinger’s proprietary physics-based computational platform. This platform enabled Schrödinger to assess 79 billion compounds computationally and synthesize only 226 compounds across all series for further screening. In a panel of approximately 300 cancer cell lines, AML cell lines were the most sensitive to SGR-2921, and AML patient samples were highly sensitive to CDC7 inhibition ex vivo. In vivo, SGR-2921 showed strong anti-tumor growth activity in multiple AML xenograft models at tolerated doses. In combination with hypomethylating agents, SGR-2921 increased the level of replication stress, DNA damage and apoptosis markers in vitro. Combination of SGR-2921 with venetoclax (BCL2 inhibitor) showed synergistic anti-tumor activity both in vitro and in vivo. SGR-2921 was highly active in AML cell lines resistant to FLT3 inhibitors, hypomethylating agents and venetoclax, and in multi-agent resistant cell lines. The combination of SGR-2921 with FLT3 inhibitors partially restored sensitivity to FLT3 inhibition in FLT3 resistant AML cell lines. Together, these data suggest that SGR-2921-mediated CDC7 inhibition could be a novel treatment regimen, with potential utility in patients with relapsed and refractory AML.

On December 12, 2022 Gamida Cell Ltd. (Nasdaq: GMDA), the global leader in the development of NAM-enabled cell therapies for patients with hematologic and solid cancers and other serious diseases, reported the closing of a senior secured convertible term loan of $25 million with certain funds managed by Highbridge Capital Management, LLC (collectively, "Highbridge") (Press release, Gamida Cell, DEC 12, 2022, View Source [SID1234625165]). Pursuant to the loan agreement, Gamida Cell’s wholly-owned subsidiary, as borrower, will draw down $25 million from the facility with a maturity date of December 12, 2024.

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"As we anticipate our shift from clinical to commercial stage, we are now in a stronger financial position to prepare for launch while continuing development of our promising NK pipeline, including our clinical stage asset GDA-201."

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The proceeds from the term loan, together with the net proceeds from Gamida Cell’s $20 million public offering of ordinary shares announced on September 27, 2022 and its existing cash and cash equivalents and trading financial assets, are expected to (i) fund commercial readiness and initial launch activities to support launch of omidubicel, if approved; (ii) fund the continued development of its NK product pipeline, including clinical stage asset GDA-201; and (iii) be used for general corporate purposes, including general and administrative expenses and working capital.

"We are pleased to secure additional capital from an existing investor as we continue to prepare for the launch of omidubicel, which is pending FDA review. Omidubicel has the potential to address the unmet need for patients with hematologic malignancies in need of an allogeneic hematopoietic stem cell transplant," said Abbey Jenkins, CEO of Gamida Cell. "As we anticipate our shift from clinical to commercial stage, we are now in a stronger financial position to prepare for launch while continuing development of our promising NK pipeline, including our clinical stage asset GDA-201."

The term loan was made at 97% of the principal amount thereof, constitutes a senior secured obligation of Gamida Cell and its wholly owned subsidiaries and will accrue interest at an annual rate of 7.5% per year The facility, which has a maturity of December 12, 2024, calls for interest only payments for the first four months and principal and interest payments amortized over the remaining term. Installment payments may be payable in cash or in ordinary shares subject to certain conditions. Subject to certain limitations, the term loan may be exchanged into Gamida Cell’s ordinary shares, in certain cases at the option of Highbridge and in others at the option of Gamida Cell, at an initial exchange rate of 0.52356 ordinary shares per $1.00 principal amount of notes (equivalent to an exchange price of $1.91 per ordinary share).

"We have been encouraged by Gamida’s milestone achievements this year, including BLA acceptance with Priority Review," commented Jonathan Segal, Co-Chief Investment Officer of Highbridge Capital Management. "We look forward to continuing to work collaboratively with Gamida Cell’s management team and board."

Gamida Cell may prepay all but not less than all of the term loan for cash, at its option, at 100% of the principal amount, plus a make whole amount comprised of all accrued and unpaid and remaining coupons due through the maturity date and a prepayment premium of 5% on the principal amount to be prepaid.

About Omidubicel

Omidubicel is an advanced cell therapy candidate developed as a potential life-saving allogeneic hematopoietic stem cell (bone marrow) transplant for patients with blood cancers. Omidubicel demonstrated a statistically significant reduction in time to neutrophil engraftment in comparison to standard umbilical cord blood in an international, multi-center, randomized Phase 3 study (NCT0273029) in patients with hematologic malignancies undergoing allogeneic bone marrow transplant. The Phase 3 study also showed reduced time to platelet engraftment, reduced infections and fewer days of hospitalization. One-year post-transplant data showed sustained clinical benefits with omidubicel as demonstrated by significant reduction in infectious complications as well as reduced non-relapse mortality and no significant increase in relapse rates nor increases in graft-versus-host-disease (GvHD) rates. Omidubicel is the first stem cell transplant donor source to receive Breakthrough Therapy Designation from the FDA and has also received Orphan Drug Designation in the US and EU. The BLA for omidubicel has been assigned a Prescription Drug User Fee Act (PDUFA) target action date of May 1, 2023. If approved, omidubicel will be the first allogeneic advanced stem cell therapy donor source for patients with blood cancers in need of a stem cell transplant.

Omidubicel is an investigational stem cell therapy candidate, and its safety and efficacy have not been established by the FDA or any other health authority. For more information about omidubicel, please visit View Source

About GDA-201

Gamida Cell applied the capabilities of its nicotinamide (NAM)-enabled cell expansion technology to develop GDA-201, an innate NK cell immunotherapy candidate for the potential treatment of hematologic and solid tumors in combination with standard of care antibody therapies. GDA-201, the lead candidate in the NAM-enabled NK cell pipeline, has demonstrated promising initial clinical study data. Preclinical studies have shown that GDA-201 may address key limitations of NK cells by increasing the cytotoxicity and in vivo retention and proliferation in the bone marrow and lymphoid organs. Furthermore, these data suggest GDA-201 may improve antibody-dependent cellular cytotoxicity (ADCC) and tumor targeting of NK cells. There are approximately 40,000 patients with relapsed/refractory lymphoma in the US and EU, which is the patient population that will be studied in the currently ongoing GDA-201 Phase 1/2 clinical trial.

For more information about GDA-201, please visit View Source For more information on the Phase 1/2 clinical trial of GDA-201, please visit www.clinicaltrials.gov.

GDA-201 is an investigational cell therapy candidate, and its safety and efficacy have not been established by the FDA or any other health authority.

About NAM Technology

Our NAM-enabling technology is designed to enhance the number and functionality of targeted cells, enabling us to pursue a curative approach that moves beyond what is possible with existing therapies. Leveraging the unique properties of NAM (nicotinamide), we can expand and metabolically modulate multiple cell types — including stem cells and natural killer cells — with appropriate growth factors to maintain the cells’ active phenotype and enhance potency. Additionally, our NAM technology improves the metabolic fitness of cells, allowing for continued activity throughout the expansion process.

On December 12, 2022 RemeGen Co., Ltd. ("RemeGen" or "the Company") (9995.HK, SHA: 688331), a commercial-stage biotechnology company, reported on December 7, 2022, that its latest antibody-drug conjugate (ADC), RC118 for injection, has been granted two orphan drug designations (ODD) by the United States Food and Drug Administration (FDA) for gastric cancer (including gastroesophageal junction cancer) and pancreatic cancer (Press release, RemeGen, DEC 12, 2022, View Source [SID1234625162]). This marks the Company’s fourth, having previously been twice granted ODD for Disitamab Vedotin (RC48) and Telitacicept (RC18) earlier this year.

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Self-developed, RC118 is RemeGen’s latest advanced antibody-drug conjugate (ADC) used to treat patients with solid tumors positive for Claudin 18.2 expressions. The product was previously approved by China’s National Medical Products Administration (NMPA) Center for Drug Evaluation (CDE) to conduct clinical trials on September 18, 2021. Phase I clinical trials for malignant solid tumors RC118 are currently being developed in Australia and China for the treatment of locally advanced unresectable or metastatic disease in patients with positive Claudin 18.2 expressions and a dose-escalation study is underway, thus far showing good safety and tolerability.

Claudin protein is a tight junction molecule whose function is mainly to regulate the permeability of the cellular barrier structure. As a member of the Claudin protein family, Claudin 18.2 is a highly tissue-specific protein that is mainly expressed in gastric epithelial cells and is also highly expressed in primary malignant tumors such as gastric, breast, colon, liver, and pancreatic cancers. Due to specific expression characteristics, Claudin 18.2 has become a popular target that many pharmaceutical companies have been paying close attention to, with no drug for this target so far being approved for marketing globally.

Orphan drugs, also known as rare disease drugs, are used for the prevention, treatment, and diagnosis of rare diseases. The ODD granted by the US FDA is applicable to drugs and biologics for rare diseases with less than 200,000 patients in the United States each year. The drugs that have been certified can potentially enjoy tax incentives in the United States, a seven-year market exclusivity period after listing, as well as other policy incentives.

"It is another positive step forward in the biotechnology development for RemeGen. We are very pleased to have received from the FDA the Orphan Drug Designation for gastric cancer and pancreatic cancer, which adds to the designation granted already for the treatment of myasthenia gravis," said Dr. Jianmin Fang, CEO and Chief Scientific Officer of RemeGen.

RemeGen is one of a handful of Chinese biopharmaceutical companies with a fully integrated ADC platform. Based on this platform, the company has continuously improved and optimized its proprietary ADC product pipeline, with no less than four products, including the latest RC118, entering clinical trials or gaining marketing approval. Among them, China’s first domestically produced ADC drug, Disitamab Vedotin (RC48), with two indications for gastric and urothelial cancers and autoimmune drug Telitacicept (RC18) have been approved by NMPA in China.

On December 12, 2022 Precigen, Inc., a biopharmaceutical company specializing in the development of innovative gene and cell therapies to improve the lives of patients, reported positive Phase 1 dose escalation data from the ongoing Phase 1/1b clinical study of PRGN-3006 UltraCAR-T in patients with r/r AML and higher risk myelodysplastic syndromes (MDS) (clinical trial identifier: NCT03927261) at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (Abstract# 4633) (Press release, Precigen, DEC 12, 2022, View Source [SID1234625161]). The presentation was delivered by David A. Sallman, MD, Assistant Member in the Department of Malignant Hematology at the H. Lee Moffitt Cancer Center & Research Institute (Moffitt) and a lead investigator for the PRGN-3006 clinical trial.

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PRGN-3006 UltraCAR-T is a multigenic autologous chimeric antigen receptor (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. PRGN-3006 UltraCAR-T drug product is manufactured via an overnight process at medical centers using the Company’s proprietary non-viral and UltraPorator systems and released for infusion in patients the next day. The decentralized, overnight UltraCAR-T manufacturing process, which does not use viral vectors or ex vivo activation and expansion of T cells, has the potential to address major limitations of current T cell therapies. PRGN-3006 UltraCAR-T has been granted Orphan Drug Designation and Fast Track Designation in patients with AML by the US Food and Drug Administration (US FDA).

The Phase 1/1b clinical study is designed to enroll in two phases, an initial dose escalation phase followed by a dose expansion phase, to evaluate safety and determine the recommended Phase 2 dose of PRGN-3006 delivered via intravenous (IV) infusion without lymphodepletion (Cohort 1) or with lymphodepletion (Cohort 2). The study is also evaluating in vivo persistence and anti-tumor activity of PRGN-3006.

Today’s ASH (Free ASH Whitepaper) presentation includes the complete data set for the Phase 1 dose escalation phase of the study. The study enrolled a total of 26 patients (N=10 non-lymphodepletion; N=16 with lymphodepletion) and included 21 patients with r/r AML, 2 patient with chronic myelomonocytic leukemia (CMML), and 3 patients with MDS. The median age was 60.5 years (range: 32-77). Patients were heavily pre-treated with a median of 3.5 prior regimens (range: 1-9) and 58% of patients (N=15) had prior allogeneic hematopoietic stem cell transplantation (allo-HSCT). Patients treated in the non-lymphodepletion cohort and lymphodepletion cohort received a single administration of 1.8 to 50 x 106 and 4.4 to 83 x 106 UltraCAR-T cells via IV infusion, respectively.

"The dose escalation data for PRGN-3006 showed robust dose-dependent expansion and persistence of PRGN-3006 in peripheral blood and bone marrow following a single infusion with no DLTs reported to date leading to an ORR of 27% in heavily pre-treated patients in the lymphodepletion cohort, which is significant for the AML patient population with limited treatment options," said David A. Sallman, MD, of Moffitt and lead investigator for the PRGN-3006 clinical study. "One patient who received PRGN-3006 following allo-HSCT has responded to treatment for more than 18 months and suggests the potential for PRGN-3006 as a bridge to allo-HSCT, a very important potential treatment pathway for these patients."

Safety Data
Cohort 1: Non-lymphodepletion
PRGN-3006 was well-tolerated with no dose-limiting toxicities (DLTs) reported to date in the cohort without lymphodepletion (TABLE 1). Overall, there was a low incidence of adverse events following PRGN-3006 infusion without lymphodepletion and the most common adverse events were decreased lymphocyte count, anemia, febrile neutropenia, cytokine release syndrome (CRS), hypotension and oral mucositis. The majority of treatment emergent adverse events (TEAEs) were either Grade 1 or 2 with only one transient Grade 3 CRS reported (Dose Level 1), which resolved in less than 24 hours with tocilizumab and dexamethasone. Other cases of CRS were Grade 1 or 2 and required either no intervention or resolved following standard CRS management. One Grade 1 immune effector cell-associated neurotoxicity syndrome (ICANS) was reported. No patients experienced a significant increase in serum IL-15, demonstrating that mbIL15 remains tethered to the UltraCAR-T cells as designed and is not released.

Cohort 2: Lymphodepletion
In the lymphodepletion cohort, PRGN-3006 was also well-tolerated with no DLTs reported to date (TABLE 1). Overall, there was a low incidence of adverse events following PRGN-3006 infusion with lymphodepletion and the most common adverse events were decreases in lymphocytes, white blood cells and neutrophil, anemia, febrile neutropenia and CRS. The majority of TEAEs were either Grade 1 or 2. Only one Grade 3 CRS was reported (Dose Level 3), which was subsequently downgraded to Grade 1 by the investigator. Other cases of CRS were Grade 1 or 2 and required either no intervention or resolved following standard CRS management. One Grade 2 ICANS was reported. No patients experienced a significant increase in serum IL-15, demonstrating that mbIL15 remains tethered to the UltraCAR-T cells as designed and is not released.

Clinical Activity

Expansion Kinetics
Excellent dose-dependent expansion and persistence of PRGN-3006 in peripheral blood and bone marrow was observed following a single infusion in both the non-lymphodepletion and lymphodepletion cohorts highlighting the ability of UltraCAR-T cells to engraft and survive even in the absence of lymphodepletion. Higher peak expansion (> 10 fold) in peripheral blood was observed in the lymphodepletion cohort compared to non-lymphodepletion cohort at the same dose level (FIGURE 1).

Change in Bone Marrow Blasts
Of the 15 evaluable patients in the lymphodepletion cohort, 60% (9 out of 15) heavily pre-treated patients had a reduction in bone marrow blasts following a single PRGN-3006 infusion, with 4 patients experiencing a substantial decrease to ≤5% (FIGURE 2).

Objective Responses
Cohort 1: Non-lymphodepletion
In the non-lymphodepletion cohort, 3 out of 10 patients had Stable Disease (SD), per European LeukemiaNet (ELN) criteria, persisting for more than 3 months with one patient experiencing durable SD for more than 7 months with concomitant reduction in peripheral blast levels.

Cohort 2: Lymphodepletion
An objective response rate (ORR) of 27% (3 out of 11) was reported for heavily pre-treated r/r AML patients with poor prognosis (median prior treatments: 4; range: 1-9) in the lymphodepletion cohort. Responders received a single PRGN-3006 dose ranging between 4.4 to 28 x 106 cells following lymphodepletion. A disease control rate (DCR) of 45% (5 out of 11) at day 28 for r/r AML patients and 100% of MDS patients, respectively, as shown in TABLE 2. One patient with CRi was bridged to allo-HSCT at three months post treatment and remains in a measurable residual disease-negative CR 18 months post-transplant, as shown in TABLE 3.

TABLE 2: Summary of Objective Responses for the Lymphodepletion Cohort

AML

MDS

CMML

Disease Control Rate (at D28)

5/11 (45%)

3/3 (100%)

0/1

Objective Response Rate (ORR)

3/11 (27%)

0/3

0/1

TABLE 3: Summary Data for Objective Responders

AML Subtype

Age

Sex

Prior

Regimens*

Safety**

Objective Response***

Persistent AML

60

F

2 prior:

CLAG and HiDAC

No incidence of CRS, neurotoxicity or DLT

CRh at Day 84

Allo-HSCT at Month 3; Surviving 18 months post-transplant

Extramedullary AML

53

M

7 prior: intensive chemo, vidasia, venetoclax, FLAG, anti-IDH1, allo-HSCT

No incidence of CRS, neurotoxicity or DLT

PR at Day 28

PR at 60

AML

61

F

4 prior:

vyxeos, HMA+venetoclax, allo-HSCT

CRS Grade 1, with SAE skin rash, (possible GVHD)

CRi at Day 28

CRh at Day 60

*CLAG=cladribine, cytarabine, and granulocyte-stimulating factor; HiDAC=high-dose cytarabine; FLAG=fludarabine, cytarabine and filgrastim; anti-IDH1=isocitrate dehydrogenases 1 inhibitor; HMA=hypomethylating agents (HMA); allo-HSCT= allogeneic hematopoietic stem cell transplant

**SAE=small ubiquitin-like modifier activating enzyme; GVHD=graft versus host disease

***(CRi) Complete Response with incomplete hematologic recovery (per ELN criteria; (CRh) Complete response with hematologic recovery per ELN criteria; PR: partial response RECIST v1.1

Analysis of peripheral blood samples post PRGN-3006 infusion showed gene expression changes consistent with improvement in the immune compartment function for anti-tumor effect in responders. There was an increase in cytotoxicity, costimulatory signaling, and lymphoid compartment and decreased apoptosis pathway scores in the lymphodepletion cohort on Days 14 and 28 post PRGN-3006 treatment compared to baseline. Furthermore, preliminary analysis shows a potential correlation between a biomarker and objective responses at different dose levels in AML patients, which will be further investigated in the ongoing Phase 1b expansion trial.

PRGN-3006 is currently being evaluated following lymphodepletion in the multicenter Phase 1b dose expansion phase of the study. In the dose expansion phase, patients can receive repeat dosing of PRGN-3006. There is no requirement for additional lymphodepletion in repeat dose patients due to the demonstrated ability of PRGN-3006 to expand in the absence of lymphodepletion.

"We are pleased with the performance of PRGN-3006 UltraCAR-T in demonstrating meaningful clinical responses for heavily pre-treated r/r AML patients who have limited therapeutic options. These data further validate our innovative approach of overnight, decentralized manufacturing of autologous CAR-T cells and demonstrate the capability of the UltraCAR-T platform to directly expand in vivo and persist in the body leading to complete and partial responses in cancer patients with highly advanced disease," said Helen Sabzevari, PhD, President and CEO of Precigen. "We believe the UltraCAR-T platform is distinctly differentiated from other cell therapy technologies with the potential to bring cutting-edge treatments to all cancer patients rapidly and economically."

Precigen: Advancing Medicine with Precision
Precigen (Nasdaq: PGEN) is a dedicated discovery and clinical stage biopharmaceutical company advancing the next generation of gene and cell therapies using precision technology to target the most urgent and intractable diseases in our core therapeutic areas of immuno-oncology, autoimmune disorders, and infectious diseases. Our technologies enable us to find innovative solutions for affordable biotherapeutics in a controlled manner. Precigen operates as an innovation engine progressing a preclinical and clinical pipeline of well-differentiated therapies toward clinical proof-of-concept and commercialization. For more information about Precigen, visit www.precigen.com or follow us on Twitter @Precigen, LinkedIn or YouTube.

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

UltraCAR-T
UltraCAR-T is a multigenic autologous CAR-T platform that utilizes Precigen’s advanced non-viral Sleeping Beauty system to simultaneously express an antigen-specific CAR to specifically target tumor cells, mbIL15 for enhanced in vivo expansion and persistence, and a kill switch to conditionally eliminate CAR-T cells for a potentially improved safety profile. Precigen has advanced the UltraCAR-T platform to address the inhibitory tumor microenvironment by incorporating a novel mechanism for intrinsic checkpoint blockade without the need for complex and expensive gene editing techniques. UltraCAR-T investigational therapies are manufactured via Precigen’s overnight manufacturing process using the proprietary UltraPorator electroporation system at the medical center and administered to patients only one day following gene transfer. The overnight UltraCAR-T manufacturing process does not use viral vectors and does not require ex vivo activation and expansion of T cells, potentially addressing major limitations of current T cell therapies.

UltraPorator
The UltraPorator system is an exclusive device and proprietary software solution for the scale-up of rapid and cost-effective manufacturing of UltraCAR-T therapies and potentially represents a major advancement over current electroporation devices by significantly reducing the processing time and contamination risk. The UltraPorator device is a high-throughput, semi-closed electroporation system for modifying T cells using Precigen’s proprietary non-viral gene transfer technology. UltraPorator is being utilized for clinical manufacturing of Precigen’s investigational UltraCAR-T therapies in compliance with current good manufacturing practices.

Trademarks
Precigen, UltraCAR-T, UltraPorator and Advancing Medicine with Precision are trademarks of Precigen and/or its affiliates. Other names may be trademarks of their respective owners.