FOXO1

Blocking a protein known as CDK7 could prevent heart damage associated with a commonly used cancer chemotherapy medication, according to a new study. Importantly, the researchers also found that inhibiting CDK7 could help enhance the medication's cancer-killing capability. Based on an animal model, the study findings could provide a foundation for future treatment strategies to reduce chemotherapy-related heart toxicity and increase treatment effectiveness. This could ultimately help increase the lifespan of people with cancer. Blocking a protein known as CDK7 could prevent heart damage associated with a commonly used cancer chemotherapy medication, according to a study led by scientists at Washington State University. Importantly, the researchers also found that inhibiting CDK7 could help enhance the medication's cancer-killing capability. Based on an animal model, the study findings could provide a foundation for future treatment strategies to reduce chemotherapy-related heart toxicity and increase treatment effectiveness. This could ultimately help increase the lifespan of people with cancer. Heart damage related to chemotherapy treatment can surface decades after treatment and can result in heart attacks, heart failure, cardiomyopathy and other types of heart disease. Published in the journal Cardiovascular Research, the WSU study focused on doxorubicin, a chemotherapy drug used to treat breast cancer, lymphoma, leukemia and other cancers. Capable of killing a wide range of cancer cells, doxorubicin and other similar chemotherapy medications are known to be toxic to the heart. Despite this toxicity, the drug still sees a lot of use. "Doxorubicin remains the mainstay treatment for certain cancer types for which targeted therapies or other better treatments are not available," said senior study author Zhaokang Cheng, an associate professor in the WSU College of Pharmacy and Pharmaceutical Sciences. Cheng has been working to unravel the underlying mechanisms of doxorubicin-induced heart toxicity to make the use of doxorubicin safer for patients who rely on the drug. This new study builds on findings from earlier research that showed that doxorubicin activates a protein known as CDK2. That protein then activates another known as FOXO1, which causes heart cells to die. Cheng's team collaborated with WSU cancer biology researcher Boyang (Jason) Wu to take a closer look at CDK7, a protein that helps fuel cell growth and has been shown to play a role in the development of cancer. The researchers found that CDK7 activated CDK2, which set off the chain of molecular signals that eventually led to heart cell death. They also showed that mice that lacked the CDK7 gene were protected from doxorubicin-induced heart toxicity. Next, they used a CDK7 inhibitor drug known as THZ1 to block the protein's activity and examine the impact on heart health and cancer growth. A similar inhibitor is currently being tested as an anticancer drug in clinical trials, but its effect on the heart is still not clear. "We are the first to study the effect of THZ1 on the heart and on tumor growth in the same model," said study first author Jingrui Chen, a WSU research associate. "And what we found is that this CDK7 inhibitor drug can increase heart function and at the same time inhibit tumor growth." Though more research is needed, the researchers said their findings suggest that combining doxorubicin and THZ1 could help prevent heart damage and increase the effectiveness of chemotherapy treatment. The researchers' next step is to test the effect of THZ1 on heart damage and cancer growth in younger mice and follow them longer. This would more closely mimic long-term doxorubicin-induced heart toxicity seen in childhood cancer survivors. They also plan to look at other proteins that may somehow be involved in the signaling pathway that underlies doxorubicin-related heart damage. Primary funding support for the study came from the National Heart, Lung and Blood Institute -- a component of the National Institutes of Health -- with additional support from the National Cancer Institute.

CAR T cell therapy has revolutionized the way certain types of cancer are treated, and the longer those CAR T cells live in a patient's body, the more effectively they respond to cancer. Now, researchers have found that a protein called FOXO1 improves the survival and function of CAR T cells, which may lead to more effective CAR T cell therapies and could potentially expand its use in difficult-to-treat cancers. CAR T cell therapy has revolutionized the way certain types of cancer are treated, and the longer those CAR T cells live in a patient's body, the more effectively they respond to cancer. Now, in a new study, researchers at Children's Hospital of Philadelphia (CHOP) and Stanford Medicine have found that a protein called FOXO1 improves the survival and function of CAR T cells, which may lead to more effective CAR T cell therapies and could potentially expand its use in difficult-to-treat cancers. The findings were published online today by the journal Nature. T cells are a type of immune cell that recognize and kill pathogens in order to protect the host. Cancer is often able to evade the body's immune system, but as a result of CAR T cell therapy, a patient's own T cells can be reprogrammed to recognize and kill these cancer cells, which has led to FDA-approved treatments for certain types of lymphomas and leukemias. However, fewer than 50% of patients who receive CAR T cell therapy remain cured after a year. One of the reasons for this is that CAR T cells often don't survive long enough in patients to completely eradicate their cancer. Prior research has demonstrated that patients who are cured through CAR T cell therapy often have CAR T cells that live longer and can more successfully fight cancerous cells. To determine what helps CAR T cells live longer, researchers wanted to understand the underlying biology behind memory T cells, which are a type of natural T cell whose purpose is to persist and retain function. One protein of interest, FOXO1, which activates genes associated with T cell memory, has previously been studied in mice but remains under-researched in human T cells or CAR T cells. "By studying factors that drive memory in T cells, like FOXO1, we can enhance our understanding of why CAR T cells persist and work more effectively in some patients compared to others," said senior study author Evan Weber, PhD, an Assistant Professor of Pediatrics at the University of Pennsylvania Perelman School of Medicine and cell and gene therapy researcher within the CHOP Center for Childhood Cancer Research (CCCR) and the Center for Cellular and Molecular Therapeutics (CCMT). To learn more about the role of FOXO1 in human CAR T cells, the researchers in this study used CRISPR to delete FOXO1. They found that in the absence of FOXO1, human CAR T cells lose their ability to form a healthy memory cell or protect against cancer in an animal model, supporting the notion that FOXO1 controls memory and antitumor activity. Researchers then applied methods to force CAR T cells to overexpress FOXO1, which turned on memory genes and enhanced their ability to persist and fight cancer in animal models. In contrast, when the researchers overexpressed a different memory-promoting factor, there was no improvement in CAR T cell activity, suggesting that FOXO1 plays a more unique role in promoting T cell longevity. Importantly, researchers also found evidence that FOXO1 activity in patient samples correlates with persistence and long-term disease control, thereby implicating FOXO1 in clinical CAR T cell responses. "These findings may help improve the design of CAR T cell therapies and potentially benefit a wider range of patients," Weber said. "We are now collaborating with labs at CHOP to analyze CAR T cells from patients with exceptional persistence to identify other proteins like FOXO1 that could be leveraged to improve durability and therapeutic efficacy." This study was supported by the National Cancer Institute Immunotherapy Discover and Development grants 1U01CA232361-A1, K08CA23188-01, U01CA260852, and U54CA232568-01; the National Human Genome Research Institute grant K99 HGHG012579 (C.A.L.); the Parker Institute for Cancer Immunotherapy; V Foundation for Cancer Research; Society for Immunotherapy of Cancer Rosenberg Scholar Award; Stand Up 2 Cancer -- St. Baldrick's -- NCI grant SU2CAACR-DT1113; and the Virginia and D.K. Ludwig Fund for Cancer Research and NCI grant U2C CA233285.

Strong start for Omisirge® (omidubicel-onlv) launch with significant payer coverage and number of transplant centers onboarded exceeding expectations Company continues to pursue strategic partnership to further support Omisirge launch Cash runway extended into Q2 2024; balance sheet strengthened with $9 million reduction in debt Company to host conference call today at 8:30 a.m. ET BOSTON--(BUSINESS WIRE)-- Gamida Cell Ltd. (Nasdaq: GMDA), a cell therapy pioneer working to turn cells into powerful therapeutics, today provided a business update and reported financial results for the quarter ended June 30, 2023. “Since the approval of Omisirge in April, Gamida Cell has made excellent progress on the launch,” said Abbey Jenkins, President and Chief Executive Officer of Gamida Cell. “We have rapidly confirmed significant payer coverage and are seeing high interest from transplant centers, exceeding our plans. This is a testament to the unmet needs that Omisirge has the potential to address for patients, as well as the exceptional work of our experienced cell therapy team. We continue to progress our discussions in our efforts to secure a strategic deal to fully resource our Omisirge commercial efforts. We are optimistic that between our progress on the Omisirge launch and our discussions with potential partners, we can accelerate efforts to expand patient access to Omisirge.” The U.S. Food and Drug Administration (FDA) approved Omisirge in April 2023 for use in adult and pediatric patients 12 years and older with hematologic malignancies planned for umbilical cord blood transplantation. The Omisirge launch is ahead of expectations in terms of both transplant center onboarding and market access, with 12 transplant centers already onboarded, eight more in the onboarding process, and active engagement with virtually all of the top 70 transplant centers. The company has also confirmed coverage with payers that cover more than 85% of commercial lives, as well as confirmed coverage and reimbursement with Medicare from the Centers for Medicare and Medicaid Services (CMS). All documents are in place for coverage under the Department of Veterans Affairs, Department of Defense and Medicaid. “We are very encouraged by the strong interest we have received from transplant centers to date, including centers that did not participate in our clinical studies,” said Michele Korfin, Chief Operating and Chief Commercial Officer of Gamida Cell. “The enthusiasm for Omisirge is consistent with expectations from the market research we conducted both pre- and post-approval, supporting our assertion that Omisirge has the potential to capture approximately 20% peak market share. We anticipate this peak share will include patients who might have been otherwise transplanted with a different donor source, as well as patients who historically would not have been able to find an appropriate donor. We have onboarded more centers at this point in our launch than we initially anticipated and are ahead of our expectations in terms of payer coverage. We look forward to engaging with and onboarding additional transplant centers in the coming months to provide more access to Omisirge for patients.” Second Quarter Highlights and Recent Developments Omisirge Commercial progress: The company is seeing strong demand from transplant centers and is ahead of its goal of onboarding 10-15 transplant centers in 2023. As of the morning of August 14, 2023, 12 transplant centers have been onboarded and eight additional transplant centers are in the onboarding process. Patients are enrolled in the company’s Gamida Cell Assist program, which means that their transplanter has the intent to utilize Omisirge as the patient’s donor source. The company has confirmed coverage with payers who cover more than 85% of commercial lives and is in ongoing discussions with additional commercial payers. CMS coverage and reimbursement has been confirmed for patients covered by Medicare. All required documentation is in place for patients who are covered under Medicaid, Department of Defense and Veterans Affairs. The company is ready to reliably deliver Omisirge within 30 days from the start of manufacturing. Publication: The company announced the publication of a prospective sub-study of the Phase 3 clinical trial for Omisirge titled “Immune Reconstitution Profiling Suggests Antiviral Protection After Transplantation with Omidubicel: A Phase 3 Substudy.” The publication is available online on the Transplantation and Cellular Therapy journal website. Corporate Developments Strategic review: The company continues to work with Moelis & Company LLC to engage and advance discussions with multiple parties as part of its efforts to explore alternatives to support a fully resourced launch. Terry Coelho, MBA, appointed Chief Financial Officer: In May 2023, Gamida Cell announced the appointment of Terry Coelho as Chief Financial Officer. Ms. Coelho, a seasoned finance executive with more than 35 years of experience across all areas of finance and business development at emerging growth companies and established global companies, is positioned to support Gamida Cell’s transition into a commercial-phase company and its pursuit of a strategic partnership. Jeremy Blank appointed to Board of Directors: In August 2023, the company’s Board of Directors appointed Jeremy Blank, Chief Investment Officer of Community Fund, to the Board, where he will serve on the Transactions Committee. “Having closely followed Gamida Cell for over a decade, it is a privilege to join the Board of Directors,” said Mr. Blank. “I have high confidence in Gamida’s team and technology and our firm invested in both of Gamida’s most recent equity offerings. I look forward to supporting Gamida’s strategic process which is a great opportunity to create shareholder value.” Mr. Blank will provide a valuable perspective to the Board as it aids the company in executing its corporate strategy. From 2005 to 2020, Mr. Blank also served as a partner at York Capital Management, a $15 billion global investment fund. Before that, he was a Vice President and credit analyst at Morgan Stanley. Mr. Blank currently serves as a Director on the boards of Insightec Ltd. and Advanced Emissions Solutions, Inc. (NASDAQ: ADES). Community Fund is a significant shareholder in Gamida Cell. Strengthened balance sheet: The company ended the second quarter with $54.1 million in cash as a result of the net proceeds of $29.8 million from both the April equity offering and the at-the-market offering (ATM), thereby extending cash runway into the second quarter of 2024. Additionally, the company reduced its outstanding principal balance in the quarter by $9.0 million, from $94.0 million to $85.0 million. Investor Day: Gamida Cell hosted an Investor Day on June 29, 2023. The event was attended by over 180 participants, both in-person and virtual, and included an update on the commercial launch of Omisirge as well as discussions with industry thought leaders. Steven Devine, M.D., Chief Medical Officer at the National Marrow Donor Program® (NMDP)/Be The Match®, discussed the unmet needs and barriers to care in stem cell transplant, and explained how Omisirge can help address some of these issues. Usama Gergis, M.D., MBA, Professor of Oncology & Director of Transplant and Cellular Therapy, Sidney Kimmel Cancer Center, Thomas Jefferson University, discussed the implications of a health outcomes economics research model developed in partnership with Gamida Cell that showed that a 20% peak market share of Omisirge may increase transplant access for eligible patients, particularly those from racially and ethnically diverse groups that are currently underserved. GDA-201 Phase 1 study: Gamida Cell’s GDA-201, an intrinsic natural killer (NK) cell therapy candidate being investigated for the treatment of hematologic malignancies, is being evaluated in an ongoing Phase 1 study for treatment of non-Hodgkin lymphoma. The study is continuing to enroll patients at six sites in the U.S. Data are expected in the first quarter of 2024. Data presented at International Society for Cell and Gene Therapy (ISCT) 2023 Annual Meeting: GDA-201 data presented at ISCT on June 2, 2023 demonstrated the robustness of cryopreserved GDA-201 and continued to support signs of strong lymphoid homing and decreased exhaustion of GDA-201 cells. New data on nicotinamide (NAM) mechanism of action: Data published in Science Translational Medicine in the July 19 edition demonstrated that culturing NK cells with NAM, which the company uses to enhance and expand cells, and IL-15 increases metabolic fitness, energy charge and glucose flux within NK cells, providing a pathway for resistance to oxidative stress and increased potency compared to NK cells cultured with IL-15 but without NAM. Through preventing degradation of the protein FOXO1, the presence of NAM was found to increase levels of CD62L, an important lymph node homing marker. This expression cascade provides evidence for the strong lymph node homing, direct killing and antibody dependent cell-mediated cytotoxicity capabilities of NK cells cultured with NAM. The publication also includes outcome data from the Phase 1 dose escalation clinical trial for Gamida Cell’s NK cell therapy candidate GDA-201 in patients with non-Hodgkin lymphoma as well as translational data from biopsy specimens. Second Quarter 2023 Financial Results Research and development expenses were $8.7 million in the second quarter of 2023, compared to $10.6 million in the same quarter in 2022. The decrease of $1.9 million was primarily due to a $1.6 million reduction associated with the discontinuation of development of our engineered NK cell therapy pipeline, and $0.7 million in lower Omisirge Phase 3 spend, including a decrease in payments for manufacturing services, partially offset by a decrease of $0.4 million in IIA (Israeli Innovation Authority) income. Commercial expenses were $3.9 million in the second quarter of 2023, compared to $3.2 million in the second quarter of 2022. The increase of $0.7 million was attributable to an increase in launch readiness activities. General and administrative expenses were $6.3 million in the second quarter of 2023, compared to $4.3 million in the same period in 2022. The increase of $2.0 million was associated with higher professional services expenses, in part due to the April 2023 follow on offering and business development activities. Financial expenses, net, were $12.9 million in the second quarter of 2023, compared to $0.5 million in the same period of 2022. The increase of $12.4 million was primarily due to non-cash expenses totaling approximately $10.4 million, including the fair value impact on our warrants liability of $4.9 million, the fair value impact on the 2022 convertible note of $4.3 million, and a decrease in capitalization of finance costs to fixed assets of $0.6 million. In addition, the increase was due to higher cash expenses of $2.0 million, including $1.7 million in issuance costs from our April 2023 underwritten public offering and an increase of $1.0 million in interest expenses associated with the 2022 convertible notes, partially offset by increased interest income of $0.5 million. Net loss was $31.7 million in the second quarter of 2023, compared to a net loss of $18.6 million in the second quarter of 2022, driven primarily by the increase in financial expenses of $12.4 million. Cash Position: As of June 30, 2023, Gamida Cell had total cash and cash equivalents of $54.1 million compared to $64.7 million as of December 31, 2022. The decrease of $10.4 million is due primarily to net cash used in operating activities of $44.3 million partially offset by $34.7 million in net cash proceeds from the issuance of shares and warrants from our underwritten public offering and the issuance of shares via the ATM facility. Subsequent to the quarter close and through August 9th, the company raised an additional $14.0 million in net proceeds via the ATM facility. The company expects its current cash and cash equivalents, including the funds raised subsequent to the close of the second quarter, to support its ongoing operating activities into the second quarter of 2024, based on Gamida Cell’s current operational plans and excluding commercialization activities beyond the initial launch of Omisirge, as well as any additional financing activities that may be undertaken. Debt Position: As of June 30, 2023, the company had reduced its principal balance on the 2022 secured convertible note by $15.0 million, from $25.0 million as of December 31, 2022, to $10.0 million at the end of the second quarter. The company also holds a 2021 convertible senior note with an aggregate principal amount of $75.0 million. Conference Call Information Gamida Cell will host a conference call today, August 14, at 8:30 a.m. ET to discuss these financial results and company updates. To access the conference call by phone, please register here and be advised to do so at least 10 minutes prior to joining the call. A live conference call webcast can be accessed here and also in the “Investors & Media” section of Gamida Cell’s website at . A webcast replay will be available approximately two hours after the event for approximately 30 days. About Gamida Cell Gamida Cell is a cell therapy pioneer working to turn cells into powerful therapeutics. The company’s proprietary nicotinamide (NAM) technology leverages the properties of NAM to enhance and expand cells, creating allogeneic cell therapy products and candidates that are potentially curative for patients with hematologic malignancies. These include Omisirge® (omidubicel-onlv), an FDA-approved nicotinamide modified allogeneic hematopoietic progenitor cell therapy, and GDA-201, an intrinsic NK cell therapy candidate being investigated for the treatment of hematologic malignancies. For additional information, please visit or follow Gamida Cell on LinkedIn, Twitter, Facebook or Instagram. Omisirge® is a registered trademark of Gamida Cell Inc. © 2023 Gamida Cell Inc. All Rights Reserved. Cautionary Note Regarding Forward Looking Statements This press release contains forward-looking statements as that term is defined in the Private Securities Litigation Reform Act of 1995, including with respect to the potentially life-saving or curative therapeutic and commercial potential of Omisirge® (omidubicel-onlv), expectations regarding the commercial launch of Omisirge and potential to capture market share, the company’s plans for commercial or strategic partnerships to support the launch of Omisirge and the company’s anticipated financial runway. Any statement describing Gamida Cell’s goals, expectations, financial or other projections, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to a number of risks, uncertainties and assumptions including those related to clinical, scientific, regulatory and technical developments and those inherent in the process of developing and commercializing product candidates that are safe and effective for use as human therapeutics. In light of these risks and uncertainties, and other risks and uncertainties that are described in the Risk Factors section and other sections of Gamida Cell’s Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on August 14, 2023, and other filings that Gamida Cell makes with the SEC from time to time (which are available at ), the events and circumstances discussed in such forward-looking statements may not occur, and Gamida Cell’s actual results could differ materially and adversely from those anticipated or implied thereby. Although Gamida Cell’s forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Gamida Cell. As a result, you are cautioned not to rely on these forward-looking statements. GAMIDA CELL LTD. AND ITS SUBSIDIARY CONDENSED CONSOLIDATED BALANCE SHEETS U.S. dollars in thousands (except share and per share data) June 30, December 31, 2023 2022 (Unaudited) ASSETS CURRENT ASSETS: Cash and cash equivalents $ 54,075 $ 64,657 Restricted Cash 138 - Inventory 2,390 - Prepaid expenses and other current assets 2,262 1,889 Total current assets 58,865 66,546 NON-CURRENT ASSETS: Restricted deposits 3,150 3,668 Property, plant and equipment, net 43,639 44,319 Operating lease right-of-use assets 4,336 7,024 Severance pay fund 1,291 1,703 Other long-term assets 1,227 1,513 Total non-current assets 53,643 58,227 Total assets $ 112,508 $ 124,773 LIABILITIES AND SHAREHOLDERS' DEFICIT CURRENT LIABILITIES: Trade payables $ 2,440 $ 6,384 Employees and payroll accruals 5,545 5,300 Operating lease liabilities 2,176 2,648 Accrued interest of convertible senior notes 1,842 1,652 Accrued expenses and other current liabilities 8,735 8,891 Total current liabilities 20,738 24,875 NON-CURRENT LIABILITIES: Convertible senior notes, net 86,117 96,450 Warrants liability 25,629 - Accrued severance pay 1,403 1,914 Long-term operating lease liabilities 2,461 4,867 Other long-term liabilities 1,873 4,690 Total non-current liabilities 117,483 107,921 CONTINGENT LIABILITIES AND COMMITMENTS SHAREHOLDERS’ DEFICIT: Ordinary shares of NIS 0.01 par value 305 211 Treasury ordinary shares of NIS 0.01 par value * * Additional paid-in capital 443,450 408,598 Accumulated deficit (469,468 ) (416,832 ) Total shareholders’ deficit (25,713 ) (8,023 ) Total liabilities and shareholders’ deficit $ 112,508 $ 124,773 * Represents an amount lower than $1 GAMIDA CELL LTD. AND ITS SUBSIDIARY CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS U.S. dollars in thousands (except share and per share data) (Unaudited) Three months ended June 30, Six months ended June 30, 2023 2022 2023 2022 Research and development expenses, net $ 8,687 $ 10,563 $ 17,527 $ 21,868 Commercial expenses 3,862 3,193 9,438 7,072 General and administrative expenses 6,253 4,290 11,417 8,429 Total operating loss 18,802 18,046 38,382 37,369 Financial expenses, net 12,874 508 14,254 1,408 Loss $ 31,676 $ 18,554 $ 52,636 $ 38,777 Net loss per share attributable to ordinary shareholders, basic and diluted 0.31 0.31 0.59 0.65 GAMIDA CELL LTD. AND ITS SUBSIDIARY CONDENSED CONSOLIDATED STATEMENTS OF CASH FLOWS U.S. dollars in thousands (except share and per share data) (Unaudited) Six months ended June 30, 2023 2022 Cash flows from operating activities: Net Income (Loss) $ (52,636 ) $ (38,777 ) Adjustments to reconcile loss to net cash used in operating activities: Depreciation of property, plant and equipment 214 224 Financing expense (income), net 1,363 (273 ) Share-based compensation 2,921 2,530 Change in Fair Value of Warrants liability 4,876 - Change in Fair Value of convertible senior note 4,254 - Warrants Issuance Costs 1,733 - Amortization of loan issuance costs 455 385 Change in assets and liabilities: Inventory (295 ) - Operating lease right-of-use assets 1,363 1,226 Operating lease liabilities (1,553 ) (1,649 ) Accrued severance pay, net (99 ) 14 Increase in prepaid expenses and other assets (211 ) (19 ) Decrease in trade payables (3,944 ) (5,535 ) Increase (decrease) in accrued expenses and other liabilities (2,728 ) 2,285 Net cash used in operating activities (44,287 ) (39,589 ) Cash flows from investing activities: Purchase of property, plant and equipment (821 ) (1,540 ) Purchase of marketable securities - (3,708 ) Proceeds from maturity of marketable securities - 26,175 Proceeds from restricted deposits - 500 Net cash provided by (used in) investing activities $ (821 ) $ 21,427 Cash flows from financing activities: Proceeds from exercise of options $ - $ 76 Proceeds from exercise of warrants liability 45 - Proceeds from share issuance and warrants liability, net 34,785 84 Payment of warrants issuance cost (166 ) - Net cash provided by financing activities 34,664 160 Decrease in cash and cash equivalents and restricted cash (10,444 ) (18,002 ) Cash and cash equivalents at beginning of period 64,657 55,892 Cash, cash equivalents and restricted cash at end of period $ 54,213 $ 37,890