CT-0508

近日，巨噬细胞疗法先驱公司Carisma Therapeutics宣布了，与Moderna合作的实体瘤项目的首个候选药物提名——一款靶向GPC3的体内CAR-巨噬（CAR-M）疗法。 这是前不久Carisma公司宣布放弃CAR-M项目，转向CAR-单核细胞后，Carisma公司在CAR-M上最新的努力成果。 GPC3靶向体内CAR-M 这份Moderna与Carisma公司的合作可以追溯到2022年1月，当时一份“mRNA LNP在体内指导产生CAR-T细胞”的研究登上了Science封面文章，引起了全球药企对于体内CAR细胞疗法的追捧。 延伸阅读：mRNA LNP体内CAR-巨噬细胞！现在是体内编程CAR-免疫细胞疗法时间 双方合作的首个提名候选药物，是一款靶向GPC3的体内CAR-M，该候选药物同时结合了Moderna的LNP mRNA技术和Carisma的工程单核细胞/巨噬细胞技术；利用LNP（脂质纳米颗粒）将mRNA递送至患者体内，利用mRNA的基因编辑功能对目标细胞进行重编程，使其转变为具备杀伤肿瘤细胞的特定靶向CAR-M细胞。 根据报道，临床前数据表明，该候选药物可以直接在体内成果产生CAR-M，并重定向内源性髓系细胞以攻击癌细胞。 此外，该候选药物的提名将触发Moderna对Carisma的200万美元里程碑付款。 放弃体外CAR-M 事实上，Carisma公司本身是放弃了体外实体瘤CAR-M项目的进一步探索，重点转向CAR-单核细胞的开发。 今年4月发布的一重大战略更新中——裁员37%，并放弃CAR-M项目CT-0508的进一步开发，以及暂停临床前CAR-单核细胞疗法CT-1119，重点专注于更有潜在前景的CAR-单核细胞疗法CT-0525之上。不过，Carisma公司的官网并未显示出以上更新。 放弃最领先的候选管线CT-0508，将赌注全压在CAR-单核细胞疗法CT-0525上，是Carisma公司现金流困境的无奈之举。 同时也是Carisma公司更看好CAR-单核细胞的实体瘤治疗潜力——CAR-单核细胞疗法有可能解决实体瘤细胞治疗的一些挑战，包括肿瘤浸润、肿瘤微环境中的免疫抑制和抗原异质性。 CT-0525是一种离体基因修饰的自体HER2 CAR-单核细胞疗法，目前正在1期临床试验中评估用于治疗HER2过表达的晚期/转移性实体瘤患者。与CAR-巨噬细胞相比，CT-0525可能具有更强的肿瘤浸润能力、持久性，以及更短的生产时间。 目前，CT-0525已经获得美国FDA授予的快速通道资格认证，用于治疗HER2过表达的实体瘤。 工程巨噬细胞的纤维化开发 尽管在实体瘤治疗上，Carisma公司放弃了CAR-M的进一步探索。 但是在纤维化和免疫学上，Carisma公司的工程巨噬细胞疗法取得积极的临床前数据： 单剂量共表达抗纤维化因子relaxin和IL-10的工程巨噬细胞，在CCL4诱导的肝纤维化模型中显著改善了纤维化，与对照组相比，纤维化减少116%；在高脂肪饮食代谢功能障碍相关脂肪性肝炎 （MASH） 模型中显著减少肝纤维化，与对照组相比，纤维化减少45%。 此外，表达显性阴性TGFβ受体的工程巨噬细胞能够使肺部促纤维化TGFβ信号传导无效，阻止了小鼠模型的肺纤维化，与对照组相比，纤维化减少90%。 Carisma公司预计将在2025年第一季度为其肝纤维化项目提名一个开发候选药物。 小结 近年来，各类免疫细胞的肿瘤治疗应用开发非常热门，包括T细胞、NK细胞、巨噬细胞、γδ-T等等，不过相较于T细胞，其他种类细胞治疗进展并不快。 延伸阅读：万物皆可CAR丨探索疾病治疗的另一种可能性 Carisma公司作为全球巨噬细胞开发的先驱者，已经率先放弃CAR-M在实体瘤治疗上的应用，对于业内实体瘤巨噬细胞疗法的开发影响还是蛮大的。 参考资料： 1.https://ir.carismatx.com/news-releases/news-release-details/carisma-therapeutics-announces-nomination-first-vivo-car-m 2.https://ir.carismatx.com/news-releases/news-release-details/carisma-therapeutics-granted-fda-fast-track-designation-ct-0525 3.https://ir.carismatx.com/news-releases/news-release-details/carisma-therapeutics-reports-first-quarter-2024-financial 本周好文推荐 如需转载请联系佰傲谷并在醒目位置注明出处 · · · · · · · ·

Announced CT-0525 as lead product candidate for anti-HER2 program; initial data expected by year-end 2024 Presented preclinical proof of concept data in liver fibrosis at ASGCT; expects to nominate a development candidate in the first quarter of 2025 Presented Regimen Level 1 data from Phase 1 sub-study utilizing CT-0508 in combination with pembrolizumab at AACR; expects to report Regimen Level 2 data in second quarter of 2024 Cash and cash equivalents of $56.5 million expected to fund the Company into the third quarter of 2025 PHILADELPHIA, May 9, 2024 /PRNewswire/ -- Carisma TherapeuticsInc. (Nasdaq: CARM) ("Carisma" or the "Company"), a clinical-stage biopharmaceutical company focused on discovering and developing innovative immunotherapies, today reported financial results for the quarter ended March 31, 2024, and highlighted recent business updates. "We enter the second quarter with a renewed focus on our programs that we believe exhibit the greatest potential and meaningful near-term milestones," said Steven Kelly, President and Chief Executive Officer of Carisma. "We are pleased by the continued clinical validation of our anti-HER2 CAR-M program as evidenced by the initial data from CT-0508 and are excited to shift our attention to the development of CT-0525, which we believe has the potential to significantly increase anti-tumor activity. The preclinical proof of concept data in liver fibrosis fuels our momentum to explore the potential of engineered macrophages beyond oncology. Carisma remains committed to advancing next-generation cell therapies that hold the potential to enhance treatment options for patients grappling with cancer and other serious disorders." First Quarter 2024 Highlights and Upcoming Milestones Ex Vivo Oncology CT-0525 (Anti-HER2 chimeric antigen receptor monocyte (CAR-Monocyte)) In late March 2024, Carisma made the decision to prioritize CT-0525 due to the potential for a CAR-Monocyte to have an approximately 2,000-fold increase in total exposure compared to a CAR-Macrophage. As a result, the Company believes that CT-0525 will be able to build on clinical anti-tumor activity observed in CT-0508, the Company's anti-HER2 CAR-Macrophage. CT-0525 is now Carisma's lead product candidate. Carisma expects to treat the first patient in the CT-0525 Phase 1 clinical study in the second quarter of 2024 and to report initial data from the study by year-end 2024. CT-0508 (Anti-HER2 CAR-Macrophage) Due to the prioritization of CT-0525, Carisma has ceased recruitment of new patients into Study 101 and its sub-studies. However, the Company will continue all study operations for enrolled subjects. On April 10, 2024, during its presentation at the American Association for Cancer Research (AACR) 2024 Annual Meeting, Carisma reported Regimen Level 1 data (n=3 patients) from the open label Phase 1 (Study 101) sub-study utilizing CT-0508 in combination with pembrolizumab, a programmed cell death protein 1 (PD-1) checkpoint inhibitor. Based on preliminary results from these three patients, the combination therapy has been generally well-tolerated after infusion with no dose-limiting toxicities. Carisma observed a best overall response of progressive disease in the first two patients and stable disease in the third patient, per RECIST 1.1 criteria. The patient who achieved stable disease presented the greatest increase in peripheral blood T cell clonality seen across all 17 patients treated to date in Study 101 and had one out of two target lesions reduced by approximately 46%. Carisma expects to report data from Regimen Level 2 in the Study 101 sub-study evaluating the co-administration of CT-0508 and pembrolizumab in the second quarter of 2024. CT-1119 (Anti-Mesothelin CAR-Monocyte) In late March 2024, Carisma made the decision to pause further development of CT-1119, pending additional financing. Fibrosis and Immunology Fibrosis On May 8, 2024, during its presentation at the American Society of Gene and Cell Therapy (ASGCT) 2024 Annual Meeting, Carisma reported preclinical proof of concept data of its engineered macrophages for the treatment of liver fibrosis. In the presentation titled "Genetically Engineered Macrophage Cell Therapy Reverses Liver and Lung Fibrosis in Preclinical Models," Carisma presented preclinical proof of concept data for engineered macrophage cell therapy in liver fibrosis. In a CCL4-induced liver fibrosis model, the data showed that a single dose of macrophages co-expressing the anti-fibrotic factor relaxin and the anti-inflammatory cytokine IL10 significantly improved established fibrosis with a 116% reduction in fibrosis relative to untreated control. In addition, systemic administration of engineered macrophages co-expressing relaxin and IL10 significantly reduced liver fibrosis in a high fat diet metabolic dysfunction-associated steatohepatitis (MASH) model, with a 45% reduction in fibrosis relative to untreated control. In both models, the relaxin-IL10 macrophage treatment also resulted in a greater reduction in liver fibrosis compared to non-engineered macrophages. The presentation also included initial preclinical data for the use of engineered macrophages in pulmonary fibrosis. The data showed that a single dose of macrophages expressing a dominant negative TGFβ receptor, which nullified pro-fibrotic TGFβ signaling in the lung, prevented fibrosis in a bleomycin mouse model of pulmonary fibrosis, with a 90% reduction in fibrosis relative to untreated control. Carisma expects to nominate a development candidate for its liver fibrosis program in the first quarter of 2025. Corporate Updates On May 2, 2024, Carisma announced the appointment of Eugene P. Kennedy, M.D., F.A.C.S. as the Company's Chief Medical Officer. Dr. Kennedy brings over 15 years of clinical and industry experience, including cross-functional leadership driving clinical development and regulatory strategies for oncology and immuno-oncology focused organizations. On April 1, 2024, Carisma announced a pipeline reprioritization and corporate restructuring. The pipeline reprioritization includes stopping recruitment of new patients in the Phase 1 clinical study of CT-0508 (Study 101) to focus the Company's efforts and resources on CT-0525 as its lead anti-HER2 product candidate, as well as pausing development of CT-1119 pending additional financing. As a result of the pipeline reprioritization and corporate restructuring, Carisma reduced its workforce by approximately 37% in the second quarter of 2024. On April 1, 2024, Carisma announced the appointment of John Hohneker, M.D. to the Board of Directors of the Company, effective April 1, 2024. Dr. Hohneker brings over 30 years of extensive experience in drug development and leadership across the biotech and pharmaceutical sectors. The Company concurrently announced the resignation of Chidozie Ugwumba from Carisma's Board of Directors, also effective April 1, 2024. First Quarter 2024 Financial Results Cash and cash equivalents as of March 31, 2024 were $56.5 million, compared to $77.6 million as of December 31, 2023. Research and development expenses for the three months ended March 31, 2024 were $17.5 million, compared to $16.6 million for the three months ended March 31, 2023. The increase of $0.8 million was primarily due to a $0.9 million increase in personnel costs due to increased stock-based compensation and payroll, $0.7 million increase in direct costs associated with pre-clinical development of CT-0525, a $0.4 million increase in direct costs associated with the pre-clinical development related to CT-1119, partially offset by a $0.7 million decrease in direct costs associated with CT-0508, a $0.4 million decrease in our facilities and other expenses associated with a decrease in sponsored research agreement fees, and a $0.1 million decrease in costs associated with a reduction in pass through studies. General and administrative expenses for the three months ended March 31, 2024 were $5.4 million, compared to $9.6 million for the three months ended March 31, 2023. The decrease of $4.1 million was attributable to a $3.5 million decrease in personnel costs including severance and related costs resulting from the Merger offset by an increase in salaries and stock-based compensation, and a $0.7 million decrease in professional fees as a result of non-recurring legal costs associated with the Merger. Net loss was $19.0 million for the first quarter of 2024, compared to a $24.6 million net loss for the same period in 2023. Outlook Carisma anticipates that its cash and cash equivalents of $56.5 million as of March 31, 2024, combined with the expected cost savings from implementing the revised operating plan, are sufficient to sustain its planned operations into the third quarter of 2025. About CT-0525 CT-0525 is a first-in-class, ex vivo gene-modified autologous chimeric antigen receptor-monocyte (CAR-Monocyte) cellular therapy intended to treat solid tumors that overexpress human epidermal growth factor receptor 2 (HER2). It is being studied in a multi-center, open label, Phase 1 clinical trial for patients with advanced/metastatic HER2-overexpressing solid tumors that have progressed on available therapies. The CAR-Monocyte approach has the potential to address some of the challenges of treating solid tumors with cell therapies, including tumor infiltration, immunosuppression within the tumor microenvironment, and antigen heterogeneity. CT-0525 has the potential to enable significant dose escalation, enhance tumor infiltration, increase persistence, and reduce manufacturing time compared to CT-0508. About CT-0508 CT-0508 is an ex vivo gene-modified autologous chimeric antigen receptor-macrophage (CAR-Macrophage) cellular therapy intended to treat solid tumors that overexpress HER2. It is being evaluated in a Phase 1 multi-center clinical trial that focuses on patients with recurrent or metastatic HER2-overexpressing solid tumors whose cancers do not have approved HER2-targeted therapies or who do not respond to treatment. The Phase 1 clinical trial marks the first time that engineered macrophages are being studied in humans. About Carisma Therapeutics Carisma Therapeutics Inc. is a clinical-stage biopharmaceutical company focused on utilizing our proprietary macrophage and monocyte cell engineering platform to develop transformative immunotherapies to treat cancer and other serious diseases. We have created a comprehensive, differentiated proprietary cell therapy platform focused on engineered macrophages and monocytes, cells that play a crucial role in both the innate and adaptive immune response. Carisma is headquartered in Philadelphia, PA. For more information, please visit . Cautionary Note on Forward-Looking Statements Statements in this press release about future expectations, plans and prospects, as well as any other statements regarding matters that are not historical facts, may constitute "forward-looking statements" within the meaning of The Private Securities Litigation Reform Act of 1995. These statements include, but are not limited to, statements relating to Carisma's business, strategy, future operations, cash runway, the advancement of Carisma's product candidates and product pipeline, and clinical development of Carisma's product candidates, including expectations regarding timing of initiation and results of clinical trials. The words "anticipate," "believe," "contemplate," "continue," "could," "estimate," "expect," "goals," "intend," "may," "might," "outlook," "plan," "project," "potential," "predict," "target," "possible," "will," "would," "could," "should," and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements are based on management's current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in, or implied by, such forward-looking statements. These risks and uncertainties include, but are not limited to, (i) Carisma's ability to realize the anticipated benefits of its pipeline reprioritization and corporate restructuring, (ii) Carisma's ability to obtain, maintain and protect its intellectual property rights related to its product candidates; (iii) Carisma's ability to advance the development of its product candidates under the timelines it anticipates in planned and future clinical trials and with its current financial and human resources; (iv) Carisma's ability to replicate in later clinical trials positive results found in preclinical studies and early-stage clinical trials of its product candidates; (v) Carisma's ability to realize the anticipated benefits of its research and development programs, strategic partnerships, research and licensing programs and academic and other collaborations; (vi) regulatory requirements or developments and Carisma's ability to obtain and maintain necessary approvals from the U.S. Food and Drug Administration and other regulatory authorities related to its product candidates; (vii) changes to clinical trial designs and regulatory pathways; (viii) risks associated with Carisma's ability to manage expenses; (ix) changes in capital resource requirements; (x) risks related to the inability of Carisma to obtain sufficient additional capital to continue to advance its product candidates and its preclinical programs; and (xi) legislative, regulatory, political and economic developments. For a discussion of these risks and uncertainties, and other important factors, any of which could cause Carisma's actual results to differ from those contained in the forward-looking statements, see the "Risk Factors" set forth in the Company's Annual Report on Form 10-K for the year ended December 31, 2023, as well as discussions of potential risks, uncertainties, and other important factors in Carisma's other recent filings with the Securities and Exchange Commission. Any forward-looking statements that are made in this press release speak as of the date of this press release. Carisma undertakes no obligation to revise the forward-looking statements or to update them to reflect events or circumstances occurring after the date of this press release, whether as a result of new information, future developments or otherwise, except as required by the federal securities laws. Investors: Shveta Dighe Head of Investor Relations investors@carismatx.com Company Codes: NASDAQ-NMS:CARM, EuronextParis:CARM