On March 31, 2025 Carisma Therapeutics Inc. (Nasdaq: CARM) ("Carisma" or the "Company") reported that its Board of Directors has approved a revised operating plan focused on evaluating strategic alternatives while reducing operational cash burn (Press release, Carisma Therapeutics, MAR 31, 2025, View Source [SID1234651695]).

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The Company’s goal is to maximize the value of its assets, including its liver fibrosis and oncology development programs, its macrophage and monocyte engineering platform and the CAR-M platform and to realize value from the potential future milestone and royalty payments under Carisma’s agreement with Moderna. To support this transition, the Company has reduced its workforce, retaining only those employees deemed essential to pursue strategic alternatives. With these actions, the Company estimates that it has cash and cash equivalents sufficient to fund its operations into the second half of 2025.

The Company will assess a full range of strategic alternatives, including but not limited to, the sale, license, monetization, and/or divestiture of one or more of the Company’s assets or technologies, a strategic collaboration, partnership, or merger with one or more parties, or the sale of the Company. The Company’s exploration of strategic alternatives may not result in the consummation of any transaction or the realization of any value for the Company or its stockholders.

"While difficult, we believe pursuing strategic alternatives coupled with a reduction in operating costs has the potential to maximize the value of our science and other assets given the challenging funding environment," said Steven Kelly, President and Chief Executive Officer of Carisma Therapeutics. "We believe deeply in the potential of our liver fibrosis and oncology programs, which have shown compelling preclinical results, and are well-positioned for future development. We are focused on finding a strategic transaction that would allow this important work to continue and maximize the value of all our assets. I’m incredibly proud of our team’s pioneering efforts and remain optimistic about the future of our technology."

Pipeline Updates

Fibrosis

Our liver fibrosis program is based upon the discovery of a key efferocytosis defect in the macrophages that reside within the livers of patients with fibrosis. Using a novel mRNA/LNP approach, our product candidate, CT-2401, aims to reverse fibrotic disease and improve the outcomes of patients with advanced liver fibrosis.
In the second quarter of 2024, we achieved pre-clinical proof of concept in our liver fibrosis program, demonstrating the anti-fibrotic potential of engineered macrophages in two liver fibrosis models.
CT-2401 has the potential to be a first-in-class efferocytosis therapy for advanced metabolic associated liver disease.
Ex Vivo Oncology

CT-1119 is a next generation CAR-monocyte designed to treat patients with advanced mesothelin-positive solid tumors, including pancreatic cancer, ovarian cancer, lung cancer, mesothelioma, and others.
Prior to pausing our research and development activities, we planned to initiate a Phase 1 clinical trial of CT-1119, a mesothelin-targeted CAR-Monocyte, in combination with tislelizumab, an anti-PD-1 antibody, in adult patients with mesothelin-positive solid tumors, in China.
In Vivo Program (Moderna Collaboration)

In June 2024, we announced that Moderna nominated the first development candidate under the collaboration, which targets Glypican-3, or GPC3.
In November 2024, we announced new pre-clinical data on our anti-GPC3 in vivo CAR-M therapy for treating hepatocellular carcinoma. These pre-clinical data demonstrated robust anti-tumor activity.
In February 2025, Moderna nominated ten additional oncology research targets and ceased development of two oncology research targets and two autoimmune research targets.
As of February 2025, Moderna has nominated all 12 oncology research targets under the collaboration for which we have the potential to receive future milestones and royalty payments.
The Company will not conduct any additional research activities under the collaboration agreement, and we will not be receiving any further research funding from Moderna under the collaboration agreement.
Moderna agreed to terminate the in vivo oncology field exclusivity, which would allow us to pursue in vivo CAR-M programs outside of the 12 nominated oncology targets and product polypeptides.
Corporate Update

On March 25, 2025, the Company’s Board of Directors approved a revised operating plan focused on evaluating strategic alternatives and preserving capital.
The Company has reduced operations to core functions necessary to support this strategic review and has paused all research and development activities at this time, pending the outcome of the review.
The Company may engage external advisors to support the evaluation of strategic alternatives and prepare for a potential wind-down of operations, if necessary.

On March 31, 2025 Abbisko Therapeutics Co., Ltd. ("Abbisko Therapeutics") reported that Merck has exercised the global commercialization option for pimicotinib (ABSK021), with an option exercise fee of USD85.0 million, under the licensing agreement signed in December 2023 (Press release, Merck & Co, MAR 31, 2025, View Source [SID1234651694]). The development represents further deepening of the collaboration, underscoring the unwavering commitment and confidence that both parties possess for the ongoing advancement of pimicotinib.

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In December 2023, Abbisko Therapeutics entered into an exclusive licensing agreement (the "Agreement") with Merck regarding pimicotinib, a CSF-1R inhibitor. Under the terms of the Agreement, Merck initially had an exclusive license to commercialize pimicotinib for all indications in the Chinese mainland, Hong Kong, Macau and Taiwan with an exclusive option for global commercial rights of pimicotinib. Merck now has exercised such option and has the exclusive license to commercialize pimicotinib worldwide. Abbisko Therapeutics has already received the one-time, non-refundable upfront payment of USD70.0 million in February 2024, and is now entitled to receive the additional option exercise fee of USD85.0 million. Additionally, Merck has the option to co-develop pimicotinib for additional indications under certain conditions. In total, Abbisko Therapeutics is eligible to receive up to USD605.5 million in payments, including upfront, development, and commercial milestones, as well as double-digit percentage royalties on annual net sales.

Pimicotinib is a novel, orally administered, highly selective, and potent small molecule CSF-1R inhibitor, independently developed by Abbisko Therapeutics. Pimicotinib’s positive topline results from the Global Phase III MANEUVER Study in tenosynovial giant cell tumor ("TGCT") were successfully released in November 2024, where MANEUVER met the primary endpoint with an objective response rate ("ORR") at Week 25 of 54.0% for pimicotinib compared with 3.2% for placebo (p<0.0001), and treatment with oral, once-daily pimicotinib was well-tolerated with very low rates of discontinuation due to treatment-related adverse events, and with no evidence of cholestatic hepatotoxicity.

Yao-Chang Xu, Chairman and CEO of Abbisko Therapeutics, said, "Pimicotinib represents a key advancement within the emerging class of CSF-1R inhibitors, demonstrating a meaningful clinical efficacy and safety profile that positions it as an innovative treatment option for worldwide TGCT patients. We look forward to deepening our collaboration with the Merck team to expedite the registration process of pimicotinib to bring benefits to patients as quickly as possible."

"Today marks a significant milestone in our partnership with Abbisko as we work together to deliver a potentially best-in-class therapy for patients with TGCT around the world," said Andrew Paterson, Chief Marketing Officer for the Healthcare business sector of Merck. "This collaboration underscores our commitment to advancing new treatment options in rare oncology for patients who need them. With this important step forward, we aim to transform the treatment landscape and offer hope to those living with TGCT, who today have very limited treatment options."

On March 31, 2025 Daiichi Sankyo reported first patient has been dosed in the DESTINYGastric05 phase 3 trial evaluating ENHERTU (trastuzumab deruxtecan) in combination with a fluoropyrimidine chemotherapy (5-FU or capecitabine) and Merck’s (known as MSD outside of the US and Canada) anti-PD-1 therapy KEYTRUDA (pembrolizumab) versus trastuzumab in combination with platinum-based chemotherapy (cisplatin plus 5-FU or oxaliplatin plus capecitabine) and pembrolizumab in previously untreated patients with unresectable, locally advanced or metastatic HER2 positive (IHC 3+ or IHC 2+/ISH+) gastric or gastroesophageal junction (GEJ) cancer with PD-L1 CPS ≥1 (Press release, Daiichi Sankyo, MAR 31, 2025, View Source [SID1234651693]). An exploratory cohort of patients with PD-L1 CPS <1 will be randomized to either ENHERTU plus fluoropyrimidine or trastuzumab plus platinum-based chemotherapy.

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ENHERTU is a specifically engineered HER2 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo (TSE: 4568) and being jointly developed and commercialized by Daiichi Sankyo and AstraZeneca (LSE/STO/Nasdaq: AZN).

Gastric cancer is associated with a poor prognosis, particularly in advanced stages of the disease where the five-year survival rate is 5% to 10%. 1 Current recommended first-line treatment for HER2 positive advanced gastric cancer with PD-L1 CPS ≥1 is trastuzumab in combination with platinum-based chemotherapy (cisplatin plus 5-FU or oxaliplatin plus capecitabine) and pembrolizumab. 2,3 New treatment strategies are needed to continue to improve survival, including additional HER2 directed treatment options.

"Following the positive overall survival results seen with DESTINY-Gastric04 in the second-line HER2 positive metastatic gastric cancer setting, the DESTINY-Gastric05 trial will explore the role of ENHERTU earlier in the metastatic setting as a first-line treatment," said Mark Rutstein, MD, Global Head, Oncology Clinical Development, Daiichi Sankyo. "With DESTINY-Gastric05, we are evaluating whether a potential platinum-free chemotherapy regimen of ENHERTU combined with immunotherapy and a fluoropyrimidine chemotherapy can further improve survival in patients with previously untreated HER2 positive metastatic gastric cancer."

ENHERTU is currently approved in more than 65 countries in the second-line or third-line metastatic setting of HER2 positive gastric cancer based on DESTINY-Gastric01, a randomized phase 2 trial, and DESTINYGastric02 and DESTINY-Gastric06, two single-arm phase 2 trials. KEYTRUDA is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

About DESTINY-Gastric05

DESTINY-Gastric05 is a global, multicenter, randomized, open-label, phase 3 trial evaluating the efficacy and safety of ENHERTU (5.4 mg/kg) in combination with a fluoropyrimidine-based chemotherapy (5-FU or capecitabine) and Merck’s (known as MSD outside of the US and Canada) anti-PD-1 therapy KEYTRUDA (pembrolizumab) versus trastuzumab in combination with platinum-based chemotherapy (cisplatin plus 5-FU or oxaliplatin plus capecitabine) and pembrolizumab in approximately 576 previously untreated patients with unresectable, locally advanced or metastatic HER2 positive (IHC 3+ or IHC 2+/ISH+) gastric or GEJ cancer with PD-L1 CPS ≥1.

The primary endpoint is progression-free survival (PFS) as assessed by blinded independent central review. The key secondary endpoint is overall survival. Additional secondary endpoints include PFS as assessed by investigator, objective response rate, duration of response and safety.

An exploratory cohort of 150 patients with PD-L1 CPS <1 will be randomized to either ENHERTU plus fluoropyrimidine (5-FU or capecitabine) or trastuzumab plus platinum-based chemotherapy (cisplatin plus 5- FU or oxaliplatin plus capecitabine).

DESTINY-Gastric05 will enroll patients across multiple sites in Asia, Europe, North America and South America. For more information about the trial, visit ClinicalTrials.gov.

About HER2 Positive Gastric Cancer
Gastric (stomach) cancer is the fifth most common cancer worldwide and the fifth leading cause of cancerrelated death.
4 Approximately one million cases were diagnosed in 2022.4 Gastric cancer is associated with a poor prognosis, particularly in advanced stages of the disease where the five-year survival rate is 5% to 10%.

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors, including gastric cancer.5 Approximately one in five gastric cancers globally are HER2 positive.Recommended first-line treatment for HER2 positive advanced gastric cancer with PD-L1 CPS ≥1 is trastuzumab in combination with platinum-based chemotherapy (cisplatin plus 5-FU or oxaliplatin plus capecitabine) and pembrolizumab.2,3 In patients with PD-L1 CPS <1 recommended first-line treatment is trastuzumab plus platinum-based chemotherapy (cisplatin plus 5-FU or oxaliplatin plus capecitabine). 2 New treatment strategies, including additional HER2 directed treatment options, are needed to continue to improve survival in patients with previously untreated advanced gastric cancer.

On March 31, 2025 Halozyme Therapeutics, Inc. (NASDAQ: HALO) (Halozyme) reported that Bristol Myers Squibb received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency, recommending approval of a new Opdivo (nivolumab) subcutaneous formulation developed with ENHANZE, Halozyme’s proprietary recombinant human hyaluronidase enzyme (rHuPH20), across multiple previously approved adult solid tumors as monotherapy, monotherapy maintenance following completion of nivolumab plus Yervoy (ipilimumab) combination therapy, or in combination with chemotherapy or cabozantinib (Press release, Halozyme, MAR 31, 2025, View Source [SID1234651692]).

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The CHMP opinion will now be reviewed by the European Commission, which has the authority to approve medicines in the European Union. A decision on the European extension of marketing authorization for the subcutaneous formulation of Opdivo is expected by June 2, 2025.

"We are delighted that the subcutaneous formulation of Opdivo developed with Halozyme’s ENHANZE drug delivery technology was recommended for approval in the European Union. Subcutaneous delivery of Opdivo would provide cancer patients a faster and more flexible treatment option and may help alleviate pressure on healthcare system resources," said Dr. Helen Torley, president and chief executive officer of Halozyme.

The CHMP positive opinion is supported by positive results from the Phase 3 CheckMate -67T trial. For more information on the study and its findings, please view Bristol Myers Squibb’s press release issued on March 28, 2025.

On December 27, 2024, nivolumab and hyaluronidase-nvhy, marketed under the brand name Opdivo Qvantig, was approved by the U.S. Food and Drug Administration.

On March 31, 2025 Theriva Biologics (NYSE American: TOVX), a diversified clinical-stage company developing therapeutics designed to treat cancer and related diseases in areas of high unmet need, reported that a second Independent Data Monitoring Committee (IDMC) review of data from the VIRAGE Phase 2b clinical trial in newly-diagnosed metastatic pancreatic ductal adenocarcinoma (PDAC) found that that VCN-01 was well tolerated in combination with standard-of-care chemotherapy (gemcitabine/nab-paclitaxel) and the adverse event (AE) profile was as expected for the patient population and the medications being studied (Press release, Theriva Biologics, MAR 31, 2025, View Source [SID1234651691]).

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The IDMC, composed of key opinion leaders in pancreatic cancer and oncolytic viruses, reviewed clinical data from the complete safety population of 101 patients enrolled across 5 sites in the U.S. and 9 sites in Spain. The VCN-01 AE profile was consistent with that observed in prior clinical trials. The most common VCN-01 related AEs (pyrexia, flu-like illness, vomiting, nausea, and elevated transaminases) were transient and reversible. These AEs were observed to be less frequent and of reduced CTCAE grade after the second VCN-01 dose (administered on day 92) compared to the first VCN-01 dose (administered on day 1). The IDMC noted that the overall type and number of AEs in the VCN-01 treatment group was as expected for the pancreatic cancer population, the duration of treatment, and the administration of an oncolytic virus. VIRAGE patient enrollment was completed in September 2024 and topline clinical outcomes data are anticipated in Q2 2025.

"This second positive IDMC review of VCN-01 safety data from a larger number of patients affirms the feasibility of repeated VCN-01 dosing in metastatic PDAC patients" said Steven A. Shallcross, Chief Executive Officer of Theriva Biologics. "We are now working towards the release of topline clinical outcomes data in Q2 2025. If positive, these data, in combination with the previously reported feedback from the FDA and EMA, will guide the design of a potential Phase 3 registrational trial for discussion with regulatory agencies later this year."

About VIRAGE
VIRAGE is a two-arm, Phase 2b open-label, randomized, controlled, multicenter clinical trial in patients with histologically confirmed, newly-diagnosed metastatic PDAC. Patients have been enrolled at 5 sites in the U.S> and 9 sites in Spain. In both the control and VCN-01 treatment arms, patients receive gemcitabine/nab-paclitaxel standard-of-care chemotherapy in repeated 28-day cycles until disease progression. In the VCN-01 treatment arm only, patients are also administered intravenous VCN-01 seven-days prior to starting the first and fourth cycles of gemcitabine/nab-paclitaxel treatment (study days 1 and ~92 respectively). Primary endpoints for the trial include overall survival and VCN-01 safety/tolerability. Additional endpoints include progression free survival, objective response rate, and measures of VCN-01 biodistribution, replication, and immune response. More information about the trial is available on Clinicaltrials.gov (NCT05673811), through the Spanish Clinical Trials Registry and European Union Drug Regulating Authorities Clinical Trials Database (EudraCT Number: 2022-000897-24).

About VCN-01
VCN-01 is a systemically administered oncolytic adenovirus designed to selectively and aggressively replicate within tumor cells and degrade the tumor stroma that serves as a significant physical and immunosuppressive barrier to cancer treatment. This unique mode-of-action enables VCN-01 to exert multiple antitumor effects by (i) selectively infecting and lysing tumor cells; (ii) enhancing the access and perfusion of co-administered chemotherapy products; and (iii) increasing tumor immunogenicity and exposing the tumor to the patient’s immune system and co-administered immunotherapy products. Systemic administration enables VCN-01 to exert its actions on both the primary tumor and metastases. VCN-01 has been administered to 142 patients in clinical trials of different cancers, including PDAC (in combination with chemotherapy), head and neck squamous cell carcinoma (with an immune checkpoint inhibitor), ovarian cancer (with CAR-T cell therapy), colorectal cancer, and retinoblastoma (by intravitreal injection).