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 Aprea Therapeutics, Inc. (Nasdaq: APRE) ("Aprea", or the "Company"), a clinical-stage biopharmaceutical company developing innovative treatments that exploit specific cancer cell vulnerabilities while minimizing damage to healthy cells, reported that a patient with HPV+ head and neck squamous cell carcinoma (HNSCC) has been dosed in the ongoing ACESOT-1051 clinical trial evaluating APR-1051 (Press release, Aprea, MAR 31, 2025, View Source [SID1234651658]). This is the first patient to be dosed in Cohort 5 (70 mg once daily) of the study. Open label data from the study are expected in the second half of 2025.

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WEE1 inhibition has emerged as a promising strategy for targeting tumor cells with high replication stress and DNA damage accumulation. HPV driven cancers, including HPV+ HNSCC, are characterized by defects in the DDR pathway, making them potentially susceptible to WEE1 inhibition. HPV+ cancers are those where the underlying cause is persistent infection with human papillomavirus, a group of viruses that infect the skin and mucous membranes. A high proportion of HNSCC cases are attributable to HPV. An estimated 70% of the 20,000 cases of oropharyngeal squamous cell carcinoma (HNSCC that occurs in the oropharynx) seen annually in the US are attributable to HPV.

APR-1051 is a potent and selective small molecule that has been designed to potentially solve tolerability challenges of the WEE1 class. The ongoing ACESOT-1051 (A Multi-Center Evaluation of WEE1 Inhibitor in Patients with Advanced Solid Tumors, APR-1051) clinical trial is a Phase 1 trial evaluating single-agent APR-1051 in patients with advanced solid tumors harboring cancer-associated specific gene alterations.

"Enrollment of the first patient with HPV+ head and neck cancer in the Phase 1 ACESOT-1051 trial is an important step and is in line with our goal of identifying patient populations most likely to benefit from WEE1 inhibition," said Philippe Pultar MD., Senior Medical Advisor and Lead WEE1 Clinical Development of Aprea. "We are pleased with the progress of the trial and encouraged by the safety profile of APR-1051 to date. We look forward to continuing the study as we work toward identifying the optimal dose for future studies. We continue to believe that APR-1051 has best in class potential."

The latest patient in ACESOT-1051 was enrolled at MD Anderson Cancer Center. Aprea recently entered into a Material Transfer Agreement (MTA) with MD Anderson to support preclinical research aimed at exploring the potential of APR-1051 in treating HPV+ and HPV- head and neck squamous cell carcinoma (HNSCC) expressing genomic markers of replication stress.

ACESOT-1051 Study Design

ACESOT-1051 (A Multi-Center Evaluation of WEE1 Inhibitor in Patients with Advanced Solid Tumors, APR-1051) is designed to assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of single-agent APR-1051 in advanced solid tumors harboring cancer-associated gene alterations. Oral APR-1051 will be administered once daily for 28-day cycles. The study consists of two parts. Part 1 is dose escalation and is expected to enroll up to 39 patients with advanced solid tumors. The first three dose levels (10mg, 20mg and 30mg) used accelerated titration. Bayesian Optimal Interval (BOIN) design is now being employed for the remaining dose levels (50mg and above). Part 2 (up to 40 patients) is designed for dose optimization, with the goal of selecting the Recommended Phase 2 Dose (RP2D).

The primary objectives of the study are to measure safety, dose-limiting toxicities (DLTs), maximum tolerated dose or maximum administered dose (MTD/MAD), and RP2D; secondary objectives are to evaluate pharmacokinetics, preliminary efficacy according to RECIST or PCWG3 criteria; pharmacodynamics is an exploratory objective. The University of Texas MD Anderson Cancer Center is the lead site, and the study will be performed at between 3 and 10 sites in the U.S. For more information refer to clinicaltrials.gov NCT06260514.

On March 31, 2025 Kazia Therapeutics Limited (NASDAQ: KZIA) ("Kazia" or "the Company"), an oncology-focused drug development company, reported the sale of all intellectual property and trademarks rights to Cantrixil for USD $1 million (Press release, Kazia Therapeutics, MAR 31, 2025, View Source [SID1234651677]).

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In March 2021, Vivesto licensed the exclusive global development and commercialization rights for Cantrixil from Kazia Therapeutics. Having decided not to pursue development of Cantrixil in ovarian cancer, as originally anticipated under the license, Vivesto is currently exploring Cantrixil preclinically for the treatment of hematological cancers. Cantrixil, a legacy molecule in the Kazia pipeline, is a product candidate consisting of the active molecule, a potent and selective third generation benzopyran SMETI inhibitor named TRXE-002-01, encapsulated in α-cyclodextrin.

"We are pleased to enter into this agreement with Vivesto, which provides a source of non-dilutive funding that will help advance our proprietary, clinical-stage pipeline," said John Friend, M.D., Chief Executive Officer of Kazia Therapeutics.

On March 31, 2025 UZ Leuven and VIB-KU Leuven, in collaboration with Seattle-based Presage Biosciences, reported the first patient treated in a Non-randomized (phase I – pharmacodynamic only) open label, single center single arm interventional pilot study (Press release, Presage Biosciences, MAR 31, 2025, View Source [SID1234651696]). By combining intratumoral treatment with systemic anti-PD1 therapy in first line patients with metastatic (stage IV) or inoperable stage III melanoma, the trial studies how patient tumors respond to up to 7 different drugs simultaneously dosed intratumorally with the help of Presage’s Comparative In Vivo Oncology (CIVO) microinjection device.

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The drugs are spatially microdosed in a patient’s tumor while they are also undergoing anti-PD1 systemic therapy with the goal of identifying drugs that have an enhanced combination effect in this patient population. The localized effect of the different drugs is analyzed with cutting edge single cell spatial technology providing new insights into melanoma biology and the anti-tumor action of the CIVO dosed drugs when combined with systemic anti-PD1 therapy.

Prof. Dr. Oliver Bechter, Medical Oncologist at UZ Leuven, comments on this innovative study design: "This is the first study of its kind studying locally administered anti-cancer drugs in combination with systemic anti-PD1 therapy in first line treated melanoma patients. With this pilot study we intend to study the effect of novel combination therapies intratumorally very early in the treatment course of melanoma patients. This pilot study will show the feasibility of such an approach to find new treatments especially for anti-PD1 refractory patients."

Prof. Dr. Chris Marine, Cancer Biologist of the VIB-KU Leuven Center for Cancer Biology added: "The introduction of this groundbreaking technology has ushered us into a new frontier in translational research, enabling us to translate our most promising laboratory discoveries directly into patients. By utilizing our expertise in advanced spatial multi-omics, we will gain an unparalleled understanding of each tumor’s biology and its sensitivity to various drug combinations. The unique data generated from this will be invaluable in accelerating our efforts to combat this disease."

This first of its kind study is made possible by the multiplex CIVO delivery technology developed by Presage that is now being used in early phase clinical studies to evaluate multiple investigational new drugs and combinations all within a single intact patient tumor. Jason Frazier, VP of Technology and Research Operations at Presage echoed the enthusiasm for this novel clinical study design: "Drs. Bechter and Marine and their teams at UZ Leuven and VIB-KU Leuven have come up with an exciting and innovative clinical study design to assess tumor response to multiple different drugs in combination with Check Point blockade using our CIVO technology. This personalized approach to identify effective combination therapies holds great promise for the treatment of melanoma patients."

On March 31, 2025 AstraZeneca reported that Calquence (acalabrutinib) in combination with bendamustine and rituximab has been recommended for approval in the European Union (EU) for the treatment of adult patients with previously untreated mantle cell lymphoma (MCL) who are not eligible for autologous hematopoietic stem cell transplantation (Press release, AstraZeneca, MAR 31, 2025, View Source [SID1234651659]).

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) based its positive opinion on the results from the ECHO Phase III trial which were presented at the European Hematology Association (EHA) (Free EHA Whitepaper) 2024 Congress.

Results from the ECHO trial showed Calquence plus bendamustine and rituximab reduced the risk of disease progression or death by 27% compared to standard-of-care chemoimmunotherapy (hazard ratio [HR] 0.73; 95% confidence interval [CI] 0.57-0.94; p=0.016). Median progression-free survival (PFS) was 66.4 months for patients treated with the Calquence combination versus 49.6 with chemoimmunotherapy alone.

This recommendation for Calquence as a combination treatment in the 1st-line MCL setting follows the recent CHMP positive opinion for Calquence as a monotherapy for the treatment of adult patients with relapsed or refractory MCL.

Martin Dreyling, MD, Department of Medicine, University Hospital LMU Munich, and investigator in the trial, said: "Results from the pivotal ECHO trial demonstrated the significant benefits of the Calquence combination in managing this rare and aggressive cancer. Today’s recommendation is an important advance within the mantle cell lymphoma first-line treatment landscape, especially for older patients who need a balance of efficacy and tolerability."

Susan Galbraith, Executive Vice President, Oncology Haematology R&D, AstraZeneca, said: "Today’s positive recommendation from the CHMP further reinforces the potential of Calquence to advance first-line treatment options in mantle cell lymphoma, with the Calquence combination demonstrating an almost one and a half year improvement in progression-free survival in this setting. If approved, Calquence has the potential to transform the standard of care as the first BTK inhibitor approved for these patients in Europe."

MCL is a rare and typically aggressive form of non-Hodgkin lymphoma, often diagnosed at an advanced stage.1,2 It is estimated that more than 6,000 patients were diagnosed with MCL in the UK, France, Germany, Spain and Italy in 2024.3

The safety and tolerability of Calquence was consistent with its known safety profile, and no new safety signals were identified.

Calquence plus bendamustine and rituximab is approved in the US and several other countries in this setting based on the ECHO results. Regulatory applications are currently under review in Japan and several other countries in this indication.

Notes

Mantle cell lymphoma (MCL)
While MCL patients initially respond to treatment, patients do tend to relapse.4 MCL comprises about 3-6% of non-Hodgkin lymphomas, with an annual incidence of 0.5 per 100,000 population in Western countries; It is estimated that there are more than 21,000 patients diagnosed with MCL in the US, UK, France, Germany, Spain, Italy, Japan and China.5

ECHO
ECHO is a randomised, double-blind, placebo-controlled, multi-centre Phase III trial evaluating the efficacy and safety of Calquence plus bendamustine and rituximab compared to SoC chemoimmunotherapy (bendamustine and rituximab) in adult patients at or over 65 years of age (n=635) with previously untreated MCL.6 Patients were randomised 1:1 to receive either Calquence or placebo administered orally twice per day, continuously, until disease progression or unacceptable toxicity. Additionally, all patients received six 28-day cycles of bendamustine on days 1 and 2 and rituximab on day 1 of each cycle, followed by rituximab maintenance for two years if patients achieved a response after induction therapy.6

The primary endpoint is PFS assessed by an Independent Review Committee; other efficacy endpoints include overall survival (OS), overall response rate (ORR), duration of response (DoR) and time to response (TTR).6 The trial was conducted in 27 countries across North and South America, Europe, Asia and Oceania.6

The ECHO trial enrolled patients from May 2017 to March 2023, continuing through the COVID-19 pandemic. Prespecified PFS and OS analyses censoring for COVID-19 deaths were conducted to assess the impact of COVID-19 on the study outcome in alignment with the FDA. Patients with blood cancer remain at a disproportionately high risk of severe outcomes from COVID-19, including hospitalisation and death compared to the general population.6,7,8

Calquence
Calquence (acalabrutinib) is a second-generation, selective inhibitor of Bruton’s tyrosine kinase (BTK). Calquence binds covalently to BTK, thereby inhibiting its activity.8 In B-cells, BTK signalling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis and adhesion.

Calquence is approved for the treatment of chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL) in the US and Japan, approved for CLL in the EU and many other countries worldwide and approved in China for relapsed or refractory CLL and SLL. Calquence is also approved for the treatment of adult patients with previously untreated MCL in the US and other countries. It is also approved for the treatment of adult patients with MCL who have received at least one prior therapy in the US, China and several other countries. Calquence is not currently approved for the treatment of MCL in Japan.

As part of an extensive clinical development programme, Calquence is currently being evaluated as a single treatment and in combination with standard-of-care chemoimmunotherapy for patients with multiple B-cell blood cancers, including CLL, MCL and diffuse large B-cell lymphoma.

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