On April 29, 2025 Pasithea Therapeutics Corp. (NASDAQ: KTTA) ("Pasithea" or the "Company"), a clinical-stage biotechnology company developing PAS-004, a next-generation macrocyclic MEK inhibitor, for the treatment of neurofibromatosis type 1 (NF1) and other MAPK pathway driven cancer indications, reported the Company has completed enrollment and initial dosing of three subjects in Cohort 6 with 30 mg capsules of PAS-004 (Press release, Pasithea Therapeutics, APR 29, 2025, View Source [SID1234652321]).

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"We are pleased to have recruited, enrolled and commenced dosing of the initial three subjects in Cohort 6 more rapidly than anticipated and we currently expect to complete enrollment of all patients in the trial by the end of 2025," said Dr. Tiago Reis Marques, Chief Executive Officer of Pasithea.

The ongoing Phase 1 clinical trial is a multi-center, open-label, dose escalation 3+3 study design to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of PAS-004 in patients with MAPK pathway driven advanced solid tumors with a documented RAS, NF1 or RAF mutation or patients who have failed BRAF/MEK inhibition (NCT06299839).

On April 29, 2025 Nuvalent, Inc. (Nasdaq: NUVL), a clinical-stage biopharmaceutical company focused on creating precisely targeted therapies for clinically proven kinase targets in cancer, reported the publication of a manuscript in Molecular Cancer Therapeutics, a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper), which supports the rational molecular design of zidesamtinib, its novel and selective ROS1 inhibitor (Press release, Nuvalent, APR 29, 2025, https://investors.nuvalent.com/2025-04-29-Nuvalent-Announces-Publication-in-Molecular-Cancer-Therapeutics-Reinforcing-Rational-Molecular-Design-of-Zidesamtinib-as-a-Novel-ROS1-Selective-Inhibitor [SID1234652317]). Zidesamtinib is currently being evaluated in the ongoing ARROS-1 Phase 1/2 trial for patients with advanced ROS1-positive non-small cell lung cancer (NSCLC) and other solid tumors, which is designed with registrational intent for tyrosine kinase inhibitor (TKI) pre-treated and TKI-naïve patients with advanced ROS1-positive NSCLC.

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The publication, entitled "Zidesamtinib Selective Targeting of Diverse ROS1 Drug-Resistant Mutations," is published online and can be accessed here: View Source

"Zidesamtinib was specifically designed with the goal of addressing the combined medical needs of treating tumors that have developed resistance, treating brain metastases and avoiding off-target adverse events. Structural studies play a critical role in the development and optimization of novel therapeutics, particularly when aiming to solve for multiple, and at times competing, challenges. To date, structural studies for ROS1-positive cancers have been hindered by a lack of ROS1 G2032R crystal structures, despite G2032R being the most commonly occurring ROS1 resistance mutation," said first author Anupong Tangpeerachaikul, Ph.D., Director, Biology at Nuvalent. "With this publication in Molecular Cancer Therapeutics, we are pleased to have shared what is, to our knowledge, the first structure of ROS1 G2032R, or any ROS1 mutation, offering a framework for understanding ROS1 TKI activity against these important drivers of disease progression. This structure further illustrates the intentional design of zidesamtinib and adds to the growing body of preclinical data supporting its ROS1-selective and TRK-sparing design."

The manuscript explores the activity of zidesamtinib and other approved or investigational ROS1 TKIs at clinically relevant concentrations against ROS1 resistance mutations, including the most commonly occurring resistance mutation, ROS1 G2032R, in preclinical mutagenesis screens and an intracranial ROS1 G2032R xenograft model. Findings presented in the manuscript show that, at clinically relevant concentrations, zidesamtinib suppressed on-target resistance in ENU mutagenesis screens simulating first-line and later-line treatment and inhibited ROS1 G2032R brain tumors more effectively than the other ROS1 TKIs evaluated. This favorable preclinical activity suggests the potential for zidesamtinib to delay tumor progression, both peripherally and intracranially.

In addition, the manuscript details the first crystal structure of ROS1 G2032R in complex with zidesamtinib, which further supports zidesamtinib’s molecular design and provides structural insights into how the ROS1 G2032R mutation affects TKI binding. Zidesamtinib was designed with the goal of being active against ROS1 and ROS1 resistance mutations while avoiding the inhibition of the structurally related tropomyosin receptor kinase (TRK) family in the central nervous system (CNS), which has been associated with neurological adverse events that can be dose limiting. The crystal structure elucidates zidesamtinib’s preclinical affinity for ROS1 G2032R and selectivity for ROS1 over TRK.

The company expects to report pivotal clinical data for TKI pre-treated patients with advanced ROS1-positive NSCLC from the ARROS-1 Phase 1/2 trial in the first half of 2025 in support of an anticipated New Drug Application submission by mid-year 2025, with an initial target indication of TKI pre-treated patients with advanced ROS1-positive NSCLC.

About Zidesamtinib
Zidesamtinib is a novel brain-penetrant ROS1-selective inhibitor created with the aim to overcome limitations observed with currently available ROS1 inhibitors. Zidesamtinib is designed to remain active in tumors that have developed resistance to currently available ROS1 inhibitors, including tumors with treatment-emergent ROS1 mutations such as G2032R. In addition, zidesamtinib is designed for central nervous system (CNS) penetrance to improve treatment options for patients with brain metastases, and to avoid inhibition of the structurally related tropomyosin receptor kinase (TRK) family. Together, these characteristics have the potential to avoid TRK-related CNS adverse events seen with dual TRK/ROS1 inhibitors and to drive deep, durable responses for patients across all lines of therapy. Zidesamtinib has received breakthrough therapy designation for the treatment of patients with ROS1-positive metastatic non-small cell lung cancer (NSCLC) who have been previously treated with 2 or more ROS1 tyrosine kinase inhibitors and orphan drug designation for ROS1-positive NSCLC.

On April 29, 2025 Nouscom, a clinical-stage biotech company developing next-generation neoantigen-targeted off-the-shelf and personalized cancer immunotherapies, reported complete safety and immunogenicity results from a Phase Ib/II study evaluating NOUS-209 in individuals with Lynch Syndrome (LS) at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2025 (Press release, NousCom, APR 29, 2025, View Source;utm_medium=rss&utm_campaign=nouscom-presents-positive-final-results-from-completed-phase-ib-ii-study-of-neoantigen-immunotherapy-nous-209-at-aacr-2025-demonstrating-a-highly-potent-and-durable-immune-response-in-lynch-syndrome [SID1234652315]). The study found that NOUS-209 monotherapy was safe, well-tolerated and induced potent, broad and durable immune responses in all LS carriers evaluated.

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LS is a common inherited condition that significantly increases a person’s risk of developing microsatellite instability (MSI)-associated cancers over their lifetime. Managing LS is limited to frequent screenings or elective organ removal surgery. NOUS-209 is an investigational off-the-shelf cancer immunotherapy that targets tumors with mismatch repair deficiency (dMMR) and/or MSI. These tumors produce markers known as frameshift peptide neoantigens (FSPs). NOUS-209 is a pioneering approach to cancer interception comprising two proprietary viral vectors that deliver 209 shared FSP neoantigens and train the immune system to recognize and attack cancerous and pre-cancerous cells before tumors can fully develop.

The completed Phase Ib/II trial evaluated safety and immunogenicity in 45 LS carriers demonstrated;

Favorable Safety Profile: NOUS-209 was well tolerated, with no serious treatment-related adverse events across the entire study population.
Potent and Durable Immunogenicity Profile: Neoantigen-specific T cell responses were reported in 100% of evaluable participants (n=37). Responses were robust, reaching a mean of ~1100 interferon-gamma (IFN-γ) spot forming cells (SFC) per million of Peripheral Blood Mononuclear Cells (PBMCs). Immune responses were durable, with tumor-specific T cells detected after 1 year in >85% of participants (n=33).
Broad, Polyspecific T Cell Response: Immune responses were confirmed against 115 different FSP neoantigens to date, validating the ability of NOUS-209 to elicit broad polyspecific immune responses.
Desired T Cell Phenotype: NOUS-209 induced neoantigen-specific CD8 and CD4 T cells, exhibiting an effector memory phenotype associated with long-lived immunity critical for sustained surveillance and ability to eliminate emerging tumor cells.
Demonstration of Tumor Cell Killing: T cells induced by NOUS-209 were shown to directly kill tumor cells ex vivo, confirming functional anti-cancer activity.
Target Validation in LS-Associated Premalignant and Cancer Lesions: The vast majority of the immunogenic FSP neoantigens were shown to be present in both pre-cancerous as well as cancer lesions from independent cohorts of LS carriers.
These data support the further clinical development of NOUS-209 as a monotherapy in LS carriers. Following positive Type B and C meetings with the US Food and Drug Administration (FDA), Nouscom has a clear path forward for the advancement of NOUS-209 to a potentially registration-enabling Phase 2/3 clinical study for cancer interception in those living with LS.

"Currently, individuals with Lynch Syndrome rely on frequent screenings, such as colonoscopies, to manage their markedly increased risk of developing cancer. These latest data are a step toward a completely new approach – leveraging the immune system for cancer interception," said the study’s principal investigator, Eduardo Vilar-Sanchez, M.D., Ph.D., Professor of Clinical Cancer Prevention at The University of Texas MD Anderson Cancer Center. "NOUS-209 has shown clear evidence that the T cells it activates can persist over time, effectively target and kill tumor cells and develop into memory cells that support long-term immune protection. These findings support NOUS-209’s potential as a cancer interception strategy."

"Nouscom’s proprietary viral vector platform is uniquely positioned to deliver rapid, potent and broad immune activation against a large number of shared neoantigens, with minimal reactogenicity and durable immune responses," said Dr. Elisa Scarselli, Chief Scientific Officer of Nouscom. "These compelling Phase Ib/II data further reinforce our confidence in NOUS-209 monotherapy to safely and effectively prime the immune system to recognize and intercept pre-malignant and cancer lesions before they progress into tumors in LS carriers."

Dr. Marina Udier, Chief Executive Officer of Nouscom, added: "We are enormously pleased with these robust Phase Ib/II data and look to progress toward a potentially registration-enabling Phase 2/3 clinical study for cancer interception in LS. We remain deeply committed to advancing NOUS-209 and bring better solutions for people living with LS who urgently need and deserve a better way to manage their cancer risk."

The study was led by researchers at MD Anderson, in collaboration with the Cancer Prevention Clinical Trials Network and sponsored by the National Cancer Institute (grant # UG1CA242609) of the National Institutes of Health. These data were presented during the Hot Topics in Cancer Prevention session, and the abstract is available on the AACR (Free AACR Whitepaper) website here.

On April 29, 2025 Moleculin Biotech, Inc., (Nasdaq: MBRX) ("Moleculin" or the "Company"), a late-stage pharmaceutical company with a broad portfolio of drug candidates targeting hard-to-treat cancers and viral infections, reported that an abstract and poster presentation regarding the Company’s next-generation anthracycline, Annamycin, was presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2025, on April 28, 2025, at the McCormick Place Convention Center in Chicago, IL (Press release, Moleculin, APR 29, 2025, View Source [SID1234652314]).

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"The case for expanding the potential markets for Annamycin continues to get stronger," said Walter Klemp, Chairman and CEO of Moleculin. "In an environment where more and more cancer treatment regimens are combinations of two or more drugs, it is encouraging to see that Annamycin appears capable of generating synergistic results with so many commonly used drugs. The latest research continues to support our view that, in addition to hematological malignancies, solid cancers including sarcoma and pancreatic cancer also represent important expansion opportunities for Annamycin. These findings may help expand the clinical use of Annamycin and consequently make our drug candidate even more attractive to prospective future partners. With five previous or current investigator-initiated clinical trials supporting development of our drug candidates, we believe that our next investigator-initiated trials could be Annamycin for the treatment of pancreatic cancer or advance soft tissue sarcomas."

The study, presented in poster form, was designed to assess the efficacy of Annamycin in combination with approved anticancer agents in order to identify novel potentially highly efficacious clinical applications of Annamycin alone and with a therapeutic partner. Annamycin in its non-liposomal form (free drug; in vitro) and Liposomal Annamycin (L-ANN; in vivo) were tested in combination with selected US Food and Drug Administration (FDA) approved drugs. Usually, the most efficacious drug combinations from the in vitro studies were then tested using well developed in vivo models of leukemia and solid tumors, including sarcoma and pancreatic cancer.

It should be noted that in a separate set of previous experiments, Annamycin activity was tested in vitro, and appeared to be highly active, against drug resistant cell lines, including cells resistant to cytarabine and venetoclax.

The research shown in the AACR (Free AACR Whitepaper) poster, described below, demonstrates that Annamycin is potentially a highly versatile drug capable of working synergistically with numerous mechanistically different FDA approved anticancer agents both in vitro and in vivo. Ongoing studies are working towards identifying new efficacious clinical applications of L-ANN drug combinations with the long-term goal of developing novel therapeutic strategies for treatment resistant cancers.

Details of the poster presentation are as follows:

Title: Combining Annamycin, a Non-cardiotoxic Potent Topo II Poison, with Azacitidine, Cytarabine, Gemcitabine, Ifosfamide, Trabectedin, or Vincristine to Synergize Anticancer Effects and Identify Potential Clinical Applications
Track: Experimental and Molecular Therapeutics
Session: PO.ET02.03. Drug Combination Strategies for Cancer Treatment
Abstract Number: 1683/ 14
Presenter: Waldemar Priebe, Ph.D., Department of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center

For more information, visit the AACR (Free AACR Whitepaper) Annual Meeting website.

On April 29, 2025 Microbiotica, a clinical-stage biopharma company developing a pipeline of oral precision microbiome medicines called live biotherapeutic products (LBPs), reported new data on the mechanism of action of MB097 at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting held in Chicago, April 25-30 (Press release, Microbiotica, APR 29, 2025, View Source [SID1234652313]). MB097 is an LBP in development as a co-therapy for immune checkpoint inhibitors (CPI) such as MSD’s (Merck & Co., Inc., Rahway, NJ, USA) anti-PD-1 therapy, KEYTRUDA (pembrolizumab).

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The composition of a patient’s intestinal microbiome is known to impact the response to immunotherapies, most noticeably CPI, but the mechanisms are poorly understood. MB097 comprises nine different species of gut commensal bacteria, all linked to positive CPI response in multiple clinical studies. Microbiotica has developed in vitro human systems using primary immune cells to investigate how gut bacteria modulate the immune response to cancer. These assays have demonstrated that three of the MB097 strains induce dendritic cells to produce high levels of IL-12, which in turn stimulates Cytotoxic T Lymphocytes and NK cells with potent tumour cell killing activity. Dr Mat Robinson, Microbiotica’s Senior Vice-President Research, presented these novel findings in a poster entitled ‘Clinical response to immune checkpoint inhibitors in melanoma is associated with distinct gut bacterial species that promote anti-tumour immunity by different mechanisms’. The poster can be accessed here.

Dr Mat Robinson, Microbiotica’s SVP Research, said, "These exciting results start to unravel the complex biology of how gut commensal bacteria drive immune checkpoint inhibitor responses. The induction of dendritic cells to produce IL-12 complement the recently reported data showing that other MB097 strains release metabolites that enhance immune-mediated cancer cell killing. Together, these findings demonstrate that the different strains within MB097 can interact with the immune system of cancer patients in multiple ways to enhance immunotherapy efficacy."

MB097 is being tested in an international Phase 1b clinical study, in combination with KEYTRUDA (pembrolizumab), MSD’s anti-PD-1 therapy, in patients with cutaneous melanoma who have failed to respond to immunotherapies. Data readout is expected by the end of 2025.