On April 28, 2025 Purple Biotech Ltd. ("Purple Biotech" or "the Company") (NASDAQ/TASE: PPBT), a clinical-stage company developing first-in-class therapies that seek to overcome tumor immune evasion and drug resistance, reported that two posters reporting new NT219 data being presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) (AACR 2025) Annual Meeting on Sunday and Monday, April 27-28, 2025 (Press release, Purple Biotech, APR 28, 2025, View Source [SID1234652245]).

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NT219, a novel dual inhibitor of IRS1/2 and STAT3, is being evaluated in a Phase 2 study in patients with recurrent and/or metastatic head and neck squamous cell cancer (R/M HNSCC) in combination with pembrolizumab (anti-PD1) and in combination with cetuximab (anti-EGFR).

"The poster presents a significant upregulation of STAT3, IRS1/2 and b-catenin in HNSCC tumors and tumor microenvironment as compared to normal tissues, and a similar trend per tumor stage. Together with the unique mechanism of NT219 as a suppressor of STAT3 and a degrader of IRS1/2, which blocks IGF1R/IRS and downstream AKT and b-catenin signaling, we revealed that the activated forms of STAT3 and IGF1R are associated with the patient response to NT219-based therapy, suggesting these targets as potential biomarkers," stated Purple Biotech VP R&D Dr. Hadas Reuveni. "STAT3 and b-catenin, as well as cancer stem cells, are major immune evasion and tumor recurrence mechanisms, suppressed by NT219. This mechanistic rationale and preclinical in-vivo and ex-vivo results demonstrating repression of anti-PD1 refractory tumors, support NT219 and anti-PD1 combination therapy that will be administered to R/M HNSCC patients in our Phase 2 clinical study."

"Activation of b-catenin or loss of its negative suppressor APC play a key role in colorectal cancer, and we have previously shown that NT219 efficiently blocks the IRS2 to b-catenin pathway, inhibiting CRC metastasis and chemo-resistance," added Hadas Reuveni. "Here we reveal that these elements may serve as potential biomarkers for NT219-based therapy in CRC, based on extended in-vivo and ex-vivo patient-derived screens."

"These biomarker and mechanism data are important guides for study design, patient selection, and combination therapy strategies for NT219," stated Purple Biotech CEO Gil Efron. "This new data is highly encouraging and support our current NT219 Phase 2 study in head and neck cancer. We were pleased to share these data at the prestigious AACR (Free AACR Whitepaper) annual meeting."

Key highlights from the posters include the following:

Poster Title—"NT219 overcomes immune evasion mechanisms in head and neck squamous cell carcinoma (HNSCC)"

● NT219 mitigates several immune evasion mechanisms including cancer stem cell-mediated resistance and resulting tumor recurrence, and sensitizes resistant HNSCC tumors to PD1 and EGFR therapies.

● NT219 inhibits major targets and signaling pathways playing a key role in tumor immune evasion, including STAT3 and IRS-to-β-catenin pathways.

● In a clinical setting, upregulation of pIGF1R and pSTAT3 were correlated with patient response and suggested as potential biomarkers for NT219 treatment.

● Immunosuppressive mechanisms such as IL-10 secretion induced by anti-PD1 treatment, were suppressed by NT219, supporting the synergistic anti-tumor activity observed

● These data demonstrate the potential of NT219 to restore the efficacy of immunotherapies and expand the patient population that can benefit from these drugs.

Poster Title—"APC-loss as a potential biomarker for NT219 treatment in colorectal cancer"

● The anti-tumor efficacy of NT219 monotherapy in screens of about 30 patient-derived xenograft (PDX) models and colorectal (CRC) patient-derived explants (PDE), along with genomic and transcriptomic analysis, suggest that the response to NT219 is associated with enhanced wnt/β-catenin signaling or loss of function mutation of its negative regulator APC (APC-loss).

● The results suggest APC-loss or upregulated β-catenin as a potential biomarker for NT219 treatment in CRC.

● In addition, NT219 reversed chemo-resistance and synergized with approved chemotherapy as demonstrated in multiple models including PDE with APC-loss and activated PI3K mutations, and in-vivo intracranial model with activating mutation in β-catenin.

The NT219’s posters will be available at the Publication section on Purple Biotech’s website following its presentation at the conference.

On April 28, 2025 Portage Biotech Inc. (NASDAQ: PRTG), a clinical-stage immuno-oncology company reported confirmatory preclinical efficacy data for PORT-7 (TT-4), a selective adenosine A2B receptor inhibitor. Dr. Luciano Mutti of the Department of Applied Clinical Sciences and Biotechnology at the University of L’Aquila, Italy, an internationally recognized expert in mesothelioma, will be presenting the data at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting at the McCormick Place Convention Center in Chicago, Illinois on April 28, 2025 (Press release, Portage Biotech, APR 28, 2025, View Source [SID1234652244]). The new data in a murine mesothelioma model demonstrated single agent activity for PORT-7 that was superior to treatment with single agent anti-PD1 antibody. Moreover, the combination of PORT-7 and anti-PD1 was superior to treatment with either anti-PD1 or PORT-7 alone. Immunohistochemistry of the tumors revealed the formation of tertiary lymphoid structures in the mice receiving the combination. This indication of a favorable immune response was accompanied by increases in immune effector cells in mice treated with the combination. Mesothelioma is an aggressive cancer with limited treatment options in need of novel approaches to overcome immune resistance. Portage is making preparations to commence a first-in-human clinical trial with PORT-7.

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Combining PORT-6 and PORT-7 for a More Comprehensive Immunotherapy Approach

In parallel, Portage is advancing the dose escalation of PORT-6, a potent and selective inhibitor of the A2A adenosine receptor. Portage’s plan is to ultimately co-administer PORT-6 with PORT-7 in the ongoing ADPORT-601 trial. This will mark the first time two highly selective A2A and A2B antagonists are combined in patients, with the aim of achieving a complete blockade of adenosine-induced immunosuppression in the tumor microenvironment. This innovative approach is designed to fully neutralize adenosine-mediated immune suppression, enhance anti-tumor responses, and broaden the impact of immunotherapy in solid tumors.

On April 28, 2025 Plexium, Inc. (Plexium), a leading next-generation targeted protein degradation company, reported multiple presentations with the Company’s selective monovalent degrader programs for SMARCA2, IKZF2 and CDK2 at the 2025 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, taking place April 25-30, 2025, in Chicago, IL (Press release, Plexium, APR 28, 2025, View Source [SID1234652243]).

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"These data highlight the clinical and preclinical progress we’ve made across our portfolio, including the use of a novel E3 ligase DCAF16, in our SMARCA2 program—an industry first that reinforces the differentiated potential of our monovalent degrader platform," said Jorge F. DiMartino, MD, PhD, Chief Medical Officer at Plexium. "We are also excited to share initial clinical data from PLX-4545, which demonstrated clinical proof of mechanism and intended pharmacological immunophenotypic effects."

Oral Presentation Details:

Title: "Discovery and characterization of novel, potent and selective CDK2 molecular glue degrader against CCNE1-amplified tumors"
Session: MS.ET09.01 – Degraders and Glues
Abstract Number: 6375
Date and Time: April 29, 2:55 PM – 3:10 PM
Presenting Author: Leenus Martin, PhD

Title: "PLX-4545, a selective IKZF2 degrader, reprograms suppressive Tregs leading to tumor growth inhibition and combination benefit with immune checkpoint therapy"
Session: MS.ET09.01 – Degraders and Glues
Abstract Number: 6380
Date and Time: April 29, 4:10 PM – 4:25 PM
Presenting Author: Peggy Thompson, PhD

Poster Presentation Highlights:

Title: "Mechanistic characterization of selective monovalent direct degraders of SMARCA2″
Session: PO.ET09.04 – Degraders and Glues 1
Abstract Number: 404
Section: 18
Date and Time: April 27, 2025, 2:00 PM – 5:00 PM
Presenting Author: Julia Toth, PhD

Plexium’s SMARCA2 degraders function by bromodomain binding and covalent modification
A CRISPR knockout screen identified DCAF16 as being required for PLX-61639 mediated SMARCA2 degradation
MOA studies demonstrate PLX-61639-mediated SMARCA2:DCAF16 protein interactions and the requirement of covalent binding to a specific DCAF16 cysteine to support a stable ternary complex and subsequent SMARCA2 degradation
Title: "Preclinical characterization of PLX-61639, a potent and orally bioavailable SMARCA2-selective monovalent direct degrader"
Session: PO.ET09.10 – Degraders and Glues 2
Abstract Number: 1653
Section: 18
Date and Time: April 28, 2025, 9:00 AM – 12:00 PM
Presenting Author: Gregory Parker, PhD

Plexium has designed PLX-61639, a potent and selective direct degrader of SMARCA2, and nominated it as a development candidate
Daily oral dosing of PLX-61639 results in deep and sustained SMARCA2 degradation, eliciting robust tumor growth inhibition and regression in SM4mut CDX and PDX models, no tumor growth inhibition is observed in a control SM4wt CDX model
PLX-61639 is currently advancing through IND-enabling studies
Title: "A first in human trial of PLX-4545, a molecular glue degrader of IKZF2, in healthy volunteers, shows pharmacologic modulation of Tregs at well-tolerated doses"
Session Title: PO.CT01.02. First-in-Human Phase I Clinical Trials 2
Abstract Number: CT150
Section: 48
Date and Time: April 29, 2025, 9:00 AM – 12 PM
Presenting Author: Jorge DiMartino, MD, PhD

PLX-4545 an oral, CRBN molecular glue degrader of IKZF2, a lineage-defining transcription factor for Tregs was tested in healthy adult volunteers
With repeated daily dosing for 14 days, all dose levels achieved complete degradation of IKZF2 in PBMCs by Day 2 leading to conversion of Tregs into effector-like T cells and an increase in activated T effector cells
TEAEs were mostly Grade 1 or 2 (mild or moderate) in severity and no Dose Limiting Toxicities were encountered. All AEs were reversible with discontinuation of dosing
The AACR (Free AACR Whitepaper) 2025 posters will be made available on the Plexium website.

On April 28, 2025 PharmaMar (MSE:PHM), global leader in research, development and commercialization of marine-derived oncology treatments, reported that it is once again participating in the Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper), being held in Chicago from April 25th to 30th, 2025 (Press release, PharmaMar, APR 28, 2025, View Source [SID1234652242]). On this occasion, the Company is presenting eleven new studies with results on the activity of its compounds: lurbinectedin (Zepzelca), ecubectedin, PM54, PM534, and trabectedin (Yondelis).

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This reinforces PharmaMar’s ongoing commitment to innovation and cancer research. "We continue to advance the study of the therapeutic potential of marine-derived molecules, both in well-established compounds and in those in earlier stages of development. Our participation this year in the world’s leading oncology research congress reflects our firm commitment to scientific innovation and the path we are building to provide potential therapeutic alternatives for patients," says Carmen Cuevas, VP of R&D at PharmaMar.

The main conclusions from the presented studies highlight the potential of two novel transcription inhibitors, PM54 and ecubectedin as innovative antitumor agents. Ecubectedin has demonstrated encouraging antitumor efficacy in both gastric and neuroendocrine-prostate cancer models. In collaboration with KU Leuven University (Belgium), data also confirm promising antitumor activity of both ecubectedin and PM54 in representative models of soft tissue sarcomas (STS).

Additionally, data on PM534 are being presented. PM534 is a novel tubulin-targeting agent, that may bypass the most common resistance mechanisms, limiting the effectiveness of standard microtubule-binding drugs.

Finally, the studies also show the antitumor activity of lurbinectedin in NUT carcinoma—a rare type of cancer that forms in the head, neck and lungs. Furthermore, new insights into the mechanism of action of trabectedin will also be shared.

The full list of all presentations supported by PharmaMar or its collaborators at the AACR (Free AACR Whitepaper) 2025 Annual Meeting is as follows:

COMPOUND TITLE LEAD AUTHOR ABSTRACT
Ecubectedin (PM14) Ecubectedin’s role in targeting transcriptional regulators in neuroendocrine prostate cancer. Laura Almalé, PhD Location: Section 22
Board Number: 23
Published Abstract Number: 1771 April 28, 2025
Ecubectedin as a promising therapeutic agent against gastric cancer through Wnt/β-Catenin modulation. Alejandro Losada, PhD Location: Section 21
Board Number: 8
Published Abstract Number: 5630 April 29, 2025
The novel transcriptional inhibitor ecubectedin demonstrates strong antitumor activity in patent-derived xenograft models of soft tissue sarcoma. Daniël Gorgels, PhD Location: Section 21
Board Number: 1
Published Abstract Number: 6857 April 30, 2025
PM534 Overcoming resistance to tubulin-targeting drugs with PM534: an innovative microtubule-targeting compound. Pablo M. Aviles, PharmD, PhD Location: Section 21
Board Number: 8
Published Abstract Number: 6864 April 30, 2025
PM54 PM54, a novel transcription inhibitor with promising broad spectrum antitumor activity. Marcelo Lima Ribeiro, PhD Location: Section 22
Board Number: 25
Published Abstract Number: 1773 April 28, 2025
The next generation transcriptional inhibitor PM54 demonstrates strong antitumor activity in patient-derived xenograft models of soft tissue sarcoma. Daniël Gorgels, PhD Location: Section 21
Board Number: 2
Published Abstract Number: 6858 April 30, 2025
Pan-inhibition of super-enhancer-driven oncogenic transcription by novel synthetic ecteinascidins yields potent anti-cancer activity Julian Obid, PhD Location: Section 21
Board Number: 13
Published Abstract Number: 1738 April 28, 2025
Trabectedin (Yondelis) Redefining the Molecular Target for Trabectedin (ET743) as Stable Covalent Bonding to N2 of Guanine in Duplex Stem-Loops of G-Quadruplexes. Laurence H. Hurley, PhD Location: Section 19
Board Number: 2
Published Abstract Number: 2972 April 28, 2025
Lurbinectedin (Zepzelca) New therapeutic approaches in NUT Carcinoma: an unmet need. María Virgina Sáchéz-Becerra, PhD Location: Section 34
Board Number: 23
Published Abstract Number: 5996 April 29, 2025
Lurbinectedin-Induced Transcriptional Reprogramming: A Pathway to Sensitise SCLC to Immunotherapy J.S. Russo-Cabrera, PhD Location: Section 23
Board Number: 13
Published Abstract Number: 5837 April 29, 2025
Lurbinectedin Irinotecan as a new therapeutic combination for Small Cell Lung Cancer Miguel Ruiz-Torres, PhD Location: Section 34
Board Number: 13
Published Abstract Number: 5986 April 29, 2025

On April 28, 2025 Orum Therapeutics, Inc. ("Orum" or the "Company") (KRX: 475830), a public biotechnology company pioneering the field of degrader-antibody conjugates (DACs), reported a strategic update to its pipeline (Press release, Orum Therapeutics, APR 28, 2025, View Source [SID1234652241]). Orum has discontinued further clinical development of ORM-5029, a HER2-targeted GSPT1 degrader-antibody conjugate (DAC). This decision follows an internal assessment of the program’s clinical progress and incorporates information previously disclosed. Concurrently, Orum announced the nomination of a new drug candidate, ORM-1153, in development for the treatment of hematologic malignancies.

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ORM-1153 is a novel DAC engineered using Orum’s proprietary Dual-Precision Targeted Protein Degradation (TPD²) approach, which combines the catalytic protein degradation mechanism of TPDs with the tumor-targeting capabilities of therapeutic antibodies. The candidate targets GSPT1, a translation termination factor highly relevant in hematologic malignancies, and an undisclosed tumor-associated antigen to enhance selectivity and broaden the therapeutic window.

In preclinical studies, ORM-1153 demonstrated potent anti-tumor activity and a favorable safety profile, including in non-human primate models. ORM-1153 demonstrated picomolar potency in target-expressing cell lines and showed greater potency than existing small molecule GSPT1 degraders. In vivo, a single dose of ORM-1153 led to strong anti-tumor activity in relevant xenograft models. Orum plans to advance the program into IND-enabling studies and anticipates presenting additional data at a scientific conference later this year.

"After careful review of available clinical and preclinical data, we have concluded clinical development of ORM-5029," said Sung Joo (SJ) Lee, Ph.D., Founder and CEO of Orum Therapeutics. "This decision reflects our continued commitment to patient safety and our strategic focus on advancing the next generation of degrader-antibody conjugates with a clearly defined risk-benefit profile. We look forward to advancing next-generation programs emerging from our proprietary platform, like ORM-1153."

Dr. Lee continued, "ORM-1153 leverages learnings from all our programs and clinical experience to build potent, selective, and tumor-targeted protein degrader therapeutics that address serious unmet needs in oncology. We remain confident in the promise of our Dual-Precision Targeted Protein Degradation GSPT1 platform and are excited to progress this new candidate toward the clinic."

About Orum’s TPD² Approach

Orum’s unique Dual-Precision Targeted Protein Degradation (TPD²) approach builds novel targeted protein degraders combined with the precise cell delivery mechanisms of antibodies to generate innovative, first-in-class, cell-selective TPDs for the treatment of cancer. Orum has developed new targeted protein degrader payloads to specifically degrade an intracellular target protein within cancer cells via the E3 ubiquitin ligase pathway. Conjugated to antibodies, the payloads are designed to be delivered specifically to target cells and precisely degrade the intracellular target protein of interest.