NT219 / Purple Biotech - LARVOL DELTA

NT219 Combined With Standard of Care Biologic Therapy in Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (clinicaltrials.gov) - P1/2 | N=29 | Active, not recruiting | Sponsor: University of Colorado, Denver | Trial primary completion date: Jun 2026 ➔ Feb 2030

Trial primary completion date • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • PD-L1

NT219 Combined With Standard of Care Biologic Therapy in Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (clinicaltrials.gov) - P1/2 | N=29 | Active, not recruiting | Sponsor: University of Colorado, Denver | Trial primary completion date: Feb 2030 ➔ Jun 2026

Trial primary completion date • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • PD-L1

NT219 Combined With Standard of Care Biologic Therapy in Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (clinicaltrials.gov) - P1/2 | N=29 | Active, not recruiting | Sponsor: University of Colorado, Denver | Recruiting ➔ Active, not recruiting

Enrollment closed • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • PD-L1

NT219, a dual inhibitor of IRS1/2 and STAT3, suppresses cancer stem cell mediated resistance to KRASG12C and KRASG12D inhibitors in solid tumors (AACR 2024) - "We present NT219 suppressive effect on mKRASi resistant and sensitive cells of both PDAC and NSCLC, as well as on cancer stem cells (CSC) known to contribute to disease recurrence.Method The inhibitory effects of NT219 as a monotherapy or in combination with either KRASG12C inhibitors (sotorasib/adagrasib) or KRASG12D inhibitor (MTRX1133) were tested in 2D cell growth and colony formation assays using mKRAS inhibitor sensitive and resistant cancer cell lines. Initial results suggest involvement of NT219 target proteins in resistance to mKRASG12C/D inhibitors. Treatment with sotorasib induced enhancement in stemness potential of mKRASG12C NSCLC, which NT219 efficiently suppressed, suggesting a novel therapy for this unmet need and a novel mechanism to combat resistance to mKRAS inhibitors"

Cancer stem • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KRAS • SOX2 • STAT3

APC-loss as a potential biomarker for NT219 treatment in colorectal cancer (CRC) (AACR 2025) - "The anti-tumor activity in CRC explants along with genomic and transcriptomic analysis propose that the response to NT219 is associated with enhanced wnt/β-catenin signaling or APC loss. The results suggest APC-loss as a potential biomarker for NT219 treatment in CRC."

Biomarker • Brain Cancer • Colorectal Cancer • Oncology • Solid Tumor • APC • DDR2 • IRS1 • IRS2 • PIK3CA • TP53 • WNT7A

Early activity and biomarker evaluation of NT219 in combination with cetuximab in a Phase 1/2 study of recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) (AACR 2024) - P1/2 | "This notion is further substantiated by the demonstration of NT219 on-target effects in on-treatment tumor biopsies. Upregulation of NT219 targets, IGF1R and STAT3, in HPV-negative SCCHN pts and their response to the NT219+cetuximab treatment, support further evaluation of this patient population."

Biomarker • Combination therapy • IO biomarker • Metastases • P1/2 data • Head and Neck Cancer • Oncology • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

NT219 overcomes immune evasion-resistant mechanisms in head and neck squamous cell carcinoma (HNSCC) (AACR 2025) - "Ex vivo patient-derived tumor explant (PDE), treated with NT219 and/or nivolumab was analyzed for efficacy and cytokine secretion. NT219 mitigates several immune evasion mechanisms including CSC-mediated resistance and tumor recurrence, and sensitizes resistant HNSCC tumors to PD1 and EGFR therapies. Upregulation of pIGF1R and pSTAT3 were correlated with patient response and suggested as potential biomarkers for NT219 treatment."

IO biomarker • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • GZMB • IL10 • IL2 • IRS1 • IRS2 • NANOG • SOX2 • TNFA

Istiratumab exhibits antiproliferative activity in Ewing sarcoma and rhabdomyosarcoma (AACR 2025) - "Istiratumab inhibits ligand binding to abrogate PI3K/AKT signaling resulting in antiproliferative activity in various cancers alone and in combination with mTOR inhibitor everolimus or chemotherapy, including in a human Ewing sarcoma model...Antiproliferative effects of istiratumab were enhanced by addition of NT219 at 0.1 μM or panobinostat in the 3 Ewing sarcoma cell lines tested... Istiratumab has antiproliferative activity in sarcomas and will be evaluated in molecularly selected pediatric malignancies and Ewing sarcoma within the AcSé-ESMART trial."

Brain Cancer • CNS Tumor • Ependymoma • Ewing Sarcoma • Glioma • Hepatoblastoma • High Grade Glioma • Nasopharyngeal Carcinoma • Neuroblastoma • Oncology • Osteosarcoma • Pancreatic Cancer • Rhabdomyosarcoma • Sarcoma • Solid Tumor • ERBB3 • IGF1 • IGF2 • IRS1 • IRS2 • NRG1

IRS2 as a driver and therapeutic target in brain metastases from colorectal cancer: a systematic review of mechanistic and translational evidence. (PubMed, Clin Transl Oncol) - "IRS2 amplification represents a recurrent but non-universal molecular alteration enriched in a subset of colorectal cancer brain metastases, with mechanistic links to β-catenin signaling and mitochondrial metabolism. Preclinical inhibition of IRS2/IRS1-2 demonstrates translational promise, positioning IRS2 as a context-dependent vulnerability and potential therapeutic target in selected CRC brain-metastatic tumors."

Journal • Review • Brain Cancer • Colorectal Cancer • Oncology • Solid Tumor • IRS2

NT219 (IRS1/2 degrader and STAT3 blocker) (GlobeNewswire) - "Ongoing NT219 Phase 2 study in recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) to evaluate NT219 in combination with pembrolizumab (Keytruda) or cetuximab (Erbitux)."

Trial status • Squamous Cell Carcinoma of Head and Neck

Purple Biotech Receives Intention to Grant a European Patent Covering NT219 Combinations with Immunotherapies or MEK Inhibitors to Overcome Tumor Resistance (GlobeNewswire) - "...European Patent Office has issued an intention to grant a European Patent for Application No. 20168234.1...Finally, the application includes claims for combinations of NT219 with selected chemotherapies or targeted agents to address cancers that develop resistance driven by KRAS amplification or mutation. The patent term, excluding extensions, runs through 2036."

Patent • Solid Tumor

NT219 Combined With Standard of Care Biologic Therapy in Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (clinicaltrials.gov) - P1/2 | N=29 | Recruiting | Sponsor: University of Colorado, Denver | Not yet recruiting ➔ Recruiting

Enrollment open • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • PD-L1

Purple Biotech Announces Initiation of Phase 2 Study of NT219 in Patients with Head and Neck Cancer (GlobeNewswire) - "Purple Biotech Ltd...announced the initiation of a Phase 2 clinical study evaluating NT219 in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN)....The Phase 2 study will evaluate NT219 in combination with either pembrolizumab (KEYTRUDA) or cetuximab, both of which are standard-of-care treatments in R/M SCCHN patients. Additionally, the study aims to evaluate potential biomarkers identified in a previous clinical study of NT219."

Trial status • Squamous Cell Carcinoma of Head and Neck

Purple Biotech Reports First Quarter 2025 Financial Results (GlobeNewswire) - "The biomarkers identified in the CM24 Phase 2 study are planned to be used for patient selection in the Phase 2b study, planned to be initiated in the second half of 2025....NT219 Phase 2 study in head and neck cancer on track to be initiated in First Half of 2025.....A Phase 2 study of NT219 for the treatment of recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) will combine NT219 with the standard-of-care anti-PD1 checkpoint inhibitor pembrolizumab (Keytruda) or with the epidermal growth factor receptor (EGFR) blocker cetuximab (Erbitux). The study will also explore potential biomarkers that were previously identified in a prior NT219 study."

New P2 trial • Squamous Cell Carcinoma of Head and Neck

NT219 Combined With Standard of Care Biologic Therapy in Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (clinicaltrials.gov) - P1/2 | N=29 | Not yet recruiting | Sponsor: University of Colorado, Denver

New P1/2 trial • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • PD-L1

Purple Biotech Announces Publication in the Neuro Oncology Journal Demonstrating the Potential of NT219 to Suppress Brain Metastasis of Colorectal Cancer (GlobeNewswire) - "Purple Biotech...announced today the publication of an independent study titled 'IRS2 as a driver of brain metastasis in colorectal cancer: a potential target for novel therapeutic strategies' in the peer reviewed journal, Neuro Oncology....'Our findings suggest that suppressing IRS2 by NT219 may serve as a powerful strategy to suppress brain metastasis and overcome chemo-resistance. Our study shows that a combination of 5-FU and NT219 inhibited the formation of colorectal cancer brain metastasis and extended animal survival. To our knowledge, this is the first successful preclinical use of drug combination to treat colorectal cancer-associated brain metastasis'."

Preclinical • Colorectal Cancer

Purple Biotech Announces Three Posters Accepted for Presentation at the 2025 American Association for Cancer Research Meeting (GlobeNewswire) - "Purple Biotech Ltd...announced upcoming poster presentations including one for CM24 in the treatment of pancreatic cancer, and two for NT219 in the treatment of colorectal and head and neck cancers, at the 2025 American Association for Cancer Research Meeting (2025 AACR), scheduled to take place from April 25th to April 30th in Chicago."

Clinical data • Colorectal Cancer • Pancreatic Cancer • Squamous Cell Carcinoma of Head and Neck

Purple Biotech Granted New U.S. Patent for NT219 in Combination with EGFR Antibody Therapy, Enhancing Global IP Protection in Major Markets (GlobeNewswire) - "Purple Biotech Ltd...announced today that the U.S. Patent and Trademark Office has issued a patent for NT219 used in combination with epidermal growth factor receptor (EGFR) antibodies for treating cancer patients who have acquired resistance to EGFR therapies. The patent, titled 'Combinations of IRS/STAT3 dual modulators and anti-cancer agents for treating cancer' addresses NT219 in combination with cetuximab (Erbitux) as well as other EGFR antibodies such as panitumumab (Vectibix) and necitumumab (Portrazza) in treating tumors resistant to EGFR therapy and in preventing or delaying cancer tumor recurrence following cessation of treatment with an EGFR therapy."

Patent • Oncology • Solid Tumor

Purple Biotech Advances NT219 into Phase 2 Head and Neck Cancer Trial (GlobeNewswire) - "Purple Biotech Ltd...announced today it is advancing into a Phase 2 study with NT219 in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN)....The Phase 2 study will assess the efficacy and safety of NT219 as a combination therapy to further investigate NT219’s role in overcoming tumor resistance to standard-of-care checkpoint inhibitors, such as pembrolizumab, and EGFR blockers, such as cetuximab."

New P2 trial • Squamous Cell Carcinoma of Head and Neck

IRS2 as a driver of brain metastasis in colorectal cancer: a potential target for novel therapeutic strategies. (PubMed, Neuro Oncol) - "Our work underscores the unique role of IRS2 in facilitating CRC brain adaptation and suggests a novel therapeutic strategy for CRC patients with BM."

Journal • Colorectal Cancer • Oncology • Solid Tumor • CTNNB1 • IRS2

A Study to Evaluate NT219 Alone and in Combination with ERBITUX® (Cetuximab) in Adults with Advanced Solid Tumors and Head and Neck Cancer (clinicaltrials.gov) - P1/2 | N=52 | Completed | Sponsor: TyrNovo Ltd. | Active, not recruiting ➔ Completed | N=110 ➔ 52

Combination therapy • Enrollment change • Metastases • Trial completion • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • BRAF • KRAS

Purple Biotech Reports First Quarter 2024 Financial Results (GlobeNewswire) - "Phase 2 study of NT219 in combination with cetuximab as a 2nd Line treatment for R/M SCCHN is planned to commence in 2024....Lead asset, IM1240, expected to be ready for Phase 1 study by early 2026."

New P1 trial • New P2 trial • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

Purple Biotech Presents Data of its Phase 1 Head & Neck Cancer of NT219 in combination with Cetuximab at ESMO TAT Congress 2024 (GlobeNewswire) - P1/2 | N=110 | NCT04474470 | Sponsor: TyrNovo Ltd. | "Purple Biotech Ltd...announced clinical results from its Phase 1/2 dose escalation study of NT219 in combination with cetuximab in the treatment of patients with recurrent/metastatic head and neck cancer (R/M SCCHN)....Pharmacokinetic analysis demonstrated dose dependent increase in NT219 plasma concentrations....Out of these 7 patients, 2 had confirmed partial responses and 3 stable diseases (all patients with partial response and stable disease have HPV negative disease), representing a 29% ORR and 71% DCR. Median follow-up across all dose levels is 9.4 months (95% CI: 3.4-10.0, 8 out of 15 patients remaining in follow up)."

P1 data • PK/PD data • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

NT219 Delivers Safety Responses in SCCHN (Targeted Oncology) - "In a phase 1/2 trial of NT219 with cetuximab in patients with squamous cell carcinoma of the head and neck, safety and tolerability responses were encouraging."

Clinical data

A Study to Evaluate NT219 Alone and in Combination With ERBITUX® (Cetuximab) in Adults With Advanced Solid Tumors and Head and Neck Cancer (clinicaltrials.gov) - P1/2 | N=110 | Active, not recruiting | Sponsor: TyrNovo Ltd. | Trial completion date: Sep 2024 ➔ Jun 2024

Combination therapy • Metastases • Trial completion date • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • BRAF • KRAS