Comprehensive Report on the Investigational Agent NT-219

I. Executive Summary

NT-219 is a novel, first-in-class, investigational small molecule therapeutic agent designed to combat cancer by targeting fundamental mechanisms of drug resistance. Identified by DrugBank ID DB17490 and CAS Number 1198078-60-2, NT-219 operates through a unique dual mechanism of action, inhibiting both the Insulin Receptor Substrate 1/2 (IRS1/2) and Signal Transducer and Activator of Transcription 3 (STAT3) pathways. These pathways are crucial mediators of cancer cell survival, proliferation, metastasis, immune evasion, and, significantly, acquired resistance to various anti-cancer treatments, including chemotherapy, targeted therapies, and immunotherapy. Preclinical studies across a wide range of cancer models (including head and neck, colorectal, pancreatic, lung, melanoma, and sarcoma) have demonstrated NT-219's ability to overcome resistance to standard-of-care agents and exhibit synergistic anti-tumor effects when used in combination. Notably, NT-219 has shown potential in reversing resistance to EGFR inhibitors and PD-1 checkpoint inhibitors. The primary clinical evaluation has been conducted through the Phase 1/2 trial NCT04474470, which assessed NT-219 both as monotherapy and in combination with cetuximab, primarily in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). The study established a recommended Phase 2 dose (RP2D) of 100 mg/kg for the combination regimen, demonstrating a manageable safety profile and encouraging preliminary efficacy signals, particularly an objective response rate (ORR) of approximately 29% in heavily pretreated R/M SCCHN patients receiving higher doses of NT-219 with cetuximab. Future development focuses on Phase 2 studies evaluating NT-219 in combination with standard-of-care biologics (cetuximab and pembrolizumab) in R/M SCCHN, leveraging its potential to resensitize resistant tumors and address a significant unmet medical need. The identification of potential biomarkers related to IRS/STAT3 pathway activation may further refine patient selection strategies.

II. Introduction to NT-219

NT-219 represents an innovative approach within oncology drug development, characterized as a first-in-class, investigational small molecule therapeutic.[1] Unlike conventional cytotoxic agents or targeted therapies that primarily inhibit oncogenic "ON" signals, NT-219 embodies a distinct therapeutic concept focused on activating cellular "OFF" switches to counteract cancer progression and treatment failure.[6] Its core strategy revolves around targeting and overcoming the complex mechanisms that drive cancer drug resistance, a major limitation in the efficacy of current anti-cancer treatments.[2]

Recognizing that tumors frequently develop resistance through the activation of compensatory survival pathways or by evading immune surveillance, NT-219 was designed primarily for use in combination regimens.[2] The rationale is to enhance the efficacy and potentially broaden the applicability of existing anti-cancer drugs—spanning chemotherapy, molecularly targeted agents, and immunotherapies—by dismantling the tumor's resistance strategies.[2]

The clinical development program for NT-219 has concentrated on advanced solid malignancies, with a particular emphasis emerging from Phase 1/2 studies on recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) and potential applications in colorectal cancer (CRC).[4] Its development addresses the significant unmet need for therapies that can restore treatment sensitivity in patients whose cancers have become refractory to standard care.

III. Drug Profile and Development History

A. Chemical Identification and Properties

NT-219 is classified as a small molecule drug.[1] Its unique chemical identity is defined by the CAS Registry Number 1198078-60-2 and DrugBank Accession Number DB17490.[18] The systematic IUPAC name for NT-219 is (E)-3-(2-bromo-3,4-dihydroxyphenyl)-N-[(3,4,5-trihydroxyphenyl)methyl]prop-2-enethioamide.[19]

Key physicochemical properties are summarized in Table 1. NT-219 possesses a molecular formula of C16H14BrNO5S and a molecular weight consistently reported around 412.25 to 412.3 g/mol.[18] Its exact mass is approximately 410.98 Da.[18] The compound exists as a solid powder under standard conditions.[20] Solubility information indicates it is soluble in Dimethyl sulfoxide (DMSO), a common solvent for in vitro and preclinical studies, while its water solubility is low (predicted 0.0172 mg/mL by ALOGPS).[18] Stability data suggests the compound is stable for shipping under ambient temperatures and should be stored dry, protected from light, at 0-4°C for short durations or -20°C for long-term preservation.[20] Notably, a patent has been granted covering a formulation method designed to maintain the stability of NT-219 and prevent its conversion to less active forms during manufacturing, storage, and handling.[21]

Table 1: NT-219 Key Identifiers and Physicochemical Properties

Property	Value	Source(s)
Name	NT-219 (also NT 219, NT219)	1
DrugBank ID	DB17490	18
CAS Number	1198078-60-2	19
Type	Small Molecule	1
IUPAC Name	(E)-3-(2-bromo-3,4-dihydroxyphenyl)-N-[(3,4,5-trihydroxyphenyl)methyl]prop-2-enethioamide	19
Molecular Formula	C16H14BrNO5S	18
Molecular Weight	412.25 - 412.3 g/mol	18
Exact Mass	410.977607 / 410.98 Da	18
Appearance	Solid powder	20
Solubility	Soluble in DMSO; Water: 0.0172 mg/mL (predicted)	18
Storage	Dry, dark; 0-4°C (short-term), -20°C (long-term)	20
Stability Patent	Method patented to maintain active form during manufacturing/storage	21

The precise identification through CAS and DrugBank IDs is crucial for accurate literature and database searches. The fundamental physicochemical characteristics, including molecular weight, formula, solubility, and stability, are essential for formulation development, preclinical testing, and understanding the compound's behavior in vitro and in vivo. Consolidating these details provides a foundational reference for researchers and developers.

B. Origin and Corporate Development Timeline

The development trajectory of NT-219 began in an academic setting at The Hebrew University of Jerusalem, where it was co-invented by Dr. Hadas Reuveni and Prof. Alexander Levitzki.[2] The intellectual property was subsequently licensed from Yissum, the university's technology transfer company.[2]

Initial development was undertaken by TyrNovo Ltd., a company led by co-inventor Dr. Reuveni, who served as its CEO.[2] TyrNovo conducted foundational preclinical research, including studies using patient-derived xenograft (PDX) models, often in collaboration with other Israeli institutions like Bar-Ilan University and Clalit Health Services.[2]

In early 2017, Kitov Pharmaceuticals acquired a controlling 56% stake in TyrNovo, signaling confidence in NT-219's potential.[6] Kitov later increased its ownership to 83% in October 2017.[2] During this period, Kitov engaged with the U.S. Food and Drug Administration (FDA), receiving a favorable response in November 2017 to a pre-Investigational New Drug (pre-IND) package outlining a clinical development plan for NT-219 in combination with gemcitabine for advanced pancreatic cancer.[8] The FDA agreed that the proposed Phase 1/2 trial design was reasonable and that supporting toxicology studies were sufficient.[8]

Subsequently, the development of NT-219 transitioned to Purple Biotech Ltd. (formerly Kitov Pharma, or through a later corporate restructuring/acquisition).[1] Purple Biotech has been responsible for advancing NT-219 into clinical trials, initiating the Phase 1/2 study NCT04474470.[4] This trial shifted focus from the initially discussed pancreatic cancer indication towards broader solid tumors in monotherapy and specifically R/M SCCHN and CRC for the combination arm with cetuximab.[4] Purple Biotech completed the dose-escalation phases, determined the RP2D for the cetuximab combination, and is planning further Phase 2 development in HNSCC.[4]

This developmental history, involving transitions from academia through multiple biotech entities (TyrNovo, Kitov, Purple Biotech), illustrates the often protracted and resource-intensive nature of bringing a novel therapeutic concept from discovery to later-stage clinical evaluation. The shift in initial clinical focus from pancreatic cancer (discussed with FDA under Kitov) to HNSCC/CRC (pursued in NCT04474470 by Purple Biotech) may reflect evolving preclinical data, strategic reassessments, funding considerations, or emerging partnership opportunities. The consistent involvement of key scientific personnel, such as Dr. Reuveni [6], likely provided crucial continuity in the scientific vision and mechanistic understanding driving the program forward despite corporate changes.

IV. Mechanism of Action: Dual IRS1/2 and STAT3 Inhibition

NT-219 employs a novel mechanism of action centered on the simultaneous inhibition of two critical signaling nodes implicated in cancer progression and therapy resistance: Insulin Receptor Substrate 1/2 (IRS1/2) and Signal Transducer and Activator of Transcription 3 (STAT3).[5]

A. Role of IRS1/2 and STAT3 Pathways in Cancer and Drug Resistance

IRS1/2 Pathway: IRS1 and IRS2 are key cytoplasmic adaptor or scaffold proteins that relay signals from upstream receptor tyrosine kinases, most notably the Insulin Receptor (IR) and Insulin-like Growth Factor 1 Receptor (IGF1R), but also others like the IL4 receptor, to downstream effector pathways.[1] These downstream pathways, including the PI3K/AKT/mTOR, RAS/MEK/ERK, and WNT/β-catenin cascades, are fundamental regulators of cell growth, proliferation, survival, metabolism, motility, angiogenesis, and metastasis.[5] Overexpression or aberrant activation of the IRS pathway is common in various malignancies and contributes significantly to the oncogenic phenotype.[5] Crucially, the IRS pathway serves as a major feedback loop and survival mechanism that cancer cells exploit to develop resistance to a wide array of anti-cancer therapies.[2] For instance, inhibition of the EGFR pathway can lead to compensatory upregulation of IRS signaling, thereby circumventing the therapeutic blockade.[10] Furthermore, IRS signaling can modulate the tumor microenvironment, potentially promoting immunosuppression through effects on tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs).[5] Specific roles have also been identified, such as IRS2 driving colorectal cancer (CRC) brain metastasis via modulation of β-catenin and oxidative phosphorylation (OXPHOS) pathways.[1]

STAT3 Pathway: STAT3 is a latent cytoplasmic transcription factor activated by numerous cytokines (e.g., IL-6, IL-10) and growth factor receptors (e.g., EGFR, VEGFR).[1] Upon phosphorylation (typically at Tyr705), STAT3 dimerizes, translocates to the nucleus, and drives the expression of genes involved in cell proliferation (e.g., cyclin D1), survival (e.g., BCL-XL, MCL1), angiogenesis (e.g., VEGF), invasion, and metastasis.[5] Persistent activation or hyperactivation of STAT3 is frequently observed across diverse cancer types and is strongly associated with tumorigenesis.[5] Beyond its direct effects on tumor cells, STAT3 is a master regulator of tumor-associated inflammation and immune evasion.[5] It promotes an immunosuppressive tumor microenvironment by inhibiting the maturation and function of dendritic cells and macrophages, suppressing cytotoxic T cell activity, promoting regulatory T cell (Treg) development, and inducing the expression of immunosuppressive factors like IL-10 and TGF-β.[5] Like IRS, STAT3 activation can also mediate resistance to conventional chemotherapy and targeted therapies.[10]

The simultaneous targeting of both IRS and STAT3 pathways by NT-219 represents a rational strategy to counteract the complex and often redundant mechanisms underlying cancer progression and treatment failure. By disrupting both pro-survival/proliferative signaling (mediated largely by IRS) and intrinsic resistance/immune evasion pathways (mediated by STAT3 and IRS), NT-219 aims to deliver a more comprehensive anti-cancer effect than inhibitors targeting single pathways, particularly in the context of acquired resistance.

B. NT-219's Molecular Action: IRS1/2 Degradation and STAT3 Inhibition

NT-219 exerts its dual inhibitory effect through distinct actions on its target proteins:

• IRS1/2 Degradation: NT-219 uniquely promotes the degradation and subsequent elimination of both IRS1 and IRS2 proteins from cancer cells.[2] This is achieved through a multi-step mechanism involving the dissociation of IRS proteins from their upstream receptor (IGF1R), induction of inhibitory serine phosphorylation on IRS1/2, and ultimately targeting the modified IRS proteins for degradation via the proteasome pathway.[10] Evidence suggests NT-219 can covalently bind to IRS2, facilitating its degradation.[29] This degradation effectively shuts down downstream signaling through critical pathways like PI3K/AKT and WNT/β-catenin.[5]
• STAT3 Inhibition: NT-219 directly inhibits the phosphorylation of STAT3, likely at the critical Tyr705 residue required for its activation.[2] By preventing STAT3 phosphorylation, NT-219 blocks its dimerization, nuclear translocation, and subsequent transcriptional activity, thereby inhibiting the expression of STAT3 target genes involved in oncogenesis and immune suppression.[19]

This explicit dual inhibition of IRS1/2 (via degradation) and STAT3 (via phosphorylation inhibition) is the defining characteristic of NT-219's mechanism.[1] Preclinical studies indicate that targeting both pathways is essential for the drug's efficacy in overcoming resistance.[10] NT-219 achieves this through specific binding to its targets.[19] Furthermore, the inhibitory effects of NT-219 on these pathways appear to be durable, with prolonged pathway inhibition observed even after short exposure times in vitro.[24]

C. Downstream Signaling Effects and Overcoming Resistance

By degrading IRS1/2 and inhibiting STAT3 activation, NT-219 effectively blocks multiple downstream signaling cascades crucial for tumor growth and survival, including PI3K/AKT/mTOR, RAS/MEK/ERK, and WNT/β-catenin pathways downstream of IRS, as well as the transcriptional programs controlled by STAT3.[2]

The primary therapeutic rationale for NT-219 stems from its ability to counteract drug resistance. By neutralizing the IRS and STAT3 pathways—which function as key feedback loops and survival mechanisms activated in response to various anti-cancer therapies—NT-219 is designed to prevent the emergence of acquired resistance and potentially re-sensitize tumors that have already become refractory.[2] This hypothesis is supported by preclinical data demonstrating NT-219's ability to overcome resistance to a diverse range of agents, including EGFR inhibitors (e.g., cetuximab, erlotinib, osimertinib), MEK inhibitors (e.g., trametinib), BRAF inhibitors (e.g., vemurafenib), mTOR inhibitors (e.g., everolimus), and conventional chemotherapies.[2]

D. Impact on Tumor Microenvironment and Immune Evasion

NT-219's mechanism of action extends beyond direct effects on tumor cell signaling to encompass modulation of the tumor microenvironment (TME). The inhibition of STAT3, a pivotal mediator of immunosuppression, is central to this aspect.[5] By blocking STAT3, NT-219 may potentially reverse the immunosuppressive milieu within the tumor, hindering the function of suppressive cell types (like Tregs or myeloid-derived suppressor cells) and reducing the production of immunosuppressive cytokines such as IL-10.[26] Indeed, preclinical studies have shown that NT-219 can suppress the IL-10 secretion induced by anti-PD1 treatment, providing a mechanistic link to its observed synergy with checkpoint inhibitors.[26]

Additionally, the IRS pathway itself contributes to establishing a tumor-protective microenvironment, potentially through effects on TAMs and CAFs.[5] By degrading IRS proteins, NT-219 may further disrupt these supportive stromal interactions.

This capacity to modulate the TME towards a more immune-permissive state likely underpins the observed preclinical synergy between NT-219 and immunotherapies, such as the anti-PD1 agent pembrolizumab (Keytruda).[9] By simultaneously targeting intrinsic tumor cell resistance pathways (IRS/STAT3) and extrinsic immune evasion mechanisms (STAT3-mediated immunosuppression), NT-219 offers a multi-pronged approach to enhancing anti-tumor immunity, particularly in combination strategies.

V. Preclinical Evidence and Validation

Extensive preclinical studies have been conducted to validate the mechanism of action and therapeutic potential of NT-219 across various cancer models.

A. In Vitro and In Vivo Monotherapy Activity

NT-219 has demonstrated standalone anti-tumor activity in multiple preclinical settings.[2] In vitro, treatment with NT-219 leads to the elimination of IRS1/2, dephosphorylation of STAT3, and subsequent induction of apoptosis in cancer cell lines.[19] In vivo, NT-219 monotherapy resulted in significant tumor growth inhibition (TGI) and even tumor regression in several PDX models, including those derived from HNSCC (e.g., 69% TGI in a pembrolizumab-resistant model) and CRC.[24]

B. Efficacy in Combination Therapy Models

The majority of preclinical work has focused on evaluating NT-219 in combination regimens, aligning with its proposed role as a resistance-breaking agent:

• Chemotherapy: NT-219 demonstrated synergy with standard chemotherapeutic agents. It enhanced the efficacy of gemcitabine in pancreatic cancer PDX models [3] and worked synergistically with 5-fluorouracil (5-FU) and oxaliplatin in CRC models, including those resistant to chemotherapy.[10] Studies specifically highlighted its ability to reverse chemo-resistance.[26]
• Targeted Therapy: NT-219 consistently showed the ability to overcome acquired resistance to various targeted agents. Synergy and resistance reversal were observed with inhibitors of EGFR (erlotinib, cetuximab, osimertinib), MEK (trametinib), mutated-BRAF (vemurafenib), and mTOR (everolimus) across different cancer models.[2] Particularly strong evidence was generated in HNSCC PDX models resistant to the EGFR antibody cetuximab, where the addition of NT-219 restored sensitivity and led to tumor regression.[24]
• Immunotherapy: Compelling preclinical data support the combination of NT-219 with immune checkpoint inhibitors. NT-219 was shown to convert tumors non-responsive to the anti-PD1 antibody pembrolizumab (Keytruda) into responders in PDX models of esophageal cancer and HNSCC.[2] This effect is linked to NT-219's ability to counteract STAT3-mediated immune evasion and suppress anti-PD1-induced immunosuppressive factors like IL-10.[5] Synergy was also noted with the immunomodulatory effects of cetuximab.[10]

The consistent demonstration of synergy across mechanistically diverse therapeutic classes (chemotherapy, various targeted agents, immunotherapy) provides strong support for the central hypothesis that NT-219 targets common, fundamental pathways of resistance. By inhibiting both IRS-mediated survival signaling and STAT3-driven resistance and immune evasion, NT-219 appears capable of re-sensitizing tumors to a broad spectrum of anti-cancer treatments, positioning it as a potentially versatile combination partner.

C. Activity Across Diverse Tumor Types

The preclinical efficacy of NT-219, particularly in combination settings, has been observed across a wide array of cancer types. These include HNSCC, CRC, pancreatic cancer, sarcoma, melanoma, non-small cell lung cancer (NSCLC), ovarian cancer, prostate cancer, esophageal cancer, breast cancer, and gastroesophageal junction (GEJ) cancer.[2] This broad activity spectrum further suggests that the IRS/STAT3 resistance axis is relevant across many different solid tumor histologies.

D. Evidence for Reversing Drug Resistance

A core element of NT-219's preclinical validation is its demonstrated ability to overcome drug resistance. Studies explicitly show it can prevent the development of acquired resistance when co-administered with other therapies and, perhaps more importantly, can reverse established resistance in tumors that have already become refractory.[2] Its efficacy in PDX models derived from patients who had progressed on therapies like pembrolizumab provides direct preclinical evidence of its potential utility in clinically relevant resistance settings.[24]

E. Specific Findings

Beyond general efficacy, specific preclinical findings highlight unique aspects of NT-219's activity:

• CRC Brain Metastasis: In a dedicated mouse model, NT-219 combined with 5-FU markedly inhibited the formation of brain metastases from CRC and significantly extended survival. This effect was linked mechanistically to the inhibition of the IRS2/β-catenin/OXPHOS axis, suggesting a potential role for NT-219 in preventing or treating metastatic disease in specific contexts.[1]
• KRAS Mutants: NT-219 demonstrated activity against cancer stem cells and showed synergy with the KRAS G12C inhibitor sotorasib in NSCLC spheroid models, suggesting potential utility in KRAS-mutant cancers, a notoriously difficult-to-treat subgroup.[23]
• Neurodegeneration Models: While outside the primary oncology focus, studies in C. elegans and mammalian cell culture indicated that NT-219, through inhibition of IGF-1 signaling, could affect the aggregation and clearance of proteotoxic species associated with neurodegenerative diseases like Alzheimer's and Huntington's.[1] This suggests broader biological effects related to IRS/IGF-1 signaling modulation.

F. Potential Biomarkers from Preclinical Data

Preclinical investigations have yielded potential biomarkers that may predict sensitivity to NT-219:

• WNT/β-catenin Pathway Status: Enhanced WNT/β-catenin signaling or loss-of-function mutations in the negative regulator APC were associated with response to NT-219 in CRC models, suggesting this pathway's status could be predictive.[26]
• IRS2 Expression/Amplification: Given the specific role identified for IRS2 in CRC brain metastasis and NT-219's ability to degrade IRS2, its expression or amplification level might serve as a biomarker.[1]
• STAT3/IGF1R Activation: The activation status (phosphorylation) of STAT3 and IGF1R (pSTAT3, pIGF1R) correlated with response to NT-219-based therapy in HNSCC models and were suggested as potential clinical biomarkers.[26]

The identification of these candidate biomarkers during preclinical development is a critical step. If validated clinically, they could enable a precision medicine approach, allowing for the selection of patients whose tumors exhibit the specific molecular characteristics (e.g., hyperactivated STAT3, aberrant IRS/β-catenin signaling) that make them most likely to benefit from NT-219's unique resistance-breaking mechanism. This would significantly enhance the drug's clinical utility and potential for regulatory success.

VI. Clinical Development Program

The translation of NT-219 from preclinical validation to human studies has primarily centered around a Phase 1/2 clinical trial designed to establish its safety, pharmacokinetic profile, and preliminary efficacy.

A. Overview of Clinical Trials

Two clinical trials involving NT-219 are mentioned in the provided documentation:

• NCT04474470: This is the main clinical study conducted to date. It is a Phase 1/2, multi-center, open-label trial involving dose escalation and expansion phases. The study evaluated NT-219 administered intravenously (IV) weekly, both as a monotherapy and in combination with the EGFR-targeting antibody cetuximab (Erbitux). The target population included adults with advanced solid tumors, with the combination arm focusing on R/M SCCHN and CRC.[4] As of late 2023/early 2024, the dose escalation portions were completed, and the trial status was listed as Active, Not Recruiting.[13]
• NCT06919666: This appears to be a planned follow-up study. It is listed as a Phase 1/2 trial investigating NT-219 combined with standard-of-care (SoC) biologic therapy (likely cetuximab or pembrolizumab based on development plans) in patients with R/M HNSCC.[11] Its status was reported as Not Yet Recruiting.[11]

B. Detailed Analysis of Phase 1/2 Trial NCT04474470

This first-in-human study provided crucial initial data on NT-219 in cancer patients.

i. Study Design and Objectives:

The trial employed a multi-center, open-label design.14 Phase 1 utilized a conventional 3+3 dose-escalation scheme to determine safety and tolerability.15 Part 1 evaluated NT-219 monotherapy across escalating dose levels (starting from 3 mg/kg up to potentially 100 mg/kg) in patients with various advanced solid tumors.4 Part 2 evaluated escalating doses of NT-219 (starting from 6 mg/kg up to 100 mg/kg) in combination with standard-dose cetuximab (IV weekly) in patients with R/M SCCHN or CRC.4 A subsequent Phase 2 expansion phase was planned at the determined RP2D.15

The primary objectives focused on assessing the safety and tolerability profile of NT-219 alone and with cetuximab, identifying any Dose-Limiting Toxicities (DLTs), determining the Maximum Tolerated Dose (MTD), and establishing the RP2D for future studies.[14] Secondary objectives included characterizing the pharmacokinetic (PK) profile (AUC, Cmax, Vss, t1/2, CL) and pharmacodynamic (PD) effects of NT-219, and obtaining preliminary evidence of anti-tumor efficacy using standard metrics like Objective Response Rate (ORR), Duration of Response (DOR), Progression-Free Survival (PFS), Overall Survival (OS), and Time to Response, assessed per RECIST v1.1.[14] Exploratory objectives included evaluating potential biomarkers, such as the phosphorylation status of STAT3 and IRS1/2 in tumor biopsies.[15]

ii. Patient Population and Baseline Characteristics:

Eligible patients were adults (age ≥18) with histologically or cytologically confirmed advanced solid tumors that were recurrent and/or metastatic and refractory to standard therapies.14 Patients needed measurable disease per RECIST 1.1, an ECOG performance status of 0 or 1, adequate organ function (including specific thresholds for albumin, bilirubin, liver enzymes, creatinine clearance, and blood counts), and must have completed prior anti-cancer therapies within specified washout periods (e.g., ≥4 weeks for chemo/experimental agents, ≥6 weeks for checkpoint inhibitors/IL-2).14 Patients with active, untreated CNS metastases or severe immunocompromise were excluded.14

The monotherapy cohort (Part 1) enrolled patients with diverse solid tumors, including CRC, pancreatic cancer, breast cancer, and GEJ cancer.[36] The combination cohort (Part 2) initially included R/M SCCHN and CRC patients [4], but later reports focused primarily on the R/M SCCHN population.[4] Baseline characteristics for the 17 R/M SCCHN patients enrolled in the combination arm (as of Jan 2024 data cut) indicated a heavily pretreated population: median age 58, all male, mostly White (95%), predominantly oral cavity primary tumors (76%), median of 2 prior lines of therapy for R/M disease, with universal prior exposure to anti-PD1 therapy (100%), frequent prior platinum chemotherapy (88%), and some prior cetuximab exposure (29%).[33]

iii. Safety and Tolerability Profile:

Safety data from NCT04474470 indicated that NT-219 was generally well tolerated, both as monotherapy and in combination with cetuximab.

• Monotherapy: In the initial dose escalation cohorts (up to 24 mg/kg), NT-219 monotherapy was well tolerated with no DLTs reported among the first 11 evaluable patients.[36] Six Grade 3 adverse events (AEs) were noted across 13 patients, with two (transient increases in alkaline phosphatase and AST) considered possibly related to NT-219.[36]
• Combination Therapy (NT-219 + Cetuximab): The combination regimen demonstrated a manageable safety profile up to the highest tested NT-219 dose of 100 mg/kg weekly.[28] Crucially, no DLTs were observed during the dose escalation phase.[28] There were no treatment-related AEs of Grade 4 or 5 reported.[39] The most common Treatment Emergent Adverse Events (TEAEs) were infusion-related reactions (reported in 76% of patients) and nausea (35%), followed by fatigue, headache, and rash (each ~24%).[33] These were predominantly Grade 1 or 2 in severity and were managed with supportive care.[33]
• RP2D Determination: Based on the overall safety, PK, PD, and preliminary efficacy data from the dose escalation, 100 mg/kg IV weekly was established as the RP2D for NT-219 when administered in combination with standard-dose cetuximab.[4]

iv. Pharmacokinetics and Pharmacodynamics:

Pharmacokinetic analyses confirmed a dose-dependent increase in plasma concentrations of NT-219 following IV administration.4 Importantly, drug exposure levels achieved at the 50 mg/kg dose were found to be comparable to those associated with efficacy in preclinical animal models, providing a bridge between preclinical and clinical findings.40 Pharmacodynamic assessments provided evidence of target engagement within patient tumors, with inhibition of IRS1/2 and STAT3 observed in biopsy samples.35 Furthermore, exploratory biomarker analyses suggested a correlation between the upregulation (activation state) of pIGF1R and pSTAT3 and clinical response, supporting their potential use as predictive biomarkers.26

v. Clinical Efficacy Results:

Preliminary efficacy signals were observed in both the monotherapy and combination settings.

• Monotherapy (Part 1): Among 11 evaluable patients with diverse advanced solid tumors, the best overall response included one confirmed partial response (PR) in a patient with GEJ cancer (DOR 5.5 months) and three patients with stable disease (SD), all with CRC (DOR ranging from 2 to over 5.2 months).[36] This provided an early indication of single-agent biological activity.
• Combination Therapy (Part 2 - NT-219 + Cetuximab in R/M SCCHN): Anti-tumor activity was primarily observed at the higher NT-219 dose levels of 50 mg/kg and 100 mg/kg.[4] In the 7 patients evaluable for efficacy treated at these dose levels (data cut Jan 2024), the ORR was 28.6% (2 confirmed PRs), and the Disease Control Rate (DCR = PR + SD) was 71.4% (2 PRs + 3 SDs).[4] Notably, all patients achieving PR or SD in this subgroup had HPV-negative disease, a subset often associated with poorer outcomes.[33] Responses appeared durable in some cases, with one patient achieving PR remaining on treatment at the time of reporting, and another SD patient continuing treatment beyond 6 months.[33] One patient with PR remained on therapy for 40 weeks.[33]

These early clinical results, particularly in the combination setting for R/M SCCHN, offer preliminary validation of the preclinical hypothesis that NT-219 can overcome resistance. The observed ORR of ~29% in heavily pretreated patients (most having failed prior immunotherapy) compares favorably to the historical ORR of ~13% reported for cetuximab monotherapy in similar patient populations.[24] While requiring confirmation in larger studies, this signal, coupled with the manageable safety profile and evidence of target engagement, supports the continued development of NT-219 as a combination partner to potentially re-sensitize tumors to EGFR inhibition in HNSCC.

Table 2: Summary of Clinical Outcomes from NCT04474470 (Combination Arm - R/M SCCHN at Higher Doses)

NT-219 Dose Level (mg/kg, IV weekly)	Evaluable Patients (N)	ORR (%) (Confirmed PRs)	DCR (%) (PR+SD)	Notable Responses / Durability	HPV Status of Responders/SD	Key Grade ≥3 TRAEs (%)	Source(s)
50 & 100	7	28.6% (2 PRs)	71.4% (2PR+3SD)	1 PR ongoing at 40 weeks	All HPV-negative	Not specified for subgroup	4 (Data cut Jan 25, 2024)

Note: Data represents interim results from a small number of patients in the dose escalation phase.

C. Status and Plans for Future Trials

The dose escalation components of NCT04474470, evaluating both monotherapy and the combination with cetuximab, have been completed.[4] The RP2D for NT-219 in combination with cetuximab was established at 100 mg/kg IV weekly.[4]

Based on these findings, Purple Biotech announced plans to advance NT-219 into Phase 2 development, primarily focusing on R/M SCCHN.[5] This Phase 2 study, planned or initiated as of early 2025, intends to evaluate NT-219 (likely at the 100 mg/kg RP2D) in combination with two different standard-of-care agents: the anti-EGFR antibody cetuximab and the anti-PD1 checkpoint inhibitor pembrolizumab.[16] This reflects the preclinical data supporting synergy with both classes of agents. The study is being conducted in collaboration with the University of Colorado Anschutz Medical Campus.[16] The trial identifier NCT06919666, listed as Phase 1/2 and Not Yet Recruiting, likely corresponds to this planned Phase 2 investigation in R/M HNSCC.[11]

While HNSCC is the current lead indication, the broad mechanism of action and preclinical activity profile suggest potential for future exploration in other tumor types, particularly CRC (given the specific mechanistic links and preclinical data) and potentially pancreatic cancer (based on early preclinical results and initial FDA discussions).[3] Continued data readouts and presentations at major oncology conferences were anticipated throughout 2023, 2024, and 2025.[1]

VII. Regulatory and Intellectual Property Landscape

A. FDA Interactions

The primary documented interaction with the FDA occurred in late 2017 when Kitov Pharmaceuticals received feedback on a pre-IND package for NT-219.[8] The FDA response was favorable regarding the proposed CMC, preclinical toxicology (accepting 1-month animal studies and not requiring combination toxicology with gemcitabine), and the clinical development plan for a Phase 1/2 trial combining NT-219 with gemcitabine in advanced pancreatic cancer.[8] However, it is noteworthy that the clinical trial ultimately initiated by Purple Biotech (NCT04474470) focused on different indications (solid tumors/HNSCC/CRC) and combinations (monotherapy/cetuximab), suggesting a potential evolution in the development strategy since that initial FDA feedback.

B. Patent Portfolio Overview

Purple Biotech has secured intellectual property protection for NT-219, particularly focusing on its use in combination therapies:

• A US patent covers pharmaceutical combinations of NT-219 specifically with small molecule EGFR inhibitors.[43]
• A more recent US patent, granted around March 2025, covers combinations of NT-219 with EGFR-targeting antibodies, explicitly mentioning cetuximab, panitumumab, and necitumumab. This patent addresses the use of the combination for treating tumors resistant to EGFR therapy and is set to expire in 2036.[4] The granting of this patent was stated to complete geographic protection (US, Europe, China, Japan) for the NT-219/cetuximab combination.[43]
• A patent has also been granted in China covering the pharmaceutical composition of NT-219 and methods to maintain its stability and active form during manufacturing and storage.[21]

This patent strategy clearly aligns with the primary development goal of positioning NT-219 as a combination agent to overcome resistance to established therapies like EGFR inhibitors (both small molecules and antibodies).

C. Regulatory Designations

Based on the provided information, NT-219 has not received any specific expedited regulatory designations such as Orphan Drug Designation or Fast Track Designation from the FDA or EMA.[19] While other drugs discussed in the source material have received such designations [47], none were mentioned for NT-219 itself.

The absence of these designations could be due to several factors. The targeted indications, particularly R/M HNSCC and CRC, while representing significant unmet needs, may not meet the strict prevalence criteria for Orphan Drug status in major territories. Fast Track designation is granted for drugs treating serious conditions with unmet needs and demonstrating potential for substantial improvement over available therapies; while NT-219 aims to address unmet needs, the designation may not have been sought or granted at this stage, or it may simply not be reported in the available documents. The strong focus on securing patents for combination therapies reinforces the strategy of leveraging NT-219 to enhance existing treatments rather than developing it for a specific, potentially rare, indication that might qualify for orphan status.

VIII. Discussion and Future Outlook

A. Synthesis of NT-219's Profile: Strengths and Potential

NT-219 emerges as a distinct investigational agent characterized by its novel dual mechanism of action targeting both IRS1/2 degradation and STAT3 inhibition.[5] Its principal strength lies in addressing fundamental pathways (IRS-mediated survival/proliferation and STAT3-mediated resistance/immune evasion) that are commonly implicated in cancer's ability to evade therapeutic interventions.[2] This dual targeting provides a strong rationale for its potential to overcome acquired resistance to a broad spectrum of anti-cancer drugs, including chemotherapy, targeted agents (like EGFR inhibitors), and immunotherapies (like PD-1 inhibitors).[2]

This potential is substantiated by extensive preclinical data demonstrating synergistic activity and resistance reversal across numerous cancer models.[9] The initial clinical data from the Phase 1/2 NCT04474470 trial, while preliminary, offers encouraging validation. The agent demonstrated a manageable safety profile both alone and in combination with cetuximab, with no DLTs observed up to the 100 mg/kg dose level in the combination setting.[28] Furthermore, the preliminary efficacy signals, particularly the ~29% ORR observed with the NT-219/cetuximab combination in heavily pretreated R/M SCCHN patients, suggest clinically meaningful activity in a population with limited options.[33]

B. Therapeutic Positioning and Potential Indications

Based on its mechanism and observed activity, NT-219 is primarily positioned as a combination therapy partner designed to restore or enhance sensitivity to standard-of-care treatments in patients whose cancers have become resistant.[2]

The current lead indication is R/M SCCHN, with a Phase 2 trial planned or underway to evaluate combinations with both cetuximab and pembrolizumab.[16] This focus is supported by the encouraging Phase 1/2 combination data and the known roles of EGFR and PD-1 pathways (and resistance thereto) in HNSCC.

Colorectal cancer represents another significant area of interest, underpinned by preclinical data showing synergy with chemotherapy and the specific finding related to IRS2/β-catenin pathway inhibition in suppressing CRC brain metastasis.[1] Pancreatic cancer also remains a potential indication, given positive preclinical combination data and the initial FDA pre-IND discussions, although it was not the primary focus of the first clinical trial.[3] The broad preclinical activity suggests potential applicability in other solid tumors where resistance mediated by IRS and/or STAT3 pathways is a clinical challenge.[2]

C. Role of Combination Therapy

The development strategy for NT-219 is fundamentally anchored in combination therapy.[2] Its value proposition lies in its potential to augment the efficacy of existing drugs by overcoming resistance mechanisms. The planned Phase 2 evaluation in HNSCC combining NT-219 with both an EGFR inhibitor (cetuximab) and a PD-1 inhibitor (pembrolizumab) is logical.[17] Combining with cetuximab directly tests the hypothesis of overcoming resistance to EGFR blockade, supported by preclinical synergy and the Phase 1/2 clinical signal.[24] Combining with pembrolizumab explores the potential to reverse immune checkpoint inhibitor resistance, leveraging NT-219's ability to inhibit the immunosuppressive STAT3 pathway and preclinical evidence of synergy with anti-PD1 agents.[5] Success in these combinations would validate NT-219's role in tackling distinct but highly relevant resistance scenarios in HNSCC.

D. Importance of Biomarker Development

The identification of patient populations most likely to benefit from NT-219 will be crucial for its successful development. Preclinical studies have pointed towards potential predictive biomarkers, including the activation status of STAT3 and IGF1R (pSTAT3, pIGF1R), the expression level or amplification of IRS2, and alterations in the WNT/β-catenin pathway (e.g., APC mutations).[1] Clinical validation of these, or identification of novel biomarkers, within the ongoing and planned Phase 2 trials is essential.[15] A validated biomarker strategy would allow for patient stratification, enriching trial populations for likely responders, increasing the probability of demonstrating significant clinical benefit, and potentially facilitating a more streamlined regulatory path based on precision oncology principles. The correlation observed in the Phase 1/2 study between pIGF1R/pSTAT3 upregulation and response provides an early clinical hint supporting this direction.[26]

E. Concluding Remarks on NT-219's Potential Impact

NT-219 represents a promising therapeutic candidate with a unique dual mechanism aimed at overcoming cancer drug resistance by targeting the IRS1/2 and STAT3 pathways. Its potential to re-sensitize tumors to various standard therapies, including chemotherapy, targeted agents, and immunotherapy, addresses a critical unmet need in oncology, particularly for patients with advanced, refractory malignancies like R/M SCCHN and potentially CRC. The preclinical data are compelling, and the initial Phase 1/2 clinical results provide encouraging signals regarding safety and preliminary efficacy, especially in combination with cetuximab.

However, the clinical development program remains at an early stage. Confirmation of efficacy and safety in larger, well-controlled Phase 2 and subsequent Phase 3 trials is necessary. The successful identification and validation of predictive biomarkers will likely be key to defining the optimal patient populations and realizing the full potential of NT-219. If further development confirms its benefit-risk profile, NT-219 could become a valuable addition to the therapeutic armamentarium, offering a novel strategy to combat treatment resistance and improve outcomes for patients with difficult-to-treat cancers.

Works cited

1. NT-219 - Drug Targets, Indications, Patents - Patsnap Synapse, accessed April 30, 2025, https://synapse.patsnap.com/drug/a8330159d1b8430bb8834cb3a0405290
2. Kitov Boosts Ownership in TyrNovo and Oncology Platform Through Exchange of Shares for Stock - FirstWord Pharma, accessed April 30, 2025, https://firstwordpharma.com/story/4457876
3. Kitov Announces Positive Pre-clinical Data from NT219 Demonstrating its Dose-Dependent Anti-Tumor Efficacy - FirstWord Pharma, accessed April 30, 2025, https://firstwordpharma.com/story/4607221
4. A Study to Evaluate NT219 Alone and in Combination with ERBITUXu00ae (Cetuximab) in Adults with Advanced Solid Tumors and Head and Neck Cancer - LarvolClin, accessed April 30, 2025, https://clin.larvol.com/trial-detail/NCT04474470
5. NT219 - Purple Biotech, accessed April 30, 2025, https://purple-biotech.com/pipeline/nt219/
6. Kitov Enters Immuno-Oncology Field Through Acquisition of TyrNovo - PR Newswire, accessed April 30, 2025, https://www.prnewswire.com/news-releases/kitov-enters-immuno-oncology-field-through-acquisition-of-tyrnovo-610550855.html
7. Kitov buys program designed to stop cancer drug resistance | Fierce Biotech, accessed April 30, 2025, https://www.fiercebiotech.com/biotech/kitov-buys-program-designed-to-stop-cancer-drug-resistance
8. www.sec.gov, accessed April 30, 2025, https://www.sec.gov/Archives/edgar/data/1614744/000121390017011197/f6k110117ex99-1_kitovpharma.htm
9. Kitov Announces Results of Study Demonstrating NT-219 Enhanced Efficacy of Keytruda, accessed April 30, 2025, https://www.americanpharmaceuticalreview.com/1315-News/340331-Kitov-Announces-Results-of-Study-Demonstrating-NT-219-Enhanced-Efficacy-of-Keytruda/
10. Abstract 2754: NT219, a novel dual inhibitor of STAT3 and IRS1/2, converts immuno-oncology resistant tumors to responders - AACR Journals, accessed April 30, 2025, https://aacrjournals.org/cancerres/article/78/13_Supplement/2754/627116/Abstract-2754-NT219-a-novel-dual-inhibitor-of
11. NT-219 Not Yet Recruiting Phase 1 / 2 Trials for Squamous Cell Carcinoma of the Head and Neck (SCCHN) / Head And Neck Cancer Treatment - DrugBank, accessed April 30, 2025, https://go.drugbank.com/drugs/DB17490/clinical_trials?conditions=DBCOND0042625%2CDBCOND0035874&phase=1%2C2&purpose=treatment&status=not_yet_recruiting
12. Malignant Head and Neck Neoplasm Recruiting Phase 1 / 2 Trials for NT-219 (DB17490), accessed April 30, 2025, https://go.drugbank.com/indications/DBCOND0052101/clinical_trials/DB17490?phase=1%2C2&status=recruiting
13. Metastatic Solid Neoplasm Active Not Recruiting Phase 1 / 2 Trials for NT-219 (DB17490), accessed April 30, 2025, https://go.drugbank.com/indications/DBCOND0080723/clinical_trials/DB17490?phase=1%2C2&status=active_not_recruiting
14. Clinical Trial: NCT04474470 - My Cancer Genome, accessed April 30, 2025, https://www.mycancergenome.org/content/clinical_trials/NCT04474470/
15. A phase 1/2 study with open-label, dose escalation phase followed by single-arm expansion at the maximum tolerated dose to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of NT219 injection alone and in combination with cetuximab in adults with advanced solid tumors and head and neck cancer. - ASCO Publications, accessed April 30, 2025, https://ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.TPS3156
16. Purple Biotech advances NT219 into Phase II recurrent/metastatic SCCHN study, accessed April 30, 2025, https://www.clinicaltrialsarena.com/news/purple-biotech-nt219-scchn/
17. Purple Biotech Advances NT219 into Phase 2 Head and Neck Cancer Trial - Stock Titan, accessed April 30, 2025, https://www.stocktitan.net/news/PPBT/purple-biotech-advances-nt219-into-phase-2-head-and-neck-cancer-o1367rbm0bov.html
18. NT-219: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed April 30, 2025, https://go.drugbank.com/drugs/DB17490
19. Nt-219 | C16H14BrNO5S | CID 135914977 - PubChem, accessed April 30, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/135914977
20. NT219 | CAS#1198078-60-2 | inhibitor| MedKoo, accessed April 30, 2025, https://www.medkoo.com/products/34337
21. Purple Biotech Reports Third Quarter 2023 Financial Results - SEC.gov, accessed April 30, 2025, https://www.sec.gov/Archives/edgar/data/1614744/000121390023088934/ea188818ex99-1_purplebiotech.htm
22. Definition of IRS1/IRS2/STAT3 inhibitor NT219 - NCI Drug Dictionary, accessed April 30, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/irs1-irs2-stat3-inhibitor-nt219
23. NT219 | IRS1/2/STAT3 Inhibitor - MedchemExpress.com, accessed April 30, 2025, https://www.medchemexpress.com/nt219.html
24. Abstract 5639: NT219, a novel dual inhibitor of STAT3 and IRS1/2 ..., accessed April 30, 2025, https://aacrjournals.org/cancerres/article/80/16_Supplement/5639/643903/Abstract-5639-NT219-a-novel-dual-inhibitor-of
25. Kitov Enters Immuno-Oncology Field Through Acquisition of TyrNovo | Contract Pharma, accessed April 30, 2025, https://www.contractpharma.com/breaking-news/kitov-enters-immuno-oncology-field-through-acquisition-of-tyrnovo/
26. Purple Biotech Reports Positive NT219 Data for Colorectal & Head & Neck Cancers, accessed April 30, 2025, https://drug-dev.com/purple-biotech-reports-positive-nt219-data-for-colorectal-head-neck-cancers/
27. Purple Biotech Reports Positive NT219 Data at AACR for Colorectal and Head and Neck Cancers - GlobeNewswire, accessed April 30, 2025, https://www.globenewswire.com/news-release/2025/04/28/3069178/0/en/Purple-Biotech-Reports-Positive-NT219-Data-at-AACR-for-Colorectal-and-Head-and-Neck-Cancers.html
28. Purple Biotech Reaches Recommended Phase 2 Dose for NT219 - BioSpace, accessed April 30, 2025, https://www.biospace.com/purple-biotech-reaches-recommended-phase-2-dose-for-nt219
29. Purple Biotech Announces Publication in the Neuro Oncology ..., accessed April 30, 2025, https://www.morningstar.com/news/globe-newswire/9423338/purple-biotech-announces-publication-in-the-neuro-oncology-journal-demonstrating-the-potential-of-nt219-to-suppress-brain-metastasis-of-colorectal-cancer
30. IRS2 Gene - GeneCards | IRS2 Protein | IRS2 Antibody, accessed April 30, 2025, https://www.genecards.org/cgi-bin/carddisp.pl?gene=IRS2
31. Purple Biotech Reports Positive NT219 Data at AACR for Colorectal and Head and Neck Cancers - FirstWord Pharma, accessed April 30, 2025, https://firstwordpharma.com/story/5953637
32. NT219 CAS No.1198078-60-2 - Ruixibiotech, accessed April 30, 2025, https://www.ruixibiotech.com/pts/nt219
33. NT219 Delivers Safety Responses in SCCHN - Targeted Oncology, accessed April 30, 2025, https://www.targetedonc.com/view/nt219-delivers-safety-responses-in-scchn
34. Cancer Immunotherapy (Inhibitors Agonists Modulators Antagonists, accessed April 30, 2025, https://www.medchemexpress.com/ResearchArea/Cancer/cancer-immunotherapy.html?enCountryName=United%20States&edm&e=BBBBB&c=DDDDD&eId=45&page=100
35. NT219 Plus Cetuximab Elicits Responses, Demonstrates Tolerability in Recurrent or Metastatic HNSCC - OncLive, accessed April 30, 2025, https://www.onclive.com/view/nt219-plus-cetuximab-elicits-responses-demonstrates-tolerability-in-recurrent-or-metastatic-hnscc
36. Interim safety and efficacy results from a phase 1 study of NT219 in adults with advanced solid tumors. - ResearchGate, accessed April 30, 2025, https://www.researchgate.net/publication/361121879_Interim_safety_and_efficacy_results_from_a_phase_1_study_of_NT219_in_adults_with_advanced_solid_tumors
37. Interim safety and efficacy results from a phase 1 study of NT219 in adults with advanced solid tumors. - ASCO Publications, accessed April 30, 2025, https://ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.3096
38. NT-219 Archives - Purple Biotech, accessed April 30, 2025, https://purple-biotech.com/category/pub/nt-219/
39. Purple Biotech Presents Data of its Phase 1 Head & Neck Cancer of NT219 in combination with Cetuximab at ESMO TAT Congress 2024 - GlobeNewswire, accessed April 30, 2025, https://www.globenewswire.com/news-release/2024/02/27/2835842/0/en/purple-biotech-presents-data-of-its-phase-1-head-neck-cancer-of-nt219-in-combination-with-cetuximab-at-esmo-tat-congress-2024.html
40. 27O - Interim results of a phase I/II trial of NT219 in combination with cetuximab in patients with advanced/metastatic squamous cell carcinoma of the head and neck (SCCHN) - OncologyPRO, accessed April 30, 2025, https://oncologypro.esmo.org/meeting-resources/esmo-targeted-anticancer-therapies-congress-2024/interim-results-of-a-phase-i-ii-trial-of-nt219-in-combination-with-cetuximab-in-patients-with-advanced-metastatic-squamous-cell-carcinoma-of-the-he
41. NT219 Plus Cetuximab Demonstrates Efficacy, Tolerability in SCCHN - OncLive, accessed April 30, 2025, https://www.onclive.com/view/nt219-plus-cetuximab-demonstrates-efficacy-tolerability-in-scchn
42. Purple Biotech Presents Data of its Phase 1 Head & Neck Cancer of NT219 in combination with Cetuximab at ESMO TAT Congress 2024 | PPBT Stock News, accessed April 30, 2025, https://www.stocktitan.net/news/PPBT/purple-biotech-presents-data-of-its-phase-1-head-neck-cancer-of-gd0vnsnin3dt.html
43. Purple Biotech Granted New U.S. Patent for NT219 in Combination with EGFR Antibody Therapy, Enhancing Global IP Protection in Major Markets - GlobeNewswire, accessed April 30, 2025, https://www.globenewswire.com/news-release/2025/03/05/3037280/0/en/Purple-Biotech-Granted-New-U-S-Patent-for-NT219-in-Combination-with-EGFR-Antibody-Therapy-Enhancing-Global-IP-Protection-in-Major-Markets.html
44. Purple Biotech Secures US Patent for NT219 Cancer Resistance Drug in EGFR Combination Therapy | PPBT Stock News, accessed April 30, 2025, https://www.stocktitan.net/news/PPBT/purple-biotech-granted-new-u-s-patent-for-nt219-in-combination-with-386wani1zrv9.html
45. Investors - Purple Biotech, accessed April 30, 2025, https://purple-biotech.com/investors/
46. Pipeline - Purple Biotech, accessed April 30, 2025, https://purple-biotech.com/pipeline/
47. EU/3/24/2966 - orphan designation for treatment of gastric cancer - EMA, accessed April 30, 2025, https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3-24-2966
48. Most FDA and EMA Oncology Drug Approvals in Q1 2025 Were New Indications for Biologics and Biosimilars - Aptitude Health, accessed April 30, 2025, https://www.aptitudehealth.com/oncology-news/most-fda-and-ema-oncology-drug-approvals-in-q1-2025-were-new-indications-for-biologics-and-biosimilars/
49. EMA Grants Orphan Drug Designation to NeoImmuneTech's NT-I7 for the Treatment of Acute Radiation Syndrome - PR Newswire, accessed April 30, 2025, https://www.prnewswire.com/news-releases/ema-grants-orphan-drug-designation-to-neoimmunetechs-nt-i7-for-the-treatment-of-acute-radiation-syndrome-302163015.html
50. Food and Drug Administration and European Medicines Agency agree to accept a single orphan drug designation annual report, accessed April 30, 2025, https://www.ema.europa.eu/en/news/food-drug-administration-european-medicines-agency-agree-accept-single-orphan-drug-designation-annual-report
51. Numbers of FDA-approved and EMA-approved drugs indicated for... - ResearchGate, accessed April 30, 2025, https://www.researchgate.net/figure/Numbers-of-FDA-approved-and-EMA-approved-drugs-indicated-for-biomarker-defined-orphan_fig2_336434286