Hepacid (pegargiminase) / Polaris Pharma, Er-Kim Pharma - LARVOL DELTA

Extracellular arginine deprivation enhances venetoclax sensitivity in acute myeloidleukemia via mitochondrial fission impairment and apoptotic priming (ASH 2025) - P1 | "One such approach involvesarginine deprivation using pegylated arginine deiminase (ADI-PEG20), which is currently under clinicalinvestigation in combination with VEN and azacitidine (ASH 2023, Borthakur; NCT05001828). AlthoughADI-PEG20 has shown efficacy in AML cells deficient in argininosuccinate synthase 1 (ASS1), a key enzymefor endogenous arginine synthesis, our previous study demonstrated its ability to similarly enhance VENand decitabine responses in ASS1-positive AML cells (ASH 2023, Yamatani)...Importantly, these mitochondrial alterations werefurther exacerbated by co-treatment with VEN. Under these conditions, mitochondrial damage appearedto exceed the threshold for repair, resulting in simultaneous BCL2-dependent apoptotic priming andmitophagy failure, ultimately culminating in apoptosis.In conclusion, our study reveals that extracellular arginine deprivation via ADI-PEG20 inducesmitochondrial stress, impairs mitochondrial fission, and primes AML cells for..."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • ANXA5 • ASS1 • GAPDH

Results of the Phase 1B study of pegargiminase (ADI-PEG 20) in combination with AZA-VEN in newly diagnosed high-risk AML patients not candidates for intensive chemotherapy (ASH 2025) - P1 | "Pegargiminase (ADI-PEG 20), ametabolism-targeting therapeutic consisting of the arginine-degrading enzyme arginine deiminasecombined with polyethylene glycol, demonstrated high synergy with VEN-decitabine in pre-clinicalmodels and anti-leukemic activity as monotherapy and with cytarabine in clinical trials...We conducted a phase 1A/B trial evaluating triplet therapy with ADI-PEG 20+ azacitidine and venetoclax (AZA-VEN) in relapsed/refractory (R/R) and newly diagnosed (ND) AML(NCT05001828).MethodsThe phase 1A dose escalation cohort in R/R AML (n=13) was previously reported...Rates of CRc and MRD-negativity were high, with durableresponses observed. OS was better than expected, in this very-high risk AML population."

Clinical • Combination therapy • P1 data • Acute Myelogenous Leukemia • Infectious Disease • Pneumonia • Respiratory Diseases • ASS1 • FLT3 • KMT2A • NF1 • NRAS • PTPN11

Exploiting arginine auxotrophy in Philadelphia-chromosome positive acute lymphoblastic leukemia to deliver personalised metabolomic treatment (ASH 2025) - "To reinforce this concept, we tested pegargiminase-TKItherapy in 5 primary samples and showed a consistent additive effect ex vivo when combined withdasatinib (8.5% inhibition increase, p= 0.034) and ponatinib (22.4% increase, p= 0.011).Finally, we tested combined pegargiminase-dasatinib in vivo using the Arf-/-p185+ cell line that rapidlyevolves ABL1-mutation mediated resistance under TKI therapy. Compared to dasatinib alone, combinedtherapy induced a deeper response (p< 0.001), prevented on-treatment relapse, and prolonged mousesurvival (p= 0.018); demonstrating activity against canonical TKI resistance.ConclusionsOur study uncovers a novel, targetable metabolic vulnerability in Ph+ ALL. Pegargiminase demonstratesrobust pre-clinical activity in arginine auxotrophic Ph+ ALL, including in the context of TKI resistance.Together, these findings provide a strong rationale for clinical evaluation of arginine depletion as a novelchemotherapy-light treatment paradigm for..."

Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • ABL1 • ASS1 • IL7 • PHGDH • PSAT1 • PYCR1 • SHMT2

Loss of Argininosuccinate Synthetase-1 (ASS1) Occurs in Esophageal Adenocarcinoma and Represents a Promising Biomarker for Therapy with Pegargiminase. (PubMed, Cancers (Basel)) - "Background/Objectives: Despite the introduction of targeted therapies such as Nivolumab, survival outcomes for patients with esophageal adenocarcinoma remain poor. This underscores the urgent need for clinical trials evaluating the efficacy of pegargiminase in this patient population. Additionally, incorporating ASS1 immunohistochemical staining into pre-neoadjuvant biopsy assessments should be considered to optimize neoadjuvant treatment strategies and advance the implementation of personalized cancer therapy."

Biomarker • Journal • Esophageal Adenocarcinoma • Esophageal Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pleural Mesothelioma • Solid Tumor • ASS1

A spatially resolved multi-omic pipeline to study metabolic therapy response in glioblastoma (SNO 2025) - "Understanding the spatial distribution of proteins and metabolites within the tumour is essential for developing effective therapies, including metabolic strategies such as arginine deprivation using ADI-PEG20 (pegylated arginine deiminase)...Our spatially resolved multi-omic workflow supports high-resolution metabolite mapping for hypothesis-driven spatial analysis of proteins from a single tissue section, making it particularly advantageous for studies involving rare or limited clinical samples. It holds strong potential for widespread application in research across diverse tissue types and disease models."

Brain Cancer • Glioblastoma • Metabolic Disorders • Solid Tumor

A spatially resolved multi-omic pipeline to study metabolic therapy response in glioblastoma (SNO 2025) - "Understanding the spatial distribution of proteins and metabolites within the tumour is essential for developing effective therapies, including metabolic strategies such as arginine deprivation using ADI-PEG20 (pegylated arginine deiminase)...Our spatially resolved multi-omic workflow supports high-resolution metabolite mapping for hypothesis-driven spatial analysis of proteins from a single tissue section, making it particularly advantageous for studies involving rare or limited clinical samples. It holds strong potential for widespread application in research across diverse tissue types and disease models."

Brain Cancer • Glioblastoma • Metabolic Disorders • Solid Tumor

A spatially resolved multi-omic pipeline to study metabolic therapy response in glioblastoma (WFNOS 2025) - "Understanding the spatial distribution of proteins and metabolites within the tumour is essential for developing effective therapies, including metabolic strategies such as arginine deprivation using ADI-PEG20 (pegylated arginine deiminase)...Our spatially resolved multi-omic workflow supports high-resolution metabolite mapping for hypothesis-driven spatial analysis of proteins from a single tissue section, making it particularly advantageous for studies involving rare or limited clinical samples. It holds strong potential for widespread application in research across diverse tissue types and disease models."

Brain Cancer • Glioblastoma • Metabolic Disorders • Solid Tumor

A spatially resolved multi-omic pipeline to study metabolic therapy response in glioblastoma (WFNOS 2025) - "Understanding the spatial distribution of proteins and metabolites within the tumour is essential for developing effective therapies, including metabolic strategies such as arginine deprivation using ADI-PEG20 (pegylated arginine deiminase)...Our spatially resolved multi-omic workflow supports high-resolution metabolite mapping for hypothesis-driven spatial analysis of proteins from a single tissue section, making it particularly advantageous for studies involving rare or limited clinical samples. It holds strong potential for widespread application in research across diverse tissue types and disease models."

Brain Cancer • Glioblastoma • Glioma • Metabolic Disorders • Oncology • Solid Tumor

A Phase 1A/B Combination Study of Pegargiminase (ADI-PEG 20), Venetoclax and Azacitidine in Patients with Acute Myeloid Leukemia (ASH 2023) - P1 | "Comparisons of time-to-event endpoints by important subgroups will be made using the log-rank tests. The trial is currently enrolling and presents a novel and promising therapeutic strategy for patients with high-risk newly diagnosed and relapsed/refractory AML."

Clinical • P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ASS1

POLARIS2020-002: Study of ADI-PEG 20, Venetoclax and Azacitidine in Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=38 | Active, not recruiting | Sponsor: Polaris Group | Recruiting ➔ Active, not recruiting | N=60 ➔ 38 | Trial completion date: Dec 2025 ➔ Jul 2026 | Trial primary completion date: Jul 2025 ➔ Dec 2025

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Pegargiminase (ADI-PEG 20), Venetoclax and Azacitidine in Patients with Relapsed/Refractory Acute Myeloid Leukemia (ASH 2024) - "With limited treatment options in these poor risk pts, inclusion of the novel metabolism therapeutic, ADI-PEG 20, may serve as a promising therapeutic strategy in select adverse risk groups. With these results in mind, we anticipate upcoming results of our ongoing trial cohort of ADI-PEG 20 with AZA-VEN in the frontline setting for pts with adverse risk AML."

Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ASS1 • TP53

PPARG and ASS1: Targets of Metabolic Alteration in Venetoclax / Decitabine Resistant Acute Myeloid Leukemia (ASH 2023) - P2 | "The combination of venetoclax (VEN), an inhibitor of the anti-apoptotic factor BCL2, with the hypomethylating agent (HMA) decitabine (DEC) is the current frontline standard therapy for elderly patients with acute myeloid leukemia (AML). In MV4-11, ADI-PEG 20 combination significantly facilitated cell growth inhibition by VEN/DEC (increased VEN/DEC growth inhibition by ADI: HL60, 7%; MV4-11, 57%, p < 0.05). Taken together, this study demonstrated that VEN/DEC treatment facilitates energy metabolism in AML cells through increased expression of PPARG and ASS1, which may in turn translate into therapeutic resistance, and that VEN/DEC /ADI-PEG 20 combination may represent a potential novel therapeutic strategy (Figure 1)."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ASS1 • BCL2 • CXCR4 • PPARG

Inhibition of pathological angiogenesis in oxygen-induced retinopathy by arginine depletion with ADI-PEG20. (PubMed, Exp Eye Res) - "ADI-PEG20 did not alter photopic-b wave or a wave amplitude. Hence, intravitreal injection of ADI-PEG20 offers a novel strategy for limiting pathological angiogenesis, promoting vascular repair, and preserving visual function in conditions of ischemic retinopathy."

Journal • Age-related Macular Degeneration • Retinal Disorders

Investigating BAP1-stratified ADI-PEG20/Gemcitabine Treatment in Epithelioid Pleural Mesothelioma: From in Vitro Studies to Novel in ovo PDX Model with Future Potential as Patient Avatar (IMIG 2025) - "Furthermore, we provided proof-of-principle that CAM-PDXs with PET/CT and/or histology read-out offer a rapid, translational platform for real-time prediction of clinical response. In future, BAP1-stratification might be useful to extend ADI-PEG20 therapy to epithelioid PM."

Preclinical • Epithelioid Pleural Mesothelioma • Malignant Pleural Mesothelioma • Mesothelioma • Pleural Mesothelioma • Solid Tumor • ASS1 • BAP1 • CASP3 • CD4

Reducing Animal use Without Reducing Impact: Applications of Chorioallantoic Membrane (CAM) Xenograft and Patient-derived Xenograft (PDX) Models in Translational Mesothelioma Research (IMIG 2025) - "Metal organic frameworks loaded with platinum/pemetrexed were bioavailable but non-toxic, accumulated within PM cells of xenografts, and induced apoptosis...The anti-tussive benproperine, an ARPC2 inhibitor, decreased histological evidence for local invasion of BAP1-altered xenografts, and ADI-PEG20/gemcitabine treatment of BAP1-normal CAM-PDX reduced tumour 18F-FDG PET signal. We have developed a suite of pathologically relevant CAM models for PM, and demonstrated their utility for evaluating diverse therapies, administered via different routes, using a range of read-outs assessed by multi-modal imaging and/or histology. These biologically informative preclinical models offer a cost-effective alternative to murine xenografts within the translational pipeline for emerging therapeutic interventions in PM."

Malignant Pleural Mesothelioma • Mesothelioma • Pleural Mesothelioma • Solid Tumor • ASS1 • BAP1 • CD4 • CD8

Prognostic Role of ASS1 Expression and Therapeutic Implications of Arginine Deprivation in Peritoneal Mesothelioma (IMIG 2025) - "Objectives:Argininosuccinate synthetase (ASS1) deficiency in cancer has been translated from the benchside to the first positive phase 3 study of the arginine-depleting agent pegylated arginine deiminase (pegargiminase), namely the pivotal ATOMIC-meso study in patients with arginine-auxotrophic non-epithelioid pleural mesothelioma (Szlosarek, JAMA Oncol 2024)...Extrapolating from our previous work in pleural mesothelioma, and based on the current data, we propose further assessment of arginine deprivation therapy in peritoneal mesothelioma informed by histological subtype and biomarker selection."

Biomarker • Epithelioid Pleural Mesothelioma • Malignant Pleural Mesothelioma • Mesothelioma • Peritoneal Mesothelioma • Pleural Mesothelioma • Solid Tumor • ASS1

Prognostic Role of ASS1 Expression and Therapeutic Implications of Arginine Deprivation in Peritoneal Mesothelioma (IMIG 2025) - "Objectives:Argininosuccinate synthetase (ASS1) deficiency in cancer has been translated from the benchside to the first positive phase 3 study of the arginine-depleting agent pegylated arginine deiminase (pegargiminase), namely the pivotal ATOMIC-meso study in patients with arginine-auxotrophic non-epithelioid pleural mesothelioma (Szlosarek, JAMA Oncol 2024)...Extrapolating from our previous work in pleural mesothelioma, and based on the current data, we propose further assessment of arginine deprivation therapy in peritoneal mesothelioma informed by histological subtype and biomarker selection."

Biomarker • Epithelioid Pleural Mesothelioma • Malignant Pleural Mesothelioma • Mesothelioma • Peritoneal Mesothelioma • Pleural Mesothelioma • Solid Tumor • ASS1

Neoadjuvant ADI-PEG 20 + Ifosfamide + Radiotherapy in Soft Tissue Sarcoma (clinicaltrials.gov) - P1/2 | N=35 | Recruiting | Sponsor: Washington University School of Medicine | Trial completion date: Jan 2028 ➔ Jan 2029 | Trial primary completion date: Jan 2026 ➔ Jan 2027

Trial completion date • Trial primary completion date • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

Study of ADI-PEG 20 Versus Placebo in Subjects With NASH (clinicaltrials.gov) - P2 | N=60 | Recruiting | Sponsor: Polaris Group | N=40 ➔ 60

Enrollment change • Hepatology • Metabolic Dysfunction-Associated Steatohepatitis

ADI-PEG 20 Plus Radiotherapy and Temozolomide in Subjects With Glioblastoma Multiforme (clinicaltrials.gov) - P2 | N=100 | Active, not recruiting | Sponsor: Polaris Group | Recruiting ➔ Active, not recruiting

Enrollment closed • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

GBM AGILE: A Trial to Evaluate Multiple Regimens in Newly Diagnosed and Recurrent Glioblastoma (clinicaltrials.gov) - P2/3 | N=1280 | Recruiting | Sponsor: Global Coalition for Adaptive Research | Trial completion date: Jun 2028 ➔ Jun 2030 | Trial primary completion date: Jun 2026 ➔ Jun 2028

Trial completion date • Trial primary completion date • Brain Cancer • Glioblastoma • Hematological Disorders • Oncology • Solid Tumor

Arginine deprivation, mTOR signalling and DNA repair response in models of ovarian cancer (EACR 2025) - "Arginine deprivation therapies, such as administration of the enzymatic drug ADI-PEG20, target tumour metabolism by removing extracellular sources of arginine that cancer cells rely on for growth and proliferation and has been shown to be especially effective in cells deficient in the rate-limiting enzyme of arginine biosynthesis, argininosuccinate synthase (ASS1). These findings highlight the potential for arginine deprivation therapies in treating genetically defined subsets of ovarian carcinoma, particularly in combination with clinically approved agents that interfere with DNA repair such as PARP inhibitors."

Oncology • Ovarian Cancer • Solid Tumor • ASS1 • PTEN • TP53

Investigation of pegargiminase targeting the Fanconi anemia pathway and its role in DNA double-strand breaks induced by melphalan in uveal melanoma. (ASCO 2025) - P1, P2/3 | "Melphalan and arginine deprivation therapy is a rational new synthetically lethal drug combination that has the potential to improve outcomes in patients with ASS1-deficient uveal melanoma. Based on the good tolerability and safety of both drugs in patients, a clinical trial of melphalan with pegargiminase is planned (ATOMIC-UM)."

Anemia • Eye Cancer • Hematological Disorders • Melanoma • Mesothelioma • Oncology • Solid Tumor • Uveal Melanoma • ANXA5 • ASS1 • BRIP1 • FANCA • FANCB • FANCD2 • FANCE • FANCI • UBE2T

ADI-PEG 20 in Combination With Gemcitabine and Docetaxel After Progression on Frontline Therapy in Non-small Cell and Small Cell Lung Cancers (clinicaltrials.gov) - P1/2 | N=114 | Recruiting | Sponsor: Washington University School of Medicine | Trial completion date: Dec 2032 ➔ Dec 2033 | Trial primary completion date: Dec 2027 ➔ Dec 2028

Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • ALK • EGFR • ROS1

Arginine deiminase-polymeric hybrid nanoconjugates: A potential biodrug for targeted treatment of arginine auxotrophic cancers. (PubMed, Int J Biol Macromol) - "Pegargiminase, a PEGylated (polyethylene glycol) formulation of Mycoplasma hominis ADI is currently in the late phase of clinical trials and has promising activity against arginine-auxotrophic malignancies...In contrast to the free enzyme, the formulation showed significant cytotoxicity with a four-fold decrease in IC50 value. Therefore, biopolymeric enzyme nanoconjugates prepared herein present a novel approach for establishing ADI as an alternative/combinational nanomedicine in cancer therapy."

Journal • Gastrointestinal Disorder • Oncology