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

MYC-ATF4-ASS1 axis governs intracellular arginine synthesis and dictates the immune microenvironment in melanoma. (PubMed, bioRxiv) - "ATF4 knockout in melanoma cells phenocopied ASS1 knockout in the same cells, both showing greater sensitivity to arginine depletors such as ADI-PEG20...Single cell transcriptomics profiled the reshaped tumor microenvironment and revealed that a subset of resident macrophages were reprogrammed by endogenous arginine blockade. Overall, our findings reveal that the MYC-ATF4-ASS1 axis not only controls arginine vulnerability of melanomas but also shapes the immune microenvironment."

Journal • Melanoma • Oncology • Solid Tumor • ASS1 • ATF4 • CD8

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

Germline HFE mutations predict for durable response to arginine depletion with pegargiminase-based chemotherapy in pleural mesothelioma (AACR 2026) - "Abstract is embargoed at this time."

Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pleural Mesothelioma • Solid Tumor

Phase I/II Study of PEGylated Arginine Deiminase (ADI-PEG20) With Carboplatin and Cabazitaxel in Men With Aggressive Variant Prostate Cancers (AVPC) (clinicaltrials.gov) - P1/2 | N=30 | Suspended | Sponsor: M.D. Anderson Cancer Center | Recruiting ➔ Suspended

Trial suspension • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor • PTEN • RB1 • TP53

Neoadjuvant ADI-PEG 20 + Ifosfamide + Radiotherapy in Soft Tissue Sarcoma (clinicaltrials.gov) - P1 | N=6 | Active, not recruiting | Sponsor: Washington University School of Medicine | Phase classification: P1/2 ➔ P1 | N=35 ➔ 6 | Trial completion date: Jan 2029 ➔ Mar 2028 | Trial primary completion date: Jan 2027 ➔ Mar 2026 | Recruiting ➔ Active, not recruiting

Enrollment change • Enrollment closed • Phase classification • Trial completion date • Trial primary completion date • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

Combination ADI-PEG 20, TMZ, and RT for Treatment of Newly Diagnosed High-grade Glioma (HGG) (clinicaltrials.gov) - P1/2 | N=97 | Not yet recruiting | Sponsor: Sabine Mueller, MD, PhD

New P1/2 trial • Brain Cancer • Diffuse Midline Glioma • Glioblastoma • Glioma • High Grade Glioma • Oncology • Solid Tumor

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=31 | Active, not recruiting | Sponsor: Washington University School of Medicine | N=114 ➔ 31 | Recruiting ➔ Active, not recruiting

Enrollment change • Enrollment closed • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • ALK • EGFR • ROS1

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 | Trial completion date: Jul 2026 ➔ Dec 2026 | Trial primary completion date: Dec 2025 ➔ May 2026

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Phase 2-3 trial of pegargiminase plus chemotherapy versus placebo plus chemotherapy in patients with non-epithelioid pleural mesothelioma (AACR 2023) - P2/3 | "Carboplatin (AUC5) was permitted in the phase 3 portion instead of cisplatin. In this first randomized trial of an arginine-depleting chemotherapy in cancer, the pegargiminase-pemetrexed-platinum triplet prolonged survival and had a favorable safety profile in pts with non-epithelioid PM (ClinicalTrials.gov Identifier NCT02709512)"

Clinical • P2/3 data • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Sarcoma • Solid Tumor • ASS1

Pegargiminase Plus First-Line Chemotherapy in Patients With Nonepithelioid Pleural Mesothelioma: The ATOMIC-Meso Randomized Clinical Trial. (PubMed, JAMA Oncol) - P2/3 | "All patients received intravenous pemetrexed (500 mg/m2) and platinum (75-mg/m2 cisplatin or carboplatin area under the curve 5) chemotherapy every 3 weeks up to 6 cycles. Pegargiminase-based chemotherapy as a novel antimetabolite strategy for mesothelioma validates wider clinical testing in oncology. ClinicalTrials.gov Identifier: NCT02709512."

Clinical • Journal • Immunology • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Solid Tumor

Phase I/II study of pegylated arginine deiminase (ADI-PEG 20) in combination with gemcitabine and docetaxel in non-small cell and small cell lung cancers. (ASCO 2024) - P1/2 | "Phase II uses a Simon optimal two-stage design per cohort for ORR with a minimum of 12 patients and a maximum of 36 patients per cohort. In the phase I, patient accrual at the maximum tolerated dose level is nearing completion and ADI-PEG in combination with G and D will be further evaluated in the phase II with separate cohorts for NSCLC and SCLC."

Combination therapy • P1/2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Sarcoma • Small Cell Lung Cancer • Soft Tissue Sarcoma • Solid Tumor • ASS1

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

Study of ADI-PEG 20 Versus Placebo in Subjects With High Arginine Level and Unresectable Hepatocellular Carcinoma (clinicaltrials.gov) - P3 | N=300 | Recruiting | Sponsor: Polaris Group | Trial completion date: Oct 2025 ➔ Dec 2028 | Trial primary completion date: Sep 2025 ➔ Sep 2028

Trial completion date • Trial primary completion date • Hepatocellular Cancer • Oncology • Solid Tumor

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

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