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

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

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

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

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 IB Study of Pegargiminase with Standard Chemoradiotherapy in Newly Diagnosed Glioblastoma (SNO 2026) - No abstract available

P1 data • Brain Cancer • Glioblastoma • 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 | Initiation date: Mar 2026 ➔ Jun 2027

Trial initiation date • Brain Cancer • Diffuse Midline Glioma • Glioblastoma • Glioma • High Grade Glioma • Oncology • Solid Tumor

Neoadjuvant ADI-PEG 20 + Ifosfamide + Radiotherapy in Soft Tissue Sarcoma (clinicaltrials.gov) - P1 | N=6 | Terminated | Sponsor: Washington University School of Medicine | Active, not recruiting ➔ Terminated; Polaris decided to close to accrual.

Trial termination • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

Germline HFE mutations predict for durable response to arginine depletion with pegargiminase-based chemotherapy in pleural mesothelioma (AACR 2026) - "In the Barts ATOMIC-Meso patient cohort, our data reveal mutant HFE as a novel pharmacogenomic biomarker for enhanced sensitivity and prolonged remission to pegargiminase-based chemotherapy for mesothelioma. Further analyses of durable responders to pegargiminase are ongoing with prospective clinical trials planned using HFE as a selection biomarker."

IO biomarker • Biphasic Mesothelioma • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pleural Mesothelioma • Sarcoma • Sarcomatoid Mesothelioma • Sarcomatoid Pleural Mesothelioma • Solid Tumor • ANXA5 • BCL2 • CASP3

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 | Terminated | Sponsor: Washington University School of Medicine | Active, not recruiting ➔ Terminated; Polaris has decided to close to accrual due to low enrollment

Trial termination • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • ALK • EGFR • ROS1

A Clinical Study of PA5 in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=49 | Recruiting | Sponsor: Chongqing Peg-Bio Biopharm Co., Ltd.

New P1 trial • Oncology • Solid Tumor

The Combined Therapeutic Effect of Lenvatinib and ADI-PEG 20 in Advanced Hepatocellular Carcinoma: A Case Report. (PubMed, In Vivo) - "This case provides clinically relevant insights into treatment selection in advanced HCC, suggesting that the combination of lenvatinib and ADI-PEG 20 may represent a promising, hypothesis-generating strategy, particularly where immunotherapy is not accessible, potentially overcoming TKI resistance through metabolic modulation. The patient achieved complete remission, with disappearance of metastatic lymph nodes and no viable liver tumor on CT in January 2026. However, these findings should be interpreted with caution given the limitations of a single case, and further studies are needed to validate this approach and define its clinical implications."

Journal • Cardiovascular • Diabetes • Fibrosis • Hepatitis B • Hepatitis C • Hepatocellular Cancer • Hypertension • Immunology • Infectious Disease • Liver Cancer • Metabolic Disorders • Nephrology • Oncology • Renal Disease • Solid Tumor

Arginine deprivation via ADI-PEG20 demonstrates subtype-specific efficacy in preclinical DMG models (ISPNO 2026) - "Resistance in H3K27M-mutant models, particularly H3.1K27M, underscores the need for combination strategies incorporating immune-based or epigenetic therapies. These findings support the clinical development of ADI-PEG20 as part of a personalised therapeutic strategy for DMG."

Preclinical • Brain Cancer • Diffuse Midline Glioma • Gene Therapies • Glioblastoma • Glioma • Solid Tumor • ASS1

Pegargiminase Suppresses the Fanconi Anemia Pathway and Promotes Melphalan-Induced DNA Double-Strand Breaks in Uveal Melanoma. (PubMed, Pigment Cell Melanoma Res) - "ADI-PEG20 downregulated multiple genes of the Fanconi anemia pathway and synergized with melphalan to increase DNA double-strand breaks. Melphalan and pegargiminase is a rational new drug combination that warrants clinical testing in uveal melanoma."

Journal • Anemia • Eye Cancer • Hematological Disorders • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • ASS1

Study of ADI-PEG 20 or Placebo Plus Gem and Doc in Previously Treated Subjects With Leiomyosarcoma (ARGSARC) (clinicaltrials.gov) - P3 | N=218 | Terminated | Sponsor: Polaris Group | Trial completion date: Dec 2027 ➔ May 2026 | Recruiting ➔ Terminated | Trial primary completion date: Dec 2027 ➔ May 2026; Lack of Efficacy, no safety concern.

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

Targeting arginine metabolism overcomes chemotherapy resistance in aggressive-variant prostate cancers. (PubMed, iScience) - "We conducted a phase 2 trial testing induction cabazitaxel plus carboplatin (CabCarb) followed by olaparib maintenance versus observation in men with AVPC. In AVPC models, arginine depletion with ADI-PEG20 enhanced CabCarb efficacy in vitro and in vivo. Together, these results provide insight into the heterogeneity of AVPCs and establish a rationale for novel combination treatment strategies to overcome chemotherapy resistance."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Arginine deprivation enhances ASS1-negative glioblastoma radiosensitivity via epigenetic silencing of DNA repair genes. (PubMed, Cell Death Dis) - "Currently, patients with GBM are treated with surgery followed by adjuvant radiotherapy and temozolomide, both of which are DNA damaging agents. Mechanistically, in both ASS1-negative patient-derived tumor cells and a patient-derived xenograft (PDX) model, ADI-PEG20 downregulated DNA repair genes, namely poly ADP-ribose polymerase 1 (PARP1) and DNA ligase 1 (LIG1), at the epigenetic level by upregulating the repressive H3K27me3 histone marker. Collectively, our findings demonstrate that arginine deprivation is an effective strategy to enhance the radiosensitivity of ASS1-negative GBM and suggest that combination therapy with PARP inhibitors should be explored."

Journal • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • ASS1 • LRIG1

GCAR-7213: Trial Designed To Evaluate Multiple Regimens In Newly Diagnosed and Recurrent Glioblastoma (GBM) (clinicaltrialsregister.eu) - P2/3 | N=120 | Active, not recruiting | Sponsor: Global Coalition For Adaptive Research Inc. | Recruiting ➔ Active, not recruiting

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

Neoadjuvant ADI-PEG 20 + Ifosfamide + Radiotherapy in Soft Tissue Sarcoma (clinicaltrials.gov) - P1 | N=6 | Active, not recruiting | Sponsor: Washington University School of Medicine | Trial completion date: May 2028 ➔ Jul 2026

Trial completion date • Oncology • Sarcoma • Soft Tissue Sarcoma • 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 | Trial completion date: Dec 2033 ➔ Jul 2026 | Trial primary completion date: Dec 2028 ➔ Jul 2026

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

GBM AGILE: A Trial to Evaluate Multiple Regimens in Newly Diagnosed and Recurrent Glioblastoma (clinicaltrials.gov) - P2/3 | N=2250 | Recruiting | Sponsor: Global Coalition for Adaptive Research | N=1280 ➔ 2250

Enrollment change • Brain Cancer • Glioblastoma • Hematological Disorders • Oncology • Solid Tumor

Pegargiminase and melphalan as a novel drug combination strategy for uveal melanoma (AACR 2024) - "This drug combination therapy has the potential to improve outcomes in patients with uveal melanoma. Based on the good tolerability and safety of both drugs in patients, a clinical trial of pegargiminase with melphalan is planned for 2024 (ATOMIC-UM)."

IO biomarker • Epithelioid Mesothelioma • Eye Cancer • Melanoma • Mesothelioma • Oncology • Solid Tumor • Uveal Melanoma • ASS1

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 | Recruiting | Sponsor: M.D. Anderson Cancer Center | Suspended ➔ Recruiting

Enrollment open • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor • PTEN • RB1 • TP53

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

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