pixatimod (PG545) / Zucero Therap - LARVOL DELTA

A Novel Series of Synthetic Heparin-Mimetics-Itaconic Acid-Containing Copolymers for Targeting Tumor Cell Coagulability and Metastasis. (PubMed, Macromol Biosci) - "The copolymers, characterized by GPC, display high efficiencies to inhibit heparanase enzymatic activity, exceeding the potency of the clinical candidate PG545...Notably, poly(SS-co-IA) copolymers displayed a thousand-fold lower binding affinity to platelet factor-4 (PF4) than unfractionated heparin (UFH), suggesting a lower risk for HIT II susceptibility. The indicated polymers represent promising heparin mimetics with superior activities in oncology for metastatic control."

Journal • Inflammatory Arthritis • Oncology • Solid Tumor • Thrombosis

A Heparan Sulfate Mimetic RAFT Copolymer Inhibits SARS-CoV-2 Infection and Ameliorates Viral-Induced Inflammation. (PubMed, Adv Sci (Weinh)) - "Of particular note, HMSA-06 demonstrated more potent anti-SARS-CoV-2 effects than PG545 and Roneparstat...The HMSA-06's inflammation inhibitory function is further confirmed using a LPS/ATP-stimulated THP-1 macrophage model. Altogether, this study has identified a promising HS mimetic to combat SARS-CoV-2-associated diseases by inhibiting viral infection and attenuating viral-induced inflammatory reaction, providing insights into the development of novel anti-coronavirus drugs in the future."

Journal • Infectious Disease • Inflammation • Novel Coronavirus Disease • Respiratory Diseases • CASP1 • IL1B • NLRP3

Involvement of heparanase in the pathogenesis of acute pancreatitis: Implication of novel therapeutic approaches. (PubMed, J Cell Mol Med) - "Thus, the current study examines the pancreato-protective effects of Aspirin, Trehalose, PG545 and SST0001 in experimental model of AP induced by cerulein in wild-type (WT) and Hpa over-expressing (Hpa-Tg) mice...Importantly, a novel newly synthesized compound termed Aspirlose effectively ameliorated the pathogenesis of AP as a single agent. Collectively, the results strongly indicate that targeting Hpa by using anti-Hpa drug combinations constitute a novel therapy for this common orphan disease."

Journal • Gastroenterology • Gastrointestinal Disorder • Inflammation • Pancreatitis

Amphiphilic Heparinoids as Potent Antiviral Agents against SARS-CoV-2. (PubMed, J Med Chem) - "Sulfated higher oligosaccharides of d-glucose or l-idose with lipophilic aglycones displayed potent anti-SARS-CoV-2 and antiheparanse activity, similar to or better than pixatimod (PG545), and were more potent than their isosteric l-iduronic acid congeners. Lipophilic groups such as cholestanol and C18-aliphatic substitution are more advantageous than functional group appended lipophilic moieties. These findings confirm that fine-tuning of higher oligosaccharides, degree of sulfation, and lipophilic groups can yield compounds with potent anti-SARS-CoV-2 activity."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Pixatimod (PG545) Plus Nivolumab in PD-1 Relapsed/Refractory Metastatic Melanoma and NSCLC and With Nivolumab and Low-dose Cyclophosphamide in MSS Metastatic Colorectal Carcinoma (mCRC) (clinicaltrials.gov) - P2 | N=14 | Completed | Sponsor: Diwakar Davar | Active, not recruiting ➔ Completed | Trial completion date: Aug 2025 ➔ Mar 2024 | Trial primary completion date: Dec 2024 ➔ Feb 2024

Combination therapy • Metastases • Pan tumor • Trial completion • Trial completion date • Trial primary completion date • Colorectal Cancer • Cutaneous Melanoma • Gastrointestinal Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • ALK • BRAF • KRAS • MET

Pixatimod (PG545) Plus Nivolumab in PD-1 Relapsed/Refractory Metastatic Melanoma and NSCLC and With Nivolumab and Low-dose Cyclophosphamide in MSS Metastatic Colorectal Carcinoma (mCRC) (clinicaltrials.gov) - P2 | N=14 | Active, not recruiting | Sponsor: Diwakar Davar | Trial completion date: Sep 2027 ➔ Aug 2025 | Trial primary completion date: Sep 2025 ➔ Dec 2024

Combination therapy • Metastases • Pan tumor • Trial completion date • Trial primary completion date • Colorectal Cancer • Cutaneous Melanoma • Gastrointestinal Cancer • Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • ALK • BRAF • KRAS • MET

One more step toward treatment of PARP inhibitor-resistant ovarian cancers. (PubMed, Oncotarget) - No abstract available

Journal • Oncology • Ovarian Cancer • Solid Tumor

Pixatimod (PG545) Plus Nivolumab in PD-1 Relapsed/Refractory Metastatic Melanoma and NSCLC and With Nivolumab and Low-dose Cyclophosphamide in MSS Metastatic Colorectal Carcinoma (mCRC) (clinicaltrials.gov) - P2 | N=14 | Active, not recruiting | Sponsor: Diwakar Davar | Recruiting ➔ Active, not recruiting | Phase classification: P2a ➔ P2 | N=61 ➔ 14 | Trial completion date: Dec 2029 ➔ Sep 2027 | Trial primary completion date: Nov 2026 ➔ Sep 2025

Combination therapy • Enrollment change • Enrollment closed • Metastases • Pan tumor • Phase classification • Trial completion date • Trial primary completion date • Colorectal Cancer • Cutaneous Melanoma • Gastrointestinal Cancer • Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • ALK • BRAF • KRAS • MET

PG545 Prevents Osteoarthritis Development by Regulating PI3K/AKT/mTOR Signaling and Activating Chondrocyte Autophagy. (PubMed, Pharmacology) - "PG545 was able to restore impaired autophagy and autophagic flux via the PI3K/Akt/mTOR pathway, thereby delaying the progression of OA, suggesting that PG545 may be a novel therapeutic approach for OA."

Journal • Immunology • Infectious Disease • Musculoskeletal Diseases • Musculoskeletal Pain • Orthopedics • Osteoarthritis • Pain • Rheumatology • ATG5 • CAT • IL1B

PG545 sensitizes ovarian cancer cells to PARP inhibitors through modulation of RAD51-DEK interaction. (PubMed, Oncogene) - "Synergistic antitumor activity of the PG545/rucaparib combination was likewise observed in an immunocompetent syngeneic ID8F3 OC model. Collectively, these results suggest that targeting DEK-HSPG interactions in the TME through the use of PG545 may be a novel method of inhibiting DNA repair and sensitizing cells to PARPis."

Journal • Oncology • Ovarian Cancer • Solid Tumor • HRD • RAD51

Pixatimod (P) in Combination with Nivolumab (N) +/- low-dose Cyclophosphamide (Cy) in Advanced Cancers: A Phase IIA Basket Trial. (SITC 2022) - P2a | "Key secondary endpoints include ORR by iRECIST, median and landmark survival (PFS, OS) and safety. Exploratory endpoints will characterize pharmacokinetics, immune contexture, immunophenotypic analyses and gut microbiome pre- and post- treatment blood, tumor and stool samples."

Combination therapy • P2a data • Pan tumor • Colorectal Cancer • Gastrointestinal Cancer • Hematological Malignancies • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD4 • CD8 • IL12A • TLR9

The heparan sulfate mimetic PG545 inhibits tumor growth in both male and female mouse model of pancreatic ductal adenocarcinoma (PDAC) with sex difference in the effect on cachexia (AACR 2023) - "PG545 has strong anti-PDAC activity in both male and female mice, at least partly through inhibition of cancer cell proliferation. Its initial negative effects on cachexia are gradually reversed with male tumor-bearing mice reversing more slowly than females. Because of the protective effect on C2C12 myotubes treated with PDAC CM, PG545 might induce some counteracting factors in vivo in the initial treatment and identification of these factors may offer molecular targets for combination therapy to counteract the negative effects while take advantage of the strong anti-cancer potential."

Preclinical • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

The role of heparan sulfate in enhancing the chemotherapeutic response in triple-negative breast cancer (AACR 2023) - "Several heparanase inhibitors have been previously identified, including OGT 2115, suramin, PI-88, and PG 545...We treated TNBC cell lines MDA-MB 231, Hs 578t, and MDA-MB 468 and non-tumorigenic immortal mammary epithelial MCF-10A cells with increasing concentrations of the chemotherapeutic agent paclitaxel in the presence of heparan sulfate and/or OGT 2115 with eATP content and cell viability being assessed...These results demonstrate that inhibiting the degradation of heparan sulfate in the tumor microenvironment enhances the susceptibility of TNBC cell lines to chemotherapy by augmenting extracellular ATP concentrations. This strategy could potentially be used to induce deeper and more durable responses in triple-negative breast cancer patients."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Pixatimod (PG545) Plus Nivolumab in PD-1 Relapsed/Refractory Metastatic Melanoma and NSCLC and With Nivolumab and Low-dose Cyclophosphamide in MSS Metastatic Colorectal Carcinoma (mCRC) (clinicaltrials.gov) - P2a | N=61 | Recruiting | Sponsor: Diwakar Davar | Trial completion date: Sep 2026 ➔ Dec 2029 | Trial primary completion date: Nov 2023 ➔ Nov 2026

Combination therapy • IO biomarker • Metastases • Pan tumor • Trial completion date • Trial primary completion date • Colorectal Cancer • Cutaneous Melanoma • Gastrointestinal Cancer • Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • ALK • BRAF • KRAS • MET

Phase Ib open-label, multicenter study of pixatimod, an activator of TLR9, in combination with nivolumab in subjects with microsatellite-stable metastatic colorectal cancer, metastatic pancreatic ductal adenocarcinoma and other solid tumors. (PubMed, J Immunother Cancer) - P2a | "Pixatimod is well tolerated at 25 mg in combination with nivolumab. The efficacy signal and pharmacodynamic changes in MSS mCRC warrants further investigation."

Clinical • Combination therapy • Journal • Metastases • P1 data • Colorectal Cancer • Gastrointestinal Cancer • Immune Modulation • Immunology • Inflammation • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CXCL8 • CXCR1 • IL6 • TLR9

Pixatimod and nivolumab in metastatic melanoma, NSCLC and MSS CRC (YouTube) - "Diwakar Davar...provides an overview of a Phase IIA basket study (NCT05061017) assessing pixatimod, a novel toll-like receptor 9 (TLR9) inhibitor, with nivolumab in solid tumors....This interview took place at the 37th Annual Meeting of the Society for Immunotherapy in Cancer (SITC 2022) in Boston, MA."

Video

An open-label, multi-center phase I study of the safety and tolerability of the novel immunomodulatory agent PG545 in subjects with advanced solid tumors. (ASCO 2017) - P1; "PG545 is well tolerated up to 100 mg once-weekly via i.v. infusion. Human exposure data at 50mg and 100mg reach exposures consistent with those required for preclinical efficacy. Preliminary PD data support the proposed mechanism of action, which represents a promising approach to improve the efficacy of existing therapies."

Adverse events • P1 data • Biosimilar • Cardiovascular • Oncology

Synthetic Heparan Sulfate Mimetic Pixatimod (PG545) Potently Inhibits SARS-CoV-2 by Disrupting the Spike-ACE2 Interaction. (PubMed, ACS Cent Sci) - "Furthermore, in a K18-hACE2 mouse model, pixatimod significantly reduced SARS-CoV-2 viral titers in the upper respiratory tract and virus-induced weight loss. This demonstration of potent anti-SARS-CoV-2 activity tolerant to emerging mutations establishes proof-of-concept for targeting the HS-Spike protein-ACE2 axis with synthetic HS mimetics and provides a strong rationale for clinical investigation of pixatimod as a potential multimodal therapeutic for COVID-19."

Journal • Infectious Disease • Novel Coronavirus Disease • Oncology • Respiratory Diseases

Heparanase Inhibition Prevents Liver Steatosis in E Mice. (PubMed, J Clin Med) - "Heparanase inhibition significantly attenuates the development of liver steatosis by decreasing tissue lipid content and by affecting the mRNA expression of key lipid metabolism regulators."

Journal • Preclinical • Hepatology • Metabolic Disorders • Non-alcoholic Fatty Liver Disease

Structural insights into pixatimod (PG545) inhibition of heparanase, a key enzyme in cancer and viral infections. (PubMed, Chemistry) - "While PG545 blocks its natural substrate HS from binding to the active site, small synthetic heparanase substrates are only partially excluded, and thus pentasaccharide or larger substrates are preferred for assaying this class of inhibitor. This study provides new insights for the design of next-generation heparanase inhibitors and substrates."

Journal • Infectious Disease • Novel Coronavirus Disease • Oncology • Respiratory Diseases

A phase Ib study of the safety and tolerability of pixatimod plus nivolumab in subjects with advanced solid tumors with an expansion cohort in metastatic pancreatic adenocarcinoma (mPDAC) (SITC 2021) - "In mPDAC subjects, there was minimal immune activation as evidenced by a lack of change in effector memory T cells or NK cells in PBMC, plasma cytokines and chemokines. Conclusions Pixatimod is well tolerated at 25 mg in combination with nivolumab but did not provide clear clinical benefit or evidence of immune activation in the mPDAC cohort."

Clinical • P1 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • Cancer antigen 19-9

A phase Ib expansion cohort of pixatimod plus nivolumab in previously treated, microsatellite stable metastatic colorectal cancer (MSS mCRC). (SITC 2021) - "Conclusions Pixatimod is well tolerated at 25 mg in combination with a standard dose of nivolumab. The efficacy signal and pharmacodynamic changes in MSS mCRC warrants further investigation of pixatimod plus nivolumab for this patient population."

IO biomarker • P1 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CCR7 • CD8 • CXCL8 • CXCR1 • IL6

Pixatimod (PG545) Plus Nivolumab in PD-1 Relapsed/Refractory Metastatic Melanoma and NSCLC and With Nivolumab and Low-dose Cyclophosphamide in MSS Metastatic Colorectal Carcinoma (mCRC) (clinicaltrials.gov) - P2a; N=61; Recruiting; Sponsor: Diwakar Davar; Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • IO biomarker • Pan tumor • Colorectal Cancer • Cutaneous Melanoma • Gastrointestinal Cancer • Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • ALK • BRAF • KRAS • MET

The Society for Immunotherapy of Cancer (SITC) invites you to attend the virtual press briefing of the society’s 36th Anniversary Annual Meeting (PRWeb) - "The abstracts selected for the press briefing represent an array of the top advances in cancer immunotherapy research. Regular and late-breaking abstracts are embargoed until 8 a.m. EST, Nov. 9, 2021. Data shared during the presentation is embargoed until that date unless otherwise stated during the press briefing."

Clinical data • Colorectal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Hepatocellular Cancer • Melanoma • Oncology • Prostate Cancer

Pixatimod (PG545) Plus Nivolumab in PD-1 Relapsed/Refractory Metastatic Melanoma and NSCLC and With Nivolumab and Low-dose Cyclophosphamide in MSS Metastatic Colorectal Carcinoma (mCRC) (clinicaltrials.gov) - P2a; N=61; Not yet recruiting; Sponsor: Diwakar Davar

Combination therapy • IO biomarker • New P2a trial • Pan tumor • Colorectal Cancer • Cutaneous Melanoma • Gastrointestinal Cancer • Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • ALK • BRAF • KRAS • MET