- |||||||||| pixatimod (PG545) / Zucero Therap
Journal: A Heparan Sulfate Mimetic RAFT Copolymer Inhibits SARS-CoV-2 Infection and Ameliorates Viral-Induced Inflammation. (Pubmed Central) - Dec 16, 2024
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.
- |||||||||| roneparstat (LB401) / Leadiant Biosci, pixatimod (PG545) / Zucero Therap
Journal: Involvement of heparanase in the pathogenesis of acute pancreatitis: Implication of novel therapeutic approaches. (Pubmed Central) - Sep 9, 2024
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.
- |||||||||| pixatimod (PG545) / Zucero Therap
Journal: Amphiphilic Heparinoids as Potent Antiviral Agents against SARS-CoV-2. (Pubmed Central) - Jul 26, 2024
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.
- |||||||||| pixatimod (PG545) / Zucero Therap, Opdivo (nivolumab) / BMS
Trial completion, Trial completion date, Trial primary completion date, Combination therapy, Pan tumor, Metastases: 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) - Jun 3, 2024
P2, N=14, Completed,
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. Active, not recruiting --> Completed | Trial completion date: Aug 2025 --> Mar 2024 | Trial primary completion date: Dec 2024 --> Feb 2024
- |||||||||| pixatimod (PG545) / Zucero Therap, Opdivo (nivolumab) / BMS
Trial completion date, Trial primary completion date, Combination therapy, Pan tumor, Metastases: 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) - Mar 2, 2024
P2, N=14, Active, not recruiting,
Active, not recruiting --> Completed | Trial completion date: Aug 2025 --> Mar 2024 | Trial primary completion date: Dec 2024 --> Feb 2024 Trial completion date: Sep 2027 --> Aug 2025 | Trial primary completion date: Sep 2025 --> Dec 2024
- |||||||||| pixatimod (PG545) / Zucero Therap, Opdivo (nivolumab) / BMS
Enrollment closed, Phase classification, Enrollment change, Trial completion date, Trial primary completion date, Combination therapy, Pan tumor, Metastases: 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) - Dec 19, 2023
P2, N=14, Active, not recruiting,
No abstract available 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
- |||||||||| pixatimod (PG545) / Zucero Therap
Journal, PARP Biomarker: PG545 sensitizes ovarian cancer cells to PARP inhibitors through modulation of RAD51-DEK interaction. (Pubmed Central) - Sep 11, 2023
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.
- |||||||||| pixatimod (PG545) / Zucero Therap, Opdivo (nivolumab) / BMS
Trial completion date, Trial primary completion date, Combination therapy, IO biomarker, Pan tumor, Metastases: 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) - Apr 7, 2023
P2a, N=61, Recruiting,
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. Trial completion date: Sep 2026 --> Dec 2029 | Trial primary completion date: Nov 2023 --> Nov 2026
- |||||||||| pixatimod (PG545) / Zucero Therap
The role of heparan sulfate in enhancing the chemotherapeutic response in triple-negative breast cancer (Section 14; Poster Board #23) - Mar 14, 2023 - Abstract #AACR2023AACR_2500;
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.
- |||||||||| pixatimod (PG545) / Zucero Therap, Opdivo (nivolumab) / Ono Pharma, BMS
Clinical, P1 data, Journal, Combination therapy, Metastases: 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 Central) - Jan 13, 2023
P2a
Pixatimod is well tolerated at 25 mg in combination with nivolumab. The efficacy signal and pharmacodynamic changes in MSS mCRC warrants further investigation.
- |||||||||| pixatimod (PG545) / Zucero Therap
Journal: Synthetic Heparan Sulfate Mimetic Pixatimod (PG545) Potently Inhibits SARS-CoV-2 by Disrupting the Spike-ACE2 Interaction. (Pubmed Central) - Jun 4, 2022
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.
- |||||||||| roneparstat (LB401) / Leadiant Biosci, pixatimod (PG545) / Zucero Therap
Preclinical, Journal: Heparanase Inhibition Prevents Liver Steatosis in E Mice. (Pubmed Central) - Mar 26, 2022
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. 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.
- |||||||||| roneparstat (LB401) / Leadiant Biosci, pixatimod (PG545) / Zucero Therap
Combination of Trehalose and Heparanase Inhibitors Treatment Ameliorates Cerulein-Induced Acute Pancreatitis in a Murine Model (Shoreline Exhibit Hall) - Sep 8, 2021 - Abstract #ACG2021ACG_2398;
All types of responses were more profound in Hpa-TG mice, as was evident by 4 and 7.5 fold increases in amylase and lipase levels, respectively. Importantly, pretreatment with PG545, Roneparstat, Aspirin or Trehalose reduced pancreatic inflammatory response, autophagy, along remarkable reduction in amylase and lipase serum levels in both WT and Hpa-Tg mice.
- |||||||||| pixatimod (PG545) / Zucero Therap
Review, Journal: Heparanase as a potential player in SARS-CoV-2 infection and induced coagulopathy. (Pubmed Central) - Jul 15, 2021
Moreover, HSPGs and Heparanase are involved in several viral infections, in which they enhance cell entry and release of the viruses. Herein we discuss the molecular involvement of HSPGs and heparanase in SARS-CoV-2 infection, namely cell entry and release, and the accompanied coagulopathy complications, which assumedly could be blocked by heparanase inhibitors such as Heparin and Pixatimod.
- |||||||||| Journal: Heparanase Inhibitors in Cancer Progression: Recent Advances. (Pubmed Central) - Apr 27, 2021
Herein we discuss the molecular involvement of HSPGs and heparanase in SARS-CoV-2 infection, namely cell entry and release, and the accompanied coagulopathy complications, which assumedly could be blocked by heparanase inhibitors such as Heparin and Pixatimod. HPIns can be a better target to be explored against various cancers.
- |||||||||| pixatimod (PG545) / TBG Diagnostics
Journal: The Heparan Sulfate Mimetic PG545 Modulates T Cell Responses and Prevents Delayed-Type Hypersensitivity. (Pubmed Central) - Mar 9, 2021
Finally, we examined the effects of other heparan sulfate mimetics PI-88 and PG562 on lymphocyte polarization and found that these likewise induced Foxp3+ Treg in vitro but did not reduce Th17 numbers or improve delayed-type hypersensitivity in this model. Together, these data indicate that PG545 is a potent inhibitor of Th1/Th17 effector functions and inducer of FoxP3+ Treg. These findings may inform the adaptation of PG545 for clinical applications including in inflammatory pathologies associated with type IV hypersensitivity responses.
- |||||||||| pixatimod (PG545) / TBG Diagnostics
Journal: Immunomodulatory Activities of the Heparan Sulfate Mimetic PG545. (Pubmed Central) - Jul 16, 2020
PG545 offers a diversity of mechanisms of action in tumor therapy that include angiogenic inhibition, inhibition of growth factor release, inhibition of tumor cell migration, tumor cell apoptosis, activation of ER stress response, dysregulation of autophagy, and NK cell activation. Further investigation into the role that heparanase and its inhibitors play in tumor therapy can lead to the development of effective tumor therapies.
- |||||||||| muparfostat (PI-88) / Medigen, pixatimod (PG545) / TBG Diagnostics
Journal: PI-88 and Related Heparan Sulfate Mimetics. (Pubmed Central) - Jul 16, 2020
Herein we summarize the preparation, physicochemical and biological properties of PI-88, and discuss preclinical/clinical and structure-activity relationship studies. In addition, we discuss the PI-88-inspired development of related HS mimetic heparanase inhibitors with improved properties, ultimately leading to the discovery of PG545 (pixatimod) which is currently in clinical trials.
- |||||||||| pixatimod (PG545) / TBG Diagnostics, paclitaxel / Generic mfg., Opdivo (nivolumab) / Ono Pharma, BMS
Journal: Heparanase Inhibition by Pixatimod (PG545): Basic Aspects and Future Perspectives. (Pubmed Central) - Jul 16, 2020
Pixatimod has been tested in combination with a number of approved anti-cancer drugs demonstrating its clinical potential, including with gemcitabine, paclitaxel, sorafenib, platinum agents and an anti-PD-1 antibody. Clinical testing has shown pixatimod to be well tolerated as a monotherapy, and it is currently being investigated in combination with the anti-PD-1 drug nivolumab in a pancreatic cancer phase I trial.
- |||||||||| roneparstat (SST0001) / Leadiant Biosciences, pixatimod (PG545) / TBG Diagnostics
Journal: Heparanase in Acute Pancreatitis. (Pubmed Central) - Jul 16, 2020
Further support for the involvement of Hpa in the pathogenesis of AP emerged from our observation that treatment of experimental AP with PG545 or SST0001(= Ronepastat), two potent Hpa inhibitors, markedly attenuated the biochemical, histological and immunological manifestations of the disease. Hpa, therefore, emerges as a potential new target in AP, and Hpa inhibitors are hoped to prove beneficial in AP along with their promising efficacy as anti-cancer compounds.
- |||||||||| pixatimod (PG545) / TBG Diagnostics
Journal: Dual targeting of dengue virus virions and NS1 protein with the heparan sulfate mimic PG545. (Pubmed Central) - Jun 15, 2020
Consistent with anti-NS1 activity, PG545 treatment also reduces systemic vascular leakage caused by DENV infection in vivo. Taken together, these findings demonstrate that the dual targeting of DENV virions and NS1 using GAG analogues offers a new avenue for DENV drug development.
- |||||||||| pixatimod (PG545) / TBG Diagnostics
Journal: The heparanase inhibitor PG545 is a potent anti-lymphoma drug: Mode of action. (Pubmed Central) - Aug 3, 2019
Importantly, PG545 had no such apoptotic effect on naïve splenocytes, further encouraging the development of this compound as anti-lymphoma drug. Surprisingly, we found that PG545 also elicits apoptosis in lymphoma cells that are devoid of heparanase activity (i.e., Raji), indicating that the drug also exerts heparanase-independent function(s) that together underlie the high potency of PG545 in preclinical cancer models.
- |||||||||| pixatimod (PG545) / TBG Diagnostics
Preclinical, Journal: Prophylactic anti-heparanase activity by PG545 is anti-viraland protects against Ross River virus disease in mice. (Pubmed Central) - Apr 21, 2019
ELISA quantification of cartilage oligomeric matrix protein (COMP) and crosslinked C-telopeptides of type II collagen (CTX-II) and knee histopathology showed increased matrix protein degradation and cartilage erosion in RRV-infected PBS-treated mice in comparison to their PG545-treated RRV infected counterparts. Taken together these findings suggest that PG545 may have a both a direct anti-viral effect on arthritogenic alphaviral infection, as well curtailing RRV-induced inflammatory disease when administered as a prophylaxis.
- |||||||||| Journal: Heparanase inhibitors restrain mesothelioma. (Pubmed Central) - Jan 11, 2019
Clinically, heparanase levels in patients' pleural effusions could distinguish between malignant and benign effusions, and heparanase H-score (immunostaining of tumor specimens) above 90 was associated with reduced patient survival. These results strongly imply that heparanase plays an important role in mesothelioma tumor progression, thus encouraging the use of heparanase inhibitors in combination with existing drugs as a new therapeutic modality in mesothelioma clinical trials.
- |||||||||| pixatimod (PG545) / Zucero Therap
Trial completion, Trial primary completion date, Metastases: Study of the Safety and Tolerability of IV Infused PG545 in Patients With Advanced Solid Tumours (clinicaltrials.gov) - Dec 1, 2016
P1, N=23, Completed,
These results strongly imply that heparanase plays an important role in mesothelioma tumor progression, thus encouraging the use of heparanase inhibitors in combination with existing drugs as a new therapeutic modality in mesothelioma clinical trials. Recruiting --> Completed | Trial primary completion date: Sep 2016 --> Jun 2016
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