muparfostat (PI-88) / Medigen Biotech, Cellxpert Biotechnology Corp - LARVOL DELTA

A phase III trial of muparfostat (PI-88) as adjuvant therapy in patients with hepatitis virus related hepatocellular carcinoma (HV-HCC) after resection (ESMO 2017) - P3; "Despite the DFS was not improved in the overall treatment group, muparfostat could significantly prolong the DFS in the microvascular-invasion subgroup, comprising 40% of the trial population. The finding potentiated muparfostat as single therapy or in combination with other anti-cancer agents for future HCC adjuvant therapy trials."

Clinical • Hepatocellular Cancer

The heparan sulfate mimetic Muparfostat aggravates steatohepatitis in obese mice due to its binding affinity to lipoprotein lipase. (PubMed, Br J Pharmacol) - "The binding activity to lipoprotein lipase of HS mimetics should be noted as an additional pharmacological effect during heparanase inhibitor drug discovery. This study also provides novel evidence for an increased risk of drug-induced liver injury in obese individuals."

Journal • Preclinical • Diabetes • Dyslipidemia • Genetic Disorders • Hepatology • Liver Failure • Metabolic Disorders • Obesity • Oncology • Type 1 Diabetes Mellitus • Type 2 Diabetes Mellitus • LPL

Study of PI-88 in Patients With Advanced Melanoma (clinicaltrials.gov) - P2 | N=88 | Completed | Sponsor: Cellxpert Biotechnology Corp. | Phase classification: P1/2 ➔ P2

Phase classification • Melanoma • Oncology • Solid Tumor

Heparanome-mediated rescue of oligodendrocyte progenitor quiescence following inflammatory demyelination. (PubMed, J Neurosci) - "We found that PI-88, a heparan sulfate mimetic, directly antagonized IFN-γ to rescue human OPC proliferation and differentiation in vitro and blocked the IFN-γ mediated inhibitory effects on OPC recruitment in vivo Importantly, heparanase modulation by PI-88 or OGT2155 in demyelinated lesion rescued IFN-γ mediated axonal damage and demyelination...We find that pathological interferon-gamma can be blocked by modulation of the heparanome following demyelination using either a heparan mimetic or by treatment with heparanase inhibitor. These studies establish the potential for modulation of heparanome as a regenerative approach in demyelinating disease."

Journal • CNS Disorders • Multiple Sclerosis • Solid Tumor • IFNG

Heparanase Inhibitors in Cancer Progression: Recent Advances. (PubMed, Curr Pharm Des) - "HPIns can be a better target to be explored against various cancers."

Journal • Immunology • Inflammation • Oncology

PI-88 in Hepatocellular Carcinoma After Hepatectomy (clinicaltrials.gov) - P2; N=172; Completed; Sponsor: Medigen Biotechnology Corporation; N=343 ➔ 172

Clinical • Enrollment change • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Oncology • Solid Tumor

Heparanase: Historical Aspects and Future Perspectives. (PubMed, Adv Exp Med Biol) - "Also, in the same year PI-88 (Muparfostat), the first heparanase inhibitor to reach and successfully complete a Phase III clinical trial was patented.Nevertheless, the cloning of heparanase (also known as heparanase-1) in 1999 gave the field an enormous boost and some surprises...Collectively, these data indicate that heparanase is a truly multifunctional protein that has the additional property of cleaving HS chains and releasing from ECM and cell surfaces hundreds of HS-binding proteins with a plethora of functional consequences. Clearly, there are many unique features of this intriguing molecule that still remain to be explored and are highlighted in this Chapter."

Journal • Hematological Malignancies • Immunology • Metabolic Disorders • Oncology • Sarcoma • Type 1 Diabetes Mellitus

Heparanase and Type 1 Diabetes. (PubMed, Adv Exp Med Biol) - "Treatment of NOD mice with the heparanase inhibitor and HS replacer, PI-88, significantly reduced T1D incidence by 50%, impaired the development of insulitis and preserved beta cell HS...In established diabetes, the interplay between hyperglycemia, local inflammatory cells (e.g. macrophages) and heparanase contributes to secondary micro- and macro-vascular disease. We have identified dual activity heparanase inhibitors/HS replacers as a novel class of therapeutic for preventing T1D progression and potentially for mitigating secondary vascular disease that develops with long-term T1D."

Journal • Diabetes • Immunology • Metabolic Disorders • Type 1 Diabetes Mellitus

PI-88 and Related Heparan Sulfate Mimetics. (PubMed, Adv Exp Med Biol) - "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."

Journal • Oncology

Update to interim phase III results for PI-88 (Progen Press Release) - P3, N=218; PATRON; Sponsor: Medigen Biotechnology Corporation; "...the results of the interim analysis carried out on the Phase III clinical trial for PI-88 indicated that it did not meet the primary endpoint of Disease Free Survival....Medigen is expecting to complete the final analysis on the total targeted recurrent 218 patients in 2015."

Anticipated P3 data • P3 data • Hepatocellular Cancer • Oncology

Progen: Annual Report 2015 (Progen) - Anticipated expiry of patent for preparation and use of sulfated oligosaccharides in 2016 in Australia, Canada, China, European Union, Israel, Japan, Korea, Mexico, New Zealand, Poland, Singapore, South Africa, Taiwan, US and Brazil 

Anticipated patent expiry • Oncology

Muparfostat: "Despite the fact that DFS was not improved in the overall treatment group, muparfostat could significantly prolong the DFS in the microvascular-invasion subgroup, comprising 41% of the trial population" (Medigen) - Clinical Trial Update

P3 data • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

The Heparan Sulfate Mimetic PG545 Modulates T Cell Responses and Prevents Delayed-Type Hypersensitivity. (PubMed, Front Immunol) - "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."

Journal • FOXP3

BRIEF—Medigen out-licenses liver cancer candidate (The Pharma Letter) - "Taiwan-based Medigen Biotechnology has licensed PI-88 (muparfostat) - a candidate for liver cancer in early stage development - to its Beijing-based joint venture Ji Ya Cell for 50 million new Taiwan dollars ($7.1 million). Through the deal, Ji Ya will gain the global right (excluding Taiwan) for PI-88's R&D and commercialization, while Medigen will receive an upfront payment, as well as development milestones and royalties on sales...It is about to enter Phase III international multicenter studies as an adjuvant therapy."

Licensing / partnership • New P3 trial