SBIR-STTR Award

The goal of this SBIR phase I project is aimed at completing a larger synthesis scale and pharmacokinetic studies for 18-mer, a lead candidate anti-inflammatory heparan sulfate oligosaccharide. 18-mer decreased neutrophil infiltration in murine diseases model of peritonitis, liver ischemia/reperfusion injury, and acetaminophen-induced acute liver failure (APAP-induced ALF). 18-mer targets to high mobility group box 1 (HMGB1) protein and attenuates HMGB1- mediated inflammation characterized by neutrophil infiltration to the injury site. In addition to these disease models, HMGB1 is involved a numerous local and systemic inflammation disorders including sepsis and trauma injury. Currently, there are no approved therapeutics targeting HMGB1-mediated inflammation. This work is focused on developing 18-mer as a therapeutic for APAP-induced ALF. Confidence to pursue 18-mer stems from screening experiments using other oligosaccharides in the APAP model that were ineffective compared to 18-mer and demonstrating 18-mer’s anti-inflammatory effect is multiple inflammatory mouse models. This SBIR phase I application contains two specific aims. In Aim 1, we plan to increase the synthetic scale to 10 g, about 30-fold increase from the current production scale. The improved synthesis will use a 12-mer intermediate as the starting material, shortening the synthetic steps to 16 from 36. Aim 2 is to develop a LC- MS/MS based method to quantify the 18-mer in blood and urine. This method will allow us to obtain pharmacokinetic parameters in the subsequent preclinical development. In the phase II studies, we will focus on increasing the scale-up synthesis to 100g, IND-enabling studies and tissue distribution of the oligosaccharides. The success of this project will provide a new approach to treat drug induced liver toxicity by targeting to HMGB1-mediated inflammation. Public Health Relevance Statement Project Narrative Heparan sulfate is a sulfated polysaccharide displaying a wide range of biological functions. In this project, Glycan Therapeutics plans to examine the potency and efficacy to protect acetaminophen-induced acute liver failure using heparan sulfate oligosaccharides. The heparan sulfate will achieve the hepatoprotection by inhibiting excessive inflammatory responses from the host. The success of the project will provide a new therapeutic to treat drug-induced liver failure.

Project Terms:
Acetaminophen ; APAP ; Acetamidophenol ; Acetominophen ; Hydroxyacetanilide ; Paracetamol ; Anti-Inflammatory Agents ; Anti-Inflammatories ; Anti-inflammatory ; Antiinflammatories ; Antiinflammatory Agents ; antiinflammatory ; Anticoagulants ; Anticoagulant Agents ; Anticoagulant Drugs ; blood thinner ; thrombopoiesis inhibitor ; Blood ; Blood Reticuloendothelial System ; Blood Coagulation Disorders ; Coagulation Disorder ; Coagulopathy ; bleeding disorder ; clotting disorder ; Brain ; Brain Nervous System ; Encephalon ; chemical synthesis ; Clinical Trials ; Disease ; Disorder ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Goals ; Heparin ; Heparinic Acid ; Heparitin Sulfate ; Heparan Sulfate ; HMGB1 Protein ; Amphoterin ; Chromosomal Protein, Nonhistone, HMG1 ; FM1 Gene Product ; HMG-1 ; HMG-1 Protein ; HMG1 ; HMG3 ; Heparin-Binding Protein p30 ; High Mobility Group Box Protein 1 ; High Mobility Group Protein 1 ; High-Mobility Group (Nonhistone Chromosomal) Protein 1 ; High-Mobility Group Box 1 ; Nonhistone Chromosomal Protein HGM1 ; SBP-1 ; Sulfoglucuronyl Carbohydrate Binding Protein ; Hospitals ; Human ; Modern Man ; Inflammation ; Ischemia ; Metabolic Clearance Rate ; clearance rate ; Methods ; Monosaccharides ; Mus ; Mice ; Mice Mammals ; Murine ; Oligosaccharides ; Peritonitis ; Drug Kinetics ; Pharmacokinetics ; Plasma ; Blood Plasma ; Plasma Serum ; Reticuloendothelial System, Serum, Plasma ; Polysaccharides ; Glycans ; Production ; Publications ; Scientific Publication ; Publishing ; Reperfusion Therapy ; reperfusion ; Reperfusion Injury ; Ischemia-Reperfusion Injury ; Reperfusion Damage ; Drug or chemical Tissue Distribution ; Tissue Distribution ; Universities ; Urine ; Urine Urinary System ; Work ; Liver Failure ; Hepatic Failure ; Mediating ; receptor for advanced glycation endproducts ; AGE receptor ; RAGE receptor ; advanced glycosylation end product receptor ; amphoterin receptor ; receptor for AGE ; receptor for advanced glycation end product ; receptor of AGE ; Acute Liver Failure ; Acute Hepatic Failure ; Fulminant Liver Failure ; Fulminating Hepatic Failure ; Fulminating Liver Failure ; fulminant hepatic failure ; Injury ; injuries ; base ; Label ; improved ; Site ; Acute ; Phase ; Series ; Hepatotoxicity ; Hepatotoxic effect ; Liver Toxicity ; Toxic effect on liver cells ; hepatic toxicity ; hepatoxicity ; sugar ; Funding ; Biological Process ; Biological Function ; Immunological response ; host response ; immune system response ; immunoresponse ; Immune response ; Therapeutic ; Therapeutic Agents ; Attenuated ; Inflammatory ; programs ; Investigation ; Kilogram ; subdermal ; subcutaneous ; Source ; Route ; Pattern ; Sulfate ; APAP overdose ; paracetamol overdose ; acetaminophen overdose ; success ; Toxicities ; Toxic effect ; Structure ; disorder model ; Disease model ; Reporting ; Neutrophil Recruitment ; Neutrophil Infiltration ; Modeling ; hepatic ischemia ; liver ischemia ; Inflammatory Response ; Complex Mixtures ; Address ; Animal Sources ; Antiinflammatory Effect ; anti-inflammatory effect ; Scheme ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Translational Research ; Translational Science ; translation research ; Preparation ; Principal Investigator ; Development ; developmental ; cost ; design ; designing ; Sepsis ; blood infection ; bloodstream infection ; novel strategies ; new approaches ; novel approaches ; novel strategy ; scale up ; Trauma ; innovation ; innovate ; innovative ; translational medicine ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; mouse model ; murine model ; stem ; therapeutic target ; drug candidate ; phase 1 study ; Phase I Study ; phase 2 study ; phase II study ; screening ; liver injury ; Injury to Liver ; hepatic damage ; hepatic injury ; liver damage ; experimental study ; experiment ; experimental research ; preclinical development ; pre-clinical development ; lead candidate ; systemic inflammatory response ; systemic inflammation ;

More than 60 million Americans consume acetaminophen (APAP) on a weekly basis.Unfortunately, an overdose of APAP causes liver toxicity and is responsible for over half of acuteliver failure cases in the US. N-acetyl cysteine is the only antidote for APAP overdose and iseffective if given within 10 hours after APAP ingestion. However, many patients don't seek outtreatment during the therapeutic window for N-acetyl cystine. Currently, a liver transplant is theonly available treatment option for these late-presenting patients. APAP toxicity is a leading causefor liver transplantation in the US and worldwide.The goal of this SBIR phase II project is to develop an anti-inflammatory synthetic heparan sulfateoligosaccharide, GLY-202, for APAP overdose patients specifically late-presenting patients. GLY-202 was selected after compound optimization studies in efforts to identify a smaller, easier tosynthesize oligosaccharide with in vivo efficacy compared to 18-mer in the APAPoverdose model.Unlike 18-mer, the synthesis of GLY-202 can be achieved in a shorter synthetic route,substantially decreasing the production cost and reducing a significant commercialization barrier.This phase II period will focus on IND-enabling studies including GLY-202 drug substancechemical, manufacturing and control (CMC) activities (Aim 1), pharmacology (Aim 2) and toxicitystudies (Aim 3). Execution of the proposed aims will demonstrate synthetic scalability andreproducibility in pilot production scale and efficacy and safety through pharmacology and toxicitystudies. During the phase II period, Glycan Therapeutics will submit an Orphan Drug Designationapplication. Benefits of Orphan Drug status include significant financial benefits through feewaivers and tax credits for clinical expenses. Furthermore, the clinical trial recruitment will becomparatively small meaning that the amount of GLY-202 required can be sufficiently preparedby Glycan Therapeutics. In the phase IIb studies, we will complete GMP manufacturing,formulation, submit IND application and conduct Phase 1 clinical trials. The success of this projectwill provide a new approach to treat drug induced liver toxicity by targeting to HMGB1-mediatedinflammation with a first-in-class therapeutic.

Public Health Relevance Statement:
Project Narrative Heparan sulfate is a sulfated polysaccharide displaying a wide range of biological functions. In this project, Glycan Therapeutics plans to examine the potency and efficacy to protect againsr acetaminophen-induced acute liver failure using heparan sulfate oligosaccharides. The heparan sulfate will achieve the hepatoprotection by inhibiting excessive inflammatory responses from the host. The success of the project will provide a new therapeutic to treat drug-induced liver failure.

Project Terms: