SBIR-STTR Award

Pancreatic cancer is a devastating disease with a very low (8%) 5-year survival rate. Therapeutic options are limited in efficacy and many have substantial toxicity. Targeted drug delivery may improve the therapeutic index of cancer drugs by enhancing drug localization to the cancer cell while minimizing off-target side effects. ?2 receptors are highly expressed in pancreatic and other cancers compared to healthy cells. Accuronix Therapeutics is developing ACXT-3102, a molecule with therapeutic potential licensed from Washington University School of Medicine in St. Louis (WUSM). ACXT-3102 is comprised of a ?2 ligand covalently bound to the ferroptosis-inducing molecule erastin. Preliminary data show that ACXT-3102 increased the cytotoxicity against pancreatic tumor cells in vitro by 35-fold compared to erastin alone. ACXT-3102 has tremendous potential as a novel treatment option for pancreatic and perhaps several other types of cancer. A series of drug optimization strategies will be explored in an effort to improve the solubility, and delivery of an already viable cancer drug. The objective of these studies will be to enhance further the efficacy of ACXT-3102. For this Phase I STTR project, Accuronix Therapeutics will work with researchers from WUSM to improve the bioactivity of its lead candidate ACXT-3102. The primary endpoint is enhanced efficacy as measured by increased survival in murine models of pancreatic cancer. We will also asses for any off-target drug effects including anemia and work to minimize these by clarifying the relationship between toxicity and dose schedule. These improvement efforts will include formulation concepts commonly applied in the pharmaceutical industry to increase drug solubility in aqueous solutions ultimately leading to increases in bioavailability and, most importantly, bioactivity. The most immediate change in relation to ACXT-3102’s current composition regards the generation of seven additional salt variants. These then will be tested using alternative vehicle compositions to enhance drug half-life. Finally, the best-performing salt/formulation will be evaluated employing detailed biodistribution (PK/PD) and efficacy studies in mice via the parenteral (IV) and oral (PO) administration routes to determine the best method of delivery. At conclusion of this Phase I STTR grant, we will have demonstrated the utility of ACXT-3102 in pancreas cancer treatment, justifying advanced studies toward clinical translation for the benefit of patients suffering from pancreatic adenocarcinoma.

Public Health Relevance Statement:
Project Narrative The primary goal of this Phase I STTR application is to develop ACXT-3102 into an improved therapeutic for the treatment of pancreatic adenocarcinoma. Targeted cancer drugs hold great promise to increase therapeutic indices while minimizing putative off-site side effects. Improvements will be accomplished by (1) generating alternative salt variants to address aqueous solubility, (2) exploring alternative vehicle compositions to enhance drug half-life and (3) performing detailed biodistribution (PK/PD) and efficacy studies in mice via the parenteral (IV) and oral (PO) administration routes to determine the best method of delivery.

Project Terms:
Address; Anemia; Antineoplastic Agents; aqueous; Asses; base; Binding; Biodistribution; Biological Availability; cancer cell; Cancer Etiology; cancer therapy; cancer type; Canis familiaris; Cell Death; Cells; Cessation of life; Clinical; clinical translation; clinically relevant; cytotoxicity; Data; design; Disease; Dose; Drops; drug candidate; Drug Delivery Systems; drug development; Drug Formulations; Drug Industry; Drug Targeting; efficacy study; erastin; Evaluation Studies; Excipients; Exhibits; Fatigue; Follow-Up Studies; Formulation; Foundations; Frequencies; Funding Mechanisms; gemzar; Generations; Glutathione; Goals; Grant; Half-Life; Hemolysis; Immunologics; improved; In Vitro; Individual; innovation; intraperitoneal; Intravenous; Lead; lead candidate; Life; Ligands; Malignant neoplasm of pancreas; Malignant Neoplasms; Measures; medical schools; Metabolic; Methods; mouse model; Mus; Nerve; novel; novel therapeutics; Oral; Oral Administration; Outcome; Oxalates; oxaliplatin; Pancreas; Pancreatic Adenocarcinoma; pancreatic cancer cells; pancreatic cancer model; Patients; Performance; Pharmaceutical Preparations; pharmacokinetics and pharmacodynamics; Pharmacology; Phase; pre-clinical; preclinical evaluation; primary endpoint; Production; Quality of life; Rattus; Reactive Oxygen Species; receptor; Research Personnel; Route; Schedule; Selection Criteria; Series; side effect; Site; Small Business Technology Transfer Research; small molecule; small molecule inhibitor; Sodium Chloride; Solubility; Survival Rate; targeted treatment; Testing; Therapeutic; Therapeutic Index; Toxic effect; tumor; tumor metabolism; United States National Institutes of Health; Universities; Variant; Washington; Work

Pancreatic cancer is a devastating disease with a very low (8%) 5-year survival rate. Therapeutic options arelimited in efficacy and many have substantial toxicity. Targeted drug delivery may improve the therapeuticindex of cancer drugs by enhancing drug localization to the cancer cell while minimizing off-target side effects.Sigma-2 receptors (S2R) are highly expressed in pancreatic and other cancers compared to healthy cells.Accuronix Therapeutics is developing ACXT-3102, a molecule with therapeutic potential licensed fromWashington University School of Medicine in St. Louis (WUSM). ACXT-3102 is comprised of a S2 ligandcovalently bound to the ferroptosis-inducing molecule dm-erastin. Preliminary data show that ACXT-3102increased the cytotoxicity against pancreatic tumor cells in vitro by 35-fold compared to dm-erastin alone.ACXT-3102 has tremendous potential as a novel treatment option for pancreatic and perhaps several othertypes of cancer. Drug optimization strategies were conducted in a Phase I STTR which resulted in a betteryield during drug synthesis, identification of a mesylate salt with high aqueous solubility and improved physicalproperties suitable for oral drug administration, demonstration of good oral efficacy and discovery that tumorslacking malic enzyme 1 (ME1) are even more sensitive to ACXT-3102.For this Phase II STTR program, Accuronix Therapeutics will continue to work with our research colleaguesfrom WUSM to prepare ACXT-3102 for Investigational New Drug (IND) submission and eventually testing thecompound in pancreatic cancer patients. We will conduct a series of preclinical studies to optimize the dosingregimen in murine pancreatic cancer models - understanding if once, twice or three times per day drugadministration improves plasma exposure and anti-tumor efficacy while maintaining safety, i.e., avoiding dose-limiting side effects. Studies will also explore if efficacy of our drug can be further improved when given incombination with gemcitabine, a current standard-of-care for pancreatic cancer. Chemical and metabolicstability of ACXT-3102 will be established using in vitro assays to guide storage conditions of the drug andunderstand which preclinical species best represents metabolism in humans. To obtain data required for thepharmacology and safety sections of the IND package, preclinical studies will be conducted according to GoodLaboratory Practice (GLP) guidelines to generate pharmacokinetic (PK) and pharmacodynamic (PD) data forcorrelating plasma exposures in different species to what is predicted in human. Similarly, formal GLPtoxicology studies will be completed using three different doses in rats and dogs to establish the "No ObservedAdverse Effect Level" (NOAEL). These data will be used to model exposure levels in humans and establish asafe, first-in-human (FIH) dose for starting our clinical trials in cancer patients. At the conclusion of the PhaseII STTR grant, we will have the pharmacology and safety information on ACXT-3102 required for the INDpackage, and will have established the first dose to be used in patients.

Public Health Relevance Statement:
Project Narrative The primary goal of this Phase II STTR application is to develop ACXT-3102 as an improved therapeutic for the treatment of pancreatic adenocarcinoma. Selectively targeted cancer drugs hold great promise to increase therapeutic efficacy while minimizing putative off-site toxicities, i.e. improving tolerability. Successful conclusion of this program will be judged by having 1) established the optimal doses and dosing schedule required for good efficacy in cancer models, 2) determined how to store the drug without losing activity, 3) generated critical pharmacology and safety data required by the FDA to submit for starting clinical trials, and 4) predicted a safe initial dose to start treating cancer patients in the first clinical trial with ACXT-3102.

Project Terms:
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