SBIR-STTR Award

Sickle cell disease (SCD) is a poorly treated debilitating condition for which we are developing a promising, new oral prophylactic therapy. A dire need exists for our drug, as millions of patients who have inherited SCD world-wide, ~100,000 in the US, continue to suffer with episodic pain, disability, and premature death. Hydroxyurea treatment has clear-cut deficiencies, and many drugs under development target treatment rather than prevention of acute events. The cause of most SCD morbidity is abnormal blood flow, notably acute pain crises that result from stoppage of microvascular flow. Defective blood flow results from multiple pathophysiologies, includin several that are independent of the paradigmatic sequence of deoxygenation -> sickle hemoglobin polymerization -> red cell sickling. Based on evidence that endothelial P-selectin is central to ongoing impairment and acute stoppage of flow, we are targeting this adhesion molecule with our therapy. In vitro and preliminary clinical data show that pentosan polysulfate sodium (PPS) improves microvascular blood flow in SCD. However, commercially available PPS is not ideal therapy because of its marginal oral bioavailability and limited duration of action. Accordingly, we have devised two synergetic plans to develop improved second generation PPS-2 that will provide increased oral bioavailability so all patients will receive therapeutic amounts of PPS and prolonged absorption so that the frequency of PPS administration will be reduced and patient compliance enhanced. One plan employs direct formulation of parent PPS; the other employs fractionation of PPS, identification of pharmaceutically superior PPS fractions, and formulation of the optimal fraction. This proposal focuses on the fractionation strategy. Lower molecular weight PPS fractions have better oral bioavailability and less anticoagulant activity than unfractionated PPS. We first will test PPS fractions of different molecular weighs to identify the two lowest molecular weight fractions that have robust P-selectin blocking activityand safe anticoagulant activity. Then we will test those two for oral bioavailability and pharmacokinetics in monkeys, the best nonhuman model of human bioavailability and pharmacokinetics. These studies will use high doses of radiolabeled PPS compounds to obtain the best bioavailability/pharmacokinetic data for PPS to date and first such dat for PPS fractions. These studies will identify the most favorable PPS fraction to be formulated and developed as PPS-2 and will enable filing a composition of matter patent. Our overarching goal is to improve the quality of life of SCD patients by bringing to market an effective oral P-selectin blocking drug for long-term administration to prevent sickle red blood cell sticking to the lining of blood vessels, improve blood flw, and avert acute painful episodes. This Phase I SBIR will provide a superior PPS fraction for PPS-2 formulation and development. Subsequent fractionation, formulation, preclinical testing in vitro and in sickle cell mice, GMP production, and IND filing ill be achieved with support of a Phase II SBIR grant.

Thesaurus Terms:
Absorption;Accounting;Activated Partial Thromboplastin Time Measurement;Acute;Acute Pain;Adhesions;Adverse Effects;Affect;Anticoagulants;Base;Binding (Molecular Function);Biological Assay;Biological Availability;Blood;Blood Flow;Blood Vessels;Cell Adhesion Molecules;Cellular Assay;Cessation Of Life;Clinic;Clinical Data;Clinical Trials;Compliance Behavior;Data;Defect;Development;Disability;Disease;Dose;Drug Formulations;Drug Kinetics;Erythrocytes;Event;Exclusion;Factor Xa;Fractionation;Frequencies (Time Pattern);Functional Disorder;Generations;Goals;Grant;Hemoglobin;Heterogeneity;Hl-60 Cells;Human;Hydroxyurea;Impairment;Improved;In Vitro;Individual;Inherited;Legal Patent;Macaca Fascicularis;Marketing;Modeling;Molecular;Molecular Weight;Monkeys;Morbidity - Disease Rate;Mus;Oral;P-Selectin;Pain;Parents;Patients;Pentosan Polysulfate;Pharmaceutical Preparations;Pharmacodynamics;Pharmacologic Substance;Phase;Pill (Pharmacologic);Polymerization;Preclinical Testing;Premature;Prevent;Prevention;Production;Property;Prophylactic;Prophylactic Treatment;Prothrombin Time Assay;Public Health Relevance;Quality Of Life;Radioactivity;Radiolabeled;Radiotracer;Recombinants;Scale Up;Sickle Cell;Sickle Cell Anemia;Sickle Hemoglobin;Sickling;Small Business Innovation Research Grant;Sodium;Sodium Compounds;Symptoms;Testing;Theories;Therapeutic;Thrombin Time Assay;United States;

Sickle cell disease (SCD) is a poorly treated, inherited, debilitating condition for which Vanguard Therapeutics, Inc. is developing a promising new long-term oral therapy. A dire need exists for our drug, as the millions of SCD patients worldwide and ~89,000 in the US continue to suffer with episodic pain episodes, disability, and premature death. Current treatments have well-defined limitations, and many drugs under development target resolution rather than prevention of acute events. Most SCD morbidity is driven by abnormal blood flow; strikingly acute pain crises are caused by stoppage of microvascular flow. While the paradigmatic sequence of deoxygenation-induced sickle hemoglobin polymerization and red cell sickling is necessary for sickle cell anemia, it is not sufficient to explain the impaired blood flow that drives the disease. Several pathophysiologies that impair blood flow are polymerization-independent; the frequency of acute painful vaso-occlusive episodes does not correlate with the number of most sickleable red blood cells (RBC) but with the number of least sickleable, stickiest RBC. Because sickle RBC adhesion to endothelial P-selectin is critical to the impairment and acute stoppage of blood flow, we are targeting P-selectin with our therapy. In vitro, in vivo, and preliminary clinical data show that the P-selectin blocker pentosan polysulfate sodium (PPS) improves microvascular blood flow in SCD. However, commercially available PPS is not ideal SCD therapy because of its marginal oral bioavailability and limited duration of action. A US patent application has been filed for an improved second- generation PPS component (VTI-1968) that has greater P-selectin blocking activity, no greater anticoagulant activity, and greater oral BA compared to PPS. Funding this Phase-II SBIR proposal will support IND-enabling activities for a superior drug product that will facilitate single daily dosing and patient compliance. Activities to be supported include validating P-selectin blocking activity in vivo in mice; designing and formulating dosage forms of VTI-1968 to increase absorption and prolong activity; optimizing the bioavailability, pharmacokinetics, pharmacodynamics; and conducting pilot tox studies in experimental animals, all of the dosage forms. These activities will advance our program toward production of good manufacturing practices (GMP) dosage forms for use as an optimized GMP drug substance in planned human trials, foster readiness for a pre-IND meeting with the FDA, and facilitate our preparation for clinical trials. The overarching goal of Vanguard is to improve the quality of life of patients with SCD by bringing to market an effective oral P-selectin blocking drug that will prevent sickle red blood cell sticking to the lining of blood vessels, improve blood flow, and avert acute painful episodes. This Phase-II SBIR will further development of a drug that will accomplish those goals and support commercial development. The activities will advance the company's ability to gain funding and partners for product commercialization.

Public Health Relevance Statement:
Sickle cell disease is a painful debilitating condition that afflicts millions of patients worldwide and approximately 89,000 in the United States. Although current treatment options available for these patients are insufficient, a drug called pentosan polysulfate sodium has been shown to improve sickle cell blood flow and could prevent the painful debilitating symptoms of the disease. Vanguard Therapeutics, Inc. is developing an improved pentosan polysulfate sodium product that will be better absorbed as a pill and if successful will deliver effective long-term therapy for sickle cell disease and provide advantages to the company for funding, partnering, and product commercialization.

Project Terms:
absorption; abstracting; Acute; Acute Pain; Address; Adhesions; Animal Model; Animals; Anticoagulants; base; Biological Availability; Blood flow; Blood Vessels; Cannulations; capsule; care burden; CD2 gene; Cell Adhesion; Cessation of life; Clinical Data; Clinical Research; Clinical Trials; combinatorial; commercialization; Compliance behavior; Computer Assisted; Data; design; Development; disability; disabling symptom; Disease; Dosage Forms; Dose; Drug Kinetics; effective therapy; Enhancers; Enteral; Enzyme-Linked Immunosorbent Assay; Erythrocytes; Event; Excipients; Formulation; Fostering; Frequencies; Functional disorder; Funding; Future; Generations; Goals; Grant; Health Care Costs; Healthcare; Hemoglobin; Human; Impairment; improved; In Vitro; in vitro Assay; in vivo; Inherited; intravital microscopy; Knockout Mice; Legal patent; Macaca fascicularis; man; Marketing; Mediating; meetings; Monitor; Morbidity - disease rate; Mus; Oral; Oral Administration; P-Selectin; Pain; Patients; Pentosan Polysulfate; Pharmaceutical Preparations; Pharmacodynamics; Phase; pill; polymerization; premature; Preparation; prevent; Prevention; Process; Product Approvals; Production; programs; prophylactic; protective effect; prototype; Qualifying; Quality of life; Rare Diseases; Rattus; Readiness; Research; research and development; research clinical testing; Research Support; Resolution; Safety; safety study; Sickle Cell; Sickle Cell Anemia; Sickle Hemoglobin; sickling; Site; Small Business Innovation Research Grant; Sodium; Stomach; Testing; Therapeutic; United States