Improved Oral P selectin Blocker for Prophylactic Sickle Cell Disease Therapy

Abstract 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 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 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 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 companyandapos s ability to gain funding and partners for product commercialization Sickle cell disease is a painful debilitating condition that afflicts millions of patients worldwide and approximately 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