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