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 recurring 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 clinical events of SCD are driven by abnormal blood
flow Strikingly acute pain crises are caused by stoppage of blood flow in small vessels While the traditional
paradigm 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
mechanisms that impair blood flow are unrelated to polymerization the frequency of acute painful vaso
occlusive episodes does not correlate with the number of red blood cells RBC that are most disposed to
sickling but rather with the number of RBC that are least sickling prone which are also the stickiest Because
sickle RBC sticking to P selectin on the cells that line blood vessels is fundamental both to the continuous
impairment and the sudden 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 blocking compound 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 homogeneity P
selectin blocking activity and oral bioavailability than PPS
Funding this Phase II SBIR proposal will support IND enabling activities for our VTI drug product
including validating P selectin blocking activity in vivo in a mouse SCD model designing and formulating
dosage forms that increase absorption and prolong activity optimizing bioavailability pharmacokinetics and
pharmacodynamics and conducting pilot tox studies in experimental animals This work will advance our
compound toward production of good manufacturing practices GMP dosage forms for use as an optimized
GMP drug substance in projected human trials foster readiness for a pre IND meeting with the FDA and
facilitate preparation for clinical trials These IND enabling activities will further the companyandapos s ability to gain
funding and partners for product commercialization Vanguardandapos s overarching goal to be supported by this
Phase II SBIR is to improve the quality of life of SCD patients by bringing to market an effective oral P selectin
blocking drug that prevents sickle red blood cell sticking to the lining of blood vessels improves blood flow and
averts acute painful episodes the once daily administration of which will promote patient compliance 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