Improved Oral P-selectin Blocker for Prophylactic Sickle Cell Disease Therapy

Period of Performance: 09/21/2017 - 08/31/2018


Phase 2 SBIR

Recipient Firm

Vanguard Therapeutics, Inc.
Half Moon Bay, CA 94019
Principal Investigator


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 ~89,000 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-1968) 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-1968 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 company's ability to gain funding and partners for product commercialization. Vanguard'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.