HLS- SBIR Phase I: Targeted platelet-capsule hybrids for on demand treatment in hemophilia

PROJECT SUMMARY ABSTRACTHemophilia A affectspeople in the USclassifying it as an Orphan Diseaseand is characterized by the inability to produce functional factor VIIIfVIIIa plasma protein necessary for blood clot formationof those with severe hemophilia A have inhibitory antibodies to the commonly used drugwhich is intravenous infusion of plasma derived or recombinant fVIIIThese patients represent a severely underserved populationas they are left with only two on demand treatment options for bleeding episodes that either require multiple infusions or long infusion timesFurther complicating treatmentpotentially fatal thrombotic side effects have been seen when newly approved prophylactic therapies are combined with on demand therapiesMoreoverit is not uncommon for these patients to spend upwards of $per year on their treatment therapy aloneTo address this severe patient needSplit Rock Therapeutics has developed a polyelectrolyte multilayerpolymermicrocapsule for the targeted delivery of fVIII for hemophilia patients with anti fVIII inhibitorsFVIII is encapsulated within the polymer shellandupon intravenous administrationbinds to and hybridizes with the patient s native plateletsThe hybridized platelets then target the capsule to sites of injury and rupture the capsule open through their natural contractile behavior in the clot formation process to facilitate aburstrelease of fVIIIImportantly for patients with inhibitorsthe fVIII is protected from the patient s inhibitors during circulation by the polymer shellso a near full dose of uninhibited fVIII is delivered at the site of injury to quickly rescue hemostasisOur recent publicationHansenCEet alACS Nanodescribes in vitro investigations into the plateletmediated mechanism of the targeted drug delivery technologyleveraging the expertise in platelet contraction behavior of DrWilbur ALamLamWet alNature MaterQiuYet alPNASMyersDet alNature MaterProof of concept in vivo investigations demonstrate safety and significantly enhanced efficacy of the fVIII loaded microcapsules compared to infusion of fVIII aloneFor this Phase I SBIRSplit Rock Therapeutics proposes investigations into pharmacological parameters of this technology to determine dosages that are safe and efficaciousIn Milestonewe propose to investigate plasma concentrations over timeorgan biodistributionand the kinetics of platelet capsule hybridizationThese studies will result in dose exposure data that will enable the determination of key pharmacokinetic parameters required for effective dosing in MilestoneDose response relationships will be determined for both hemostatic and adverse responses in MilestoneThis pharmacodynamic data will enable calculation of dosages that are efficacious and exhibit a low risk of side effectsThis proposal will facilitate a partnership with pharmaceutical companies in order to conduct further investigations with an already FDA approved fVIII drugFuture areas of investigation include metabolism and elimination of the therapyadditional injury models of varying severityand investigation into non specific safety biomarkers PROJECT NARRATIVE The objective of this project is to develop and commercialize a targeted drug delivery technology designed for patients with hemophiliaa life threatening genetic bleeding disorderwho develop a reaction in which their immune system attacks the standard medication rendering it ineffective and putting those patients at high risk for hemorrhage with little therapeutic optionsIn this Phase I SBIRSplit Rock Therapeutics proposes an eleganttargeted delivery technology in which the standard therapy for hemophiliathe pro coagulant therapyfactor VIIIis shielded in aTrojan Horsemanner to evade the patient s immune systemenabling the drug to be more efficacious at a lower infusion volume to decrease treatment time and the amount of drug usedSpecificallywe propose to investigate the storage stability as well as the safety and efficacy of our targeted drug delivery technology using a well established hemophilia A mouse model which will allow us to formulate a plan for manufacturing and distribution