HLS- A Phase 1 Open-Label Dose-Escalation with Expansion Study of SX-682 in MDS Patients

This SBIR Fast Track proposal meets the objectives of NHLBI Small Business Topic of Special Interest for Fiscal YearCode HLSMyelodysplastic syndromesMDSare genetically and morphologically diverse hematopoietic neoplasms that arise from a small pool of mutant clones within hematopoietic stem and progenitor compartmentsOnly three drugs have received regulatory approval specifically for MDS treatmentall with suboptimal response rates of andltand of limited durabilitytypicallyyearsOnce these agents are no longer effectivethere is no standard of care established for second line treatmenti ein the relapsed refractory settingFurthermoreprognosis after hypomethylating agent failure is dismalwith median survival estimated at andltmonths for higher risk patientsand andltmonths for lower risk patientsClearly there is a significant unmet need for a new MDS treatment that bothaeradicates preleukemic stem cells and leads to long term remission and normalization of cytopeniasandbachieves this goal without the heavy cost of side effectsparticularly in lower risk MDSStem cells and early progenitors from MDS patients consistently overexpressed the chemokine CXCLILand its receptorCXCRInhibition of CXCRselectively arrested the growth of stem cells from MDS patients but not healthy controlsdemonstrating preclinical therapeutic proof of principle and validating CXCRas a therapeutic target in MDSAdditionallymyeloid derived suppressor cellsMDSCsare markedly increased in the bone marrow of MDS patients where they induce myelodysplasia and impair immune surveillance and clearance of mutant clonesCXCRand CXCRare pivotal in MDSC recruitmentDual CXCRand CXCRCXCRinhibition is therefore a novel therapeutic strategy to treat MDS with aonetwo punchtoithe mutant MDS cells directly andiithe MDSC driven immunosuppressive marrow microenvironmentDeveloped by Syntrix in a decadeandapos s long discovery effort supported by NHLBIIND open for melanomaSXis a new in class oralsmall moleculeimmuno oncologyIOtherapy directed at disrupting CXCRsignalingWe hypothesize that in MDSSXwill lead to long term remissions and normalization of cytopeniasbut with only a mild side effect effect profile compared to other therapiesIf successfulSXwould revolutionize the existing treatment landscape in MDSThrough execution of the Specific Aimswe will advance SXthrough a Phaseopen label dose escalation and expansion trial to evaluate SXin MDS patients who had progression or were intolerant to prior therapyThe SXMDS INDwas opened on Septemberand enrollment for this trial may begin Myelodysplastic syndromeMDSis a life threatening disease that affects andgtpeople in the United StatesThis proposal would advance the newly discovered immunotherapeutic small molecule SXinto clinical evaluation in patients suffering from MDS