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 Year 2017 Code HLS17-04. Myelodysplastic syndromes (MDS) are genetically and morphologically
diverse hematopoietic neoplasms that arise from a small pool of mutant clones within hematopoietic stem and
progenitor compartments. Only three drugs have received regulatory approval specifically for MDS treatment,
all with suboptimal response rates of <50% and of limited durability, typically 1-2 years. Once these agents are
no longer effective, there is no standard of care established for second-line treatment (i.e., in the
relapsed/refractory setting). Furthermore, prognosis after hypomethylating agent failure is dismal, with median
survival estimated at <6 months for higher-risk patients, and <18 months for lower-risk patients. Clearly there
is a significant unmet need for a new MDS treatment that both (a) eradicates preleukemic stem cells and leads
to long-term remission and normalization of cytopenias, and (b) achieves this goal without the heavy cost of
side effects, particularly in lower-risk MDS.
Stem cells and early progenitors from MDS patients consistently overexpressed the chemokine CXCL8
(IL-8) and its receptor, CXCR2. Inhibition of CXCR2 selectively arrested the growth of stem cells from MDS
patients but not healthy controls, demonstrating preclinical therapeutic proof-of-principle and validating CXCR2
as a therapeutic target in MDS. Additionally, myeloid-derived suppressor cells (MDSCs) are markedly
increased in the bone marrow of MDS patients where they induce myelodysplasia and impair immune
surveillance and clearance of mutant clones. CXCR2 and CXCR1 are pivotal in MDSC recruitment. Dual
CXCR1 and CXCR2 (CXCR1/2) inhibition is therefore a novel therapeutic strategy to treat MDS with a “one-
two punch” to (i) the mutant MDS cells directly and (ii) the MDSC-driven immunosuppressive marrow
microenvironment.
Developed by Syntrix in a decade's long discovery effort supported by NHLBI (IND open for melanoma
4/16), SX-682 is a new-in-class oral, small-molecule, immuno-oncology (IO) therapy directed at disrupting
CXCR1/2 signaling. We hypothesize that in MDS, SX-682 will lead to long-term remissions and normalization
of cytopenias, but with only a mild side-effect effect profile compared to other therapies. If successful, SX-682
would revolutionize the existing treatment landscape in MDS. Through execution of the Specific Aims, we will
advance SX-682 through a Phase 1, open label dose-escalation and expansion trial to evaluate SX-682 in
MDS patients who had progression or were intolerant to prior therapy. The SX-682 MDS IND 131,876 was
opened on September 1, 2017, and enrollment for this trial may begin.
