First-in-Class Investigational SX-682 Demonstrates Single-Agent Efficacy in Patients with Hypomethylating Agent Failure Myelodysplastic Syndromes

-- Phase 1 Findings Presented in Oral Session at 2022 American Society of Hematology (ASH) Meeting Support CXCR1/2 as Promising Target in MDS –

-- 50 Percent of Patients Treated with the Recommended Phase 2 Dose Achieved an Objective Response (mCR, Hematologic Improvement) --

AUBURN, Wash., Dec. 9, 2022 /PRNewswire/ -- Syntrix Pharmaceuticals today announced results from a single-arm, open-label Phase 1 trial of single-agent SX-682, an investigational CXCR1/2 inhibitor, in patients with any-risk myelodysplastic syndromes (MDS) in whom front-line hypomethylating-agent (HMA) had failed, a high unmet need population.  Results support the clinical activity of SX-682.  The data will be presented by David Sallman, MD of the H. Lee Moffitt Cancer Center and Research Institute, an investigator for the clinical trial, during an afternoon oral session on December 12, 2022 at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition (Abstract #855).

At this planned interim analysis after dose-escalation, 17 patients had been treated with twice-daily (BID) oral doses of 25 (n=3), 50 (n=3), 100 (n=3), 200 (n=6) and 400 (n=2) mg SX-682 in six continuous 28-day cycles with responding patients continuing treatment.  All patients were transfusion-dependent and all had failed prior HMA and 24% lenalidomide (range 1-4 failed prior therapies).  The median age was 76, and patients were low (n=1), intermediate-1 (n=10), intermediate-2 (n=5) and high (n=1) risk by the International Prognostic Scoring System (IPSS).

There was a dose-dependent increase in overall response rate (ORR) from 0% at 25 mg BID to 50% at 200 mg BID (response assessments per 2006 IWG MDS criteria).  Across all doses, 8 of 17 (47%) patients had a reduction in marrow blasts after initiating SX-682 with 2 of 6 pts (33%) achieving a marrow complete remission (mCR) at the 200 mg BID dose. There was hematologic improvement (HI) in 3 patients with one having a durable near-CR response (on SX-682 >500 days) consisting of trilineage HI (hemoglobin > 10 g/dL) and transfusion independence for over 4 months (patient required 16 transfusions in the 7 weeks before starting SX-682 therapy).

SX-682 was well tolerated with no maximally tolerated dose and no patient discontinued treatment for adverse events. Treatment-emergent adverse events > grade 3 were most common in the 200 and 400 mg dose cohorts, and those related to neutrophils were consistent with being related to SX-682. Effects on neutrophils reversed on cessation of drug dosing.  Based on pharmacodynamic response, ORR, marrow blast responses and safety, the 200 mg BID dose was selected for the expansion phase of the trial.

"Results presented at ASH reinforce the clinical potential of CXCR1/2 inhibition with SX-682 in patients with MDS failing frontline HMA therapy," said John Zebala, MD, PhD, President and CEO, Syntrix Pharmaceuticals. "We look forward to initiating additional trials in MDS and AML, which will be a significant step forward for this exciting next-generation therapy targeting both leukemic cell growth and the disease-promoting bone marrow immune microenvironment."

SX-682 is investigational and not approved anywhere globally. Its efficacy and safety have not been established. More information about clinical trials with SX-682 is available at https://clinicaltrials.gov/.

About Myelodysplastic Syndromes (MDS)

Myelodysplastic syndromes (MDS) are a type of cancer caused by poorly formed or dysfunctional blood cells in the bone marrow. Approximately 15,000 people are diagnosed with MDS in the U.S. each year, and no treatments with new mechanisms have been approved in 14 years. MDS can also develop into AML. Approximately 20,000 Americans will be diagnosed with AML each year.

About the Phase 1 Trial

This Phase 1 dose-escalation with expansion study, which is being funded by the National Heart and Lung and Blood Institute (NHLBI) of the NIH (HL142389, NCT04245397), is designed to evaluate the safety, tolerability and efficacy of single-agent SX-682 in HMA failure MDS.  Patients are treated with BID doses of SX-682 in six continuous 28-day cycles with responding patients continuing treatment. Response assessment is at the end of cycles 1, 3 and 6 and every third cycle thereafter using IWG criteria.  This trial, which is ongoing, aims to enroll a total of 40 patients in the expansion phase of the trial.

About SX-682

SX-682 is an oral allosteric small-molecule inhibitor of CXCR1 and CXCR2 (CXCR1/2) being investigated in several Phase 1/2 clinical trials.  CXCR1/2 is a signaling pathway that acts as a "master switch" in the tumor microenvironment.  It is involved in the recruitment of immunosuppressive MDSCs and autocrine growth of disease-initiating leukemic stem cells in AML and myelodysplastic syndromes (MDS).  CXCR2 overexpression is predictive of transfusion dependence in MDS.  CXCR2 inhibition reduces proliferation of leukemic cell lines and primary MDS/AML patient samples in vitro.  SX-682 has been validated in major solid tumor models, where it exhibits mono-agent activity, blocks metastasis, depletes MDSCs, activates infiltration and killing by immune effector cells, reverses chemo-resistance, and enhances immune-checkpoint blockade.

About Syntrix

Syntrix is a pharmaceutical company committed to discovering and delivering innovative therapies to solve the most difficult clinical problems. Convergent Science & Strategy. Breakthrough Medicines.

Disclosure Notice

This release contains forward-looking information that is based on company management's current beliefs and expectations and are subject to currently unknown information, risks and circumstances. Actual results may vary from what is projected.  Syntrix does not undertake any obligation to publicly update these forward-looking statements, whether as a result of new information, future events or otherwise.

Media Contact: Aaron Schuler, PhD, 253-833-8009, x21

SOURCE Syntrix Pharmaceuticals