Results of a single-arm, open-label Phase 1 dose-escalation with expansion study, funded by the National Heart and Lung and Blood Institute (NHLBI) of the National Institutes of Health (NIH) supports single-agent SX-682 as a new, promising, first-in-class agent in the treatment of patients diagnosed with any-risk myelodysplastic syndromes (MDS) in whom front-line hypomethylating-agent (HMA) has failed.

Myelodysplastic syndromes 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.

Novel treatment option
SX-682 is an oral allosteric small-molecule inhibitor of C-X-C chemokine receptor 1 or CXCR1 and C-X-C chemokine receptor 2 or CXCR2 (CXCR1/2), validated immune-oncology targets, being investigated in several Phase 1/2 clinical trials. The investigational drug is being developed by Syntrix Pharmaceuticals.

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In clinical studies 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.

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The investigational agent has nanomolar potency, satisfies Lipinski’s rules a, and is highly selective for CXCR1/2 versus off-targets.  SX-682 has ansi completed GLP toxicology, and exhibits an exceedingly safe profile with no dose-limiting toxicities.

As a dual-inhibitor that blocks tumor signaling via both CXCR1 and CXCR2, SX-682 is the only therapeutic in development for oncology that blocks all parts of the CXCR1/2 signaling axis, and is thus best-in-class for oncology.

Master switch
CXCR1/2 mediate the initiation and development of various cancers including breast cancer, prostate cancer, lung cancer, colorectal carcinoma and melanoma. They are signaling pathways acting as a “master switch” in the tumor microenvironment. CXCR1/2 is involved in the recruitment of immunosuppressive MDSCs and autocrine growth of disease-initiating leukemic stem cells in AML and myelodysplastic syndromes (MDS).

Overexpression of CXCR2 is predictive of transfusion dependence in MDS and inhibition of CXCR2 reduces proliferation of leukemic cell lines and primary MDS/AML patient samples in vitro.

David Sallman, MD, is an Assistant Member in the Department of Malignant Hematology at Moffitt Cancer Center.

Planned analysis
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).

The investigational agent was well tolerated with no maximally tolerated dose (MTD) 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.

“The results presented [..] 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.”

The study results presented during the annual meeting support the clinic activity of SX-682 were presented will 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 Monday, December 12, 2022 at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition (Abstract #855).

Note: a Lipinski’s rule of five, also referred to asPfizer’s rule of five and the Rule of Five(RO5), is a rule of thumb to help determine if a chemical compound with a certain pharmacological or biological activity has chemical and physical properties that would make it a likely orally active drug in humans. The rule was originally formulated in 1997 by Christopher A. Lipinski, based on the observation that most orally administered drugs are relatively small and moderately lipophilic molecules. [2][3] While Lipinski’s rule of five describes molecular properties important for a drug’s pharmacokinetics in the human body, including their absorption, distribution, metabolism, and excretion (ADME), it does not predict if an investigational drug is pharmacologically active. However, most drug candidate that conform to Lipinski’s rule of five tend to have lower attrition rates during clinical trials and hence have an increased chance of reaching the market. [2][3]

Clinical trials
SX-682 Treatment in Subjects With Myelodysplastic Syndrome Who Had Disease Progression or Are Intolerant to Prior Therapy – NCT04245397

Reference
[1] Sallman DA, DeZern AE, Gayle AA, Kahn SJ, Padron E, Lancet JE, Kuykendall A, et al. Phase 1 Results of the First-in-Class CXCR1/2 Inhibitor SX-682 in Patients with Hypomethylating Agent Failure Myelodysplastic Syndromes.  Abstract 855, Presented during the 64th ASH Annual Meeting and Exposition, held in News Orleans, La, December 10 -13, 2022.

Featured image: American Society of Hematology 64th Annual Meeting at the Ernest N. Morial Convention Center, being held December 10 – 13, 2022. Photo courtesy: © 2022 ASH/Nick Agro. Used with permission.

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