Preclinical data on SY-1425, Syros Pharmaceuticals’ selective retinoic acid receptor alpha (RARα) agonist, suggest this is a promising treatment to be used in combination with Vidaza (azaciditine), a standard of care treatment for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), and with anti-CD38 therapies, in patients with AML and MDS.
SY-1425 is currently being evaluated in a Phase 2 trial of AML and MDS patients (NCT02807558). The findings have led to the expansion of the ongoing trial to include an arm assessing the safety and efficacy of SY-1425 plus Vidaza, and may lead to a new trial investigating its combination with anti-CD38 therapies.
Syros recently presented the findings at the American Association for Cancer Research (AACR) 2017 Annual Meeting in Washington, D.C.
In a first presentation, “SY-1425 (tamibarotene), a selective RARα agonist, shows synergistic anti-tumor activity with hypomethylating agents in a biomarker selected subset of AML,” Syros researchers showed that SY-1425 works in synergy with drugs like Vidaza that induce epigenetic changes in the DNA and that are currently used as standard of care in AML and MDS.
The researchers used mice injected with patient-derived AML cells that had high RARa levels and treated them with SY-1425 plus Vidaza. Results showed that the combination approach results in better clearance of tumor cells and longer duration of response compared to either drug alone. The combo also reduced tumor burden to less than 5 percent in bone marrow and other tissues. No unexpected safety events were observed.
In the second presentation, “SY-1425, a selective RARα agonist, induces high levels of CD38 expression in RARA-high AML tumors creating a susceptibility to anti-CD38 therapeutic antibody treatment,” scientists demonstrated that SY-1425 induces the expression of CD38 in AML cells with high RARa levels. The anti-CD38 antibody, Darzalex (daratumumab) is currently approved to treat various CD38-positive multiple myeloma populations. But AML cells do not usually express this protein, which makes them unresponsive to the treatment.
The findings show that SY-1425 induces CD38 levels in RARa-high AML cells that are similar to those in multiple myeloma cells which respond to Darzalex. Consistently, when combined with Darzalex, SY-1425 triggers robust activation of the immune system against RARa-high AML cells.
A third presentation, “AML patient clustering by super-enhancers reveals an RARA associated transcription factor signaling partner,” showed that, like RARa, high levels of the IRF8 protein also predict response to SY-1425 treatment. AML cells with high IRF8 are 1,000 times more sensitive to the drug than cells with low IRF8.
Based on the findings, Syros plans to use both RARa and IRF8 to select patients for enrollment in its Phase 2 trial. The company estimates that about one-third of AML and MDS patients will have one or both markers.
“Our clinical strategy with SY-1425 is to quickly and efficiently explore its potential as both a single agent and in combination for AML and MDS patients whose disease is driven by the abnormal expression of RARA pathway-associated genes, including RARA and IRF8,” Syros CEO Nancy Simonian, MD, said in a press release. “The new data presented at AACR provide the foundation for our rational combination strategy, supporting the expansion of our ongoing Phase 2 clinical trial to include a combination dosing arm with hypomethylating agent therapy, as well as the future clinical investigation of SY-1425 in combination with anti-CD38 therapies.”