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RVU120, a CDK8 inhibitor for the treatment of anemia in MDS and AML

Aug 1, 2021
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The symptom burden of anemia is considerable for patients with myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and Diamond-Blackfan anemia (DBA), along with other forms of anemia. Patients are often treated with erythropoiesis stimulators or undergo transfusion, but resistance can develop, and problems may be encountered with iron overload. Therefore, there is still a need for anemia treatments that do not have serious toxicity associated with them.

RVU120 inhibits cyclin dependent kinase (CDK)8, along with its paralog CDK19, and it is currently being tested in a phase I study (NCT04021368) for the treatment of patients with AML and high-risk MDS. CDK8 is a transiently associated part of the Mediator complex, which regulates transcription and cell lineage determination. During the European Hematology Association (EHA)2021 Virtual Congress, Tomasz Rzymski spoke about RVU120 as a candidate for the treatment of MDS and AML.1

In vitro studies

The rationale for targeting CDK8 in anemia comes from studies that showed that CDK8 inhibition activates super-enhancer associated genes in AML, including STAT genes. In vitro studies demonstrated that AML cell lines treated with RVU120 show different levels of cytotoxicity that correlate with the level of phosphorylation of STAT1 and 5. Cell lines that show high levels of phosphorylation are killed by treatment with RVU120. In addition, AML cells that are sensitive to RVU120 express stem cell markers such as CD34+. In cells from patients with AML, loss of viability is associated with lineage commitment; the fraction of lineage-negative/CD34+ AML cells is decreased, which suggests RVU120 increases apoptosis and differentiation in AML cells.

In vivo models

In vivo models showed that RVU120 had an antileukemic effect and allowed for a partial recovery of the bone marrow. No clear signs of toxicity were evident. In addition, RVU120 has been found to affect impaired erythropoiesis and stimulate differentiation, which leads to anemia rescue in vivo.

Gene screening analysis has also identified CDK8 inhibitors as a potential treatment for anemia in patients with DBA. Cells taken from patients with DBA demonstrated the stimulatory effect RVU120 treatment had on erythroid differentiation and DBA patient cell proliferation.

TEX cells

The main model that was used to show the potential of RVU120 to induce erythroid commitment was TEX cells. These cells from cord blood have been transduced with a fusion gene (16;21)(p11;q22), which is associated with primary AML and secondary MDS/AML. TEX cells showed increased self-renewal capacity, proliferation and changed erythroid differentiation following transduction.

When the TEX cells were treated with RVU120, they showed an altered morphology indicating the differentiation potential of the CDK8 inhibitor. Cell growth was also inhibited by RVU120 treatment.

Gene profiling

TEX cells treated with RVU120 were profiled using RNA sequencing and ChIP sequencing and showed significant deregulation of transcription, with increased RNA polymerase II occupancy and transcription. The enriched genes following RVU120 were associated either with regulating erythroid commitment, such as GATA1, or with hemoglobin metabolism. Master erythroid regulators were induced as a result of RVU120 treatment.

Flow cytometry analysis showed a loss of stemness in cells treated with RVU120 as shown by an increase in CD38 and a decrease in CD34 cell surface markers. Treated cells showed induced commitment to erythroid lineage, as shown by the presence of CD71+CD41+ progenitors.

Phase Ib trial results

A phase Ib trial is currently underway for RVU120 for patients with AML and MDS, in which seven patients have been enrolled. Out of these patients, only two are still receiving RVU120 therapy. Of the other patients, two discontinued because of disease progression and three discontinued for other reasons (such as unacceptable toxicity, death, or primary investigator decision). The patients that discontinued did so after ~1 month of treatment.

In the two patients still being treated, an erythroid response has been seen at Cycle 5 Day 8 to Cycle 7 Day 15 in the patient with MDS. The other patient, who has AML and is in complete remission, has shown complete hematological recovery. The patient with AML also demonstrated resolution of leukemia cutis lesions.

Conclusion

The results of these in vitro and in vivo studies show the potential of RVU120 to treat anemia in patients with AML, MDS, and DBA by stimulating erythroid differentiation. RVU120 has also shown promise as an antileukemic therapy. The ongoing phase Ib trial has shown some encouraging data, but this requires more time to reach the final results.

  1. Rzymski T, Pakulska U, Goller K, et al. RVU120/SEL120 CDK8/19 inhibitor - a drug candidate for the treatment of MDS can induce erythroid differentiation in transformed CD34+ hematopoietic progenitor cells. Oral abstract #S164. European Hematology Association (EHA)2021 Virtual Congress; Jun 9, 2021. Virtual.

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