RVU120

P2, N=230, Not yet recruiting, Ryvu Therapeutics SA

P2, N=94, Recruiting, Ryvu Therapeutics SA

P2, N=41, Not yet recruiting, GCP-Service International West GmbH

P1, N=112, Active, not recruiting, Ryvu Therapeutics SA | Recruiting --> Active, not recruiting

P2, N=98, Recruiting, Ryvu Therapeutics SA | Trial completion date: Dec 2027 --> Sep 2026 | Trial primary completion date: Jun 2027 --> Feb 2026

P1/2, N=120, Recruiting, Ryvu Therapeutics SA | Trial completion date: Nov 2023 --> May 2025 | Trial primary completion date: Nov 2023 --> May 2025

P2, N=98, Recruiting, Ryvu Therapeutics SA | Not yet recruiting --> Recruiting

P2, N=98, Not yet recruiting, Ryvu Therapeutics SA

RAS mutations also decrease efficacy of the BCL2 inhibitor venetoclax now widely used in AML, suggesting an anti-apoptotic influence of MAPK signaling...Using GSEA we found that gilteritinib stimulated adaptive interferon/inflammatory gene signatures at 16h drug treatment, but this response was restrained by addition of SEL120...We speculate this latter effect may in part alter an AML cell's differentiation state to sensitize cells to apoptosis, though further study to explore this hypothesis is needed. Our in vitro and in vivo efficacy data further validated combined FLT3i/CDK8i as a promising investigational strategy to pre-empt or overcome MAPK-mediated FLT3 TKI resistance.

Moreover, single-cell studies offer insights into its inhibitory effects on LSC-enriched populations and capacity for inducing differentiation. Overall, these results support RVU120 as a frontline candidate in AML therapy, countering therapeutic failure caused by persistent LSCs.

We investigated the expression of mediator complex components in a large database of MDS CD34+ marrow samples and age-matched controls. Our findings revealed that MED12, a critical component of the mediator complex, was significantly overexpressed in MDS samples from refractory anemia with excess blasts (RAEB), a higher risk subset of MDS(p=0.018) (Fig A). Furthermore, we observed that this overexpression of MED12 was associated with a higher rate of transformation to AML.

The presented results provide clinical and preclinical evidence for RVU120 as a candidate for a novel erythroid stimulating agent. Treatment with RVU120 could be a promising addition to the current treatment options for patients with lower-risk MDS who are transfusion-dependent and failing first-line therapies.

In the ongoing phase 1 trial, RVU120 shows clinical activity in both AML and HR-MDS, inducing RBC transfusion independence and blast reduction with a tolerable safety profile. Clearance of BM blasts including a formal CR were observed in patients treated at different dose levels. Relevant target inhibition is achieved from 110 mg onwards with expected higher pSTAT 5 inhibition with further dose escalation.

RECIST assessments of 15 patients demonstrated radiologic SD in 13 patients. Dose escalation is currently ongoing with PK modeling indicating high target engagement.

Results from patients dosed up to 110 mg have shown a favorable safety profile of RVU120. Clinically significant signs of efficacy were observed above 100 mg indicating that higher exposure mayresult in more pronounced anti-leukemic activity of RVU120. Currently available data warrant further exploration of RVU120 in AML and HR-MDS and enrollment is ongoing at 135 mg.

RVU120, a first in-class CDK8/19 inhibitor in phase I clinical trial demonstrated preclinical efficacy in acute myeloid leukemia PDX models. The potential benefit of CDK8/19i+niraparib combination will be further explored in PARPi-resistant models. Molecular studies are underway to explore potential biomarkers associated with synergy response, and to analyze the downstream effects on DNA Damage Response.

In the dose-escalation phase of the study, RVU120 shows clinical activity in AML and HR-MDS with a tolerable safety profile. Relevant target inhibition is achieved at the current dose level and is expected to increase at higher doses. Currently available data warrant further testing of RVU120 in hematologic disorders, and dose escalation in the Phase Ib study continues.

Clear hallmarks of erythroid differentiation were further identified in several patients by specific changes in surface markers. These patients achieved meaningful clinical responses such as reduction of blasts and transfusion independence, respectively.

RVU120 demonstrates a favorable safety profile at the tested dose levels. In a heavily pretreated, unselected all-comer population, disease stabilization was observed in 2 patients. Available data warrant continuation of dose escalation and collection of additional clinical data.

Meaningful PD activity and clinical efficacy were observed at 50 and 75 mg doses. Enrollment is currently ongoing at 85 mg cohort

Preliminary evidence of clinical response to RVU120 has been also shown in R/R AML and HR-MDS patients positive for DNMT3A mutations. Further molecular studies in greater number of patients under RVU120 treatment are ongoing and will provide evidence for predictive markers of response to RVU120 in AML.

A 43 YO pt stage IV thymic carcinoma, metastases to the lung, mediastinum, pleura and lymph nodes, progressing under cisplatin/etoposide, stopped study drug at the end of cycle 3 for PD in non-target lesions, target lesions increased by 11%. In the first dose escalation level with single agent RVU120, no DLTs or ≥G3 AEs were observed in patients with previously progressive solid tumors. Initial assessments in 3 pts demonstrated stable disease in 2 patients. Collection of further data at higher doses is ongoing with 2 patients enrolled at 100 mg.

Single agent efficacy of RVU120 has been confirmed in subcutaneous TNBC xenograft models in vivo at well tolerated doses. Overall, these studies provide rationale for further development of RVU120 in TNBC patients.

In Cohort #4 (75 mg), a R/R AML patient with DNMT3A mutation achieved a Complete Remission (CR) being in disease progression under venetoclax/decitabine treatment...The first patient, with history of early post-transplant relapse, TP53 biallelic mutation and complex karyotype with disease progression under prior treatment with venetoclax/azacytidine, experienced worsening of nausea and vomiting from the first day of study drug administration... RVU120 shows preliminary signs of efficacy in AML and HR-MDS with a tolerable safety profile, including a CR and an ER in patients previously treated with venetoclax combination therapy. Enrollment is ongoing in cohort 4 to gather additional safety data Keywords: AML, MDS, RVU120, SEL120, CDK8/CDK19 inhibitor

Inhibition of CDK8 by RVU120 triggers inhibition of cell proliferation and apoptosis in cell lines and LICs in T-ALL. Further clinical study is warranted to study the efficacy of RVU120 and CDK8 inhibition in T-ALL. Keywords: CDK8, RVU120, apoptosis, T-ALL, LICs in PDX model Reference 1 Girardi, T., Vicente, C., Cools, J. & De Keersmaecker, K. Blood 129 , 1113-1123, doi:10.1182/blood-2016-10-706465 (2017).

At study entry, this patient had progressed after venetoclax/decitabine, with pancytopenia and >50% BM monocytic blasts and skin leukemia. AML PDCs with DNMT3 mutations show increased sensitivity to RVU120 treatment both in vitro and in vivo. The anti-cancer efficacy of RVU120 was strongly associated with transcriptomic reprogramming and lineage commitment. Preliminary evidence of response to RVU120 has also been shown in a R/R AML patient positive for DNMT3A mutation that has achieved a CR.

Single agent efficacy of RVU120 has been confirmed in subcutaneous TNBC xenograft models in vivo at well tolerated doses. These studies provide rationale for further development of RVU120 in TNBC patients.

Cohort 4 patient, at 75 mg dose level, is a 62-year-old male with persistent AML and extramedullary skin leukemia, who failed prior venetoclax/decitabine. The first signal of activity is observed at doses 50 to 75 mg. Enrollment is currently ongoing, with switching to 3+3 design.

Synergistic interaction between SEL120 and Venetoclax resulted in apoptotic cell death in established cell lines and patient derived AML cells. Finally, using murine models of subcutaneous or disseminated AML, we found complete remissions of AML and associated recovery of normal cells in bone marrow of animals treated with both SEL120 and Venetoclax.Conclusion Taken together, these data provided rationale for a novel clinical strategy that may lead to durable responses in AML patients.

Other key inclusion criteria are Eastern Cooperative Oncology Group performance status of 0-2, white blood cell (WBC) count 10000/µL, adequate organ function defined as: aspartate aminotransferase and alanine aminotransferase ≤3x the upper limit of normal (ULN), total bilirubin ≤1.5x ULN, creatinine clearance ≥60 ml/min, left ventricular ejection fraction ≥40%. The study is currently running in the United States and is planned to be completed in 2020. The ClinicalTrials.gov Identifier: NCT04021368.