SEL-120

Inhibiting a transcriptional kinase already explored in oncology can suppress the pathological cellular transition associated with cartilage breakdown in osteoarthritis (OA), according to preclinical findings published in Bone Research. The study, led by Scott J. Roberts at the Royal Veterinary College (RVC) in London, UK, provides in vivo evidence that cyclin-dependent kinase 8 (CDK8) inhibition can modulate processes involved in endochondral ossification and OA, reducing cartilage pathology in a spontaneous mouse model while affecting cartilage, bone, and inflammatory pathways. OA affects hundreds of millions of people worldwide, yet no disease-modifying OA drug (DMOAD) has reached the market. As the paper's authors note, "despite OA being the commonest form of arthritis, there are no disease-modifying therapeutics and clinical development of single-target approaches, including IL-1β and ADAMTS5, has failed despite promising data from preclinical models." CDK8, a kinase subunit of the Mediator transcriptional complex, was elevated in chondrocytes from human OA cartilage (Mankin scores 5–10) compared with non-lesion tissue, and lentiviral overexpression of CDK8 in chondrocyte models recapitulated pro-degenerative transcriptional signatures — supporting a functional rather than merely correlative role. The central mechanism involves CDK8's phosphorylation of STAT1 at serine-727 and its regulation of downstream Wnt, TGF-β, BMP, and NF-κB pathways, all of which govern chondrocyte differentiation state. In healthy articular cartilage, chondrocytes maintain a stable, non-hypertrophic phenotype; in OA, they aberrantly transition toward hypertrophy — upregulating mineralization markers and degradative enzymes while losing matrix-producing capacity. CDK8 inhibition, the authors propose, acts as a transcriptional rheostat that stabilizes the non-hypertrophic state by suppressing this axis. The in vivo component used male STR/Ort mice, a spontaneous OA model, dosed orally with 5 mg/kg of the selective CDK8/19 inhibitor MSC2530818 (MSC-818; biochemical IC₅₀ = 2.5 nmol/L) three times per week for 12 weeks, beginning at 22 weeks of age. Treated animals (n = 12 limbs from 6 mice) showed reduced Osteoarthritis Research Society International (OARSI) histological scores compared with vehicle-treated controls (n = 10 limbs from 5 mice), indicating attenuated cartilage degradation. Complementary matrix integrity scoring and Masson's Trichrome staining supported preservation of collagen architecture. Micro-computed tomography analysis showed reduced growth plate bridge number and areal density, particularly in the lateral compartment. Treadmill-based gait analysis indicated functional differences in treated animals consistent with reduced joint pathology. No overt toxicity was observed over the 12-week dosing period, though the study was not designed for formal safety profiling. In vitro, the chondroprotective effects were validated across multiple structurally distinct CDK8 inhibitor series, reducing the likelihood that findings reflect off-target compound activity. Bulk RNA sequencing identified downregulation of NF-κB and JAK-STAT inflammatory pathways and upregulation of extracellular matrix organization programs. Seahorse metabolic profiling indicated that CDK8 inhibition shifted chondrocytes away from glycolysis-dominant metabolism toward preserved oxidative phosphorylation capacity — a metabolic profile associated with healthier chondrocyte function. Effects were directionally consistent across primary equine articular chondrocytes from six donors and in THP-1-derived macrophages, where CDK8 inhibition reduced phospho-STAT1 and pro-inflammatory cytokine expression. A parallel 2025 publication reported that CDK8 promotes OA pathology via an NF-κB/senescence-associated secretory phenotype (SASP) axis — a distinct mechanistic angle that independently corroborates CDK8's relevance as an OA target. No CDK8 inhibitor has entered clinical development for any musculoskeletal indication. In oncology, the most clinically advanced agent in this class is romaciclib (RVU120), developed by Poland-based Ryvu Therapeutics, which is currently in Phase II trials for relapsed/refractory acute myeloid leukemia and myelodysplastic syndrome, including the RIVER-81 study (NCT06191263). Other molecules include Biocad's BCD-115 (Senexin B), a selective CDK8/19 inhibitor. SEL120-34A, the same compound as romaciclib, was among the CDK8 inhibitors screened in the paper's in vitro chondrocyte platform. MSC-818 itself has not entered clinical trials in any indication and remains a research-stage tool compound. Biosplice Therapeutics submitted an NDA to the FDA in January 2026 for lorecivivint, a CLK2/DYRK1A inhibitor that modulates Wnt signaling via alternative splicing and is administered by intra-articular injection — described at submission as the first DMOAD candidate ever filed for FDA approval, though no approval has been confirmed as of the current date. Sprifermin, a recombinant FGF18 developed by Merck KGaA in collaboration with Nordic Bioscience, completed Phase II with five-year cartilage thickness benefit in the FORWARD study; no confirmed active Phase III trial has been identified. The authors describe CDK8/19 inhibition as "a promising disease-modifying strategy for targeting whole-joint disease in OA," citing its simultaneous effects across cartilage, bone, and inflammatory cell types. The study was conducted by a consortium spanning the RVC, University College London, Middlesex University, the Institute of Cancer Research, and the University of Oxford, with human cartilage sections provided by Erasmus MC in Rotterdam. Authors Wells and Roberts disclosed a patent application (WO2023/237861) relating to CDK8/19 inhibitor development. Spot something wrong? Report an issue with this article

Romaciclib in acute myeloid leukemia (AML): In the RIVER-81 Phase II study, romaciclib combined with venetoclax (VEN) shows encouraging anti-leukemic activity, including durable responses, in patients with relapsed/refractory AML (r/r AML) after VEN-based therapy failure. These results support further clinical development at the selected dose. On May 28, 2026, the Food and Drug Administration (FDA) reactivated the IND, enabling the initiation of the expansion cohort at the recommended dose of 150 mg once daily (QD). Romaciclib in myelofibrosis (MF): In the POTAMI-61 Phase II study, romaciclib demonstrates a favorable safety profile and clinical activity in myelofibrosis (MF), both as monotherapy and in combination with ruxolitinib (RUX). The observed spleen volume reductions and hematologic tolerability support continued clinical evaluation. Eight patients from POTAMI-61 will continue treatment in the ROVER-01 study, reflecting ongoing clinical benefit in a subset of patients. Krakow, Poland – June 11, 2026 – Ryvu Therapeutics (WSE: RVU), a clinical-stage drug discovery and development company focusing on novel therapies that address emerging targets in oncology, presents romaciclib (RVU120) data at the European Hematology Association Congress (EHA), June 11-14, 2026, in Stockholm, Sweden. Hendrik Nogai, M.D., Chief Medical Officer of Ryvu Therapeutics said: We are pleased to share updated clinical data at EHA that reinforce the potential of romaciclib across hematologic malignancies. The poster presentations highlight consistent clinical activity and a manageable safety profile, both as a single agent and in rational combinations, including in difficult-to-treat patient populations. Importantly, the FDA review of the program and the recent reactivation of the RIVER-81 IND in the US as well as the continued treatment of patients from POTAMI-61 in the ROVER-01 study, are meaningful signals reflecting both regulatory progress and continued patient benefit. These milestones strengthen our confidence in romaciclib’s differentiated mechanism of action and support its continued clinical advancement. Program updates: In the RIVER-81 trial of patients with r/r AML, Ryvu is initiating an expansion cohort of approximately 30 patients to confirm the positive efficacy demonstrated in the dose cohort of 150 mg QD romaciclib combined with 400 mg QD venetoclax. Following completion of the required regulatory steps, including an updated study protocol and submission of documentation under the existing IND, the FDA reactivated the IND for RIVER-81 study on May 28, 2026. In the POTAMI-61 study investigating romaciclib’s efficacy in MF, eight patients will be transferred into the ROVER-01 study rollover protocol, underscoring that a subset of patients continue to derive meaningful clinical benefit from romaciclib treatment. These patients will continue to receive treatment with romaciclib as long as they benefit in ROVER-01. EHA poster presentations: Poster (PF529):  Updated findings from the Phase 2 RIVER-81 study of romaciclib (RVU120) combined with venetoclax in acute myeloid leukemia after first-line venetoclax and hypomethylating agent failure Poster session date and time: Friday, June 12 (6:45 – 7:45 PM CEST) Venetoclax (VEN) combined with hypomethylating agents is the standard first-line treatment for patients with acute myeloid leukemia (AML) ineligible for intensive chemotherapy, yet ~70% experience relapsed/refractory disease with a median survival of under three months. Romaciclib, a first-in-class CDK8/CDK19 inhibitor, has shown single-agent activity in AML and preclinical synergy with VEN through enhanced apoptotic signaling and attenuation of resistance pathways. In the ongoing Phase 2 RIVER-81 trial, romaciclib in combination with VEN demonstrates anti-leukemic activity in patients with poor prognostic AML. While responses have been observed across dose levels, the most consistent responses were seen at romaciclib 150 mg QD + VEN 400 mg QD, including two complete remissions with (CR) and one without (CRi) full hematologic recovery, resulting in a CR/CRi rate of 43% (3/7). The mean duration of response (DoR) of the CRs was 156 days, reported with a cut-off date of 12 May 2026. Based on safety, PK, and preliminary efficacy findings, this regimen was selected as the recommended dose for expansion. Poster (PS2008):   Romaciclib (RVU120), a selective CDK8/19 inhibitor, as monotherapy or in combination with ruxolitinib in patients with myelofibrosis: Updated results from the phase II POTAMI-61 study Poster session date and time: Saturday, June 13 (6:45 – 7:45 PM CEST) Myelofibrosis (MF) is driven by dysregulated JAK/STAT signaling, and while JAK inhibition with ruxolitinib (RUX) improves splenomegaly and symptoms, cytopenias and suboptimal responses remain clinical challenges. Romaciclib is a first-in-class, oral CDK8/19 inhibitor that modulates STAT-dependent transcription and shows synergy with RUX in preclinical MF models. In the ongoing Phase II POTAMI-61 study, romaciclib administered as monotherapy or combined with RUX demonstrates a manageable safety profile in patients with MF without significant treatment-related cytopenias. Prolonged exposure, spleen volume reductions, including in patients with high-molecular-risk mutations, and favorable hematologic tolerability support continued clinical development. The posters are available online and can be accessed via the conference website:  https://ehaweb.org/ and Ryvu’s website: https://ryvu.com/ The project entitled “The conduct of a phase II, multicentre, open-label clinical trial (RIVER-81) evaluating the safety and efficacy of RVU120 in combination with venetoclax in patients with relapsed/refractory acute myeloid leukemia who have failed prior therapy with venetoclax and a hypomethylating agent.”, carried out by Ryvu Therapeutics S.A., is co-financed by the Medical Research Agency from the state budget under the “Development of targeted or personalised medicine based on medicinal products involving nucleic acids and small-molecule compounds” call (ABM/2022/6). Total Project value: PLN 132,471,740.70 Total funding: PLN 62,268,848.90 RYVU Therapeutics Leona Henryka Sternbacha 2 30-394 Kraków, Poland