cirtuvivint (SM08502) / Biosplice Therap - LARVOL DELTA

Trial in progress: A phase I study evaluating the safety of cirtuvivint (CIRT) as monotherapy and in combination with ASTX727 in patients with myelodysplastic syndromes (MDS) and Acute Myeloid Leukemia (AML) (ASH 2025) - P1 | "Outcomes afterresistance to venetoclax-based therapy are particularly poor with a median OS of 2.5 monthsindependent of the type of salvage therapy used (Maiti et al., Haematologica 2020). ConclusionsThis phase I trial will establish the safety and RP2D for CIRT as monotherapy in R/R AML or R/R MDS(cohort I and II) and in combination with ASTX727 for untreated higher-risk MDS (cohort III). The trial isactively recruiting and aims to inform future phase II studies."

Clinical • Combination therapy • Monotherapy • P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Solid Tumor • XIAP

SM08502-Mediated β-Catenin Repression Synergizes with Olaparib to Inhibit Tumor Progression. (PubMed, Cancer Res Commun) - "Overcoming PARPi resistance will provide patients with therapeutic options. The study shows, in the context of resistant disease, the potential of targeting CDC-like kinase/dual-specificity tyrosine phosphorylation-regulated kinase alone and in combination with PARP inhibitors."

IO biomarker • Journal • Oncology • BRCA1 • BRCA2 • CTNNB1 • HRD • PD-1 • PD-L1

CIRTUSARC: A multicenter, open-label phase II trial of cirtuvivint as second-line therapy in selected advanced soft-tissue sarcomas (ESMO 2025) - "A single-stage design (n=25 evaluable) tests PFSR-3m ≥70% vs. ≤45% (α=0.05, β=0.20). The trial is enrolling at 8 centers in Spain."

Clinical • Metastases • P2 data • Ewing Sarcoma • Liposarcoma • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Synovial Sarcoma

Cirtuvivint/Olaparib in Breast Cancer Susceptibility Gene/Homologous Recombination Deficiency Platinum Resistant Ovarian Cancer (clinicaltrials.gov) - P1 | N=50 | Recruiting | Sponsor: University of Colorado, Denver | Not yet recruiting ➔ Recruiting

Enrollment open • Platinum resistant • Breast Cancer • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor • BRCA

RNA processing kinase inhibitors and epigenetic inhibitors in combination with oncology drugs or investigational agents in multi-cell type patient-derived tumor cell line spheroids. (PubMed, Cancer Chemother Pharmacol) - "These findings may provide guidance for development of clinical trial combination regimens including cirtuvivint, CC-671 or iadademstat. Full data sets are available on PubChem."

IO biomarker • Journal • Preclinical • Oncology • Targeted Protein Degradation • KRAS

Biosplice Therapeutics Announces First Patient Dosed in NCI-Sponsored Clinical Trial of Cirtuvivint in Acute Myeloid Leukemia and Myelodysplastic Syndromes (GlobeNewswire) - "The trial (NCT06484062) is evaluating the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of cirtuvivint, both as a monotherapy and in combination with ASTX727 (INQOVI, oral decitabine/cedazuridine)..."

Trial status • Acute Myelogenous Leukemia • Myelodysplastic Syndrome

DYR895: An orally bioavailable, brain-penetrant small molecule kinase inhibitor for simultaneous targeting of cancer growth and stemness (ACS-Fall 2025) - "The compound is orally bioavailable, well-tolerated, and exhibits excellent brain penetration with minimal efflux. Despite its multi-targeted nature, DYR895 remains relatively selective within the kinome, outperforming reference compounds cirtuvivint and abemaciclib."

Brain Cancer • Colorectal Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • FLT3

Small Cell Lung Cancer Irinotecan and CDC2-like Kinase Inhibition Trial (SLICK Trial) (clinicaltrials.gov) - P1/2 | N=42 | Not yet recruiting | Sponsor: Washington University School of Medicine

New P1/2 trial • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

CIRTUSARC: Cirtuvivint in Selected Advanced Soft-Tissue Sarcomas (clinicaltrials.gov) - P2 | N=25 | Recruiting | Sponsor: Asociación Europea y Latinoamericana SELNET para la Investigación en Sarcomas

New P2 trial • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

RNA processing kinase inhibitors and epigenetic inhibitors in combination with oncology drugs or investigational agents in multi-cell type patient-derived tumor cell line spheroids. (PubMed, Res Sq) - "We investigated the activity of two CLK inhibitors, cirtuvivint and CC-671, and the LSD1 inhibitor iadademstat alone and in combination with anticancer drugs or investigational agents...These agents included the XPO1 inhibitor, eltanexor, and the KRAS G12D specific inhibitor MRTX-1133 which had activity in tumor lines harboring the KRAS G12D mutation. LSD1 inhibition was effective with ubiquitin proteasome pathway inhibitors. The full data sets are available on PubChem."

IO biomarker • Journal • Preclinical • Oncology • Targeted Protein Degradation • KRAS

Testing the Anti-cancer Drug, Cirtuvivint, and Its Combination With ASTX727 to Improve Outcomes in Patients With Acute Myeloid Leukemia and Myelodysplastic Syndromes (clinicaltrials.gov) - P1 | N=54 | Recruiting | Sponsor: National Cancer Institute (NCI) | Suspended ➔ Recruiting

Enrollment open • Monotherapy • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

The CLK/DYRK inhibitor SM09419 shows potent efficacy across a broad panel of pediatric preclinical xenograft models - A report from the Pediatric Preclinical In Vivo Testing Consortium (PIVOT) (AACR 2025) - P1 | "SM09419 exhibited promising activity in preclinical models of TP53- and FLT3-mutated acute myeloid leukemia, and its analog cirtuvivint (SM08502) exhibited broad preclinical activity and evidence of therapeutic benefit in solid tumors. SM09419 exhibited broad antitumor activity across several pediatric cancers (e.g., ALL and NB), with activity also observed for ES and HB. Lower activity was seen in the RMS and OS models. The promising results support further evaluation of CLK/DYRK as therapeutic targets."

Preclinical • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • CNS Tumor • Ewing Sarcoma • Hematological Malignancies • Hepatoblastoma • Leukemia • Neuroblastoma • Oncology • Osteosarcoma • Rhabdoid Tumor • Rhabdomyosarcoma • Sarcoma • Solid Tumor • Wilms Tumor • FLT3 • TP53

Cirtuvivint inhibits Ewing sarcoma (ES) growth by suppressing EWS-FLI-1 expression and inducing alternate EWS-FLI1 splice variants (AACR 2025) - "Treatment of ES cells (A673, CHP100, and MHH ES1) with increasing concentrations of cirtuvivint, as well as its analog SM09419, significantly reduced cell viability (LD50 ~250 nM) both in vitro and in vivo, This treatment suppressed EWS-FLI-1 expression and generated multiple alternative EWS-FLI-1 variants within 4-6 hours, marked by the loss of whole exons. Mechanistic studies showed reduced β-catenin and c-myc expression, however, siRNA experiments targeting these genes did not affect cell growth. To investigate the role of these alternative EWS-FLI1 splice variants, transcripts generated by cirtuvivint treatment were cloned, sequenced, and inserted into eukaryotic expression vectors, including a Tet-inducible system and vectors for cell-free protein expression."

Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • CDK1 • CTNNB1 • EWSR1 • FLI1 • MYC

Biosplice Announces First Patient Dosed in Phase 2 Trial of Cirtuvivint for Advanced Soft-Tissue Sarcomas (GlobeNewswire) - "Biosplice Therapeutics...announced that the first patient has been dosed in a Phase 2 clinical trial evaluating cirtuvivint in patients with advanced soft-tissue sarcomas. The multicenter, open-label trial, led by Principal Investigator Dr. Javier Martin Broto, is sponsored by SELNET (Sarcoma European and Latin American Network) and is being conducted at eight clinical sites across Spain....The 'Multicenter, Open-Label Phase 2 Trial of Cirtuvivint as a Second-Line Therapy in Selected Advanced Soft-Tissue Sarcomas' will evaluate cirtuvivint monotherapy in approximately 30 patients whose disease has progressed following initial standard of care."

Trial status • Soft Tissue Sarcoma

Development of orally bioavailable multi-targeted inhibitors of Wnt signaling for the treatment of colorectal cancer (AACR 2025) - "Our lead compound, DYR895, demonstrates improved Wnt signaling inhibition over phase 1b clinical candidate Cirtuvivint (WNT reporter EC50: 5.1 nM vs. 230 nM), while being well tolerated in mouse models (MTD >50 mg/kg) and orally bioavailable (F%: 81%)...Further optimization of DYR895 with the goal of reducing CNS exposure while enhancing Wnt inhibition led to the discovery of DYR1055, with a 10x improvement in affinity for some target kinases while maintaining key surrogate ADME attributes. Investigations into the efficacy of DYR1055 in disease models are ongoing."

Colorectal Cancer • Oncology • Solid Tumor • BRAF • CDK7 • PIK3CA

Cirtuvivint/Olaparib in Breast Cancer Susceptibility Gene/homologous Recombination Deficiency Platinum Resistant Ovarian Cancer (clinicaltrials.gov) - P1 | N=50 | Not yet recruiting | Sponsor: University of Colorado, Denver

New P1 trial • Breast Cancer • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor • BRCA

Testing the Anti-cancer Drug, Cirtuvivint, and Its Combination With ASTX727 to Improve Outcomes in Patients With Acute Myeloid Leukemia and Myelodysplastic Syndromes (clinicaltrials.gov) - P1 | N=54 | Suspended | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Suspended

Trial suspension • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Testing the Anti-cancer Drug, Cirtuvivint, and Its Combination With ASTX727 to Improve Outcomes in Patients With Acute Myeloid Leukemia and Myelodysplastic Syndromes (clinicaltrials.gov) - P1 | N=54 | Recruiting | Sponsor: National Cancer Institute (NCI) | Not yet recruiting ➔ Recruiting | Initiation date: Dec 2024 ➔ Sep 2025

Enrollment open • Trial initiation date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Testing the Anti-cancer Drug, Cirtuvivint, and Its Combination With ASTX727 and ASTX727 With Venetoclax to Improve Outcomes in Patients With Acute Myeloid Leukemia and Myelodysplastic Syndromes (clinicaltrials.gov) - P1 | N=48 | Not yet recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jan 2027 ➔ Jun 2028 | Trial primary completion date: Jan 2027 ➔ Jun 2028

Monotherapy • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Biosplice Therapeutics Announces Initiation of Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS) Trial Sponsored by the National Cancer Institute (NCI) (GlobeNewswire) - "Biosplice Therapeutics, Inc...is pleased to announce that the U.S. Food and Drug Administration (FDA) has cleared the NCI-sponsored Investigational New Drug (IND) application for cirtuvivint....This clearance allows for the initiation of a new clinical trial of cirtuvivint, both as a standalone treatment for patients with relapsed/refractory AML and MDS as well as in combination with ASTX727 for patients with frontline high-risk MDS."

IND • New P1 trial • Acute Myelogenous Leukemia • Myelodysplastic Syndrome

Targeting the CLK2/SRSF9 splicing axis in prostate cancer leads to decreased ARV7 expression. (PubMed, Mol Oncol) - "Inhibition of the Cdc2-like kinase (CLK) family by the small molecules cirtuvivint or lorecivivint results in the decreased expression of ARV7. Both inhibitors show potent anti-proliferative effects in enzalutamide-treated or -naive PC models. Thus, targeting aberrant alternative splicing at the 3'UTR of ARV7 by disturbing the CLK2/SRSF9 axis might be a valuable therapeutic approach in late stage, ARSI-resistant PC."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • ARSI • CDK1 • CLK2 • SRSF9

The splicing modulator CLK1 is a candidate oncogenic dependency in pediatric high-grade gliomas. (PubMed, bioRxiv) - "Inhibition of CLK1 with Cirtuvivint in the pediatric HGG KNS-42 cell line significantly decreased both cell viability and proliferation in a dose-dependent manner...Our findings highlight a dependency of pediatric HGGs on CLK1 and its roles contributing to tumor splicing heterogeneity through transcriptional dysregulation of splicing factors and transcriptional modulation of oncogenes. Overall, aberrant splicing in HGGs and other pediatric brain tumors represents a potentially targetable oncogenic pathway contributing to tumor growth and maintenance."

Journal • Brain Cancer • CNS Tumor • Glioma • Oncology • Pediatrics • Solid Tumor

A Study Evaluating the Safety and Pharmacokinetics of Orally Administered SM08502 in Subjects With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=82 | Terminated | Sponsor: Biosplice Therapeutics, Inc. | Active, not recruiting ➔ Terminated; Study was terminated due business reasons by Sponsor.

Metastases • Trial termination • Breast Cancer • Colorectal Cancer • Endometrial Cancer • Gastrointestinal Cancer • Hepatocellular Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Prostate Cancer • Solid Tumor • Triple Negative Breast Cancer

A Study Evaluating the Safety, Pharmacokinetics, and Preliminary Efficacy of Orally Administered SM08502 Combined With Hormonal Therapy or Chemotherapy in Subjects With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=30 | Terminated | Sponsor: Biosplice Therapeutics, Inc. | Phase classification: P1b ➔ P1 | Active, not recruiting ➔ Terminated; Study was terminated due business reasons by Sponsor.

Metastases • Phase classification • Trial termination • Castration-Resistant Prostate Cancer • Colorectal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Prostate Cancer • Solid Tumor • ALK • NTRK

Testing the Anti-cancer Drug, Cirtuvivint, and Its Combination With ASTX727 and ASTX727 With Venetoclax to Improve Outcomes in Patients With Acute Myeloid Leukemia and Myelodysplastic Syndromes (clinicaltrials.gov) - P1 | N=48 | Not yet recruiting | Sponsor: National Cancer Institute (NCI)

Combination therapy • Monotherapy • New P1 trial • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology