Cirtuvivint

Overview

Cirtuvivint (SM08502) is an orally bioavailable small‑molecule inhibitor of CDC‑like kinases (CLKs) and dual‑specificity tyrosine‑regulated kinases (DYRKs) being developed by Biosplice Therapeutics for oncology. It is in early clinical development across solid tumors and, more recently, hematologic malignancies (AML/MDS). (biosplice.com)

Mechanism of action

• Target: pan‑CLK/DYRK inhibition leading to modulation of alternative pre‑mRNA splicing. In preclinical GI cancer models, SM08502 reduced phosphorylation of serine/arginine‑rich splicing factors (SRSFs), disrupted spliceosome function, and downregulated Wnt‑pathway gene expression; oral dosing inhibited tumor growth in xenografts. Pharmacodynamic biomarkers in patients included changes in CLK1 exon inclusion and SRSF5 intron retention. (pubmed.ncbi.nlm.nih.gov)
• The NCI Drug Dictionary also describes SM08502 as a Wnt‑pathway inhibitor based on decreased expression of Wnt‑related genes, consistent with the splicing‑modulation mechanism. (cancer.gov)

Efficacy

Evidence to date comes from early‑phase studies and meeting presentations; peer‑reviewed human efficacy results with mature response metrics have not yet been published.

• Monotherapy (first‑in‑human ONC‑01; NCT03355066): In a 71‑patient Phase 1 study across multiple solid tumors, tumor shrinkage >10% was observed in 6 subjects (examples: NSCLC −27% and −14%; CRPC −25%; endometrial −20% and −11%; bile duct −19%). PSA declines ≥30% occurred in 3 CRPC subjects; reductions in circulating tumor cells (including AR‑V7–positive CTCs) were reported in several CRPC patients. Durable stable disease through cycle 6 and beyond was seen in 12 subjects. (biosplice.com)

• Combination therapy (Phase 1b ONC‑03; NCT05084859): In early dose‑finding/expansion cohorts combining cirtuvivint with abiraterone (mCRPC), FOLFIRI ± panitumumab (CRC), or docetaxel (NSCLC), preliminary activity included one partial response (−44% tumor shrinkage) among 9 evaluable patients at the data cutoff, with additional cases of stable disease. PSA30/PSA50 reductions were also illustrated in individual mCRPC patients receiving cirtuvivint plus abiraterone. Dose escalation was ongoing at the time of reporting. (biosplice.com)

• Hematologic malignancies: An NCI‑sponsored Phase 1 study in AML/MDS (NCT06484062) opened in 2024 and was recruiting as of 2025; the first patient was dosed on September 9, 2025. No efficacy data have been reported yet. (globenewswire.com)

• Additional development: An investigator‑initiated Phase 2 study in selected advanced soft‑tissue sarcomas (Spain; SELNET‑sponsored) began dosing in May 2025. Results have not yet been reported. (globenewswire.com)

Safety

• In ONC‑01 (n=71), the maximum tolerated dose (MTD) was 120 mg given 5 days on/2 days off. Four dose‑limiting toxicities were reported overall. Common treatment‑emergent adverse events across doses included nausea (63%), diarrhea (59%), fatigue (38%), vomiting (38%), and decreased appetite (27%). Grade ≥3 adverse events occurring in ≥10% included anemia (~14%). (biosplice.com)

• In ONC‑03 combinations, interim reports stated no unexpected safety signals beyond those known for cirtuvivint or the partner agents during dose escalation. Detailed rates were not provided. (biosplice.com)

Ongoing and recent trials

• NCT03355066 (Phase 1 monotherapy; advanced solid tumors): dose escalation/dose finding completed; expansion ongoing/closed at various sites; institution listings note “not enrolling” at some centers. (dana-farber.org)
• NCT05084859 (Phase 1b combinations in mCRPC/NSCLC/CRC): dose escalation and expansion ongoing at time of presentation. (biosplice.com)
• NCT06484062 (Phase 1 AML/MDS; monotherapy and with oral decitabine/cedazuridine [ASTX727]): recruiting; first patient dosed September 9, 2025. (globenewswire.com)

Further reading

• Tam BY et al. The CLK inhibitor SM08502 induces anti‑tumor activity and reduces Wnt pathway gene expression in gastrointestinal cancer models (preclinical, Cancer Letters, 2019/2020). (pubmed.ncbi.nlm.nih.gov)
• ESMO 2022 oral presentation slides: Preliminary evidence of clinical activity from Phase 1 and 1b trials of the CLK/DYRK inhibitor cirtuvivint (includes safety, PK/PD, and early activity data). (biosplice.com)
• NCI Drug Dictionary entry for SM08502 (mechanism summary). (cancer.gov)
• Clinical trial listings and status:
• NCT03355066 (advanced solid tumors, Phase 1). (dana-farber.org)
• NCT05084859 (combinations in mCRPC/NSCLC/CRC, Phase 1b). (biosplice.com)
• NCT06484062 (AML/MDS, Phase 1; recruiting). (dana-farber.org)
• Press updates on new studies:
• First patient dosed in NCI‑sponsored AML/MDS trial (Sept 9, 2025). (globenewswire.com)
• Phase 2 investigator‑initiated trial in advanced soft‑tissue sarcomas (May 1, 2025). (globenewswire.com)

Note: As of November 11, 2025, publicly available human data consist of early‑phase results presented at scientific meetings; peer‑reviewed publications of clinical efficacy and safety outcomes (e.g., objective response rate, PFS) have not yet been identified. (biosplice.com)

Last updated: Nov 2025