cirtuvivint (SM08502)

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.

P1, N=30, Terminated, Biosplice Therapeutics, Inc. | Phase classification: P1b --> P1 | Active, not recruiting --> Terminated; Study was terminated due business reasons by Sponsor.

P1, N=82, Terminated, Biosplice Therapeutics, Inc. | Active, not recruiting --> Terminated; Study was terminated due business reasons by Sponsor.

P1b, N=30, Active, not recruiting, Biosplice Therapeutics, Inc. | Recruiting --> Active, not recruiting | N=150 --> 30 | Trial primary completion date: Jul 2026 --> Jul 2024

In vivo, tumor growth inhibition studies testing cirtuvivint at exposures ~2X below the MTD resulted in significant disease control (≥50% TGI) in 38/46 PDX and 38/43 CDX models. These observations indicate broad cancer relevance, at least in the preclinical setting, and expose vulnerabilities to CLK-DYRK-regulated splicing that can potentially be therapeutically addressed with pan CLK/DYRK inhibitors.

P1b, N=150, Recruiting, Biosplice Therapeutics, Inc. | Not yet recruiting --> Recruiting

Consistent with this, combination of the BCL-2 inhibitor venetoclax with cirtuvivint was sufficient to induce tumor regressions in AML xenograft models (KG-1 and HL-60) that were resistant to either single-agent drug at the same concentrations. These observations support further evaluation of CLK/DYRK inhibitors as a therapeutic strategy for heme malignancies dependent upon alternative pre-mRNA splicing.

We therefore utilized a series of selective pan-CLK/DYRK1A inhibitors, including SM09419 and SM08502, that potently suppress SR protein phosphorylation. Therapeutically, pharmacologic inhibition of SR protein function via inhibiting CLK/DYRK1A-mediated phosphorylation of splicing factors is an effective strategy used in combination with venetoclax or to overcome venetoclax resistance. Overall, our findings underscore the central importance of RNA splicing in drug response and provides a therapeutic rationale for modulating RNA splicing to enhance current AML therapies.

P1b, N=150, Not yet recruiting, Biosplice Therapeutics, Inc.

While CDK4/6 inhibitors such as palbociclib (Palbo) have shown efficacy in this cancer type, overcoming resistance to these agents is an unmet need for patients...SM08502 impaired parental (EC50=0.22 µM) and Palbo-R (EC50=0.41 µM) T47D cell proliferation, while CDK4/6 inhibitors (Palbo, abemaciclib, ribociclib) were only effective on parental cells...In vivo antitumor effects and tolerability of oral SM08502 (25mg/kg QD) alone or combined with fulvestrant (F) ± Palbo in a CDK4/6 inhibitor-sensitive model were assessed in mice bearing orthotopic MCF7 xenografts (n=8/group)...Together, these data suggest that SM08502 has potential antitumor activity in HR+ BC and may provide clinical benefit as a single agent or combined with standard therapy. A Phase 1 study of SM08502 in subjects with advanced solid tumors is ongoing (NCT03355066).