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.

P3, N=496, Completed, Biosplice Therapeutics, Inc. | Active, not recruiting --> Completed

P3, N=276, Completed, Biosplice Therapeutics, Inc. | Active, not recruiting --> Completed | Trial completion date: Sep 2024 --> Jun 2023 | Trial primary completion date: Sep 2024 --> Jun 2023

P3, N=496, Active, not recruiting, Biosplice Therapeutics, Inc. | Trial completion date: Oct 2023 --> Feb 2024 | Trial primary completion date: Oct 2023 --> Feb 2024

Use of azole antifungals that are not strong CYP3A4 inhibitors (e.g., isavuconazole) is permitted. The phase 2 part of the study will commence after the RP2D has been identified and confirmed and aims at evaluating therapeutic activity in R/R AML (Cohort 2a) or R/R HR-MDS (Cohort 2b), in addition to confirmation of the safety profile. Clinical trial registry number: NCT05732103

ConclusionOur results suggest that targeting RNA splicing may be a promising approach for treatment of therapy-refractory MRT. Further pre-clinical in vivo studies are warranted to fully establish a rationale for clinical evaluation of SM09419 in MRT patients.

Assessment of CTX-712 safety profile for hematologic malignancies is ongoing. CTX-712 showed preliminary anti-tumor efficacy for both AML and MDS.

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.