RVT-2001

Notably, such integration will enable the rational design of isoform‑specific combination regimens to dismantle drug‑resistance circuits. It is anticipated that the present review will assist the scientific community, including both basic and translational researchers, in translating these findings into interventions that mitigate therapeutic failure in recalcitrant cancers.

The AE profile was similar to that reported previously, with a slightly higher incidence of atrial fibrillation. However, the low RBC-TI rate suggests insufficient efficacy of H3B-8800 at the dose levels tested. Further exploration of dosing schedules is warranted.

P1, N=127, Terminated, Hemavant Sciences GmbH | N=200 --> 127 | Trial completion date: Dec 2024 --> Feb 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Sep 2024 --> Feb 2024; The study was terminated after conducting an interim analysis of the available data where it became evident that the observed efficacy results were not in alignment with the initially set expectations.

Here, we showed that cohesin mutations are biomarkers of sensitivity to drugs targeting the splicing factor 3B subunit 1 (SF3B1) H3B-8800 and E-7107...Furthermore, we demonstrated that treatment of cohesin-mutant cells with SF3B1 modulators not only resulted in impaired DNA damage response and accumulation of DNA damage, but it sensitized cells to subsequent killing by poly(ADP-ribose) polymerase (PARP) inhibitors and chemotherapy and led to improved overall survival of PDX models of cohesin-mutant AML in vivo. Our findings expand the potential therapeutic benefits of SF3B1 splicing modulators to include cohesin-mutant MDS and AML.

Using the H3B-8800 splicing modulator, we show, for the first time in CLL, cytotoxic effects in vitro in primary CLL samples and in SF3B1-mutated isogenic CLL cell lines, accompanied by major splicing changes and delayed leukemic infiltration in a CLL xenotransplant mouse model. H3B-8800 displayed preferential lethality towards SF3B1-mutated cells and synergism with the BCL2 inhibitor venetoclax, supporting the potential use of SF3B1 inhibitors as a novel therapeutic strategy in CLL.

Despite the approval of several drugs for AML, cytarabine is still widely used as a therapeutic approach. H3B-8800 and venetoclax combination showed the best efficacy in vitro, demonstrating synergistic effects in patient samples and no toxicity in healthy hematopoietic progenitors. Our results establish that RNA splicing inhibition, alone or combined with venetoclax, could be useful for the treatment of newly diagnosed or relapsed/refractory AML.

Pre-treatment of cohesin-mutant cells with H3B-8800 for 3 days increased their sensitivity to the PARP inhibitor talazoparib 10-fold, while the sensitivity of wild-type cells to talazoparib was unaffected (Figure 1A)...In addition to talazoparib, we demonstrated significantly improved overall survival of STAG2-mutant AML PDX mice receiving sequential treatment of E-7107 and standard induction chemotherapy (doxorubicin and cytarabine), further expanding this strategy beyond PARP inhibitors...In summary, our study identifies a critical connection between cohesin mutations and splicing modulation in AML, creating a novel therapeutic strategy for these patients with very limited treatment options and poor outcomes. Our findings not only expand the potential therapeutic benefits of SF3B1 splicing modulators to include cohesin-mutant MDS/sAML but we also propose this as a broader strategy for therapeutic targeting of other DNA damage-repair deficient cancers.

P1, N=200, Recruiting, Hemavant Sciences GmbH | Trial completion date: Nov 2022 --> Dec 2024 | Trial primary completion date: Nov 2022 --> Sep 2024

Nevertheless, this set of simulations discloses that the K700E mutation and H3B-8800 binding affect the overall SF3b internal motion, which in turn may influence the way SF3b interacts with other spliceosome components. Finally, we unveil the existence of a putative druggable SF3b pocket in the vicinity of K700E that could be harnessed in future rational drug-discovery efforts to specifically target mutant SF3b.

P1, N=200, Recruiting, H3 Biomedicine Inc. | Trial completion date: Apr 2022 --> Nov 2022 | Trial primary completion date: Apr 2022 --> Nov 2022