Hemavant is a clinical-stage biopharmaceutical company dedicated to developing innovative targeted therapeutics to improve the lives of patients with blood disorders and hematological malignancies.
Chief Medical Officer
Chief Financial Officer
Program and Alliance Management
SVP Clinical Operations
Frank Torti, MD
Vant Chair, Roivant Sciences
Eric Venker, MD
President & Chief Operating Officer, Roivant Sciences
Myelodysplastic syndromes (MDS)
Myelodysplastic syndromes comprise a heterogeneous group of hematologic malignancies, which are characterized by cytopenia(s) and abnormal hematopoiesis such as anemia, neutropenia or thrombocytopenia. In the US, an estimated 17,000 new cases are diagnosed each year, translating into an estimated 115,000 patients living with MDS in the US¹. MDS is categorized into high- or lower-risk by the Revised International Prognostic Scoring System (IPSS-R) and roughly two thirds of patients have lower-risk disease².
Splicing factor 3B subunit 1 (SF3B1) Mutation in MDS
Spliceosome protein SF3B1 is a genetically validated target that is mutated in up to 80% of certain MDS patient subsets³. Aberrant splicing of genes involved in hematological cell differentiation has been observed in MDS patients, particularly in those carrying SF3B1 mutations, suggesting that correction of splicing defects could potentially reverse defective erythropoiesis in this patient population⁴. MDS with SF3B1 mutations is generally categorized as lower risk (encompassing very low to intermediate risk categories) by the IPSS-R and initially treated with erythropoiesis-stimulating agents (ESAs). However, the effect of ESAs will diminish in most patients, who may become red blood cell transfusion-dependent⁵.
RVT-2001 (H3B-8800) Small Molecule Inhibitor of SF3B1
RVT-2001 is an oral investigational product for anemia associated with lower-risk MDS that utilizes a novel mechanism to modulate aberrant splicing caused by SF3B1 mutations⁶
Chemical Structure of RVT-2001
Therapeutic Potential of Targeting Spliceosome Mutations
SF3B1 mutations cause global splicing alterations and are thought to be an initiating event in MDS⁷
Figure adapted from .
Therapeutic Hypothesis: SF3B1 Mutants Contribute to Pathogenesis
Erythropoiesis takes place in bone marrow with the series of cell differentiation from hematopoietic stem cells (HSC)⁹. SF3B1 mutations are generally early genetic events that affect erythropoiesis at multiple stages¹. By targeting SF3B1, RVT-2001 may correct abnormalities caused by SF3B1 mutations from early to late stages of the erythropoiesis.
Figure adapted from .
Our Science - Citations
- Cazzola M. Myelodysplastic Syndromes. N Engl J Med, 2020. 383(14): p. 1358-1374.
- Greenberg P., et al. Revised International Prognostic Scoring System for Myelodysplastic Syndromes. Blood, 2012. 120 (12): p. 2454–2465.
- Mortera-Blanco, T., et al. SF3B1-initiating mutations in MDS-RSs target lymphomyeloid hematopoietic stem cells. Blood, 2017. 130(7): p. 881-890.
- Shiozawa Y., et al. Gene expression and risk of leukemic transformation in myelodysplasia. Blood, 2017. 130(24): p. 2642-2653.
- Park S., et al. Outcome of Lower-Risk Patients With Myelodysplastic Syndromes Without 5q Deletion After Failure of Erythropoiesis-Stimulating Agents. J Clin Oncol, 2017. 35(14): p. 1591-1597.
- Seiler, M., et al. H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers. Nat Med, 2018. 24(4): p. 497-504.
- Malcovati L., et al. SF3B1-mutant MDS as a distinct disease subtype: a proposal from the International Working Group for the Prognosis of MDS. Blood, 2020. 136(2): p.157-170.
- Xu, J., et al. Modeling human RNA spliceosome mutations in the mouse: not all mice were created equal. Exp Hematol, 2019. 70: p. 10-23.
- Zivot, A., et al. Erythropoiesis: insights into pathophysiology and treatments in 2017. Mol Med, 2018. 24(1): p. 1-15.
RVT-2001 is an investigational drug product that is a potent, selective, and orally bioavailable small molecule modulator of SF3B1, a component of the spliceosome commonly mutated in lower-risk (LR) MDS. The Encore-MDS trial will evaluate RVT-2001 safety and efficacy against anemia experienced by LR-MDS patients with SF3B1 mutations.
Learn more about Encore-MDS study:
Roivant Licenses Splicing Modulator and Announces Upcoming Presentation at 40th Annual J.P. Morgan Healthcare Conference
Seiler, M., et al. (2018). H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers. Nature medicine, 24(4), 497–504. https://doi.org/10.1038/nm.4493
Rioux, N., et al. (2020). Metabolic disposition of H3B-8800, an orally available small-molecule splicing modulator, in rats, monkeys, and humans. Xenobiotica; the fate of foreign compounds in biological systems, 50(9), 1101–1114. https://doi.org/10.1080/00498254.2019.1709134
Steensma, D. P., et al. (2021). Phase I First-in-Human Dose Escalation Study of the oral SF3B1 modulator H3B-8800 in myeloid neoplasms. Leukemia, 35(12), 3542–3550. https://doi.org/10.1038/s41375-021-01328-9
Zhou, Y., et al. (2020). Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia. Cancer discovery, 10(9), 1388–1409. https://doi.org/10.1158/2159-8290.CD-19-1436
Finci, L. I., et al. (2018). The cryo-EM structure of the SF3b spliceosome complex bound to a splicing modulator reveals a pre-mRNA substrate competitive mechanism of action. Genes & development, 32(3-4), 309–320. https://doi.org/10.1101/gad.311043.117
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