RVT-2001 / Eisai, Roivant - LARVOL DELTA

High HDAC8 Creates Targetable Vulnerabilities in Acute Myeloid Leukemia through Dysregulation of BRCA1-Related RNA Splicing Machinery and Defective DNA Damage Repair (ASH 2024) - "First, we evaluated the effects of H3B-8800 (H3B; an orally bioavailable small molecule inhibitor for SF3B complex) and PARPi (Olaparib or Talazoparib) in primary murine CM-AML cells. Compared to MV4-11-Luci-EV mice, significantly prolonged survival was seen for MV4-11-Luci-HDAC8 mice treated with H3B (HDAC8 : 39 vs. EV : 31 days; p=0.0001) or Talazoparib (HDAC8 : 36 vs. EV : 29 days; p=0.0002). Overall, these results indicate that both splicing modulator and PARPi can effectively target HDAC8-high AML cells, including inv(16) AML, offering novel therapeutic avenues for inv(16) AML and AML with aberrant high-HDAC8 activity."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCLAF1 • BRCA1 • CD34 • HDAC8 • U2AF1

Identification of BAY61-3606 Derivatives With Improved Activity in Splicing Modulation That Induces Inclusion of Cassette Exons Similar to the Splicing Factor 3B Subunit 1 Mutation. (PubMed, Chem Biol Drug Des) - "Particularly, cassette exon inclusion was highly upregulated by this compound, and clustering analysis revealed that these effects resembled those in splicing factor 3b subunit 1 (SF3B1) K700E mutant cells but contrasted with those of the splicing inhibitor H3B-8800. Additionally, a group of serine/arginine-rich (SR) protein genes was identified as representatively affected, likely via modulation of poison exon inclusion. This finding could guide further analysis of the mode of action of these compounds on splicing, which could be valuable for developing drugs for diseases associated with splicing abnormalities."

Journal • SF3B1

Altered mRNA splicing mimics chromosome loss and drives pancreatic cancer* (AACRPanCa 2024) - "We are starting a phase 2 trial for Gemcitabine/Abraxane with escalating doses of H3B-8800 for tumors that have either SF3B1K700E, RBM10 loss, or neomorphic p53, all of which have aberrant RNA splicing. This work has determined novel drivers and mechanisms of PDAC development and a precision therapeutic strategy for treating PDAC patients."

Gastrointestinal Cancer • Hematological Disorders • Hematological Malignancies • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS • RBM10 • SF3B1 • TP53

Encore-MDS: A Study of H3B-8800 (RVT-2001) in Participants With Lower Risk Myelodysplastic Syndromes (clinicaltrials.gov) - P1 | N=127 | Terminated | Sponsor: 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.

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • SF3B1

Roivant’s risky Hemavant bet to wind down after discontinuing ex-Eisai drug (FierceBiotech) - "Roivant’s Hemavant has discontinued development of its only asset, a former Eisai drug dubbed RVT-2001 that was being studied in a midstage trial for patients with myelodysplastic syndromes (MDS)."

Discontinued • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

Splicing modulators impair DNA damage response and induce killing of cohesin-mutant MDS and AML. (PubMed, Sci Transl Med) - "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."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • BRCA1 • BRCA2 • SF3B1

m6A-modified circTET2 interacting with HNRNPC regulates fatty acid oxidation to promote the proliferation of chronic lymphocytic leukemia (IWCLL 2023) - "The identification of circTET2 was performed using northern blotting, RNase R treatment, actinomycin D assay, nucleocytoplasmic separation and RNA-FISH...Furthermore, We applied five inhibitors: indisulam (targeting splicing by inducing RBM39 degradation), H3B-8800 (a modulator of the SF3b complex), and the three pre-mRNA splicing inhibitors isoginkgetin, madrasin, and CP028...The mTOR inhibitor dactolisib and FAO inhibitor perhexiline exert a synergistic effect on CLL cells... In summary, we identified m6A-modified circTET2 as a prognostic marker in CLL. CircTET2 that was upregulated in CLL was modulated by the splicing factors RBMX and YTHDC1, and that circTET2 interacted with HNRNPC, occupying a vital role in the modulation of lipid metabolism and cell proliferation of CLL. The data generated by this study collectively provide new evidence for a role and underlying mechanism for circRNAs in CLL lipid metabolism, and this may engender novel potential targets in..."

Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • HNRNPC • YTHDC1

SF3B1 mutation-mediated sensitization to H3B-8800 splicing inhibitor in chronic lymphocytic leukemia. (PubMed, Life Sci Alliance) - "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."

IO biomarker • Journal • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Transplantation • MAP3K7 • SF3B1

Posttranslational splicing modifications as a key mechanism in cytarabine resistance in acute myeloid leukemia. (PubMed, Leukemia) - "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."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Splicing Modulators Impair DNA Damage Response and Induce Killing of Cohesin-Mutant MDS/AML (ASH 2022) - P1 | "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."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • BRCA1 • BRCA2 • SF3B1 • STAG2

A Study of H3B-8800 (RVT-2001) in Participants With Myelodysplastic Syndromes, Acute Myeloid Leukemia, and Chronic Myelomonocytic Leukemia (clinicaltrials.gov) - P1 | N=200 | Recruiting | Sponsor: Hemavant Sciences GmbH | Trial completion date: Nov 2022 ➔ Dec 2024 | Trial primary completion date: Nov 2022 ➔ Sep 2024

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • SF3B1

Roivant Sciences Reports Financial Results for the Quarter Ended December 31, 2021 and Provides Business Update (GlobeNewswire) - "Hemavant...plans to develop RVT-2001 as an oral therapy for transfusion-dependent anemia in patients with lower-risk MDS, with a robust open-label expansion of the ongoing Phase 1/2 clinical trial for RVT-2001 in the first half of calendar year 2022."

Trial status • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

10-Step total synthesis of spliceosome modulator pladienolide B (ACS-Sp 2022) - "Two of its analogues, E7107 and H3B-8800, have entered into clinical trials for the treatment of myeloid malignancies harboring splicing factor mutations. Herein, we report a 10-step total synthesis of pladienolide B, which bears 10 stereogenic centers, employing alcohol-mediated syn- and anti-diastereoselective carbonyl crotylations as key transformations."

Hematological Malignancies • Oncology

The Spliceosome As a New Therapeutic Target in Cytarabine-Resistant Acute Myeloid Leukemia (ASH 2021) - "The combination of H3B-8800, a spliceosome inhibitor, with venetoclax was tested in ex vivo samples from AML patients and healthy donors. enjoys a research grant from the Spanish Society of Hematology and Hemotherapy and R.GV. a FPU grant from the Ministry of Science, Innovation and Universities."

Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • SRSF2 • SRSF9

Investigating the Molecular Mechanism of H3B-8800: A Splicing Modulator Inducing Preferential Lethality in Spliceosome-Mutant Cancers. (PubMed, Int J Mol Sci) - "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."

Journal • Hematological Malignancies • Leukemia • Oncology • SF3B1

Total Syntheses of Pladienolide-Derived Spliceosome Modulators. (PubMed, Molecules) - "The potential of pladienolides as anti-cancer agents is confirmed by H3B-8800, a synthetic analog of this natural product class, which is currently under Phase I clinical trials. Since its isolation in 2004 and the first total synthesis in 2007, a dozen total syntheses and synthetic approaches toward the pladienolide class have been reported to date. This review focuses on the eight completed total syntheses of naturally occurring pladienolides or their synthetic analogs, in addition to a synthetic approach to the main framework of the natural product."

Journal • Review • Oncology

A Study of H3B-8800 in Participants With Myelodysplastic Syndromes, Acute Myeloid Leukemia, and Chronic Myelomonocytic Leukemia (clinicaltrials.gov) - P1; N=200; Recruiting; Sponsor: H3 Biomedicine Inc.; Trial completion date: Apr 2022 ➔ Nov 2022; Trial primary completion date: Apr 2022 ➔ Nov 2022

Clinical • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • SF3B1

PHASE I DOSE ESCALATION CLINICAL TRIAL OF H3B-8800, A SPLICING MODULATOR, IN PATIENTS WITH ADVANCED MYELOID MALIGNANCIES (EHA 2019) - P1; "Dose exploration is ongoing for both schedules. Clinical trial information: NCT02841540."

Clinical • P1 data

Results of a Clinical Trial of H3B-8800, a Splicing Modulator, in Patients with Myelodysplastic Syndromes (MDS), Acute Myeloid Leukemia (AML) or Chronic Myelomonocytic Leukemia (CMML) (ASH 2019) - P1; "Results from this first-in-human multicenter prospective clinical trial of a splicing modulator in myeloid neoplasms demonstrate dose-dependent target engagement and predictable PK profile of H3B-8800, and safety even with prolonged dosing. Although no objective CR or PR were achieved, decreased RBC or platelet transfusion requirements were observed in 12 (14%) of enrolled patients."

Clinical • SRSF2

"Great presentation by Irene Lopez-Oreja at #iwCLL2021 👩‍⚕️🙌 🔸 H3B-8800 delays CLL infiltration 🔸 SF3B1 mutation ➡ alternative splicing in genes involved in diverse biological processes 🔸 MAP3K7 aberrant splicing drives NF-kB hyperactivation and p38 deactivation #CLLsm #LEUsm" (@VJHemOnc)

Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • SF3B1

[VIRTUAL] Effects of SF3B1 K700E mutation in chronic lymphocytic leukemia and the opportunity for targeted therapy with SF3B1-binding splicing modulator H3B-8800 (IWCLL 2021) - No abstract available

Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • SF3B1

[VIRTUAL] Effects of SF3B1 K700E mutation in chronic lymphocytic leukemia and the opportunity for targeted therapy with SF3B1-binding splicing modulator H3B-8800 (IWCLL 2021) - No abstract available

Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • SF3B1

Phase I First-in-Human Dose Escalation Study of the oral SF3B1 modulator H3B-8800 in myeloid neoplasms. (PubMed, Leukemia) - "Elevated pre-treatment expression of aberrant transcripts of Transmembrane Protein 14C (TMEM14C), an SF3B1 splicing target encoding a mitochondrial porphyrin transporter, was observed in MDS patients experiencing RBC TI. In summary, H3B-8800 treatment was associated with mostly low-grade TAEs and induced RBC TI in a biomarker-defined subset of MDS."

Journal • P1 data • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Fatigue • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • SF3B1

[VIRTUAL] STUDY OF THE ROLE OF SR PROTEINS IN CYTARABINE TREATMENT RESISTANCE IN ACUTE MYELOID LEUKEMIA (EHA 2021) - "Certainly, the study of phospho-SR proteins at diagnosis could serve as a possible predictive biomarker of cytarabine response. The combination of cytarabine plus spliceosome inhibitors as H3B-8800, a small molecule that binds to the SF3b spliceosome complex, could improve the response in AML patients."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • SRSF2 • SRSF9

Current and emerging strategies for management of myelodysplastic syndromes. (PubMed, Blood Rev) - "Several promising drugs are in the horizon, including the hypoxia-inducible factor stabilizer roxadustat, telomerase inhibitor imetelstat, oral hypomethylating agents (CC-486), TP53 modulators (APR-246 and ALRN-6924), and the anti-CD47 antibody magrolimab. Targeted therapies approved for acute myeloid leukemia treatment, such as isocitrate dehdyrogenase inhibitors and venetoclax, are also being studied for use in MDS. In this review, we provide a brief overview of pathogenesis and current treatment strategies in MDS followed by a discussion of newer agents that are under clinical investigation."

Journal • Review • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • TP53