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H3 Biomedicine Preclinical Proof-of-Concept Data on First-in-Class Spliceosome-Modulator Therapy for Genomically Identified Patients with Hematological Cancers Published in Nature Medicine

H3B-8800 is first known investigational therapy to target RNA splicing factor mutations, highly prevalent in many hematologic cancers

Initial data on H3B-8800 expected in 2018 from ongoing Phase 1 clinical trial

Cambridge, Mass., February 20, 2018 - H3 Biomedicine Inc., a clinical stage biopharmaceutical company specializing in the discovery and development of next generation cancer therapies using its data molecular science and precision chemistry product engine, today announced publication of the discovery and preclinical characterization of H3B-8800, its oral, first-in-class modulator of the SF3b spliceosome complex. The publication highlights the significant anti-tumor activity of H3B-8800 in several in vivo models, including patient-derived xenografts (PDX) of hematological malignancies with recurrent mutations in RNA splicing factor genes that comprise the spliceosome. The H3B-8800 data generated by H3 Biomedicine scientists and collaborators appear in the most recent issue of Nature Medicine and can be accessed online at (Seiler M. et al, "H3B-8800, a novel oral splicing modulator, induces lethality in spliceosome-mutant cancers").

RNA splicing is the biological process by which pre-cursor messenger RNA (pre-mRNA) is edited into a mature mRNA. Splicing factors are proteins that carry out the editing process which is catalyzed by the core spliceosome complex. Mutations in genes encoding for certain of these RNA splicing factors that form the spliceosome are among the most common mutations found in patients with Acute Myeloid Leukemia (AML), Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML) and Chronic Lymphocytic Leukemia (CLL), and occur in subsets of patients with solid tumors.

Despite the high prevalence of these mutations in cancer, no known spliceosome mutation-targeting cancer therapies are approved currently. Based on these promising preclinical data, H3 Biomedicine is a leader in this emerging area of drug discovery, and is currently evaluating H3B-8800 in a Phase 1 clinical trial for patients with AML, MDS and CMML identified by certain splicing factor mutations, and expects to present initial clinical data from this ongoing study in 2018. In 2017, H3B-8800 was granted orphan drug designation for AML and CMML.

"The significant anti-tumor activity shown in this publication demonstrates preclinical proof-of-concept of H3B-8800 in several hematological cancers of high unmet medical need," said Peter Smith, Ph.D., Chief Scientific Officer of H3 Biomedicine, Inc. "No therapies currently exist to affect mutations in the spliceosome in cancers, and H3B-8800 is the first known investigational therapy to modulate and target cancer cells with mutated genes in this complex. The discovery of H3B-8800 highlights the power of the H3 Biomedicine product engine to create highly differentiated investigational therapies to address molecular traits driving cancers in subsets of patients."

The Nature Medicine publication outlines the discovery process led by H3 Biomedicine scientists to create and characterize a highly potent and selective, oral, first-in-class modulator of the SF3b complex to target cancer cells with mutations in RNA splicing factor genes. Data highlights of the publication include:

  • Dose-dependent anti-leukemic efficacy and splicing modulation of H3B-8800 in a cell line xenograft model of SF3B1-mutant leukemia and significant anti-tumor activity in an SF3B1-mutant AML PDX model;
  • Anti-leukemic efficacy of H3B-8800 in mice with SRSF2-mutant CMML in which ten-day treatment with H3B-8800 substantially reduced leukemic burden in peripheral blood, spleen and liver;
  • Differential anti-tumor efficacy in in vitro and in vivo models with mutant genes in the spliceosome compared to wild-type or normal genes in the complex; and
  • In mechanism of action studies, H3B-8800 was shown to exploit a synthetic lethality imposed by aberrant splicing leading to differential cell killing in tumor cells harboring spliceosome mutations whereas normal cells were substantially less affected. This phenomenon is not shared by other small molecule spliceosome modulators.

H3B-8800 is one of three investigational therapies of H3 Biomedicine in clinical trials. The two additional investigational therapies include:

  • H3B-6545, an oral, first-in-class ESR1 covalent antagonist targeting wild-type and mutant estrogen receptor in endocrine-therapy resistant metastatic breast cancer patients; and
  • H3B-6527, an oral, potent and highly selective small molecule covalent inhibitor of FGFR4 for treatment of hepatocellular carcinoma (HCC) patients with overexpression of FGF19.

Portions of the work described in the Nature Medicine publication were originally presented at the 2016 American Society of Hematology (ASH) Meeting by lead author Silvia Buonamici, Ph. D., Executive Director, Target Biology and Translational Research, H3 Biomedicine.

About H3B-8800

H3B-8800 is a potent, selective, and orally bioavailable small molecule modulator of wild-type and mutant SF3b complex, a key component of the spliceosome. Recurrent heterozygous mutations in several core members (SF3B1, U2AF1, SRSF2, ZRSR2) of the spliceosome have been identified in both hematological malignancies, including myelodysplastic syndrome, acute myelogenous leukemia and chronic lymphocytic leukemia, as well as solid tumors such as skin, lung, breast and pancreatic cancers. Preclinical data indicates that H3B-8800 modulates RNA splicing and shows preferential antitumor activity in a range of spliceosome mutant cancer models. H3 is conducting initial clinical development in patients with hematological malignancies (including MDS, AML, and CMML) that may carry mutations in the core spliceosome genes to assess the safety and preliminary efficacy of H3B-8800.

About H3 Biomedicine

H3 Biomedicine is a Cambridge, Massachusetts-based biopharmaceutical company combining long-term vision with operational excellence and specializing in the discovery and development of precision oncology treatments. Using modern synthetic chemistry, chemical biology, and human genetics, the company seeks to bring the next generation of cancer treatments to market with the goal of improving the lives of patients. H3 was established as a subsidiary of Eisai's U.S. pharmaceutical operation, Eisai Inc. which provided essential research funding and access to global pharmaceutical capabilities and resources. For more information, please visit

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