April 4, 2017

Cambridge, MA — H3 Biomedicine Inc., a clinical stage biopharmaceutical company specializing in the discovery and development of precision medicines for oncology and a member of Eisai’s global Oncology Business Group, announced today that company scientists will give four presentations at the 2017 American Association of Cancer Research (AACR) Annual Meeting in Washington, D.C. The posters will describe details of the company’s RNA splicing platform that explores approaches to modulate RNA splicing in cancer cells as a novel approach to cancer therapy.

“Recent research, including work from H3 Biomedicine, indicates that dysregulated RNA splicing and metabolism is a hallmark of cancer. This is exemplified by the identification of spliceosome mutations in a range of hematological malignancies and solid tumors.” said Markus Warmuth, M.D., President and CEO of H3 Biomedicine. “H3’s presentations at AACR from our splicing platform demonstrate our leading position in understanding and drugging RNA splicing defects in cancer.”

The titles and details of H3’s poster presentations include:

H3B-8800, a novel orally available SF3b modulator, shows preclinical activity across spliceosome mutant cancers.
H3B-8800 is a novel orally bioavailable small molecule SF3B1 modulator that demonstrates preferential lethality in spliceosome mutant cells. H3B-8800 potently binds to SF3b complexes containing either wildtype (WT) or mutant SF3B1 protein and modulates splicing in in vitro biochemical splicing assays and cellular pharmacodynamic assays. Oral dosing of H3B-8800 leads to selective antileukemic activity in spliceosome mutant xenograft models grown in mice. Furthermore, work in collaboration with researchers at Memorial Sloan Kettering Cancer Center shows H3B-8800 has potent activity in patient-derived xenograft models of chronic myelomonocytic leukemia (CMML) bearing SRSF2 mutations. Mechanism of action studies have revealed selective intron retention in genes encoding spliceosome components underlies the selective lethality of H3B-8800. H3B-8800 is currently undergoing clinical evaluation in patients with myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and CMML.

Survey of spliceosome gene mutations and associated splicing defects across 33 cancer types
Hotspot mutations in the core spliceosome genes SF3B1, U2AF1, SRSF2 have been reported at high frequency in hematological malignancies and with lower occurrence in solid tumors. Here, through analysis of TCGA Exome-seq and RNAseq data from 33 tumor types, we define the landscape of spliceosome mutations and associated splicing defects in human cancers. The range of hotspot and loss-of-function mutations in multiple spliceosome genes and associated splicing alterations indicate that aberrations in RNA splicing are a hallmark of cancer.

Novel SF3B1 deletion mutations result in aberrant RNA splicing in CLL patients.
Recurrent heterozygous mutations in SF3B1, a component of the U2snRNP complex involved in branch site recognition during the first step of splicing catalysis, are found in various malignancies including myelodysplastic syndromes (MDS) and chronic lymphocytic leukemia (CLL). To provide broader insight into the effects of SF3B1 mutations on RNA splicing in CLL, RNAseq analysis was performed on 215 CLL patient samples in collaboration with researchers at Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute. This work identified novel in-frame deletions in SF3B1 around K700 that result in aberrant RNA splicing in patients with CLL. The common mechanism of action of SF3B1 mutations and deletions suggest that they should also be sensitive to splicing modulators.

A chemogenomic approach reveals the action of splicing modulators at the branch point adenosine binding pocket defined by the PHF5A/SF3b complex.
The identification of compounds with RNA splicing-modulating activity represents a promising therapeutic approach for the treatment of cancers with dysregulated RNA splicing. Natural products such as pladienolide, herboxidiene and spliceostatin have been identified as potent splicing modulators that bind SF3B1, a member of the SF3b subcomplex that assembles into the U2 snRNP. Using integrated chemogenomic, structural and biochemical approaches, we show that PHF5A, another core component of the SF3b complex, is also targeted by these inhibitors. These findings are allowing iterative design of new compounds to target driver RNA splicing events in cancer cells.

“H3B-8800, as the lead program from our splicing platform, is currently in clinical development as a potential treatment option for patients with spliceosome mutations.” said Pete Smith, Ph.D., Chief Scientific Officer of H3 Biomedicine. “The splicing platform at H3 Biomedicine continues to build an understanding of the importance of RNA splicing defects in cancer and we look forward to progressing our drug discovery pipeline to deliver the next set of splicing modulators.”

About H3B-8800

(Spliceosome Modulator)
H3B-8800 is an oral, potent and selective small molecule modulator of splicing factor 3b subunit 1 (SF3B1) that is being developed by H3 Biomedicine as an anticancer therapeutic agent. In pre-clinical studies, H3B-8800 showed dose dependent modulation of canonical and aberrant splicing when dosed orally at tolerated doses. Oral administration of H3B-8800 also demonstrated preferential antitumor activity in several pre-clinical xenograft models carrying spliceosome mutations. H3 Biomedicine’s lead research and discovery programs in splicing are designed to develop drugs that target the vulnerabilities related to deregulated RNA homeostasis in cancer.

About H3 Biomedicine Splicing Platform

H3 Biomedicine has built a drug discovery platform that identifies small molecules and Splice Modulator Loaded Antibodies (SMLAs) capable of modulating RNA splicing for the potential treatment of cancer. An integrated research program starts with large scale analytics of cancer patient data to discover driver RNA splicing alterations in defined populations. Our target modulation approach uses structural, biochemical and cell-based methodologies to identify the appropriate modulation strategy to drug driver RNA splicing events. Translational research, diagnostics and preclinical development engines rapidly transform proof-of-concept compounds into investigational new agents for clinical development.

About H3 Biomedicine Inc.

H3 Biomedicine is a Cambridge, Massachusetts-based biopharmaceutical company specializing in the discovery and development of precision oncology treatments, which was established as a subsidiary of Eisai’s U.S. pharmaceutical operation Eisai Inc. Leveraging this collaboration with Eisai Co., Ltd., who through this partnership provides essential research funding and access to the capabilities and resources of this global pharmaceutical company, H3 Biomedicine combines long-term vision with operational independence. Using modern synthetic chemistry, chemical biology, and human genetics, H3 Biomedicine seeks to bring the next generation of cancer treatments to market with the goal of improving the lives of patients. For more information, please visit www.h3biomedicine.com.

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