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H3 Biomedicine Publishes Preclinical Data Describing Mechanistic Insights into Splicing Factor Mutations in Multiple Cancers

Article published in current issue of Cell Reports details that SF3B1 mutations found in cancer use alternate branch point and aberrant 3' splice site selection

Cambridge, MA, October 26, 2015 — H3 Biomedicine Inc., a biopharmaceutical company specializing in the discovery and development of precision medicines for oncology, announced today that data about one of its lead oncology programs targeting SF3B1, found in multiple cancers, has been published in the current issue of Cell Reports. www.cell.com/cell-reports/abstract/S2211-1247(15)01078-5

The (November 3, 2015) publication reports that recurrent hotspot mutations in SF3B1- found in multiple cancers- induce defects in RNA splicing. More specifically, these mutations induce cryptic 3' splice site selection through the use of a different branch point. The report also highlights that approximately 50% of the aberrantly spliced mRNAs undergo nonsense mediated decay, resulting in down regulation of canonical transcripts and protein expression – an effect termed “spliceosome sickness.”

“The mechanistic insights into SF3B1 mutations reported in this paper provide a framework for further dissection of the pathogenic effects of SF3B1 mutations that may lead to the development of novel therapies for some of the hardest-to-treat cancers, including advanced myeloid malignancies and certain solid tumors” said Peter Smith, Ph.D., Vice President of Target Biology at H3 Biomedicine. “Indeed, our drug discovery efforts have led to the identification of a lead investigational SF3B1 modulator that aims to exploit the spliceosome sickness induced by SF3B1 mutations. We are advancing this program toward clinical studies which are projected to begin early next year.”

The Cell Reports article details the robust genomics-driven, and cancer biology focused discovery process led by H3 Biomedicines’ scientists during target validation and therapeutic discovery efforts.

The highlights of the Cell Reports piece include:

1. SF3B1 hotspot mutations are neomorphic and induce aberrant 3' splice site Selection;

2. Mutant SF3B1 utilizes a different branch point than that used by wild-type SF3B1;

3. SF3B1 mutants require the canonical 3' splice site to induce aberrant splicing; and

4. ~50% of aberrant mRNAs undergo NMD leading to down regulation of canonical isoforms.

“The Cell Reports article demonstrates the strength of expertise at H3 Biomedicine in understanding the consequences of somatic mutations in the spliceosome found in multiple cancers,” said Markus Warmuth, M.D., President and CEO of H3 Biomedicine. “Our world-class research team continues to build on this work with a goal to discover the next generation of therapies for the treatment of cancers with defective RNA splicing.”

H3 Biomedicine is scheduled to present further data about this discovery program at the American Society of Hematology meeting, December 4-7, in Orlando, FL. The company is expected to submit an Investigational New Drug (IND) Application in 2016.

About SF3B1

SF3B1 (splicing factor 3B subunit 1) is a component of the splicing machinery. Recent publications have implicated mutations in SF3B1 in both hematological malignancies, including myelodysplastic syndrome, secondary AML and chronic lymphocytic leukemia, as well as solid tumors such as those found in skin, breast and pancreatic cancers.H3 Biomedicine’s lead research and discovery programs in splicing are designed to develop drugs that target the vulnerabilities related to SF3B1’s disease-causing mechanisms.

About H3 Biomedicine Inc.

H3 Biomedicine is a Cambridge, Massachusetts based biopharmaceutical company specializing in the discovery and development of precision oncology treatments. Leveraging an unprecedented collaboration with Eisai, which provides research funding and access to the capabilities and resources of a global pharmaceutical company, H3 Biomedicine combines long-term vision with operational independence. 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. For more information, please visit h3biomedicine.com.

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