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Cancer Discovery Features H3 Biomedicine Paper Highlighting Effects of Selective Estrogen Receptor Covalent Antagonists (SERCAs) in ERα Wild-Type and Mutant Breast Cancer Models

Next-generation endocrine therapy exhibits differentiated mechanism of action versus standard-of-care therapies and potently inhibits the ERα pathway

H3 Biomedicine’s first SERCA development candidate, H3B-6545, is currently in a Phase 1/2 study in patients with ERα-positive breast cancer

Cambridge, Mass., July 10, 2018 – H3 Biomedicine, Inc., a clinical stage biopharmaceutical company specializing in the discovery and development of next-generation cancer medicines using its data science and precision chemistry product engine, announced today the publication of a paper in Cancer Discovery examining the effects of an investigational new class of estrogen receptor (ERα) antagonist, Selective Estrogen Receptor Covalent Antagonists (SERCAs). In the paper, when comparing H3 Biomedicine’s orally available SERCA with standard-of-care (SoC) endocrine therapies in ERα wild-type and mutant breast cancer models, the SERCA exhibited a novel mechanism of action and potent inhibition of the ERα pathway over standard-of-care (SoC) endocrine therapies. SERCAs may represent a critical advance in the treatment ERα-positive breast cancer.

“Our discovery of SERCAs highlights H3 Biomedicine’s ability to interrogate the biology of cancer-driving pathways, uncover fundamentally novel science, and then pair those insights with our chemistry product engine to rapidly progress potential first-in-class medicines,” said Lihua Yu, Ph.D., President and Chief Data Science Officer at H3 Biomedicine. “Despite the remarkable progress made in the treatment of breast cancer, a significant and acute need remains for many patients. We’re pleased to have quickly advanced our lead SERCA candidate, H3B-6545, to clinical development as a critical step toward potentially addressing this need.”

Endocrine therapies, a standard treatment option for ERα-positive breast cancer patients, block the oncogenic ERα function. However, a significant percentage of patients become resistant to endocrine therapy, resulting in cancer growth, metastases and poor outcomes. ERα mutations are detected in up to 30% of patients who initially respond to endocrine therapy but subsequently relapse. Patients who present with or develop endocrine-refractory metastatic disease have a 5-year survival rate of less than 25% and are currently incurable. A significant need exists to develop next-generation endocrine therapies for breast cancer.

In the Cancer Discovery paper, H3 Biomedicine reported that its SERCA irreversibly inactivated ERα by covalently binding a cysteine residue in ERα that is not present in other nuclear hormone receptors. It is believed that binding of SERCA to ERα induced a unique conformation in the receptor, leading to divergent biological activity that is differentiated from classical Selective Estrogen Receptor Modulators (SERMs) and Selective Estrogen Receptor Degraders (SERDs), two classes of SoC endocrine therapies. The manuscript was composed by H3 scientists with Manav Korpal, Ph.D., Associate Director, Target Discovery, serving as lead scientist on the study.

The SERCA showed an improved potency profile over SoC agents, including fulvestrant and tamoxifen. In vitro comparisons of the inhibitor with SoC and experimental agents confirmed potent SERCA activity across a panel of ERα wild-type and ERα mutant cell lines. The SERCA also demonstrated significant single-agent antitumor activity in in vivo, cell line and patient-derived xenograft models representing ERα wild-type and ERα mutant breast cancer. Furthermore, enhanced potency was observed when combining CDK4/6 and mTOR inhibitors with H3 Biomedicine’s SERCA in both ERα wild-type and mutant cell lines and/or tumor models.

“We’re very encouraged by the differentiated MOA exhibited by SERCAs. As we’ve described in this paper, this novel approach irreversibly inactivates the ERα receptor by locking it in the ‘off’ conformation and preventing recruitment of coactivators, which are necessary for pathway activation,” said Peter Smith, Ph.D., Chief Scientific Officer at H3 Biomedicine. “We look forward to seeing how this novel science translates to the clinical setting with the development of H3B-6545, our first-in-class orally available, potent and selective SERCA that is currently in a Phase 1/2 study.”

H3 Biomedicine presented data at the 2017 San Antonio Breast Cancer Symposium, demonstrating that H3B-6545 inhibited the growth of cell line and patient-derived xenograft models of wild-type and mutant ERα with improved activity over SoC therapies.

About H3 Biomedicine Inc.

H3 Biomedicine, a Cambridge, Massachusetts-based biopharmaceutical company specializing in the discovery and development of precision oncology treatments, is a subsidiary of Eisai’s U.S. pharmaceutical operation, Eisai Inc. H3 Biomedicine combines long-term vision with operational excellence, leveraging its collaboration with Eisai Co., Ltd., who provides essential research funding and access to the capabilities and resources of a global pharmaceutical company. Using modern synthetic chemistry, chemical biology and human genetics, H3 Biomedicine seeks to bring the next generation of genomics-based 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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