On March 10, 2023 Sermonix Pharmaceuticals Inc., a privately held biopharmaceutical company developing innovative therapeutics to specifically treat metastatic breast and gynecological cancers harboring ESR1 mutations, and Guardant Health, Inc. (Nasdaq: GH), a leading precision oncology company, reported the initiation of a registrational Phase 3 clinical study comparing targeted lasofoxifene in combination with the CDK 4/6 inhibitor abemaciclib versus fulvestrant plus abemaciclib in pre- and post-menopausal subjects with locally advanced or metastatic ER+/HER2- breast cancer with an ESR1 mutation (Press release, Guardant Health, MAR 10, 2023, View Source;and-Post-Menopausal-Patients-with-Locally-Advanced-or-Metastatic-ERHER2–Breast-Cancer-with-an-ESR1-Mutation-as-Detected-by-Guardant-Heal/default.aspx [SID1234628418]).

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This global randomized study will enroll 400 subjects (pre- and post-menopausal women or men) with locally advanced or metastatic ER+/HER2- breast cancer with an ESR1 mutation, who have progressed on palbociclib or ribociclib plus an aromatase inhibitor (AI) and up to one line of chemotherapy. Subjects will be randomized 1:1 to receive either lasofoxifene or fulvestrant, and both groups will also receive 150 mg of abemaciclib twice daily. Study subjects will be prospectively screened for an ESR1 mutation using the Guardant360 CDx liquid biopsy, a next generation sequencing (NGS)-based test that detects genomic alterations using circulating tumor DNA from blood. Eli Lilly and Company – which provided abemaciclib (Verzenio) for the ELAINE-2 study – has entered into a new clinical trial collaboration and drug supply agreement with Sermonix and will provide abemaciclib for the ELAINE-3 study.

"The totality of data we have compiled on lasofoxifene to date, including from our completed ELAINE-1 and ELAINE-2 Phase 2 studies, show compelling anti-tumor activity against tumors with increasingly prevalent ESR1 mutations," said Dr. Paul Plourde, vice president for clinical oncology development at Sermonix. "We look forward to further studying lasofoxifene in a large, rigorously designed Phase 3 study, which will include the use of the Guardant360 CDx test to identify patients who have an ESR1 mutation upon progression after first line therapy."

The primary efficacy endpoint is progression-free survival (PFS). Key secondary endpoints include overall response rate (ORR) and overall survival (OS). Additional secondary endpoints to be assessed include clinical benefit rate (CBR), duration of response (DoR), time to disease recurrence (TTR), time to chemotherapy, quality of life, patient reported outcomes on vaginal and sexual health, and safety. Sermonix anticipates dosing the first subject in the first half of 2023.

"The initiation of this Phase 3 combination study is a significant step forward for Sermonix, as we work to develop a novel targeted endocrine treatment option for metastatic breast cancer patients who are post-CDK4/6i with an ESR1 mutation and have limited treatment options that can provide meaningful clinical response," said Dr. David Portman, Sermonix founder and chief executive officer. "We believe the inclusion of the Guardant360 CDx liquid biopsy to accurately identify eligible trial participants will enable us to execute this important study as efficiently as possible. We look forward to dosing the first patients very soon in this area of great unmet medical need."

The Guardant360 CDx test is the first U.S. Food & Drug Administration-approved blood test for comprehensive genomic profiling for all solid tumors. It provides doctors with guideline-complete genomic results in seven days from a simple blood draw to inform treatment decisions.

"We are very pleased to partner with Sermonix on the continued development of lasofoxifene, a promising investigational treatment for select metastatic breast cancer patients who are increasingly resistant to existing endocrine therapies," said Helmy Eltoukhy, co-CEO of Guardant Health. "The Guardant360 CDx test has played a key role in the pivotal trials of several recent precision cancer therapies, and we are excited to partner with Sermonix and support its efforts to address this important and underserved patient population."

About Lasofoxifene
Lasofoxifene is an investigational novel endocrine therapy in clinical development which has demonstrated robust target engagement as an ESR1 antagonist in the breast particularly in the presence of ESR1 mutations. Lasofoxifene has demonstrated anti-tumor activity as monotherapy and in combination with abemaciclib in Phase 2 studies and has unique tissue selectivity distinguishing it from other current and investigational endocrine therapies with beneficial effects seen on vagina and bone in previous clinical studies. Lasofoxifene, which Sermonix licensed globally from Ligand Pharmaceuticals Inc. (NASDAQ:LGND), has been studied in previous comprehensive Phase 1-3 non-oncology clinical trials in more than 15,000 postmenopausal women worldwide. Lasofoxifene’s bioavailability and activity in mutations of the estrogen receptor could potentially hold promise for patients who have acquired endocrine resistance due to ESR1 mutations, a common finding in the metastatic setting and an area of high unmet medical need. Lasofoxifene’s novel activity in ESR1 mutations was discovered at Duke University and Sermonix has exclusive rights to develop and commercialize the product in this area. Lasofoxifene, a novel targeted and tissue-selective oral endocrine therapy with additional potential benefits on bone, lipid and vaginal health, could, if approved, play a critical role in the precision medicine treatment of advanced ER+ breast cancer.

About Sermonix
Sermonix Pharmaceuticals Inc. is a privately held biopharmaceutical company focused on the development of female-specific and patient-centric oncology products and has currently completed two Phase 2 clinical studies of lasofoxifene, its lead investigational drug. The Sermonix management team, led by founder Dr. David Portman, has significant experience in all stages of the drug development, regulatory and commercialization processes. Paul Plourde, M.D., vice president of oncology clinical development, has many decades of experience at AstraZeneca in the breast cancer drug development arena. Barry Komm, Ph.D., chief scientific officer, is recognized for his expertise in nuclear receptor biology. Miriam Portman, M.D., is co-founder and chief operating officer, with expertise in clinical trial conduct and patient recruitment. Elizabeth Attias, M.M.Sc., Sc.D., chief strategy and development officer, has extensive experience in pharmaceutical drug commercialization. Simon Jenkins, Ph.D., vice president of operations, has over 30 years of experience in global drug development leadership. Sermonix non-executive chairman of the board is Anthony Wild, Ph.D., former president of both Parke-Davis Pharmaceuticals and Warner-Lambert’s Pharmaceutical Division. Learn more at SermonixPharma.com.