In 2014 David Portman, MD, a leading clinical researcher and expert in women’s health, sexual medicine and menopause, and selective estrogen receptor modulators (SERM) founded Sermonix Pharmaceuticals, is a privately held biotechnology company focused on the development and commercialization of female-specific oncology products.

With a precision medicine focus for bringing targeted oncology products through development, approval, and commercialization, the team at Sermonix is hard at work in developing oral lasofoxifene, a potent, nonsteroidal bioavailable third-generation selective estrogen receptor modulator (SERM; also known as an estrogen agonist/antagonist) with high affinity for the estrogen receptor 1 (ESR1) receptor.

In an edition of The Onco’Zine Brief, recorded during the 42nd San Antonio Breast Cancer Symposium (SABCS), held December 10 – 14, 2019 in San Antonio, Texas, Peter Hofland talks with leading breast cancer experts, and patients about metastatic breast cancer and health-related quality of life hrQoL issues including sexual intimacy, bone health, and joint pain. In this roundtable, panelists will also discuss liquid biomarkers for disease progression in the metastatic setting. Click on the link to listen to the program.

Based on results from previous clinical trials, lasofoxifene has a differentiated safety profile that could prove useful in the treatment of postmenopausal women and premenopausal women on ovarian suppression with locally advanced or metastatic estrogen receptor-positive (ER+) breast cancer. Studies have also suggested potential benefits to breast, bone, and vaginal tissue.

Sermonix is currently focused on the study of lasofoxifene for advanced or metastatic breast cancer treatment, particularly in patients with locally advanced or metastatic estrogen receptor-positive (ER+)/human epidermal growth factor 2-negative (HER2-) breast cancer who have developed an ESR1 mutation.

New activity in ESR1 mutations was discovered in the laboratory of Donald McDonnell, MD, at Duke University, and Sermonix has exclusive rights to develop and, if FDA-approved, commercialize lasofoxifene in this important area of unmet medical need.

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In a new interview series ‘Onco’Zine Insights‘, we spoke with David Portman,M.D., founder and chief executive officer of Sermonix Pharmaceuticals.

Onco’Zine (O): What makes Sermonix different – While other companies and drug developers are also developing oncology products for the treatment of metastatic breast cancer how is the company, emphasizing the development of female oncology products in the precision medicine’ different?  Why is this important?©

Photo: David Portman, M.D., Chief Executive Officer, and Chief Medical Officer of Sermonix Pharmaceuticals, is a principal investigator for the phase II and III lasofoxifene trials and a consultant during drug development. Photo Courtesy: © 2020 Sermonix Pharmaceuticals. Used with permission.

David Portman (DP): Sermonix’s development program is different in that it is specifically focused on ESR1 mutations, whereas other trials in the endocrine arena focus on “all comers” – with or without an ESR1 mutation. As part of the ELAINE 1 and 2 trials in the precision medicine arena, potential patients are screened with a state of the art, liquid biopsy blood test to identify ESR1 mutations.  This assay is highly sensitive and specific.

As a company whose leaders and management team have decades of experience in women’s healthcare, we not only have our lens on the tumors but also on the woman with breast cancer and her quality of life. They’re not just breast cancer patients, but individuals seeking to live life to its fullest.

Sermonix is developing lasofoxifene with the patient front and center. In addition to studying their progression-free survival, we’re also investigating patient-reported outcomes on quality of life such as urogenital symptoms and other side effects traditionally associated with endocrine therapies. Metastatic breast cancer treatment takes a tremendous toll on a patient’s quality of life. It is thoroughly and deeply impactful on them, and we keep that in mind with everything we do. Unlike SERDs in development, which are focused on demonstrating efficacy and limiting toxicity, our drug lasofoxifene, with potential best-in-class efficacy in ESR1 mutations and benefits the side effects of estrogen deprivation and other breast cancer treatments such as vaginal dryness and bone loss, offers a unique value proposition.

O: What are some of the highlights seen with Sermonix and lasofoxifene? Preclinical trial data/updates? Phase I data?

DP: Lasofoxifene was fast-tracked by the FDA and is currently enrolling in a Phase 2 study we call ELAINE — the Evaluation of Lasofoxifene in ESR1 Mutations. The study compares lasofoxifene to fulvestrant (Faslodex®; AstraZeneca) in progressive breast cancer with an ESR1 mutation. Data from the preclinical, conducted at Duke University and the University of Chicago this year, was published in Molecular Cancer Therapeutics and presented at the annual meeting of the American Association for Cancer Research (AACR), the American Society for Clinical Oncology (ASCO), and the San Antonio Breast Cancer Symposium (SABCS).[1][2][3][4]

Lasofoxifene retains potency and shows significant tumor reduction and prevention of metastases compared to fulvestrant in a mouse intraductal model. And important to the upcoming ELAINE 2 study in collaboration with Lilly and their CDK 4 and 6 inhibitor, abemaciclib (Verzenio®), recently presented preclinical data with lasofoxifene and a CDK 4/6 inhibitor in a similar model demonstrated significant synergism.

O: Why the partnership/collaboration with Lilly?

DP: As noted above, with synergism between these two classes of drugs seen in our preclinical program, along with the use of endocrine therapy and the CDK 4/6 inhibitor class as well-established to provide improvement in disease control above that seen with endocrine therapy alone, makes this an attractive combination study. Given lasofoxifene’s potential best-in-class endocrine therapy against ESR1 mutations, abemaciclib and lasofoxifene is an important combination to study, looking particularly at safety, and with secondary efficacy endpoints.

Both drugs are once-daily oral dosing, making this a convenient open-label trial for patients progressing with ESR1 mutations after multiple lines of endocrine and other therapies. Lilly also has great experience with targeted oncology and SERM therapy, which fits nicely with Sermonix’s focus.

O: What are your expectations for the future?

DP: In addition to our work on ELAINE 1 and 2, we’re planning for larger efficacy studies, the investigation of other combinations, and looking to earlier intervention based on liquid biopsy surveillance for the emergence of ESR1 mutations.

O: Are you involved in the development of other drugs?

DP: Sermonix is focused on getting lasofoxifene approved in monotherapy and potentially with other combinations to improve outcomes in patients with ER+/HER2- breast cancer.

Clinical trials
Evaluation of Lasofoxifene Versus Fulvestrant in Advanced or Metastatic ER+/HER2- Breast Cancer With an ESR1 Mutation – NCT03781063
Evaluation of Lasofoxifene Combined With Abemaciclib in Advanced or Metastatic ER+/HER2- Breast Cancer With an ESR1 Mutation (ELAINEII) – NCT04432454

Highlights of Prescribing information
Abemaciclib (Verzenio®; Eli Lilly and Company) [Print][Online]

[1] Andreano KJ, Baker JG, Park S, et al. The Dysregulated Pharmacology of Clinically Relevant ESR1 Mutants is Normalized by Ligand-activated WT Receptor. Mol Cancer Ther. 2020;19(7):1395-1405. doi:10.1158/1535-7163.MCT-19-1148
[2] Laine M, Greene M, Chang Y-F, Phung L, Hiipakka R, Komm B, Greene GL. Lasofoxifene decreases breast cancer lung and liver metastasis in a mammary intraductal (MIND) xenograft model of mutant ERα+ breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl): Abstract nr PD7-09.
[3] Laine M, Fanning SW, Greene M, Chang Y, Phung L, Tan TT, Hiipakka R, Komm B, Greene GL. Lasofoxifene as a potential treatment for ER+ metastatic breast cancer. Journal of Clinical Oncology 2019, 37: 15_suppl, 1056-1056.
[4] Laine M, Kurleto J. Greene M, Chang Y, Phung L, Tan TT, Hiipakka R, Komm B, Greene GL. Lasofoxifene Alone or in Combination With Palbociclib as an Effective Treatment for Therapy-Resistant ER+ Metastatic Breast Cancer. PO.EN02.01 – Molecular, Preclinical, and Clinical Endocrinology 2 AACR 2020 Abstract ID: 4370/ 13 Date + Time: June 22, 2020. Poster.

Featured image: Images of the San Antonio Breast Cancer Symposium (SABCS) being held at the Henry B. Gonzalez Convention Center in San Antonio, TX. Photo courtesy © 2019 Sunvalley Communication.

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