Fablyn (lasofoxifene)

P2, N=100, Active, not recruiting, Sermonix Pharmaceuticals Inc. | Trial completion date: Feb 2024 --> Dec 2024 | Trial primary completion date: Feb 2024 --> Dec 2024

P2, N=29, Active, not recruiting, Sermonix Pharmaceuticals Inc. | Trial completion date: Jan 2024 --> May 2024 | Trial primary completion date: Jan 2024 --> May 2024

P1/2, N=35, Not yet recruiting, Azure Biotech Inc.

P3, N=400, Recruiting, Sermonix Pharmaceuticals Inc.

No abstract available

Lasofoxifene plus abemaciclib had an acceptable safety profile, was well tolerated, and exhibited meaningful antitumor activity in women with ESR1-mutated, ER+/HER2- mBC after disease progression on prior CDK4/6i. Observed decreases in ESR1-mutant ctDNA with lasofoxifene concordant with clinical response suggest target engagement. If the ELAINE 2 findings are confirmed in the initiated, phase III, ELAINE 3 trial, these data could be practice-changing and help address a critical unmet need.

Lasofoxifene demonstrated encouraging antitumor activity versus fulvestrant and was well tolerated in patients with ESR1-mutated, endocrine-resistant mBC following progression on AI plus CDK4/6i. Consistent with target engagement, lasofoxifene reduced ESR1 MAF, and to a greater extent than fulvestrant. Lasofoxifene may be a promising targeted treatment for patients with ESR1-mutated mBC and warrants further investigation.

P2, N=29, Active, not recruiting, Sermonix Pharmaceuticals Inc. | Trial completion date: Feb 2023 --> Jan 2024 | Trial primary completion date: Feb 2023 --> Jan 2024

P3, N=400, Recruiting, Sermonix Pharmaceuticals Inc. | Not yet recruiting --> Recruiting

Of the 29 patients (median age 60 yrs) enrolled, mutations in ESR1 were identified in 26 by Guardant360; all these 26 patients had received prior CDK4/6i, 21 (81%) prior fulvestrant, and 12 (46%) prior chemotherapy for mBC. Using Guardant360 ctDNA profiling from patients in ELAINE 2, we demonstrate that other baseline genomic alterations are frequently detected concurrently with mESR1 in the endocrine resistant setting, but without apparent compromise on the efficacy of LAS plus Abema. These results should be interpreted with caution considering the small numbers of patients and the exploratory nature of the analysis. The ELAINE 2 study suggests the potential of LAS plus Abema for treating ESR1-mutated, ER+/HER2- mBC in the post-CDK4/6i setting.

Key inclusion criteria are pre- and postmenopausal women and men aged ≥18 years; ER+/HER2-, locally advanced and/or metastatic BC (measurable and/or non-measurable disease); ≥1 acquired ESR1 mutation; progression on an aromatase inhibitor plus palbociclib or ribociclib as their first hormonal treatment for advanced/metastatic BC; and ≤1 line of chemotherapy in the advanced/metastatic setting...Expected PFS is ≥10.3 months for lasofoxifene/abemaciclib and 7 months for fulvestrant/abemaciclib (PFS hazard ratio of 0.68 at final analysis). The target sample size is 400, to achieve 90% power with a one-sided type I error rate of 0.025 after 285 PFS events. Full recruitment is expected to occur over 18 months at 125 global sites.

P3, N=400, Not yet recruiting, Sermonix Pharmaceuticals Inc. | Initiation date: Mar 2023 --> Aug 2023

The TIME Trial network opened earlier and enrolled the first study patients. These results demonstrate that the Just-in-TIME model, along with a Traditional model, can improve enrollment in biomarker-driven studies.

With longer ELAINE 2 follow up, LAS/Abema continues to be well tolerated with clinically meaningful efficacy in women with mESR1, ER+/HER2- mBC that had progressed on ET and CDK4/6is. Decreases in mESR1 ctDNA suggest effective target engagement of LAS. The PFS (median ~13 mos) and ORR (56%) with LAS/Abema are promising and a confirmatory phase 3 study (ELAINE 3) will begin in 2023.

P2, N=100, Active, not recruiting, Sermonix Pharmaceuticals Inc. | Trial completion date: Feb 2023 --> Feb 2024 | Trial primary completion date: Feb 2023 --> Feb 2024

Subjects will be followed yearly for 10 years post-surgery for recurrence free survival and overall survival. Initial results are expected 2024. Conclusion(s): This trial will assess the potential feasibility of lasofoxifene as NET among women with HR+, HER2-, locally advanced breast cancer.

"Sermonix Pharmaceuticals is starting a Phase III trial of endocrine therapy lasofoxifene for patients with locally advanced or metastatic ER+/HER2-breast cancer with an estrogen receptor 1 (ESR1) mutation, the company said on Thursday. Sermonix has partnered with Guardant Health for the trial and will use the Guardant360 CDx liquid biopsy assay, a blood-based sequencing test that detects mutations from circulating tumor DNA, to determine eligibility by screening patients for ESR1 variants. The trial, dubbed the ELAINE-3 study, will compare lasofoxifene against fulvestrant, an estrogen receptor antagonist, both in combination with Eli Lilly's CDK4/6 inhibitor Verzenio (abemaciclib)....Sermonix expects to dose the first patient for the trial in the first half of this year and plans to enroll 400 patients in total."

P3, N=400, Not yet recruiting, Sermonix Pharmaceuticals Inc.

To improve our understanding of these ERα structure-transcriptional relationships, we develop a series of chemically unconventional antagonists based on the antiestrogens elacestrant and lasofoxifene...Interestingly, they favor a 4-hydroxytamoxifen-like accumulation of ERα in breast cancer cells but lack uterotrophic activities in an endometrial cell line. Importantly, RNA sequencing shows that the lead molecules engage transcriptional pathways similar to the selective estrogen receptor degrader fulvestrant. This advance shows that fulvestrant-like genomic activities can be achieved without affecting ERα accumulation in breast cancer cells.

P2, N=29, Active, not recruiting, Sermonix Pharmaceuticals Inc. | Trial completion date: Nov 2022 --> Feb 2023 | Trial primary completion date: Nov 2022 --> Feb 2023

P2, N=100, Active, not recruiting, Sermonix Pharmaceuticals Inc. | Trial completion date: Feb 2022 --> Feb 2023 | Trial primary completion date: Feb 2022 --> Feb 2023

Our data demonstrate that LAS more effectively decreased or cleared mutESR1 than Fulv. Further, mutESR1 clearance was associated with prolonged PFS and more CB in LAS but not Fulv pts, suggesting that LAS results in robust mutESR1 target engagement. Taken together, our data suggest mutESR1 as a potential liquid biomarker for predicting response to LAS in mutESR1, endocrine-resistant mBC pts.

29 patients (median of 2 prior metastatic therapies: 97% CDK4/6i, 79% fulvestrant, 48% chemotherapy) had BL mutESR1 of Y537S (66%), D538G (45%), Y537N (28%), and other less frequently detected mutations; 14 (48.3%) patients were polyclonal. In ELAINE 2, 81% of patients had decrease/cleared (ND) mutESR1 after 4 wks of LAS plus Abema, which correlated with clinical benefit. All mutESR1 detected appear targeted with this therapy. High sensitivity and favorable PPV were observed in patients with decreased MAF, and even more so in those with ND MAF; however, increased MAF was less specific and not as predictive of treatment failure.

The L391F mutation resulted in an increased binding affinity for Lasofoxifene (LAS) (dAff -0.34), Giredestrant (GIR) (dAff -0.18), Elacestrant (ELA) (dAff -0.08) and Amcenestrant (AMC) (dAff -0.41), while a decreased binding affinity was observed for 4OH-Tamoxifen (TAM) (dAff 0.01), Imlunestrant (IML) (dAff 0.15), Fulvestrant (FUL) (dAff 0.43), and Camizestrant (CAM) (dAff 0.02). The study suggests that genomic variability in drug targets detectable through ctDNA may modulate therapeutic response. Preclinical models are under development to investigate the combined endocrine resistance mechanism suggested by the significant co- occurrence between ESR1 mutations in SERDs/SERMs docking sites and ESR1 hotspot mutations and provide valuable additional insights for drug development and future treatment algorithms.

Together these results show that chemical reduction of ERα cellular lifetime is not necessarily the most crucial parameter for transcriptional antagonism in ESR1 mutated breast cancer cells. Importantly, our studies show how small chemical differences within a scaffold series can provide compounds with similar antagonistic activities, but with greatly different effects of the cellular lifetime of the ERα, which is crucial for achieving desired SERM or SERD profiles.

P2, N=29, Active, not recruiting, Sermonix Pharmaceuticals Inc. | Trial primary completion date: May 2022 --> Nov 2022

LAS, a third-generation selective estrogen receptor modulator, as monotherapy or combined with a CDK4/6i, was shown to have superior efficacy over fulvestrant (FVT) in preclinical breast cancer models expressing ESR1 mutations. LAS combined with Abema in the ELAINE 2 trial was well tolerated and demonstrated robust and meaningful efficacy in women with ER+/HER2- mBC and an ESR1 mutation who had progressed on previous CDK4/6i therapies.

P2, N=100, Active, not recruiting, Sermonix Pharmaceuticals Inc. | Recruiting --> Active, not recruiting

Tamoxifen is approved for treatment and prevention of breast cancer; acts as an endometrial estrogen agonist. Raloxifene is approved for prevention and treatment of osteoporosis and prevention of breast cancer...Ospemifene is approved to treat dyspareunia. Lasofoxifene is in development for resistant ER positive breast cancer. Estetrol (E4), synthesized by human fetal liver, has dual weak-estrogenic/antiestrogenic features, now approved as a contraceptive.

P2, N=29, Active, not recruiting, Sermonix Pharmaceuticals Inc. | Recruiting --> Active, not recruiting

We report for the first time the anti-tumor activity of lasofoxifene in mouse models of endocrine therapy-resistant breast cancer. The results demonstrate the potential of using lasofoxifene as an effective therapy for women with advanced or metastatic ER+ breast cancers expressing the most common constitutively active ERα mutations.

P2, N=100, Recruiting, Sermonix Pharmaceuticals Inc. | Trial completion date: Sep 2020 --> Feb 2022 | Trial primary completion date: Jul 2020 --> Feb 2022

P2, N=24, Recruiting, Sermonix Pharmaceuticals Inc. | Not yet recruiting --> Recruiting | Initiation date: Jul 2020 --> Sep 2020

Moreover, a significant benefit was seen in pre-clinical models with lasofoxifene either as monotherapy or in combination with a CDK4/6i over fulvestrant (with or without a CDK4/6i) in breast cancer cells expressing ESR1 mutations...Also, studies have shown that abemaciclib has meaningful clinical activity in patients previously exposed to other CDK4/6i (palbociclib/ribociclib) and chemotherapy...Ten centers in the US will be participating. Recruitment status will be provided at the time of presentation.

P2, N=24, Not yet recruiting, Sermonix Pharmaceuticals Inc.

Specifically, dysregulated pharmacology was only evident in cells in which the mutants were overexpressed relative to ligand-activated ERWT; a finding that highlights the role of allelism in determining ER mutant pharmacology. Importantly, we demonstrated that the antagonist activity of the SERM, lasofoxifene, was not impacted by mutant status; a finding that has led to its clinical evaluation as a treatment for patients with advanced ER-positive breast cancer whose tumors harbor ESR1 mutations.

Agents targeting the ER pathway including aromatase inhibitors (AIs), fulvestrant and tamoxifen along with CDK 4/6 inhibitors are considered standard for first and 2nd line treatment. It is assumed that lasofoxifene will double the median PFS compared to fulvestrant in this ESR1 mutation patient population for a hazard ratio 0.5 and a power of 89% to reach a 1-sided p of <0.05.The study will commence in 4Q2018 and will complete recruitment in 1 year. It is anticipated that 25-30 centers in the US will be participating.