Z-endoxifen / Atossa Therap - LARVOL DELTA

Atossa Therapeutics…announced the publication of a peer-reviewed preclinical study in npj Breast Cancer evaluating five novel chemical entities structurally related to (Z)-endoxifen (PRNewswire) - "The study...reported anti-estrogenic and anti-cancer activity across multiple estrogen receptor-positive breast cancer models, including models harboring clinically relevant activating mutations in ESR1....In certain experimental settings and models, selected compounds combined with abemaciclib demonstrated additive to synergistic activity that was comparable to or greater than the activity observed with abemaciclib plus (Z)-endoxifen. The compounds also showed activity in models containing activating ESR1 mutations, which are associated with endocrine resistance and recurrent or metastatic estrogen receptor-positive breast cancer."

Preclinical • Estrogen Receptor Positive Breast Cancer

Novel (Z)-endoxifen-related new chemical entities exhibit potent anti-cancer activity in ERα+ breast cancer. (PubMed, NPJ Breast Cancer) - "(Z)-Endoxifen (ENDX), the most abundant active metabolite of tamoxifen, is a potent, orally bioavailable, selective estrogen receptor modulator currently in development for breast health indications. During its synthesis, structurally related compounds are generated as byproducts termed here as new chemical entities (NCEs): AT416E, AT416Z, AT402E, AT402Z, and AT300, which have not been previously studied...Some NCEs also combined favorably with abemaciclib, producing additive to synergistic effects comparable to or greater than ENDX. Together, our findings support further investigation of select NCEs for ERα-positive breast cancer, particularly for tumors with ESR1 activating mutations and as potential second- or third-line options for recurrent disease."

Journal • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor

Effect of (Z)-endoxifen on estrogen receptor signaling inhibition across clinically relevant ESR1 mutations. (ASCO 2026) - "While selective estrogen receptor degraders (SERDs) are under development for ESR1-mutant disease, the activity of (Z)-endoxifen, the active metabolite of tamoxifen, across clinically relevant ESR1 mutations has not been fully characterized... ER transcriptional activity was measured in human ER+ breast cancer cells using clinically relevant concentrations of (Z)-endoxifen (746–20 nM), elacestrant (224–56 nM), and imlunestrant (269–67.25 nM)... At clinically relevant concentrations, (Z)-endoxifen demonstrates robust and consistent inhibition of ER signaling across key ESR1 mutations, including those associated with resistance to current endocrine therapies. These data support (Z)-endoxifen as a promising therapeutic approach in ESR1-mutant ER+ breast cancer and highlight its potential clinical relevance in a patient population with limited treatment options."

Clinical • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER

A phase 2 clinical trial in progress of (Z)-endoxifen plus goserelin as neoadjuvant therapy in premenopausal women with ER+/HER2– breast cancer (EVANGELINE). (ASCO 2026) - P2 | "In premenopausal women, tamoxifen with or without ovarian function suppression (OFS) results in suboptimal Ki-67 suppression compared with aromatase inhibitor + OFS. Secondary objectives include examining safety and tolerability, residual cancer burden, and PEPI score. Correlative analyses include examining effect of treatment on select tumor and plasma biomarkers."

Clinical • P2 data • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PRKCB

Preclinical Data Abstract Demonstrates Robust Estrogen Receptor (ER) Inhibition in ESR1-Mutant Breast Cancer Models at Clinically Relevant Concentrations (PRNewswire) - "(Z)-endoxifen demonstrated robust dose-dependent and statistically significant inhibition of ER signaling across clinically relevant concentrations. In parental MCF-7 breast cancer cells, ER activity was reduced to 16-26% of control (p < 0.001). In ESR1 wild-type models, studied therapies reduced ER signaling to <5% of control (p < 0.001). (Z)-endoxifen maintained consistent ER inhibition across key ESR1 mutations (Y537N, Y537S, D538G) (p < 0.01). Comparator oral Selective Estrogen Receptor Degraders (SERDs), including elacestrant and imlunestrant, showed reduced efficacy in ESR1-mutant settings, particularly in D538G, as compared to (Z)-endoxifen."

Preclinical • Estrogen Receptor Positive Breast Cancer

Atossa Therapeutics Announces ASCO 2026 Abstracts Highlighting (Z)-Endoxifen…Ongoing EVANGELINE Phase 2 Trial (PRNewswire) - "EVANGELINE is evaluating (Z)-endoxifen plus ovarian function suppression (OFS) as a neoadjuvant therapy in premenopausal women with ER+/HER2-negative, cT2-3, cN0-1 breast cancer. The primary objective is to determine the proportion of patients with baseline Ki-67 >10% who achieve Ki-67 of 10% or less after 4 weeks of therapy. A Simon two-stage design is being used to study whether, after four weeks, at least 65% of patients treated achieved a Ki-67 of 10% or less, with 20 patients enrolled in the first stage and, if promising, another 25 patients enrolled in the second stage (cohort A). A parallel cohort of 20 patients with baseline Ki-67 of 10% or less (cohort B) is enrolled to assess objective response rate at 24 weeks per RECIST v1.1."

P2 data • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer

Atossa Therapeutics Announces Publication of KARISMA Endoxifen Trial Demonstrating Significant Reduction in Mammographic Breast Density in Healthy Premenopausal Women (PRNewswire) - "In the KARISMA Endoxifen trial, both the 1 mg and 2 mg Endoxifen dose levels produced statistically significant reductions in MBD compared with placebo. The 1 mg dose reduced MBD by 19.3% versus placebo (p=0.004), while the 2 mg dose reduced MBD by 26.5% (p<0.001) versus placebo....Both levels demonstrated a favorable tolerability profile. However, the similar tolerability profile between the 1 mg dose and placebo with effective MBD reduction is significant for potentially addressing future breast cancer risk reduction."

P2 data • Breast Cancer

Mechanistic characterization of (Z)-endoxifen in ESR1-mutant and endocrine-resistant breast cancer (AACR 2026) - P2 | "(Z)-Endoxifen, the active tamoxifen metabolite, inhibits ER signaling, but its impact on ESR1-mutant signaling and therapy-resistant disease is not yet fully defined. HEK293T cells were transfected with ESR1-WT or mutant plasmids together with an ERE-luciferase reporter and Renilla control. In summary, (Z)-endoxifen and elacestrant both suppress ER-dependent transcription in ESR1-WT and mutant models, and clinically relevant (Z)-endoxifen concentrations are sufficient to inhibit mutant ESR1 activity. Endoxifen additionally reprograms key transcriptional and metabolic pathways associated with ESR1-mutant resistance and metastasis. These results support further evaluation of (Z)-endoxifen's pathway-level effects in ESR1-mutant breast cancer, and ongoing studies are testing its ability to block mutant ESR1-driven proliferation in preclinical models."

Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ELF3 • ER • FOXA1 • POU5F1 • SOX11 • SPDEF

(Z)-endoxifen modulates estrogen receptor and cell-cycle signaling to induce synergistic antiproliferative effects with CDK4/6 inhibition in endometrial cancer models (AACR 2026) - "The active tamoxifen metabolite (Z)-endoxifen exhibits dual SERM/SERD-like activity, modulating ER function while exerting additional noncanonical antiproliferative effects...This study investigated the molecular and functional effects of (Z)-endoxifen, alone and in combination with the CDK4/6 inhibitor abemaciclib, across diverse EC models to define mechanistic activity and translational potential. ER+ (Ishikawa, HCI-EC23, patient derived organoid U1561.005) and ER-variable (ARK1, ARK2) EC models were treated with estrogen (0-10 nM), (Z)-endoxifen (125 nM-10 µM) or fulvestrant (0-2.5 μM), and abemaciclib (0-10 μM), as single agents or in combination... (Z)-Endoxifen demonstrates dual ER-dependent and ER-independent activity in EC preclinical models. Synergy was observed in combination a CDK 4/6 inhibitor. These findings broaden the current understanding of (Z)-endoxifen's efficacy and support further exploration of its potential therapeutic role in ER-driven..."

Preclinical • Endometrial Cancer • Gynecologic Cancers • Oncology • Solid Tumor • AURKA • ER

Neoadjuvant (Z)-endoxifen in premenopausal ER+, HER2- breast cancer: Evaluation of the first pharmacokinetic cohort of the EVANGELINE trial (AACR 2024) - P2 | "Background: Ovarian function suppression (OFS) combined with tamoxifen (TAM) or an aromatase inhibitor (AI) is standard for premenopausal (PM) ER+, HER2- breast cancer (BC)...Following PK run-in, the randomized phase II goal is to assess whether the ESD rate with ENDX is non-inferior to exemestane plus goserelin... ENDX (40 mg/day) exhibits promising antitumor activity for PM ER+/HER2- BC but with ENDX Css below target. Enrollment is ongoing to the 80 mg/day dose level."

Clinical • PK/PD data • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PRKCB • PRKCH

A randomized phase 2 non-inferiority trial of (Z)-endoxifen + goserelin and exemestane + goserelin as neoadjuvant treatment for premenopausal women with ER+/HER2- breast cancer (EVANGELINE) (AACR 2025) - P2 | "However, many premenopausal women are intolerant of AI + OFS, leaving tamoxifen (with or without OFS) as their only option. Comprehensive biomarker evaluations will be conducted using paired tumor biopsies and blood samples collected at baseline and week four, as well as 6 month surgical specimens. Enrollment in the PK run-in phase (n-22) was completed in Fall 2024 with the second portion of the trial slated to begin early in 2025."

Clinical • Head-to-Head • P2 data • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PRKCB

SMART 2.0 Interval breast cancer reduction study: A phase 3 randomized, double-blind, placebo-controlled trial of oral Z-endoxifen in women at high risk for breast cancer (AACR 2025) - "Endocrine therapies such as tamoxifen reduce mammographic density and lower the risk of breast cancer in healthy women. All data will be summarized using proportions/percentages for categorical data and means/medians with standard deviations/inter-quartile ranges for quantitative outcomes. Additionally, a multivariate logistic regression model will assess this endpoint, adjusting for treatment group and relevant covariates, and testing for multiplicative interaction terms as necessary.Outcome: The goal of this study is to achieve regulatory approval for low-dose (Z)-endoxifen as a therapy to reduce the incidence of interval breast cancer in high-risk women, identified by an AI-based mammogram screening algorithm."

Clinical • P3 data • Breast Cancer • Oncology • Solid Tumor • PRKCB

Novel (Z)-endoxifen-related chemical entities exhibit potent anti-cancer activity in ERα+ breast cancer (AACR 2025) - "(Z)-Endoxifen (ENDX), an active metabolite of tamoxifen, is a potent, orally bioavailable selective estrogen receptor modulator with a favorable safety profile now under development for breast health applications. Its synthesis yields endoxifen-related byproducts that are new chemical entities (NCEs), including AT416E, AT416Z, AT402E and AT402Z...These findings highlight four NCEs with notable anti-cancer activity, with some matching or surpassing ENDX in several cancer-relevant cellular readouts, marking them as novel candidates for ERα+ breast cancer therapy. Further studies will advance one or more of these NCEs into in vivo models to confirm their therapeutic efficacy and potential for clinical application."

Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor

Transcriptomic Profiling Reveals Inflammatory and Epithelial-Mesenchymal Transition Pathway Activation in Endoxifen-Resistant Estrogen Receptor–Positive Breast Cancer (NCCN 2026) - "Background: (Z)-Endoxifen, the active metabolite of tamoxifen, demonstrates superior anti-estrogenic activity and favorable tolerability in estrogen receptor–positive (ER+) breast cancer. Endoxifen resistance involves transcriptional rewiring characterized by sustained estrogen pathway suppression, activation of inflammatory and epithelial-mesenchymal transition programs, and reversal of mechanistic target of rapamycin complex 1 pathway regulation. These changes highlight candidate biomarkers (e.g., PRKCB, IFI44, CXCL8) and therapeutic vulnerabilities, supporting strategies that incorporate immune-inflammatory and epithelial-mesenchymal transition modulators for managing resistant ER+ breast cancer."

Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • CXCL8 • ER • PRKCB • PRKCH • TNFA

Atossa Therapeutics Maintains Strong Market Position for (Z)-Endoxifen for Duchenne Muscular Dystrophy as Congress Reauthorizes Priority Review Voucher Program (PRNewswire) - "The program extends the Company's ability to be eligible to receive a future PRV upon the U.S. Food and Drug Administration's ('FDA') approval following the FDA granting Rare Pediatric Disease ('RPD') designation to (Z)-endoxifen for the treatment of DMD late last year."

FDA event • Duchenne Muscular Dystrophy

Atossa Therapeutics (ATOS) has received the orphan drug designation from the U.S. Food and Drug Administration for its drug candidate, Z-endoxifen. (Gurufocus) - "This designation is for the potential treatment of Duchenne muscular dystrophy, a rare and debilitating condition."

Orphan drug • Duchenne Muscular Dystrophy

Atossa Therapeutics Receives FDA "Study May Proceed" Letter for (Z)-Endoxifen Investigational New Drug Application for Metastatic Breast Cancer (PRNewswire)

IND • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer

(z)-endoxifen maintains erα antagonist function against esr1 mutants via inactive conformation stabilization and reversal of mutant esr1-associated transcriptional signatures (SABCS 2025) - "In this in silico modeling study, we examined the biophysical behavior and downstream transcriptional impacts of (Z)-endoxifen, an active tamoxifen metabolite, a selective estrogen receptor modulator (SERM), across ESR1 variants to further elucidate its mechanism of action and therapeutic potential. (Z)-Endoxifen demonstrates robust biophysical and functional activity against ESR1 mutations. It stabilizes inactive ERα conformations and reverses mutant-driven transcriptional programs, showing greater transcriptional breadth than next-generation SERDs like elacestrant. These findings support (Z)-endoxifen's potential as a precision therapy for ESR1-mutant ER+ MBC and justify further clinical investigation in endocrine-resistant settings."

Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • ER • GLIS2

Atossa Therapeutics Details Accelerated FDA Strategy to Advance (Z)-Endoxifen Across Breast Cancer Continuum (PRNewswire) - "During the meeting, the FDA provided the Company feedback on potential expedited regulatory pathways and development options across metastatic disease, neoadjuvant treatment, and breast cancer risk-reduction settings...This includes multiple high-value clinical settings, including: Metastatic breast cancer (mBC): A dose-ranging study is in preparation as part of the Company's strategy to support registrational development; Neoadjuvant ER+/HER2- breast cancer: Enrollment and data generation continue in the Phase 2 EVANGELINE trial; Breast cancer risk-reduction: Development includes a low-dose strategy targeting mammographic breast density and overall breast cancer risk....The Company also anticipates additional IND submissions in 2026 to advance combination strategies and explore opportunities beyond monotherapy and breast cancer."

FDA event • IND • Trial status • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer

Atossa Therapeutics Announces Year-End 2023 Financial Results and Provides Corporate Update (GlobeNewswire) - "(i) Full enrollment of Phase 2 Karisma-Endoxifen Clinical Trial:...Full enrollment was achieved in November 2023 and data is expected in the second half of 2024; (ii) Full enrollment of Phase 2 I-SPY 2 Clinical Trial:....Full enrollment was achieved in February 2024 and data is expected in the second half of 2024; (iii) First patient dosed with (Z)-endoxifen in RECAST DCIS study - the Re-Evaluating Conditions for Active Surveillance Suitability as Treatment: Ductal Carcinoma In Situ (RECAST DCIS) study is an ongoing Phase 2 platform study designed to offer women diagnosed with DCIS six months of neoadjuvant endocrine therapy..."

P2 data • Trial status • Breast Cancer

Initial results from RECAST DCIS: Multicenter platform trial testing active surveillance and novel endocrine therapy agents for DCIS management (Atossa Therapeutics Press Release) - "RECAST is testing whether short-term endocrine therapy plus MRI response can identify appropriate DCIS patients for long-term active surveillance while avoiding surgery' Early results show excellent tolerability and steady enrollment, with many patients electing to continue active surveillance, suggesting feasibility of this patient-centered 'window of opportunity' approach."

P2 data • Breast Cancer

Atossa Therapeutics Receives FDA Rare Pediatric Disease Designation for (Z)-Endoxifen for Duchenne Muscular Dystrophy (PRNewswire) - "Designation expands (Z)-Endoxifen program into rare pediatric neuromuscular disease and may qualify Atossa for a future Priority Review Voucher upon approval."

FDA event • Duchenne Muscular Dystrophy

Atossa Therapeutics Announces Issuance of U.S. Patent Covering Enteric Oral (Z)-Endoxifen Formulations and Methods of Treating Patients Using (Z)-Endoxifen (PRNewswire) - "The newly issued patent includes 100 claims directed to enteric oral formulations of highly pure (Z)-endoxifen free base, as well as methods of using those compositions to treat a range of hormone-dependent breast disorders and other estrogen-related conditions. The patent also covers specific solid oral dosage forms and stable formulations providing therapeutically meaningful and sustained systemic exposure to (Z)-endoxifen....New patent further strengthens global intellectual property estate supporting Atossa's lead program across the breast cancer spectrum and other hormone-driven conditions."

Patent • Breast Cancer

Atossa Therapeutics and Quantum Leap Healthcare Announce I-SPY 2 Clinical Trial to Evaluate (Z)-Endoxifen in Combination with Abemaciclib (VERZENIO) in Women with ER+/HER2- Breast Cancer (Atossa Therapeutics Press Release) - "Atossa Therapeutics...and Quantum Leap Healthcare Collaborative...announced the initiation of a new study to evaluate Atossa’s proprietary (Z)-endoxifen in combination with abemaciclib (VERZENIO), a cyclin-dependent kinase (CDK) 4/6 inhibitor marketed by Eli Lilly and Company, in women with ER+/HER2- breast cancer....The new study arm will enroll approximately 20 women with newly diagnosed Estrogen Receptor positive (ER+) / Human Epidermal Growth Factor Receptor 2 negative (HER2-) invasive breast cancer. Participants will receive 40mg (Z)-endoxifen once daily in combination with 150mg abemaciclib twice daily for a total of 24 weeks prior to surgery."

Trial status • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer

Low dose (Z)-endoxifen in the I-SPY2 Endocrine Optimization Pilot (Atossa Therapeutics Press Release) - "The daily 10 mg (Z)-endoxifen dose was well tolerated, with 95% of patients completing ≥75% of therapy and low-grade side effects, demonstrating strong feasibility in an endocrine-naïve HR+/HER2- population; Biologic activity was evident, with meaningful reductions in Ki-67, MRI functional tumor volume (–72% median), and ctDNA clearance observed in 70% of patients who were initially ctDNA-positive, indicating endocrine responsiveness; Clinical impact was modest but supportive, with one mPEPI-0 outcome; the program is now escalating to 40 mg/day (targeting both ERα and PKCβ1) with or without abemaciclib to further optimize neoadjuvant endocrine therapy." "

P2 data • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer