Z-endoxifen / Atossa Therap - LARVOL DELTA

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

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

(Z)-Endoxifen Maintains ERα Antagonist Function Against ESR1 Mutants via Inactive Conformation Stabilization and Reversal of Mutant ESR1-Associated Transcriptional Signatures (Atossa Therapeutics Press Release) - "(Z)-Endoxifen shown to maintain potent ERα antagonist activity across key ESR1 mutations (Y537S, D538G) by stabilizing inactive receptor conformations, with computational, energetic, and metadynamics analyses showing ESR1 mutants still retain antagonist-compatible states; Functional assays confirmed strong suppression of ER signaling in both wild-type and mutant ESR1 backgrounds, demonstrating robust inhibitory activity even under estrogen-rich conditions and validating the mechanistic modeling findings; Transcriptomic analyses showed that (Z)-endoxifen reverses multiple mutant ESR1–associated oncogenic pathways (e.g., estrogen response, E2F, Myc) while restoring beneficial programs (oxidative phosphorylation, p53), highlighting its therapeutic potential for ER+ / ESR1 mutant breast cancer."

Clinical data • Estrogen Receptor Positive Breast Cancer

A Randomized Phase 2 Non-Inferiority Trial of (Z)-Endoxifen + Goserelin vs Exemestane + Goserelin as a Neoadjuvant Treatment for Premenopausal Women with ER+/HER2- Breast Cancer (EVANGELINE) (Atossa Therapeutics Press Release) - "EVANGELINE is the first trial to evaluate (Z)-endoxifen with OFS as a neoadjuvant therapy for patients with premenopausal ER+/HER2– breast cancer, addressing a major unmet need for patients who cannot tolerate AI with OFS therapy; Pharmacodynamic run-in data showed strong early biologic activity, with 86% of patients achieving a Week 4 Ki-67 ≤10%, supporting the selection of 40 mg (Z)-endoxifen with OFS for Phase II, and demonstrating promising antiproliferative efficacy; The study design incorporates a Simon two-stage approach to test whether (Z)-endoxifen with OFS can meet or exceed a 65% Ki-67 response threshold, with secondary endpoints including safety, RCB, PEPI score, and MRI-based tumor response."

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

A Phase 2 Trial of (Z)-endoxifen + Goserelin as Neoadjuvant Treatment for Premenopausal Women with ER+, HER2-, Breast Cancer (EVANGELINE) (SABCS 2025) - P2 | "Problematically, only 41% of patients reach this threshold with tamoxifen compared to 78% with AI+OFS (Nitz JCO 2022)...Eligible patients are premenopausal women with Stage IIA/IIB ER+/HER2- breast cancer.• Part 1 (PK Run-in): assessed 40mg vs 80mg ENDX (+/- OFS) in 22 patients.• Part 2: patients with baseline Ki-67 >10% were randomized to 40 mg ENDX + goserelin or exemestane + goserelin for 6 months with the primary objective being 4-week ESD rate...EVANGELINE is the first trial to evaluate (Z)-endoxifen + OFS as neoadjuvant therapy in premenopausal ER+/HER2- breast cancer. By targeting both ER and PKC pathways, ENDX may offer a well-tolerated alternative to AI-based regimens and expand endocrine therapy options for this population. Clinical Trial Registration: NCT05607004"

Clinical • 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

Atossa Therapeutics Selects PSI as Contract Research Organization for Pivotal Dose-Ranging Study of (Z)-Endoxifen in Metastatic Breast Cancer (PRNewswire) - "The global Phase 2, multi-center dose-ranging study is designed to evaluate (Z)-endoxifen monotherapy for safety, pharmacokinetics/pharmacodynamics, and preliminary anti-tumor activity. Patient enrollment is expected to follow the Investigational New Drug (IND) filing in Q4 2025, with topline data anticipated in 2026."

New P2 trial • Breast Cancer

I-SPY 2 - Endocrine Optimization Pilot Analysis (Combination therapy of 40 mg (Z)-endoxifen and Eli Lilly’s abemaciclib) (Atossa Therapeutics Press Release) - "Patient recruitment continues at a faster rate than anticipated, with 41 patients initiated as of July 29, 2025."

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

Atossa Therapeutics Announces Positive FDA Feedback, Advances Toward IND for (Z)-Endoxifen Clinical Program in ER+/HER2- Metastatic Breast Cancer (PRNewswire) - "Atossa Therapeutics...announced positive written feedback from the U.S. Food and Drug Administration (FDA) regarding the company's proposed dose optimization trial of (Z)-endoxifen for the treatment of estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer...The FDA has provided highly constructive responses ahead of the scheduled pre-Investigational New Drug (IND) meeting, affirming key elements of Atossa's clinical development plan, negating the need for a virtual meeting, and paving the way for a potential IND submission targeted for the fourth quarter of 2025...FDA agreed that existing clinical and nonclinical data are sufficient to initiate Part A (monotherapy) of the proposed dose optimization study and provided clear guidance on randomization cohort sizes and study design enhancements....Agreement on Cardiac Safety Assessments for Monotherapy."

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

Atossa Therapeutics Announces Full Results from I‑SPY 2 Endocrine‑Optimization Sub‑Study Evaluating Low‑Dose (Z)‑Endoxifen (Nasdaq) - P2 | N=5,000 | I-SPY (NCT01042379) | "Atossa Therapeutics, Inc...today reported full results from the Phase 2 Endocrine Optimization Pilot (EOP) sub‑study within the I‑SPY 2 TRIAL evaluating low‑dose oral (Z)‑endoxifen (10 mg daily) as a neoadjuvant treatment in 20 women with stage II/III estrogen‑receptor–positive (ER+), HER2‑negative breast cancer....95 percent of participants (19/20) completed at least 75 percent of planned dosing, far exceeding the predefined 75 percent threshold. Median Ki‑67 fell from 10.5 percent at baseline to 5 percent by Week 3 (prior to ovarian suppression); 65 percent of patients achieved Ki‑67 ≤ 10 percent at that time point, and suppression was maintained at surgery. Median functional tumor volume (FTV) measurement (performed at baseline, week 3, week 12, and at surgery) decreased 77.7 percent (range 9.0 cc → 1.2 cc) from baseline to surgery, and the longest tumor diameter from baseline to preoperative MRI was reduced by 36.8 percent."

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

Join Atossa Therapeutics' Exclusive Live Investor Webinar and Q&A Session on May 22 (ACCESSWIRE) - "Attendees will gain insight into Atossa's strategic approach to redefining breast cancer treatment through its lead clinical candidate, (Z)-endoxifen - a next-generation SERM with best-in-class potential.... The presentation will highlight recent progress across key development programs, upcoming milestones, and how the Company's differentiated science and capital-efficient model are designed to deliver both clinical impact and long-term shareholder value."

Clinical data • Breast Cancer

Atossa Therapeutics Announces First Quarter 2025 Financial Results and Provides a Corporate Update (PRNewswire) - "Announced Strategic Decision to Pursue Metastatic Breast Cancer Indication: Atossa announced plans to target metastatic breast cancer as its lead program for (Z)-endoxifen.....Significantly Strengthened (Z)-endoxifen Patent Portfolio with Three New U.S. Patents: Atossa continued to bolster the intellectual property portfolio of (Z)-endoxifen with the grant of three new U.S. patents covering 31 claims directed at: sustained release compositions of (Z)-endoxifen (U.S. Patent No. 12,201,591); enteric oral formulations of (Z)-endoxifen and salts thereof as well as their use in treating hormone-dependent breast and reproductive tract disorders (U.S. Patent No. 12,275,684); and 58 claims covering (Z)-endoxifen formulations, including various levels of purity and stability as well as methods of using those formulations (U.S. Patent No. 12,281,056)."

Patent • Pipeline update • Breast Cancer

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

Atossa Therapeutics Announces Issuance of U.S. Patent No. 12,275,684, Further Strengthening (Z)-endoxifen Portfolio (Atossa Therapeutics Press Release) - "Atossa Therapeutics, Inc...announced that the United States Patent and Trademark Office (USPTO) has granted a new patent (U.S. Patent No. 12,275,684) directed to enteric oral formulations comprising (Z)-endoxifen as well as methods of treating subjects with those oral formulations. This newly granted patent further fortifies Atossa’s intellectual property portfolio surrounding its proprietary (Z)-endoxifen formulations, encompassing novel compositions and methods related to (Z)-endoxifen, a potent Selective Estrogen Receptor Modulator (SERM). Specifically, the patent covers enteric oral formulations of (Z)-endoxifen and salts thereof as well as their use in treating hormone-dependent breast and reproductive tract disorders."

Patent • Breast Cancer