Development Pipeline

Development Pipeline

Our lead product, (Z)-endoxifen, is a selective estrogen receptor modulator (SERM) and is the most active metabolite of tamoxifen. In addition to its anti-estrogen effects, (Z)-endoxifen at higher concentrations has been shown to target PKCβ1, a known oncogenic protein.  We are currently evaluating a low dose of (Z)-endoxifen as a potential breast cancer preventive by reducing mammographic breast density (MBD) which is thought to be correlated with a reduction in breast cancer.  At higher doses, we are evaluating (Z)-endoxifen as an alternative to aromatase inhibitors plus goserelin (ovarian suppression) for the treatment of premenopausal women with ER+/HER2- breast cancer. The investigational new drug application for (Z)-endoxifen was recently cleared by the FDA and we are excited to launch our first study in the USA for breast cancer treatment.  The prevention trial is ongoing in Sweden.

Additionally, we are investigating treatments for radiation-induced lung injury with our AT-H201 product. Atossa continues to look for additional opportunities to help patients and their families with unmet medical needs. With widespread availability of SARS-CoV-2 vaccines and other therapies now approved to treat COVID-19, Atossa is now aligning our development pipeline to address unmet needs in oncology and has discontinued COVID related programs.

Pipeline

Atossa has multiple programs underway to treat breast cancer, and other breast conditions:

If you are interested in partnering with Atossa Therapeutics, please contact us.

Clinical Trials

(Z)-endoxifen

(Z)-endoxifen is the most active metabolite of the FDA approved Selective Estrogen Receptor Modulator (SERM), tamoxifen. Studies by others have demonstrated that the anti-estrogenic effects of tamoxifen are driven in a concentration-dependent manner by (Z)-endoxifen. In addition to its anti-estrogen effects, (Z)-endoxifen at higher concentrations has been shown to target PKCβ1, a known oncogenic protein.

Atossa has developed a proprietary oral formulation of (Z)-endoxifen that does not require liver metabolism to achieve therapeutic concentrations and is encapsulated to bypass the stomach as acidic conditions may render (Z)-endoxifen inactive. Atossa’s (Z)-endoxifen has been shown to be well tolerated in Phase 1 studies and in a small Phase 2 study of women with breast cancer (AG-1001-AU-02). We currently are studying a low dose of our (Z)‑endoxifen in healthy women with measurable breast density and at higher doses in premenopausal women with ER+/HER2- breast cancer.

Atossa has previously investigated different presentations of (Z)-endoxifen, including topical (ATOS-010, NCT04616430), tablet, and capsule. Based on results of clinical studies conducted, the topical and tablet forms were discontinued and further development of (Z)-endoxifen is focused on the capsule presentation.

Atossa has been issued U.S. Patent No. 11,261,151, titled “Methods for Making and Using Endoxifen” which is directed to compositions of storage-stable (Z)-endoxifen and methods of treating hormone-dependent breast disorders using the storage-stable (Z)-endoxifen. This patent is not expected to expire until 2038.

ATOS-016R – low dose (Z)-endoxifen for reduction of mammographic breast density

Approximately ten million women in the U.S. have mammographic breast density (MBD), for which there is no FDA-approved treatment. Studies conducted by others have shown that MBD reduces the ability of mammograms to detect cancer and increases the risk of developing breast cancer. Although oral tamoxifen is approved to prevent breast cancer in “high-risk” women (typically based on responses to a questionnaire), it is used by less than 5% of women with an increased risk of developing breast cancer because of the actual or perceived side effects and risks of tamoxifen.  (Z)-endoxifen may provide an option for women to proactively reduce the density of their breasts and may improve mammography accuracy and patient care by unmasking cancerous tumors that are otherwise hidden by breast density.

ATOS-016R, is a Phase 2, randomized, double-blind, placebo-controlled, dose-response study of Atossa’s proprietary oral (Z)-endoxifen in healthy premenopausal women with measurable breast density. It will include approximately 240 participants who will receive daily doses of oral (Z)-endoxifen or placebo for six months. The primary objective of the study is to determine the dose-response relationship of daily oral (Z)-endoxifen on breast density reduction. The primary endpoint is a change from baseline measurable breast density at 6 months measured using iCAD® software (change in BI-RADS category).

Secondary endpoints will assess safety and tolerability, and the trial includes an exploratory endpoint to assess durability of the breast density changes.

The study is being led by principal investigator Per Hall, M.D., Ph.D., Head of the Department of Medical Epidemiology and Biostatistics at Karolinska Institutet.

More information can be found on clinicaltrials.gov (NCT05068388) or at clinicaltrialsregister.eu (EudraCT 2020-004828-42).

ATOS-Z-201 – higher dose (Z)-endoxifen for the treatment of premenopausal women with ER+/HER2- breast cancer

Breast cancer is the most frequently diagnosed cancer in premenopausal women worldwide. It is estimated that almost half of the cancers that occur in women aged 15-49 is breast cancer.  An overwhelming majority (75%) of premenopausal breast cancer falls under luminal A (ER+/HER2-) or B (ER+/HER2+) subtypes. Ovarian function suppression, when combined with either tamoxifen or an aromatase inhibitor, is the standard of care for the endocrine management of premenopausal ER+/HER2- breast cancer.

ATOS-Z-201 is a randomized Phase 2 noninferiority trial of (Z)-endoxifen and exemestane + goserelin as neoadjuvant treatment in premenopausal women with ER+/HER2- breast cancer.  Also known as “EVANGELINE,” the study is designed to investigate (Z)-endoxifen for the neoadjuvant treatment of premenopausal women ages 18 and older with early stage (Grade 1 or 2) ER+/HER2- breast cancer and to assess if (Z)-endoxifen is potentially effective without requiring ovarian function suppression.

This study is a multicenter study in United States. It will enroll about 175 patients and is designed with two cohorts:  a PK Run-In Cohort to investigate pharmacokinetics and identify a dose for the Treatment Cohort and a Treatment Cohort to investigate the safety and efficacy of (Z)-endoxifen compared with a prospective control (exemestane + goserelin, two drugs often used in combination to treat this patient population).

The primary objective of the study is to assess whether the endocrine sensitive disease rate at 4 weeks with (Z)-endoxifen is non-inferior to exemestane plus goserelin in premenopausal women with ER+/HER2- breast cancer. Endocrine sensitivity, or the effect of endocrine therapy on the tumor, will be measured by Ki-67%, a biomarker for tumor cell proliferation. Ki-67 is known to be prognostic for 5-year disease-free survival in the neoadjuvant endocrine treatment of ER+/HER2- breast cancer. The neoadjuvant setting of this study will allow Atossa to investigate several translational endpoints using paired tumor samples.

Patients will be enrolled with the intent of surgical treatment in the involved breast(s) after completing neoadjuvant study treatment. Patients will receive neoadjuvant study treatment for up to six months. Surgery will be performed within seven days of the last dose of study treatment.

This study will be registered at clinicaltrials.gov prior to enrollment.

AT-H201

AT-H201 consists of two drugs previously approved by the FDA to treat other diseases. AT-H201 is intended to be inhaled via nebulizer with the goal of preventing or reducing lung injury in cancer patients that may be caused by fibrin deposition, fluid build-up and secondary infection.

In July 2022, we completed dosing in both Parts A-C (of four parts) of Phase 1/2a Clinical Trial of AT-H201 in healthy volunteers in Australia.  This study evaluated AT-H201 as an inhalation therapy.  The study originally included a Part D which was designed to assess the effects of the treatment regimen in hospitalized COVID-19 patients with moderate illness. However, due to the rapidly shifting COVID-19 treatment landscape and the introduction of effective vaccines limiting hospitalizations, Atossa evaluated indications for AT-H201 beyond COVID-19 patients, including treating and/or preventing lung injury in patients undergoing certain cancer treatments.

Rather than conducting Part D of the Phase 1/2a clinical study, Atossa is shifting the development of AT-H201 to closely align with its oncology focus by continuing the development in patients with compromised lung-function due to the damaging effects of cancer treatment.

Atossa is currently evaluating study designs for further development of AT-H201.

Publications and Presentations

Topical Endoxifen for Mammographic Density Reduction-A Randomized Controlled Trial The Oncologist | Volume 27Issue 7 | July 2022 |

Microcatheter Technology

We are developing our patented microcatheter technology to deliver therapeutics through the nipple directly to the site of early breast cancer.  The goals of this direct delivery method are to increase the amount of the therapy getting to the targeted area while likely reducing the side effects that would otherwise be caused by delivering the drug through the blood stream.

Fulvestrant Microcather Program. We believe our patented intraductal microcatheter technology may be useful in delivering a number of drugs directly to the breast. The initial drug we are studying using microcatheters is fulvestrant. Fulvestrant is FDA-approved for metastatic breast cancer. It is administered as a monthly intramuscular injection of two injections, typically into the buttocks.

We are currently conducting a Phase 2 study using our microcatheter technology at Montefiore Medical Center. This trial is a Phase 2 study in women with ductal carcinoma in situ (DCIS) or Stage 1 or 2 breast cancer (invasive ductal carcinoma) scheduled for mastectomy or lumpectomy within 30 to 45 days. This study is assessing the safety, tolerability, cellular activity and distribution of fulvestrant when delivered directly into breast milk ducts of these patients compared to those who receive the same drug by injection. Of the 30 patients required for full enrollment, six will receive the standard intramuscular injection of fulvestrant and 24 will receive fulvestrant with our microcatheter device technology.

The primary endpoint of the clinical trial is to compare the safety, tolerability and distribution of fulvestrant between the two routes of administration (intramuscular injection or through microcatheters). The secondary endpoint of the study is to determine if there are changes in the expression of Ki67 as well as estrogen and progesterone receptors between a pre-fulvestrant biopsy and post-fulvestrant surgical specimens. Digital breast imaging before and after drug administration in both groups will also be performed to determine the effect of fulvestrant on any lesions as well as breast density of the participant.

Immuno-Oncology Microcatheter Program. We are also developing our proprietary intraductal microcatheter technology for Chimeric Antigen Receptor Therapy, or CAR-T. We plan to use our proprietary intraductal microcatheter technology to deliver CAR-T or other types of modified cells into the ducts of the breast for the potential targeted treatment of breast cancer. This program is currently in the research, or pre-clinical phase.

Our novel approach uses our proprietary intraductal microcatheter technology for the potential transpapillary, or “TRAP,” delivery of T-cells that have been genetically modified to attack breast cancer cells. We believe this method has several potential advantages: reduced toxicity by limiting systemic exposure of the T-cells; improved efficacy by placing the T-cells in direct contact with the target ductal epithelial cells that are undergoing malignant transformation; and, lymphatic migration of the CAR-T cells along the same path taken by migrating cancer cells, potentially extending their cytotoxic actions into the regional lymph system, which could limit tumor cell dissemination. This program is in the research and development phase and has not been approved by the FDA or any other regulatory body. Pre-clinical studies, and clinical studies demonstrating safety and efficacy among other things, and regulatory approvals will be required before commercialization.

The transpapillary (TRAP) delivery of therapeutics in breast cancer clinical trials have demonstrated “that cytotoxic drugs can be safely administered into breast ducts with minimal toxicity” (Zhang B, et al. Chin J Cancer Res. 2014 Oct;26(5):579-87; www.ncbi.nlm.nih.gov/pubmed/25400424). T cells are removed from a patient and modified so that they express receptors specific to the patient’s particular breast cancer. The T cells, which can then recognize and kill the cancer cells, are reintroduced into the patient using a microcatheter into the natural ducts of the breast.

Chimeric antigen receptors (or, “CARs” and also known as chimeric immunoreceptors, chimeric T cell receptors, artificial T cell receptors or CAR-T) are engineered receptors, which graft an arbitrary specificity onto an immune effector cell (T cell). Typically, these receptors are used to graft the specificity of a monoclonal antibody onto a T cell, with transfer of their coding sequence facilitated by retroviral vectors. The receptors are called chimeric because they are composed of parts from different sources.

CAR-T technology has recently been the subject of much attention, as pioneer CAR-T company Kite Pharma recently announced its acquisition by Gilead, and the FDA recently approved Novartis’s Kymriah™ for treatment of B-cell Acute Lymphoblastic Leukemia.

Atossa Therapeutics, Inc. is a clinical-stage biopharmaceutical company seeking to develop innovative medicines in areas of significant unmet medical need in oncology with a current focus on breast cancer and radiation-induced lung injury.

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