We currently have four programs underway: two using our proprietary endoxifen (oral and topical formulations) and two using our patented microcatheter technology.
Endoxifen is the most active metabolite (ingredient) of the FDA-approved drug tamoxifen, which has been used since its approval in 1977 for breast cancer survivors to prevent recurrence as well as the development of new cancer.
We are developing both oral and a topical formulation of endoxifen. In mid-2017 we completed a Phase 1 clinical study which was conducted by a leading Clinical Research Organization in Australia. The study was a placebo-controlled, repeat dose study of 48 healthy female volunteers. The objectives were to assess safety, tolerability and pharmacokinetics of both formulations of endoxifen over 28 days. All objectives were successfully met in the topical arms of the study. We reported results from the oral arm on 25 October 2017.
Topical Endoxifen Program. The topical formulation of our proprietary endoxifen is being developed for women with a condition call mammographic breast density, or MBD, which has been shown in third-party studies to result in a higher risk of developing breast cancer. To date, 30 U.S. states require that findings of MBD be directly communicated to the patient. Although oral tamoxifen has been shown to reduce MBD, the benefit-risk ratio is generally not acceptable to most physicians and their patients. For example, it is estimated that no more than 5% of women at high-risk of developing breast cancer, including those with MBD, take oral tamoxifen to prevent breast cancer because of the risk of, or actual side-effects of, oral tamoxifen.
In mid-2017 we completed a Phase 1, placebo-controlled study of our proprietary topical Endoxifen. All objectives of that study were successfully met:
The data from the Phase 1 study demonstrate the suitability of topical Endoxifen for further clinical development.
We have initiated a Phase 2 study of our topical endoxifen in women with MBD. The study will be conducted at Stockholm South General Hospital in Sweden and will be led by principal investigator Dr. Per Hall, MD, Ph.D., Head of the Department of Medical Epidemiology and Biostatistics at Karolinska Institute. The placebo-controlled, double-blinded study is expected to enroll up to 480 subjects. The primary endpoint is MBD reduction, which will be measured after six and twelve months of dosing, as well as safety and tolerability.
We are also developing our proprietary topical Endoxifen for male breast cancer and gynecomastia. Gynecomastia is male breast enlargement and accompanying pain. It is the most common male breast disorder and is caused by a hormone imbalance where testosterone is low compared to estrogen. Gynecomastia is caused by, among other things, any number of commonly prescribed medications, such as androgen deprivation therapy to treat prostate enlargement and prostate cancer, anti-anxiety medications, cancer treatments (chemotherapy), and some heart medications. Gynecomastia is not only painful and embarrassing, it can also cause men to stop taking these important medications. In prostate cancer treatment, testosterone is suppressed resulting in higher estrogen levels that usually triggers gynecomastia. Prophylactic breast bud irradiation is commonly used in prostate cancer patients, but must often be repeated. There are no FDA-approved therapeutics for gynecomastia. Breast-bud irradiation, use of compression garments and plastic surgery are the most common approaches used to treat gynecomastia. Similar to women, the treatment for male breast cancer is typically surgery (with or without radiation) and chemotherapy. Breast cancer in men is deadlier than breast cancer in women: men with early-stage breast cancer have a lower five-year survival rate than women and breast cancer in men tends to be detected at a later stage of development than women. Although tamoxifen is the standard of care for women to prevent new and recurrent breast cancer, there is no FDA-approved treatment for male breast cancer.
Oral Endoxifen Program. Research indicates that low endoxifen levels in breast cancer patients taking oral tamoxifen correlate with a higher risk of recurrence and new cancer as compared to breast cancer patients with adequate endoxifen levels. We believe that up to 50% of the approximately one million patients taking tamoxifen in the United States each year are refractory, meaning that they have inadequate endoxifen levels (for any number of reasons including low levels of a liver enzyme) and they have an increased risk for breast cancer recurrence. Subject to favorable results from our Phase 1 study, we are planning to begin a Phase 2 study of oral endoxifen for these patients who are refractory to tamoxifen.
We are also evaluating endoxifen in the neo-adjuvant setting, meaning it would be use to treat breast cancer before surgery to remove the cancerous tumor.
We are developing our patented microcatheter technology to deliver therapeutics through the nipple directly to the site of the cancer. The goals of this delivery method are to increase the amount of the therapy getting to the targeted area while 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 tissue. The initial drug we are studying using our 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 own one issued patent and several pending applications directed to the treatment of breast conditions, including cancer, by the intraductal administration of therapeutics, including fulvestrant.
We are currently conducting a Phase 2 study using our microcatheter technology to deliver fulvestrant 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.
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 our 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.
Microcatheter CAR-T Cell Program. We are also developing our proprietary microcatheter technology for Chimeric Antigen Receptor Therapy, or CAR-T. We plan to use our proprietary intraductal microcatheter technology to deliver CAR-T cells into the ducts of the breast for the potential targeted treatment of breast cancer.
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.