“We have made tremendous progress with our clinical programs. We opened enrollment in two phase 2 clinical studies: one study using our proprietary topical Endoxifen for breast density reduction, and another study using our proprietary oral Endoxifen for reducing breast cancer tumor cell activity in the “window of opportunity” between diagnosis of breast cancer and surgery. We also completed dosing and patient visits in our phase 1 study of topical Endoxifen in men. Our intraductal microcatheter immunoOncology pre-clinical program was launched and we contracted with an additional manufacturer for Endoxifen. We have had a very busy and productive first six months of 2018 as we continue the momentum in the advancement of our clinical programs.” – Steve Quay, President and CEO.
Endoxifen is the most active metabolite (ingredient) of the FDA-approved drug tamoxifen. Tamoxifen has been used since its approval in 1977 for breast cancer survivors to prevent recurrence as well as the development of new cancer. Tamoxifen is a “pro-drug,” in that it must be metabolized by the liver into active metabolites in order to have activity in the body. Many patients, however, do not properly metabolize tamoxifen which means they receive little or no benefit from tamoxifen.
By delivering the metabolite endoxifen directly to the body, the need for liver metabolism is bypassed. Moreover, results from our phase 1 study show that our orally administered endoxifen gets to a “steady-state” in as little as seven days whereas studies by other have shown that steady-state levels of endoxifen from oral tamoxifen can take up to 120 days.
We are developing both topical and oral presentations of endoxifen.
We have developed a proprietary Topical Endoxifen formulation for transdermal delivery (meaning it can be applied by the patient directly to the skin like a lotion), and have completed randomized, double-blinded, 3-dose level Phase 1 study of its safety, tolerability and pharmacokinetics in 24 healthy female and 24 male volunteers. These studies showed:
Safety: There were no clinically significant safety signals and no clinically significant adverse events in participants receiving topical Endoxifen.
Tolerability: Topical Endoxifen was well tolerated at each dose level and for the dosing duration utilized in the study.
Pharmacokinetics: In the female study, Topical Endoxifen crossed the skin barrier when applied daily to the breast, as demonstrated by low but measurable Endoxifen blood levels detected in a dose-dependent fashion.
To date, we are developing Topical Endoxifen to address two important populations: to reduce mammographic breast density (MBD) and to prevent/reduce gynecomastia in prostate cancer patients starting androgen deprivation therapy.
Mammographic breast density, or MBD, has been shown to be an independent risk factor for developing breast cancer, and one large third-party study concluded that women with high breast density (BI-RADS 75 or higher) have a 5.3 fold increased risk of developing breast cancer.
Women get routine mammograms to screen for early evidence of breast cancer. Mammograms will also show if the breast tissue is “dense.” Breast density can mask breast cancers and can increase the risk of developing breast cancer. For this reason, approximately 30 states in the U.S. 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 patients and their physicians, because of the risk of, or actual side-effects of, oral tamoxifen. Providing transdermal endoxifen to the breast is may provide the same benefit of tamoxifen in reducing MBD with limited body-wide exposure.
We have initiated a Phase 2 study of our Topical Endoxifen in women with MBD. The study is being conducted at Stockholm South General Hospital in Sweden and is being led by Dr. Per Hall, MD, Ph.D., Head of the Department of Medical Epidemiology and Biostatistics at Karolinska Institute. The randomized, double-blinded, placebo-controlled, study is planned to enroll 90 subjects. The primary endpoint is MBD reduction, which will be measured after three and six months of dosing, as well as safety and tolerability.
Gynecomastia is male breast enlargement and accompanying pain.
Men and women both have estrogen and testosterone. Gynecomastia is caused by a hormone imbalance where testosterone is lower than 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 can result in social discomfort, it can also be the main reason why some men stop taking these important medications.
In prostate cancer treatment, testosterone is purposely suppressed to reduce growth of tumors that use testosterone to grow. This results in higher estrogen levels, triggering gynecomastia. Although prophylactic breast bud irradiation is commonly used in these 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.
We have completed a Phase 1 study using our Topical Endoxifen in men and we plan to advance into a Phase 2 study to prevent and/or reduce gynecomastia in men undergoing prostate cancer therapy.
We have developed an oral presentation of endoxifen, and subjected it to a randomized, double-blinded, 3-dose level Phase 1 study of its safety, tolerability and pharmacokinetics in 24 healthy female volunteers. These studies showed:
Safety: There were no clinically significant safety signals and no clinically significant or serious adverse events in participants receiving oral Endoxifen.
Tolerability: Oral Endoxifen was well tolerated at each dose level throughout the study.
Pharmacokinetics: Oral Endoxifen yielded blood levels that met or exceeded the published therapeutic levels in the adjuvant setting in breast cancer patients.
We are developing Oral Endoxifen with the hope that it can augment current breast cancer therapy.
“Window of Opportunity.” The Window of Opportunity is described as the time from the diagnosis of breast cancer until surgery. Because orally administered endoxifen achieves a steady-state in ~ 7-days, we believe there may be an advantage to ‘turn-down” the tumor cell activity prior to surgery. Therefore, we have initiated a Phase 2 clinical study to determine if our proprietarty Oral Endoxifen reduces tumor cell activity from the time of diagnosis until surgery.
“Tamoxifen Refractory.” 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 therefore have an increased risk for breast cancer recurrence.
The liver breaks tamoxifen into active metabolites, including endoxifen. It can take from over one month to as long as 6 months of daily tamoxifen administration to achieve a steady-state of endoxifen, whereas our Phase 1 study showed that it takes approximately 7-days to achieve a steady state of endoxifen from daily Oral Endoxifen administration.
Because low endoxifen levels in breast cancer patients who take oral tamoxifen correlate with an increased risk of developing new tumors or recurrence, the delay in achieving a steady state of endoxifen levels could have an impact on breast cancer patients after their initial treatment.
We plan to commence a Phase 2 study of our proprietary Oral Endoxifen in patients who are “refractory” to tamoxifen.
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.