Sometimes called “compassionate use,” expanded access is a potential pathway for a patient with serious disease or condition, or an immediately life-threatening condition, to gain access to an investigational medical product (drug, biologic, or medical device) for treatment outside of clinical trials when no comparable or satisfactory alternative therapy options are available
Atossa Genetics Inc. (ATOS), a clinical-stage biopharmaceutical company developing novel therapeutics and delivery methods to treat breast cancer and other breast conditions, updated (Thursday) the status of the pre-menopausal, estrogen-receptor positive (ER+) breast cancer patient who received preoperative oral Endoxifen therapy under an FDA-approved “expanded access” program. The purpose of this therapeutic approach was to reduce the activity of the cancer cells prior to surgery. The patient received daily doses of Atossa’s oral Endoxifen for approximately three weeks prior to surgery. There were no safety or tolerability issues and her surgery was completed successfully. To determine if the oral Endoxifen reduced the biological activity of the cancer cells, the test results obtained from the initial biopsy were compared with those from the specimen obtained during surgery. A reduction of the cancer cell biological activity was observed by a significant reduction in estrogen receptor content of the tumor. Endoxifen interacts with the estrogen receptor preventing it from functioning. Recent research by others suggests that endoxifen also destroys the receptor. Following her diagnosis, the patient sought options to the current standard of care following surgery, which typically consists of ovarian suppression and aromatase inhibitors. Because she was not a candidate for tamoxifen therapy due to low liver enzyme (CYP2D6) activity, and she did not want to go into early menopause, her physician explored other treatment options. This search led to Atossa’s oral Endoxifen and the request to the FDA for expanded access (single-patient) in the “window of opportunity” setting in the U.S. Under the FDA expanded access IND program, the use of Atossa’s proprietary oral Endoxifen is restricted solely to this patient.
Dr. Steven C. Quay, President, and CEO of Atossa stated, “We are very encouraged by these results. There is a significant opportunity and need to reduce cancer cell activity prior to surgery. As such, we are currently conducting a Phase 2 study with our proprietary oral Endoxifen in this pre-operative, or ‘window of opportunity,’ setting in Australia.”
Endoxifen is a cytochrome P450 mediated, the active metabolite of tamoxifen, which is an FDA-approved drug to prevent new as well as recurrent disease in breast cancer patients. Tamoxifen itself must be broken down by the liver into active compounds (metabolites), of which Endoxifen is the most active. Studies by others have shown that breast cancer patients with endoxifen levels of 30 nM and above have a lower risk for developing future breast cancer. Up to half of the patients taking tamoxifen do not produce therapeutic levels of endoxifen, frequently because of limited liver metabolism capability.
Studies by others indicate that endoxifen’s molecular mechanisms of action are concentration dependent and different than that of other anti-estrogens, including fulvestrant. Pathway analysis of differentially regulated genes revealed substantial differences related to endoxifen concentrations including significant induction of cell cycle arrest and markers of apoptosis following treatment with high, but not low, concentrations of endoxifen.
Many patients taking tamoxifen eventually stop responding, becoming tamoxifen refractory. In a small study by others of oral endoxifen use by tamoxifen-refractory patients, endoxifen provided an acceptable safety profile and promising antitumor activity. Another class of drugs called aromatase inhibitors are also frequently used to treat breast cancer; however, they are not FDA-approved for use in pre-menopausal women and can only be given to pre-menopausal women in conjunction with drugs for ovarian suppression/oblation, which can cause cardiovascular and other toxicities. Additionally, 20-30 percent of those taking aromatase inhibitors may experience fractures, bone pain or osteoporosis. Because of these potential advantages, Atossa is developing oral and topical forms of Endoxifen.
Atossa is currently conducting a Phase 2 study of its oral Endoxifen in Australia in the “window of opportunity” between diagnosis of breast cancer and surgery. The Pilot Phase of the study will initially enroll up to eight newly-diagnosed patients with ER+ and HER2 negative (HER2-) stage 1 or 2 invasive breast cancer, requiring mastectomy or lumpectomy. Patients will receive Atossa’s proprietary oral Endoxifen for at least 21 days from the time of diagnosis up to the day of surgery. Provided tumor activity reduction is demonstrated in at least two patients, an additional 17 patients will be enrolled for a total of 25. The primary endpoint is to determine if the administration of oral Endoxifen reduces tumor activity as measured by Ki-67. The secondary endpoints are safety and tolerability and assessment of the study drug on expression levels of both estrogen and progesterone receptors. The impact on additional markers of cellular activity will also be explored. The Phase 2 study is being conducted on behalf of Atossa by CPR Pharma Services Pty Ltd., Thebarton, SA, Australia. CPR Pharma recently completed the successful Phase 1 study of Atossa’s oral and topical Endoxifen in women.