BZL101 oral botannical entering phase II

[Rich66]

BZL101 is an oral drug designed for the treatment of advanced breast cancer with a novel mechanism of action. BZL101 targets diseased cells while leaving normal cells healthy and intact. Normal cells depend primarily on the citric acid cycle (>85%) and very little on glycolysis (<7%) for energy production. In contrast, cancer cells depend largely on glycolysis (>85%) for energy production. BZL101 stops the production cycle of energy in cancer cells by inhibiting glycolysis. This leads to DNA damage and cancer cell death while normal cells remain unharmed.
Antiproliferative Activity
BZL101 was evaluated for antiproliferative activity on five breast cancer cell lines (SK-BR-3, MCF7, MDA-MB-231, BT-474, and MCNeuA). BZL101 showed >50% growth inhibition on a panel of breast, lung, prostate and pancreatic cancer cell lines. BZL101 at the same dose did not cause >25% of growth inhibition on normal human mammary cells (HuMEC), demonstrating selectivity to cancer cells. BZL101 was also orally active in preventing tumor formation in a mouse xenograph model.
Phase 1 Clinical Results
Bionovo’s lead cancer candidate has been evaluated in two Phase 1 clinical trials and a total of 47 women with advanced breast cancer have been treated with BZL101. Data from the Phase 1 clinical trials of BZL101 indicate the drug is well tolerated and safe for clinical use.
Next Steps: Phase 2 Clinical Trial
A multi-center, Phase 2, open-label, non-randomized clinical trial to assess ongoing safety and preliminary efficacy of BZL101 for the treatment of metastatic breast cancer is being conducted under the directorship of Dr. Charles L. Shapiro at the Ohio State University Medical Center. Once a maximum tolerated dose is determined from the second Phase 1, dose escalation trial, a total of 80 women with histologically confirmed breast cancer and measurable stage IV disease will be enrolled to the Phase 2 trial. Of the 80 women, 40 will have hormone receptor-positive disease and 40 will have hormone receptor-negative disease. The primary outcome measure will be response to therapy evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST). Secondary measures of efficacy will include: duration of overall objective response, progression-free survival, overall survival, and patient reported quality of life measures. Recruitment for the clinical trial is taking place at 17 clinical sites throughout the United States. Click here to visit Bionovo's BZL101 clinical trial website.

About the Principal Investigator
Dr. Charles L. Shapiro is an Associate Professor of Internal Medicine in the Division of Hematology/Oncology. He is the Director of Breast Medical Oncology, Co-Director of the Comprehensive Breast Health Services, and Director of the Lance Armstrong Center of Excellence at Ohio State University Medical Center (OSUMC) and Comprehensive Cancer Center (CCC). Dr. Shapiro’s research interests are focused on the long-term side effects of adjuvant therapy, and the development of novel therapies for breast cancer. In particular, he has studied anthracycline-related cardiac effects and the impact of chemotherapy-induced ovarian failure on skeletal health in young women. He is currently the principal investigator on a randomized Cancer and Leukemia Group B (CALGB) trial evaluating zolendronic acid in women with chemotherapy-induced ovarian failure. He also serves as principal investigator on a number of investigator-initiated trials in advanced breast cancer combining taxanes with biological agents including bortezomib, bevacizumab, and low-dose suramin. Dr. Shapiro is the Director of the Clinical Scientific Review Committee for the OSUCCC, and the Chair of the Symptom Intervention Committee of the CALGB. In addition, he co-chairs the ASCO Committee on adult survivorship guidelines, and has been appointed to the newly formed NCI Symptom Management and Health-Related Quality of Life Steering Committee.

[Rich66]

EMERYVILLE, Calif., Nov. 3 /PRNewswire-FirstCall/ -- Bionovo, Inc. (Nasdaq: BNVI) announced today that its drug candidate for metastatic breast cancer, BZL101, will advance to Phase 2 clinical testing after the successful completion of a second Phase 1 clinical trial.
The Phase 1B clinical trial was conducted to identify the maximum tolerated dose of BZL101 and to determine the safety and feasibility of the company's novel, oral, anticancer treatment. A total of 27 women with metastatic breast cancer were enrolled to this Phase 1B trial. A total of 48 women with advanced breast cancer have been treated with BZL101 in all clinical trials to date. Results from the Phase 1B show Bionovo's lead drug candidate for advanced breast cancer continues to be safe and well-tolerated, with early signs of clinical efficacy. The company will present the findings from the Phase 1B in an oral presentation of the best scoring abstracts at the Society of Integrative Oncology's Fifth International Conference on November 20, 2008 in Atlanta, Georgia.
"We are encouraged by the results of the Company's second Phase 1 trial in women with advanced breast cancer," said Isaac Cohen, President and CEO, Bionovo. "There are currently over 160,000 women in the United States living with advanced breast cancer who are eagerly awaiting an oral anticancer drug with minimal side effects and the ability to extend life without profoundly diminishing quality of life. We believe BZL101 may be an important new anticancer agent because its biological selectivity allows the drug to kill cancer cells without affecting normal cells. This will lead to a dramatically lower side effect profile."

[Rich66]

Breast Cancer Res Treat. 2007 Sep;105(1):17-28. Epub 2006 Nov 17. Links

Phase I trial and antitumor effects of BZL101 for patients with advanced breast cancer.

Rugo H, Shtivelman E, Perez A, Vogel C, Franco S, Tan Chiu E, Melisko M, Tagliaferri M, Cohen I, Shoemaker M, Tran Z, Tripathy D.
University of California, San Francisco Carol Franc Buck Breast Care Center, San Francisco, USA.
BACKGROUND: Botanical therapies are often used by breast cancer patients yet few clinical trials have evaluated their safety and efficacy. We studied mechanisms of activity and performed a phase I clinical trial in patients with advanced breast cancer to evaluate BZL101, an aqueous extract from Scutellaria barbata. METHODS: Preclinical studies were conducted in vitro to characterize cell death induced by BZL101. In a phase I trial, eligible patients had histologically confirmed, measurable metastatic breast cancer. Treatment consisted of 350 ml per day of oral BZL101, administered as sole cancer therapy until disease progression, toxicity or personal preference to discontinue. Primary endpoints were safety, toxicity and tumor response. RESULTS: BZL101 extract induced strong growth inhibition and apoptosis of breast cancer cell lines. In the phase I trial, 21 patients received BZL101. Mean age was 54 years (30-77) and mean number of prior treatments for metastatic disease was 3.9 (0-10). There were no grade III or IV adverse events (AEs). The most frequently reported BZL101-related grade I and II AEs included: nausea (38%), diarrhea (24%), headache (19%) flatulence (14%), vomiting (10%), constipation (10%), and fatigue (10%). Sixteen patients were evaluable for response. Four patients had stable disease (SD) for >90 days (25%) and 3/16 had SD for >180 days (19%). Five patients had objective tumor regression, one of which was 1 mm short of a PR based on RECIST criteria. CONCLUSIONS: BZL 101 inhibits breast cancer cell lines by inducing apoptosis. In a phase I clinical trial, BZL101 was safe and had a favorable toxicity profile. BZL101 demonstrated encouraging clinical activity in this heavily pretreated population.

[Rich66]

Cancer Biol Ther. 2008 Apr;7(4):577-86. Epub 2008 Jan 7. Links

Molecular mechanisms underlying selective cytotoxic activity of BZL101, an extract of Scutellaria barbata, towards breast cancer cells.

Fong S, Shoemaker M, Cadaoas J, Lo A, Liao W, Tagliaferri M, Cohen I, Shtivelman E.
BioNovo, Inc., Emeryville, California 94608, USA.
We studied the mechanism of the cytotoxic activity of BZL101, an aqueous extract from the herb Scutellaria barbata D. Don, which is currently in phase II clinical trial in patients with advanced breast cancer. The phase I trial showed favorable toxicity profile and promising efficacy. We report here that BZL101 induces cell death in breast cancer cells but not in non-transformed mammary epithelial cells. This selective cytotoxicity is based on strong induction by BZL101 of reactive oxygen species (ROS) in tumor cells. As a consequence, BZL101 treated cancer cells develop extensive oxidative DNA damage and succumb to necrotic death. Data from the expression profiling of cells treated with BZL101 are strongly supportive of a death pathway that involves oxidative stress, DNA damage and activation of death-promoting genes. In breast cancer cells oxidative damage induced by BZL101 leads to the hyperactivation of poly (ADP-ribose) polymerase (PARP), followed by a sustained decrease in levels of NAD and depletion of ATP, neither of which are observed in non-transformed cells. The hyperactivation of PARP is instrumental in the necrotic death program induced by BZL101, because inhibition of PARP results in suppression of necrosis and activation of the apoptotic death program. BZL101 treatment leads to the inhibition of glycolysis selectively in tumor cells, evident from the decrease in the enzymatic activities within the glycolytic pathway and the inhibition of lactate production. Because tumor cells frequently rely on glycolysis for energy production, the observed inhibition of glycolysis is likely a key factor in the energetic collapse and necrotic death that occurs selectively in breast cancer cells. The promising selectivity of BZL101 towards cancer cells is based on metabolic differences between highly glycolytic tumor cells and normal cells.

[Rich66]

The generic form:

1: Nan Fang Yi Ke Da Xue Xue Bao. 2008 Oct;28(10):1835-7. Links

[Antitumor and immune-modulating effects of Scutellaria barbata extract in mice bearing hepatocarcinoma H22 cells-derived tumor.]

[Article in Chinese]


Dai ZJ, Liu XX, Tang W, Xue Q, Wang XJ, Ji ZZ, Kang HF, Diao Y.
Department of Oncology, Second Hospital of Xi'an Jiaotong University, Xi'an 710004, China. E-mail: dzj0911@126.com.
OBJECTIVE: To investigate the effects of Scutellaria barbata extract (ESB) in suppressing tumor growth and modulating the immune functions in mice bearing tumors derived from hepatocarcinoma H22 cells. METHODS: Fifty mice inoculated subcutaneously with H22 cells were equally divided into the model group, high-, moderate-, and low-dose ESB groups, and 5-Fu group, with corresponding treatments for 10 days. Another 10 mice with only saline injection served as the normal control group. The body weight, tumor mass, thymus index and spleen index of the mice were measured, and the lymphocyte proliferation activity, NK cell activity and interleukin-2 (IL-2) production by the splenocytes were detected. RESULTS: Moderate- and high-dose ESB significantly suppressed the tumor growth with tumor inhibition rate of 28.68% and 36.98%, respectively. ESB treatment at moderate and high doses significantly increased the thymus index and spleen index (P<0.01), which were decreased significantly in 5-Fu group. The lymphocyte proliferation activity, NK cell activity and IL-2 production by the splenocytes were significantly lower in the model group than in the normal group (P<0.05). Compared with the model group, ESB at the high dose obviously increased the three indexes above mentioned. The NK cell activity was also significantly improved in moderate-dose ESB group (P<0.05). CONCLUSION: ESB can suppress the growth of H22 implant tumor and enhance the immune function of the tumor-bearing mice.

[chrisy]

I've seen the info you posted from the phase I study at UCSF. The response rate of stable disease (and one almost partial response) is encouraging, especially considering the number of prior treatments some of the participants had (0-10).

[Rich66]

Bionovo Presents Positive Results from Phase 1B Trial of BZL101 for Metastatic Breast Cancer at the Society for Integrative Oncology EMERYVILLE, Calif., Nov. 20 /PRNewswire-FirstCall/ -- Bionovo, Inc. (Nasdaq: BNVI) announced the company will present results from the Phase 1B clinical trial of their lead drug candidate for advanced metastatic breast cancer, BZL101, at the Society for Integrative Oncology's Fifth International Conference in Atlanta, Georgia. The Company's oral presentation was selected as a top scoring abstract and will be presented as a part of the Best of the SIO Session on November 20, 2008.
The Phase 1B clinical trial was conducted at seven US clinical sites under the directorship of Dr. Charles Shapiro, Professor of Medicine and Director of Breast Oncology at Ohio State University. The primary objective of the study was to identify the maximum tolerated dose of BZL101 and to determine the safety and feasibility of the company's novel, oral anticancer therapy. A total of 27 women with metastatic breast cancer were enrolled to the Phase 1B trial. To date, 48 women with advanced breast cancer have been treated with BZL101 in two early phase trials. Results from the Phase 1B trial show that BZL101 continues to be safe and well-tolerated, with early signs of clinical efficacy.
Seventeen of the twenty-seven participants in the Phase 1B clinical trial were evaluable according to the Response Evaluation Criteria in Solid Tumors (RECIST). Of these seventeen evaluable women, six were stable on study medication for greater than 90 days and three were stable on study medication for greater than 180 days. One active patient on the trial has been stable for 12 months with radiographic evidence of tumor shrinkage.
"We are eager to advance BZL101 to Phase 2 clinical testing as the drug continues to have an improved safety profile over more traditional chemotherapeutic agents, and shows encouraging clinical activity in a cohort of women who have been heavily, but unsuccessfully, pretreated for metastatic breast cancer," said Dr. Mary Tagliaferri, President and Chief Medical Officer of Bionovo.
Overall compliance with study medication was excellent with 90% of prescribed doses taken. The most common side effects experienced by women in the Phase 1B clinical trial were mild diarrhea and nausea.
"We are encouraged by the results of the Company's second Phase 1 trial in women with advanced breast cancer," said Isaac Cohen, Chairman and CEO of Bionovo. "There are currently over 160,000 women in the United States living with advanced breast cancer who are eagerly awaiting an oral anticancer drug with minimal side effects and the ability to extend life without profoundly diminishing their quality of life. We believe BZL101 may be an important new anticancer agent because its biological selectivity allows the drug to kill cancer cells without affecting normal cells. This will lead to a dramatically lower side effect profile."
Phase 2 Clinical Trial
The Phase 2 clinical trial is currently enrolling 80 women diagnosed with advanced, measurable breast cancer who have received no more than two prior cytotoxic cancer therapies.
The trial is open at the following clinical sites under the directorship of the listed investigators:

Institution Site Principle Investigator
California Cancer Care Inc.,
Greenbrae/San Mateo, California Dr. Peter Eisenberg
Columbia Presbyterian Medical Center,
New York, New York Dr. Dawn Hershman
Comprehensive Cancer Center at Desert Regional
Medical Center, Palm Springs, California Dr. Gail Leichman
Duke University, Durham, North Carolina Dr. Gretchen Kimmick
Lynn Regional Cancer Center, Boca Raton, Florida Dr. Reshma Mahtani
MD Anderson, Houston, Texas Dr. Banu Arun
Memorial Cancer Institute, Hollywood, Florida Dr. Alejandra Perez
Montefiore Medical Center, Bronx, New York Dr. Tianhong Li
Ohio State University, Columbus, Ohio Dr. Ewa Mrozek
St. Vincent's Medical Center, New York, New York Dr. Paula Klein
University of California, San Francisco, California Dr. Hope Rugo
University of Chicago, Chicago, Illinois Dr. Gini Fleming
University of Miami, Miami, Florida Dr. Alberto Montero
University of Pittsburg Magee Women's Hospital,
Pittsburg, Pennsylvania Dr. Adam Brufsky
University of Southern California, Los Angeles,
California Dr. Agustin Garcia
University of Texas, Southwestern, Dallas, Texas Dr. Jenny Li

BZL101
BZL101 is an oral drug designed for the treatment of advanced breast cancer with a novel mechanism of action. BZL101 targets diseased cells while leaving normal cells healthy and intact. Normal cells depend primarily on the citric acid cycle (>85%) and very little on glycolysis (<7%) for energy production. Cancer cells depend largely on glycolysis (>85%) for energy production. BZL101 stops the production cycle of energy in cancer cells by inhibiting glycolysis. This leads to DNA damage and cell death in cancer cells while normal cells remain unharmed.
There are currently no effective therapeutic cures for advanced breast cancer and treatment is primarily aimed at palliation of symptoms as well as improving overall survival. Over 200,000 women in the United States are diagnosed with breast cancer each year and breast cancer is the second leading cause of cancer death in women. Although survival after breast cancer treatment is improving, there are still over 40,000 deaths per year due to the disease in the Unites States alone.
Bionovo, Inc.
Bionovo is a pharmaceutical company focused on the discovery and development of safe and effective treatments for women's health and cancer, markets with significant unmet needs and billions in potential annual revenue. The company applies its expertise in the biology of menopause and cancer to design new drugs derived from botanical sources which have novel mechanisms of action. Based on the results of early and mid-stage clinical trials, Bionovo believes they have discovered new classes of drug candidates within their rich pipeline with the potential to be leaders in their markets. Bionovo is headquartered in Emeryville, California and is traded on the NASDAQ Capital Market under the symbol, "BNVI". For more information about Bionovo and its programs, visit http://www.bionovo.com.
Forward Looking Statements
This release contains certain forward-looking statements relating to the business of Bionovo, Inc. that can be identified by the use of forward-looking terminology such as "believes," "expects," or similar expressions. Such forward-looking statements involve known and unknown risks and uncertainties, including uncertainties relating to product development, efficacy and safety, regulatory actions or delays, the ability to obtain or maintain patent or other proprietary intellectual property protection, market acceptance, physician acceptance, third party reimbursement, future capital requirements, competition in general and other factors that may cause actual results to be materially different from those described herein as anticipated, believed, estimated or expected. Certain of these risks and uncertainties are or will be described in greater detail in our filings with the Securities and Exchange Commission, which are available at http://www.sec.gov. Bionovo, Inc. is under no obligation (and expressly disclaims any such obligation) to update or alter its forward-looking statements whether as a result of new information, future events or otherwise.