Aeterna Zentaris: Encouraging Preclinical Data for Perifosine in Hodgkin Lymphoma Presented at ASH Meeting

Aeterna Zentaris: Encouraging Preclinical Data for Perifosine in Hodgkin Lymphoma Presented at ASH Meeting

QUÉBEC CITY, Dec. 12, 2011 /PRNewswire/ - Aeterna Zentaris Inc. (NASDAQ: AEZS) (TSX: AEZ) (the "Company") today reported encouraging preclinical data for its oral anticancer Akt inhibitor, perifosine, in Hodgkin Lymphoma. In vitro data from Hodgkin lymphoma (HL) cell lines showed that perifosine combined with sorafenib induced increased apoptosis, while in vivo data for the same combination treatment for HL significantly increased survival in mice. Data were presented over the weekend by Silvia Locatelli, PhD, Fondazione IRCCS Instituto Nazionale Tumori, Milan, Italy, during the American Society of Hematology (ASH) Annual Meeting and Exposition currently being held in San Diego, California, until December 13, 2011.
Dr. Carlo-Stella, associate professor of Oncology at the University of Milano and head of the Experimental Therapeutics Unit at Humanitas Cancer Center stated, "Identification of rationale drug combinations represent the strategy to be pursued to correct aberrant cancer cell signalling and optimize targeted therapy. Our preclinical study investigating perifosine and sorafenib combination therapy for HL is a typical example of translational research. Our study has in fact shown that perifosine and sorafenib exert a potent cytotoxic activity against HL cell lines in vitro and in vivo in mice. Additionally, biomarkers have also been identified. Based on these data, a Phase 2 study is currently ongoing. Thus, laboratory data can be efficiently used to build up Phase 2 clinical studies. We believe that this bench-to-bedside model is required for designing clinical trials exploring rationale combinations of targeted agents."
Juergen Engel, PhD, President and CEO of Aeterna Zentaris added, "The encouraging preclinical results underline perifosine's potential in combination therapy with anti-cancer agents. We are looking forward to see how these preclinical results will translate into an improved clinical outcome in this tumor indication."
The Study
The study was conducted to investigate, in vitro and in vivo, the activity and mechanism(s) of action of perifosine in combination with sorafenib by using three HL cell lines (HD-MyZ, L-540, HDLM-2).
Results
In the in vitro experiments perifosine/sorafenib treatment resulted in synergistic cell growth inhibition and cell death induction in HD-MyZ and L-540 cell lines, but not in the HDLM-2 cell line. Cell cycle arrest, down-modulating of the MAPK and PI3K/Akt pathways as well as Caspase-independent cell death was observed, which was associated with severe mitochondrial dysfunction. Further, expression of genes involved in amino acid metabolism, cell cycle, DNA replication and cell death was shown to be modulated. In addition, overexpression of the tribbles homologue 3 [TRIB3] was observed.
In vivo, perifosine/sorafenib treatment significantly increased survival in the HD-MyZ model (45 vs 81 days, as compared to controls), with 25% tumor free mice at the end of the 200-day observation period. In the L-540 model, subcutaneous tumor volume was also reduced as compared to controls (by 42%), perifosine (by 35%) or sorafenib (by 46%) alone. In HD-MyZ and L-540 but not HDLM-2, the combined treatment induced an increase in tumor necrosis (2- to 8-fold, P ≤.0001) and in tumor apoptosis (2- to 2.5-fold, P ≤.0001)
Conclusions
In 2 of 3 HL cell lines, perifosine/sorafenib combination treatment induced potent antitumor effects. Striking increase of mitochondrial injury and apoptosis, and marked reduction of cell viability was observed in the in vitro experiments. In vivo combination treatment increased survival and inhibited tumor growth.
The abstract titled, "Preclinical Rationale for the Use of Combined Treatment with the Akt Inhibitor Perifosine and the Multikinase Inhibitor Sorafenib in Hodgkin Lymphoma", Locatelli S.L., Giacomini A., Guidetti A., Cleris L., Magni M., Di Nicola M., Mortarini R., Gianni A.M., Anichini A., Carlo-Stella C. can be viewed online through the following link.
About Hodgkin Lymphoma
Hodgkin Lymphoma (HL) is a cancer of the immune system. The two major types of HL are classical HL and nodular lymphocyte-predominant HL. The most common symptom of HL is the painless swelling of the lymph nodes in the neck, underarm or chest. Other symptoms include fever, weight loss, fatigue, or night sweats. According to the National Cancer Institute, there will be 8,830 news cases of HL in the United States in 2011, resulting in 1,300 deaths.
About Perifosine
Perifosine is a novel, oral anticancer treatment that inhibits Akt activation in the phosphoinositide 3-kinase (PI3K) pathway. The product works by interfering with membranes of cancer cells thereby inhibiting Akt signaling which then affects cell death, growth, differentiation and survival. Perifosine, in combination with chemotherapeutic agents, is currently being studied for the treatment of colorectal cancer, multiple myeloma and other cancers, and is the most advanced anticancer agent of its class. Perifosine, as monotherapy, is being explored in other indications. The FDA has granted perifosine orphan-drug designation in multiple myeloma and neuroblastoma, and Fast Track designations in both multiple myeloma and refractory advanced colorectal cancer. Additionally, an agreement was reached with the FDA to conduct the Phase 3 trials in both of these indications under a Special Protocol Assessment. Perifosine has also been granted orphan medicinal product designation from the European Medicines Agency (EMA) in multiple myeloma. Furthermore, perifosine has received positive Scientific Advice from the EMA for both the multiple myeloma and advanced colorectal cancer programs, with ongoing Phase 3 trials for these indications expected to be sufficient for registration in Europe. Perifosine rights have been licensed to Keryx Biopharmaceuticals, Inc. (NASDAQ: KERX) for North America, to Yakult Honsha for Japan, to Handok for Korea and to Hikma Pharmaceuticals for the Middle East and North Africa (MENA) region.
About Aeterna Zentaris Inc.
Aeterna Zentaris is a late-stage oncology drug development company currently investigating potential treatments for various cancers including colorectal, multiple myeloma, endometrial, ovarian, prostate and bladder cancer. The Company's innovative approach of "personalized medicine" means tailoring treatments to a patient's specific condition and to unmet medical needs. Aeterna Zentaris' deep pipeline is drawn from its proprietary discovery unit providing the Company with constant and long-term access to state-of-the-art therapeutic options. For more information please visit www.aezsinc.com
Forward-Looking Statements
This press release contains forward-looking statements made pursuant to the safe harbour provisions of the U.S. Securities Litigation Reform Act of 1995. Forward-looking statements involve known and unknown risks and uncertainties that could cause the Company's actual results to differ materially from those in the forward-looking statements. Such risks and uncertainties include, among others, the availability of funds and resources to pursue R&D projects, the successful and timely completion of clinical studies, the risk that safety and efficacy data from any of our Phase 3 trials may not coincide with the data analyses from previously reported Phase 1 and/or Phase 2 clinical trials, the ability of the Company to take advantage of business opportunities in the pharmaceutical industry, uncertainties related to the regulatory process and general changes in economic conditions. Investors should consult the Company's quarterly and annual filings with the Canadian and U.S. securities commissions for additional information on risks and uncertainties relating to forward-looking statements. Investors are cautioned not to rely on these forward-looking statements. The Company does not undertake to update these forward-looking statements. We disclaim any obligation to update any such factors or to publicly announce the result of any revisions to any of the forward-looking statements contained herein to reflect future results, events or developments, unless required to do so by a governmental authority or by applicable law.

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