NOV-002 is an injectable small-molecule compound based on a proprietary formulation of oxidized glutathione, or "GSSG" in a 1000:1 ratio of GSSG with cisplatin, which improves the bioavailability of NOV-002 in vivo. NOV-002 is believed to act as an immunomodulator and anti-tumor agent by regulating redox-sensitive cell signaling pathways. NOV-002 has been administered to approximately 1,000 cancer patients in clinical trials. NOV-002 has an extensive safety database and has been shown to be well-tolerated. Moreover, NOV-002 can be distinguished from other pharmaceuticals on the market or in development because, in several clinical trials, NOV-002 displayed a unique profile of safety, potentiation of chemotherapy (increased survival rates and/or better anti-tumor effects) and improved recovery from chemotherapy toxicity. This profile was not observed in the Phase 3 trial in NSCLC. Recent findings suggest that, due to its anti-tumor immunomodulatory activities, NOV-002 may be particularly well-suited for combination with certain 'immunogenic' chemotherapy agents including cyclophosphamide and doxorubicin which are commonly used to treat breast cancer.



NOV-002 is currently being developed for use in combination with standard of care chemotherapies for the treatment of solid tumors.

NOV-002 in Neoadjuvant Treatment of Breast Cancer
We are developing NOV-002 to treat breast cancer in combination with chemotherapy. Breast cancer remains a serious public health concern throughout the world. According to the American Cancer Society, approximately 192,000 women in the U.S. were expected to be diagnosed with breast cancer in 2009, and approximately 41,000 were expected to die from the disease. Neoadjuvant or preoperative systemic chemotherapy is commonly employed in patients with locally advanced stage-III breast cancer and in some patients with stage-II tumors. Administration of neoadjuvant chemotherapy reduces tumor size, thus enabling breast conservation surgery in patients who otherwise would require a mastectomy. Furthermore, several studies have shown that pathologic complete response (pCR) following neoadjuvant chemotherapy is associated with a significantly higher probability of long-term survival. However, only a small fraction of patients with HER-2 negative breast cancer achieve a pCR with standard chemotherapy.

A U.S. Phase 2 trial to evaluate the ability of NOV-002 to enhance the effectiveness of such chemotherapy commenced in June 2007 at the Medical University of South Carolina (MUSC) Hollings Cancer Center. The trial is currently ongoing at the Braman Family Breast Cancer Institute at the Sylvester Comprehensive Care Center at the University of Miami Miller School of Medicine (Sylvester). Alberto Montero, MD, Assistant Professor of Medicine at Sylvester, is the Principal Investigator. This Phase 2 open-label, single-arm, Simon 2-Stage trial was designed to determine if preoperative administration of NOV-002 in combination with doxorubicin and cyclophosphamide followed by docetaxel in up to 46 patients with stage IIB-IIIC HER-2/neu negative invasive breast cancer results in at least a doubling in the rate of pathologic complete response (pCR) compared to a historical control. For NOV-002 to be declared active at the end of the trial, a minimum of 12 patients must achieve a pCR.

On July 12, 2010, we announced the 12th pathologic complete response (pCR) in the Phase 2 breast cancer trial, thereby achieving the tumor response target of the trial. A total of 39 patients have been enrolled in the Phase 2 breast cancer trial. However, the 12 pCRs were achieved in the first 31 patients who completed chemotherapy and underwent surgery, for a current pCR rate of 39%. The historical control pCR rate is in the range of 10-20%. We continue to enroll patients in the trial, and some patients are still in the treatment stage. Therefore, the current pCR rate of 39% does not represent a final result, but rather a preliminary result based only on the first 31 patients in the trial. We submitted the trial results for presentation to the AACR Breast Cancer Symposium taking place in San Antonio, TX, in December 2010.

We intend to work with Dr. Montero, Sylvester Comprehensive Cancer Center, as well as key opinion leaders and the FDA on a design for a possible larger randomized controlled trial in breast cancer.

We believe that activity of NOV-002 in this trial may reflect its immunomodulatory effects in combination with the specific cytotoxic chemotherapeutic agents employed. Cytotoxic chemotherapy is generally regarded as immunosuppressive because of toxicity towards dividing cells in the bone marrow and peripheral lymphoid tissue. It is now understood, however, that some chemotherapeutic agents referred to as "immunogenic" may enhance the antitumor effects of immunotherapy by acting directly on the tumor and host environment. Immunogenic chemotherapy agents commonly used in the treatment of breast cancer include cyclophosphamide, anthracyclines (such as doxorubicin) and gemcitabine. NOV-002 is believed to act via generation of oxidative signals that mimic physiological regulatory mechanisms for a variety of redox-sensitive cell processes and functions. In tumors, this results in inhibition of cell proliferation and of tumor invasiveness/metastasis. Of particular interest in the context of breast cancer therapy, NOV-002 displays multiple forms of in vivo immunomodulation which, when combined with immunogenic chemotherapy, may increase anti-tumor efficacy. Thus, NOV-002 alone increased effector T cell responsiveness to tumor antigens and elevated levels of memory T cells in tumors and spleen in animal tumor models. When combined in such models with the immunogenic chemotherapy agent cyclophosphamide, NOV-002 increased survival and decreased tumor growth compared to chemotherapy alone. It also inhibited the activity of myeloid-derived T cell suppressor cells. Such data supports the hypothesis that the immunomodulatory activities of NOV-002 may enhance the anti-cancer efficacy of immunogenic chemotherapy such as that commonly used in treating breast cancer.

NOV-002 in Chemotherapy (Platinum)-Resistant Ovarian Cancer
We are also developing NOV-002 to treat platinum-resistant ovarian cancer. According to the American Cancer Society, approximately 22,000 U.S. women were expected to be diagnosed with ovarian cancer in 2009 and 15,000 women are expected to die from it. There is a lack of effective treatment, particularly in the case of patients who are chemotherapy refractory (those who do not respond to chemotherapy) or resistant (those who relapse shortly after receiving chemotherapy).

First-line chemotherapy treatment is typically the same in ovarian cancer as in NSCLC, i.e., carboplatin and paclitaxel chemotherapy in combination. Doxorubicin and topotecan alternate as second- and third-line chemotherapy treatments.

Refractory/resistant ovarian cancer patients have a very poor prognosis because they are faced with inadequate therapeutic options. Once a woman’s ovarian cancer is defined as platinum resistant, the chance of having a partial or complete response to further platinum therapy is typically less than 10%, according to an article by A. Berkenblit in the June 2005 issue of the Journal of Reproductive Medicine.

In a single-arm, U.S. Phase 2 chemotherapy-resistant ovarian cancer trial at the Massachusetts General Hospital and Dana-Farber Cancer Institute from July 2006 through May 2008, NOV-002 (plus carboplatin) slowed progression of the disease in 60% of evaluable patients (9 out of 15 women). The median progression-free survival was 15.4 weeks, almost double the historical control of 8 weeks. These results were presented at the American Society of Clinical Oncology in May 2008.

NOV-002 in NSCLC
We announced in February 2010 that the primary endpoint of improvement in overall survival was not met in our pivotal Phase 3 trial of NOV-002 in advanced NSCLC. Following evaluation of the detailed trial data, we announced in March 2010 that the secondary endpoints also were not met in the trial. Adding NOV-002 to paclitaxel and carboplatin chemotherapy was not statistically or meaningfully different in terms of efficacy-related endpoints or recovery from chemotherapy toxicity versus chemotherapy alone. NOV-002 was safe, as it did not add to the overall toxicity of chemotherapy. We expect to present detailed results of this Phase 3 trial at the 2010 annual meeting of the American Society of Clinical Oncology (ASCO) in June 2010.

This randomized, controlled, open-label Phase 3 trial, was conducted under a Special Protocol Assessment and Fast Track designation, enrolled 903 patients with stage IIIb/IV NSCLC, and included all histological subtypes. The trial, conducted across approximately 100 clinical sites in 12 countries, evaluated NOV-002 in combination with first-line paclitaxel and carboplatin chemotherapy (in 452 patients) versus paclitaxel and carboplatin alone. The primary efficacy endpoint of the trial was improvement in overall survival. The secondary endpoints included progression-free survival, response rate and duration of response, recovery from chemotherapy-induced myelosuppression, determination of immunomodulation, quality of life and safety. Based on the results from the Phase 3 trial, we have determined to discontinue development of NOV-002 for NSCLC in combination with first-line paclitaxel and carboplatin chemotherapy.

We commenced the Phase 3 trial on the basis of three previously conducted Phase 2 trials (two conducted in Russia and one in the U.S) that had demonstrated clinical activity and safety of NOV-002 in combination with first-line chemotherapy in advanced NSCLC.

Advanced NSCLC is a very difficult to treat indication. Platinum-based chemotherapy regimens are standard first-line treatment for advanced NSCLC patients. During treatment, patients are subject to serious chemotherapy-induced adverse effects. According to results of 12 Phase 3 clinical trials published from 2001-2008, the one-year survival rate for patients receiving paclitaxel and carboplatin first-line therapy was on average only about 40%, the weighted average for median survival was 9.7 months and the objective tumor response (defined as greater than 30% tumor shrinkage) rate was about 27%. Overall, fewer than 5% of advanced non-small cell lung cancer patients survive five years. Improving on the standard of care in unselected advanced NSCLC remains challenging and elusive. Approximately 20 Phase 3 first-line trials have failed in NSCLC, including some drugs that are on the market for other cancer indications. The compounds that went into these Phase 3 trials had promising Phase 2 results. Furthermore, the two compounds that did demonstrate a statistically significant improvement in survival in advanced NSCLC when added to first-line chemotherapy, did not succeed when combined with other first-line chemotherapy agents. For example, Roche’s AVASTINreg;, which succeeded in NSCLC with paclitaxel and carboplatin chemotherapy (2 months median survival advantage), failed in a Phase 3 trial in NSCLC with gemcitabine and cisplatin. Lilly’s ERBITUX®, which succeeded in NSCLC with vinorelbine and cisplatin chemotherapy (5 week median survival advantage), did not work in two separate NSCLC Phase 3 trials when combined with paclitaxel and carboplatin chemotherapy or with taxane and carboplatin chemotherapy.

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