Extended Adjuvant Treatment with Letrozole Improves Outcome in Women with Early-Stage Breast Cancer who Complete 5 Years of Tamoxifen The study published online in the JCO suggests that postmenopausal breast cancer patients who took the aromatase inhibitor Letrozole (Femara) after stopping Tamoxifen three years earlier, on average had a reduced risk of developing a new breast tumor and lower risk of distant metastases compared with former tamoxifen takers who were given placebos. The MA.17 study, led by the National Cancer Institute of Canada Clinical Trials Group, reported in 2003, that letrozole was effective in reducing the risk of breast cancer recurrence if initiated 3 months after completing 5 years of tamoxifen therapy. The new data from the same study showed that this benefit persisted even among women who had finished tamoxifen one to seven years before starting letrozole. Among 1,579 women who had been taking a placebo in the earlier part of the study and then switched to letrozole (PLAC-LET group), 95.1% remained free of breast cancer six years later and 97.7% remained free of metastasis, compared with 91% and 95.6% respectively, of the 804 women who continued taking a placebo (PLAC-PLAC group). In a separate analysis of that same trial, researchers found that the reduced risk of breast cancer recurrence persisted among all age groups, including women over 70. The new finding suggests that younger women could benefit from taking an aromatase inhibitor once they go into menopause, even if they have been off tamoxifen for quite a while, says Nancy Lin, a medical oncologist at the Dana-Farber Institute in Boston who wrote an editorial accompanying the study. Source: JCO, ASCO

A Splice Variant of Pyruvate Kinase is Important for Cancer Metabolism and Tumor Growth In 1930, German biochemist Otto Warburg observed that tumor cells have increased

uptake of glucose and lactate production in the presence of oxygen, a process termed aerobic glycolysis.

more on pg-2

FDA Approves TREANDA for the Treat-ment of Patients with CLL Cephalon, Inc. announced that the US FDA has approved TREANDA (R) (bendamustine hydro-chloride), an intravenously administered alkylat-ing agent, for the treatment of patients with chronic lymphocytic leukemia (CLL). Cephalon anticipates that TREANDA(R) will be available to physicians and patients in the United States in April 2008.

more on pg-5 Abbott Collaborates with Genentech, Roche and OSI on Lung Cancer Drug Test Abbott's molecular diagnostics business has en-tered into an agreement with Genentech, F. Hoffmann-La Roche and OSI Pharmaceuticals to develop a gene test to potentially assess the clini-cal benefit of Tarceva.

more on pg -6

In This Issue….. Clinical Development Pg-2 • Long-Term Protection with

Cervarix • Zevalin(R) Efficacious in

Follicular NHL • Neoadjuvant Therapy for

Triple-Negative Breast Cancer • MyVax(R) Development Suspended Research Highlights Pg-3 • Activation of p53 by a MDM2

Inhibitor • Bcl-2 Antagonist Apogossypol

Superior to Gossypol • Let-7 microrna Suppresses

NSCLC • Yes and PI3K Bind CD95 to Signal

Invasion of GBM Biomarkers Pg-4 • High Estrogen Associated

with Breast Cancer Recur-rence

• CETC Measurement in Breast Cancer

• Methylation of Promoter Region of Genes in NSCLC

• Vermillion's Marker Panel for Ovarian Cancer

Regulatory Focus Pg-5 • FDA Panel Votes for

Restricted ESA Use • Tyverb (lapatinib) European

regulatory Update • Additional Confirmatory

Data for Genasense® • Evoltra Application Withdrawn Business News Pg-6 • EUSA Pharma to Acquire

Cytogen • RAV18 under Agreement

with CMC ICOS Biologics

March 25, 2008 Volume 1, Issue 7

Oxidative phosphorylation and anaerobic glycolysis

From Nature reviews in cancer 2004; 4:891

ONCOLOGY Newsletter March 25, 2008

2

A Splice Variant of Pyruvate Kinase is Important for Cancer Metabolism and Tumor Growth

Contd. from pg 1 Normal cells produce their ATP in the mitochondria through oxidative phosphorylation, unless oxygen is limiting, in which case glucose is converted to lactate to produce ATP. Many tumor cells opt for the second pathway even in the presence of oxygen- known as the ‘Warburg effect’. Warburg postulated that this change in metabolism is the fundamental cause of cancer. The mechanism by which this altered metabolic phenotype is established and whether it is required for tumorigenesis is not understood. Glycolysis produces only two ATP molecules per glucose molecule compared with 38 for complete oxidation. But for a cancer cell it is very efficient to produce ATP quickly to promote growth and proliferation. The pyruvate kinase is the enzyme that regulates the final step of glycolysis and is frequently upregulated in tumors. Lewis Cantley and colleagues now report in a study published in Nature that the human M2 isoform of pyruvate kinase promotes Warburg effect. Among the four isoforms of pyruvate kinase, M1 is expressed in most adult tissues and the M2 isoform, a splice variant of M1, is expressed during embryonic development and preferentially in tumor cells. The authors knockdown M2 isoform of pyruvate kinase and replaced with the M1 isoform and this switch led to reversal of the Warburg effect and reduced lactate production. This was also associated with increased oxygen consumption and reduced ability to form tumors in nude mice. These results demonstrate that M2 pyruvate kinase isoform expression is necessary for aerobic glycolysis and this switch provides a selective growth advantage for tumor growth in vivo. Source: Nature GSK Cervical Cancer Candidate Vaccine Cervarix Demonstrates Protection for More Than Six Years New data demonstrating GSK’s cervical cancer vaccine, Cervarix’s significant protection for women against the four most

common cancer-causing human pailloma virus (HPV) types for 6.5 years, was presented at the Society of Gynecologic Oncologists’ annual meeting in Tampa, FL. HPV types 16, 18, 45 and 31 are responsible for approx. 80% of cervical cancers globally. The study was an extended follow-up analysis of 776 women for 76 months, who had earlier received Cervarix on a 0, 1 and 6 month schedule. Women were evaluated for the presence of HPV DNA by PCR using cervical samples and annual cervical cytology evaluations were performed. Data showed that 100% of women in the study maintained high levels of antibodies against virus types 16 and 18 for nearly 6.5 years. This signifies the longest duration of consistently high antibody levels demonstrated by a cervical cancer vaccine. The vaccine also showed 78% and 60% efficacy in preventing incident infection caused by virus type 45, and 31 respectively. This data can give the GSK vaccine an edge over rival product Gardasil, by Merck & Co, which was granted FDA approval 2 years ago. Source: GSK Radioimmunotherapy with Zevalin Produces 96% Complete Remission Rate in First-Line Treatment of Patients with Follicular NHL Cell Therapeutics Inc. (CTI) announced Phase II results of FLUMIZ (Fludarabine, Mitoxantrone, Zevalin) trial which provided evidence for the feasibility, tolerability, and efficacy of fludarabine and mitoxantrone plus Zevalin® (90Y-ibritumomab tiuxetan) in untreated patients with follicular NHL. These results were published in the online edition of The Lancet Oncology. A total of 61 patients enrolled in the trial received six cycles of fludarabine and mitoxantrone; 57 patients (43 with complete remission and 14 with partial remission) were subsequently treated with Zevalin therapy. Consolidation with Zevalin converted 12 of 14 partial remissions (86%) to complete remissions for a complete response rate of 96%. With a median follow-up of 30 months, 3-year progression-free survival was estimated to be 76% and 3-year overall survival 100%. The side effects were generally mild without any signs of cumulative toxicity. Jack W. Singer, M.D., Chief Medical Officer at CTI stated that this study underscores the potential use of radioimmunotherapy with Zevalin to convert the majority of partial remissions to complete remissions and to

induce molecular remissions after conventional chemotherapy, both of which correlate with durable progression-free survival rates. Source: CTI, The Lancet Oncology Response to Neoadjuvant Therapy and Long-Term Survival in Patients with Triple-Negative Breast Cancer Triple-negative breast cancers (TNBCs) are characterized by the lack of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2). In TNBC patients, treatment with endocrine therapy or trastuzumab is not effective as they lack the appropriate targets for these drugs. In the present study published in recent issue of JCO, Liedtke et al. compared response to neoadjuvant chemotherapy and survival between patients with TNBC and non-TNBC. The study included 1,118 patients who received neoadjuvant chemotherapy for stage I-III breast cancer. Out of total patients enrolled, 23% had TNBC. Increased pathological complete response (pCR) rates were observed for patients with TNBC compared with non-TNBC (22% vs 11%; p= 0.034). However, 3-year progression-free survival rates were decreased in patients with TNBC compared to non-TNBC (63% vs 76%; p < 0.0001). In addition, 3-year overall survival rates were also decreased for patients with TNBC compared with non-TNBC. Patients with TNBC had higher rates of recurrence in visceral organs and soft tissue, lower rates of bone disease (p = .027), and shorter post-recurrence survival (p < 0.0001). Recurrence and death rates were significantly higher for TNBC only in the first 3 years. Notably, the results showed that patients who achieved pCR had excellent survival regardless of receptor status. Therefore, patients with TNBC might be best treated with third generation adjuvant or neoadjuvant chemotherapy regimens that achieve the highest possible pCR rates. The findings also indicated that patients with TNBC and residual disease after neoadjuvant chemotherapy had significantly shorter overall and post-recurrence survival than patients with non-TNBC and residual cancer. These results illustrate the need for development of new therapeutic interventions for this sub-group of patients. Source: JCO

Clinical Development

ONCOLOGY Newsletter March 25, 2008

3

Structure of MI-219 and predicted binding model in complex with MDM2

From Shangary et al. PNAS, March 11, 2008

Let-7 induction inhibits cell proliferation and enhances cell death in lung cancer cell lines

From M.S. Kumar et al. PNAS, March 11, 2008

Genitope Corporation to Suspend Development of MyVax® Personalized Immunotherapy Phase III clinical trial results of MyVax® personalized immunotherapy did not meet its primary endpoint showing no statistically significant difference in the progression-free survival of patients receiving MyVax® compared to the control group. After reviewing this data, the FDA recommended Genitope, for one or more additional Phase III clinical trials for MyVax® before accepting a Biologics License Application. But the company recognized that the costs and time required for further clinical development of MyVax® personalized immunotherapy are prohibitive and decided not to pursue further clinical trials prior to the FDA approval. Source: Genitope Inhibitor of p53-MDM2 Interaction is Selectively Toxic to Tumors and Inhibits Tumor Growth in Animal Models Tumor suppressor p53 is inactivated or deleted in ~50% of all human cancers and

plays a critical role in regulating cell cycle and apoptosis. Activation of p53 induces either cell cycle arrest and/or apoptosis. In tumors expressing wild type p53, its function is inhibited by MDM2 (mouse double-minute 2, also known as HDM2 in humans) which facilitates its degradation by the ubiquitin pathway. Several approaches have been taken to restore p53 function in tumor cells. One attractive approach is to use a small molecule to inhibit the MDM2-p53 interaction. Typically, protein:protein interactions have been difficult to target by small molecule inhibitors.

The discovery of small molecule inhibitors of MDM2-p53 interaction, known as Nutlins, by researchers at Roche demonstrated the feasibility of this approach. In a study published in PNAS, Shaomeng Wang and colleagues used a structure-based approach to design a potent, highly selective small molecule inhibitor of the MDM2-p53 interaction. This compound termed MI-219 binds to MDM2 with a Ki value of 5 nM and activates the p53 pathway in cells with the wild type p53 leading to cell cycle arrest in normal cells and apoptosis in tumor cells. However, in normal mouse tissues, this compound was not toxic. In mouse xenograft models, this compound induced rapid activation of p53 and complete inhibition of tumor growth. This study suggests that blocking MDM2-p53 interaction is an attractive therapeutic strategy for tumors expressing wild type p53. Source: PNAS Bcl-2 Antagonist Apogossypol Displays Superior Efficacy with Less Toxicity Compared with Gossypol In many human cancers and leukemias, Bcl-2 and other antiapoptotic members of the same family are overexpressed. These antiapoptotic proteins suppress tumor cell death induced by chemotherapy, radiation and hormonal therapies used in the treatment of malignancy. Thus, new therapeutic agents are required to inhibit antiapoptotic Bcl-2 family proteins. Gossypol is an orally active compound that binds and inhibits Bcl-2 family proteins. The aldehydes in gossypol make it reactive, hence reducing the available concentrations of active drug and causing toxicity. Shinichi Kitada and colleagues have previously shown that apogossypol, a semisynthetic analog of gossypol, in which the aldehydes were removed, retained full activity against antiapoptotic Bcl-2 family proteins. In the present study published in Blood, investigators have compared the toxicity and efficacy of gossypol and apogossypol in mice. Daily oral dosing studies showed that mice tolerated doses of apogossypol 2- to 4-times higher than gossypol. These findings suggest opportunities for greater antitumor activity using higher doses of this compound. Apogossypol exhibited far less hepatotoxicity or gastrointestinal toxicity compared with gossypol. In vitro, Bcl-2–expressing B cells from transgenic mice were more sensitive to cytotoxicity induced by apogossypol than

gossypol, with LD50 values of 3 to 5 µM and 7.5 to 10 µM, respectively. In vivo, as a single agent at 120 µmol/kg daily, apogossypol exhibited cytoablative activity in Bcl-2–transgenic mice as measured by spleen weight, size, and B-cell counts. Even at low doses (60 µmol/kg), apogossypol showed superior in vivo activity compared with gossypol. These results highlighting the superiority of apogossypol over gossypol support further development of this compound for cancer therapy. Source: Blood Let-7 microRNA Suppresses Non-small Cell Lung Cancer MicroRNAs (miRNAs) are short, highly conserved noncoding RNAs that bind to the

3’-untranslated regions of mRNAs suppressing their translation and also increasing their turnover in some cases. Individual miRNAs can target many different mRNAs affecting the expression of many genes. Many miRNAs target mRNAs involved in cell proliferation, survival, and differentiation. In particular, the let-7 miRNA family is believed to function in tumor suppression since reduced expression of let-7 is common in non-small cell lung cancer (NSCLC) and expression of let-7 was known to functionally inhibit the mRNAs of oncogenes such as the Ras family, c-Myc etc. In a study published in the recent issue of PNAS, Tyler Jacks and his team showed that let-7 inhibits NSCLC development in murine animal models. They employed the tet-inducible and constitutive expression systems to show that let-7 expression in NSCLC cell lines with mutant K-Ras induced both cell cycle arrest and cell death. Further let-7 expression was also shown to suppress tumor growth both in xenograft and in a

Research Highlights

ONCOLOGY Newsletter March 25, 2008

4

Schematic model for CD95 signaling of invasion in Glioblastoma

Cancer Cell, March 2008

mouse lung tumor model. However, notably although expression of let-7 led to initial suppression of tumors, let-7 resistant tumors eventually emerged. The system described in this study provides insights into miRNA-mediated tumor suppression and is also useful for understanding the basis of resistance. Source: PNAS Yes and PI3K Bind CD95 to Signal Invasion of Glioblastoma Glioblastoma mutiforme (GBM) is the most frequent glioma with a median survival of

10-12 months. GBM tumor cells have a tendency to invade surrounding brain tissue and can also develop resistance to multiple apoptotic stimuli, thus hindering development of effective curative therapy. CD95/CD95L (Apo1L/FasL) system is associated with apoptosis, and CD95 Ligand expression is increased at the tumor/host interface. Earlier studies have shown that binding of trimerized CD95L to the CD95 receptor commits the cell to apoptosis by activation of downstream effector caspases. This study, published in Cancer Cell by Kleber et al, showed that this signaling cascade is absent in apoptosis-resistant GBM and unraveled that CD95 mediates invasion via the PI3K/GSK3ß/MMP pathway. Binding of CD95 Ligand to CD95 receptor on glioblastoma cells recruits the Src family kinases- Yes and the p85 subunit of phosphatidylinositol-3 kinase to CD95 which signals invasion via the glycogen synthase kinase 3-ß pathway and subsequent expression of matrix metalloproteinases. Neutralization of CD95 activity dramatically reduced the number of invading cells in a

murine model of GBM. Considering that current treatments of GBM are not very effective because of the highly invasive nature of these tumors, these results provide evidence that targeting the CD95/CD95L is a promising approach for GBM. Source: Cancer Cell High Levels of Estrogen Associated with Breast Cancer Recurrence In postmenopausal women, serum concentrations of endogenous sex hormones are strongly associated with risk for primary breast cancer. Evidence linking sex hormone concentrations with risk for recurrence in women diagnosed with breast cancer is limited. But beneficial effects of antiestrogenic therapy observed on recurrence-free survival suggest that these hormones affect progression and risk for recurrence. In a study published in the recent issue of Cancer Epidemiology, Biomarkers & Prevention, Cheryl Rock and colleagues examined, using a nested case-control design, whether baseline serum concentrations of estradiol, testosterone and sex hormone binding globulin (SHBG) are associated with recurrence-free survival. Participants for this study werse drawn from the larger Women’s Healthy Eating and Living Study (WHEL), a randomized dietary intervention trial. In 153 case-control pairs of perimenopausal and postmenopausal women in this analysis, serum concentrations of total estradiol, bioavailable estradiol and free estradiol were each associated with risk for recurrence. Women who recurred had an average total estradiol concentration that was double that of nonrecurred women (22.7 versus 10.8 pg/mL; p=0.05). Besides genetic and metabolic factors that may influence the relationship between circulating sex hormones and risk of breast cancer recurrence, this study provides solid evidence that higher concentrations of estrogen in the blood contribute to risk for recurrence in women diagnosed with early stage breast cancer. Source: Cancer Epidemiology, Biomarkers & Prevention Monitoring the Response of Circulating Epithelial Tumor Cells to Adjuvant Chemotherapy in Breast Cancer Allows

Detection of Patients at Risk of Early Relapse Relapse and metastasis is frequent in malignant breast tumors and there is no tool to monitor the effect of adjuvant chemotherapy after surgery. Breast tumors can seed tumor cells into the peripheral blood, which may metastasize even after complete resection of the tumor. Detection of such circulating tumor cells may help in determining the response to therapy and relapse rate. In a study published in JCO, Pachmann et al. did a repeated quantitative analysis of circulating epithelial tumor cells (CETC) during adjuvant therapy in 91 primary nonmetastic breast cancer patients using MAINTRAC method. This method involves direct analysis of CETCs without enrichment. CETC numbers were analyzed before the surgery, before each new cycle of chemotherapy, and at the end of chemotherapy. Three response groups were identified; first group had 28 patients with 10-fold decrease in cell numbers indicating good response to therapy. Second group included 30 patients with marginal changes (<10 fold) in cell numbers and third group had 33 patients with increase or an initial decrease followed by re-increase (>10-fold) in numbers of CETCs. Relapses occurred more in patients with less favorable prognostic markers. In total, 20 relapses were observed within the followup time of 40 months, including one patient from group 1, five from group 2, and 14 patients from group 3. Decreases in CETCs were more frequent in patients receiving anthracycline-based therapy including fluorouracil than in patients receiving anthracycline therapy without fluorouracil. Therefore, serial measurement of CETCs may serve as an indicator of response to therapy and can be used to tailor therapy for individual patients. Source: JCO Association between Methylation of Promoter Region of Genes and Early Recurrence in Stage I NSCLC The standard of care for patients with stage I non–small-cell lung cancer (NSCLC) is surgery with curative intent. Despite surgery, approximately 30 to 40% of NSCLC patients with discrete lesions and histologically negative lymph nodes die of recurrent disease. In a recent study published in NEJM, Malcolm Brock and colleagues investigated

Biomakers

ONCOLOGY Newsletter March 25, 2008

5

whether methylation of seven genes in tumor and lymph nodes was associated with tumor recurrence. These genes are frequently methylated and considered important for the biological development of lung cancer. 167 patients with stage I NSCLC were included in the study that underwent curative resection; these included 51 case patients who had recurrence within 40 months after resection and 116 control patients without a recurrence within 40 months. In a multivariate model, promoter methylation of the cyclin dependent kinase inhibitor 2A gene p16, the H-cadherin gene CDH13, the Ras association domain family 1 gene RASSF1A, and the adenomatous polyposis coli gene APC in tumors and in histologically tumor-negative lymph nodes was associated with tumor recurrence. This association was independent of NSCLC stage, age, sex, race, smoking history, and histologic characteristics of the tumor. Methylation of promoter regions of p16 and CDH13 in both the tumor and the mediastinal lymph nodes was associated with the estimated odds ratio for recurrence of 15.50 in the original cohort. When this cohort was combined with validation cohort of 20 patients then the estimated odds of recurrence was 25.25 for case patients as compared with controls. The results indicate that detection of promoter methylation of certain genes may identify cells with potential for metastatic spread. These findings will need further evaluation in larger studies before the four gene panel can be used in clinical practice. Source: NEJM Vermillion's Biomarkers Found Effective in Detecting Ovarian Cancer Vermillion Inc., a molecular diagnostics company, has multiple ovarian cancer diagnostic tests in development. The company presented data from three studies demonstrating the benefits of their ovarian cancer protein biomarker panel, at the Society of Gynecologic Oncologists' 39th Annual Meeting. The first study found that calgranulin A and B, two proteins commonly found in malignant ovarian cysts, may be useful in helping diagnose and predict prognosis of ovarian cancer. Researchers used surface enhanced laser desorption ionization time-of-flight (SELDI-TOF) mass spectrometry to analyze ovarian cyst fluids and identify the underlying proteins. Fluids from benign (n=45), malignant (n=15), and low malignant potential (n=13) ovarian

tumors were examined. The calgranulin proteins were increased in malignant ovarian cyst fluids as compared to benign cyst fluids (p<0.001). The second study, examining Vermillion's marker panel for ovarian cancer, provided independent validation that it can distinguish malignant tumors from benign pelvic masses. The third study showed that Vermillion's panel of biomarkers in combination with CA-125 could more accurately identify early- stage ovarian cancer than could CA-125 alone. When examining stage-1 disease, the combination of the two markers correctly identified 87% of the cancers. Source: Vermillion FDA Approves TREANDA for the Treatment of Patients with CLL

Contd. from pg 1 A randomized, controlled, multicenter trial comparing TREANDA(R) to chlorambucil as first-line treatment for CLL in 301 treatment-naive patients showed that the overall response rate was 59% for TREANDA(R) versus 26% for chlorambucil (p <0.0001). In addition, complete response and median progression-free was significantly better with TREANDA(R) compared to chlorambucil. TREANDA(R) has been granted orphan drug status by the FDA for the treatment of CLL, thus providing it a marketing exclusivity in this indication until March 2015. Source: Cephalon FDA Panel Votes for Restrictions for ESA’s Use The Oncologic Drugs Advisory Committee (ODAC) was called to review the use of erythropoiesis-stimulating agents (ESA’s), due to recent data on increased mortality rates with their use. The ODAC panel allowed ESAs to be marketed for the chemotherapy-induced anemia (CIA) but restricted their use for CIA in patients with metastatic, breast and head and neck cancer, and patients treated with curative intent. The panel recommended the implementation of signed informed consent for treatment of CIA with ESA’s and that the FDA should not mandate a restricted distribution system for oncology patients receiving ESAs. In

response to this guidance, Ortho Biotech Products, a Johnson & Johnson company, has modified prescribing information for Procrit (epoetin alfa). The boxed warnings have been modified to now read: "Warnings: increased mortality, serious cardiovascular and thromboembolic events and tumor progression." Source: ASCO Tyverb (lapatinib) European Regulatory Update The Committee for Medicinal Products for Human Use (CHMP) issued a positive Conditional Marketing Authorization for Tyverb in December 2007, for the treatment of patients with advanced or metastatic breast cancer with ErbB2 (HER2) overexpression. Now EU Commission has referred Tyverb (lapatinib) back to CHMP for further review, after getting new data from pharmacovigilance review of clinical trials and post-marketing reports. Data showed that hepatotoxicity (predominately elevated liver enzymes) may occur during treatment with Tyverb at incidence of 0.4%. It is expected that Tyverb will be discussed at the next meeting of the CHMP (April 21 to 24). GSK believes that this data will not change the positive benefit-risk profile for Tyverb in the proposed indication and Tyverb will get final marketing authorization from CHMP. Source: gsk FDA Indicates that Genasense® Approval in CLL will require Additional Confirmatory Data The FDA’s Center for Drug Evaluation and Research (CDER) found the data of Genasense® (oblimersen sodium) injection for treatment of patients with relapsed or refractory CLL, inadequate for FDA approval. This decision was issued in response to an appeal filed by Genta in October 2007. The FDA agreed that the endpoint of complete response was achieved, supporting the efficacy of the drug but “confirmatory evidence” in the New Drug Application (NDA) to approve the drug was found insufficient. CDER suggested that the company either conduct an additional clinical trial or collect additional information regarding the clinical course and progression of disease in patients from the previous pivotal trial to gather confirmatory evidence. The company proposed a new confirmatory

Regulatory Focus

ONCOLOGY Newsletter March 25, 2008

6

randomized controlled trial at first or second relapse in patients who are “non-refractory”. All patients will receive fludarabine plus cyclophosphamide (Flu/Cy) and they will be randomly assigned to receive Genasense or no additional therapy. The purpose of the trial will be to confirm that the addition of Genasense increases complete responses (CR) in patients who receive Flu/Cy chemotherapy. Source: Genta Genzyme Withdraws Bioenvision’s European Filing of Evoltra® in Elderly AML Patients Genzyme Corp. announced the withdrawal of the European application to extend the Evoltra® (clofarabine) product label to include the treatment of elderly patients with AML. The company withdrew the application because CHMP assessed that the data from the BIOV121 study was not sufficient to support a recommendation for market. This application was filed by Bioenvision, Ltd. before the company was acquired by Genzyme last year. The company will develop a new submission to include data from one or more ongoing clinical studies of clofarabine in this patient population. Source: Genzyme Abbott Collaborates with Genentech, Roche and OSI on Lung Cancer Drug Test

Contd. from pg 1 Tarceva, an oral tablet, is used to treat patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after

failure of at least one prior chemotherapy regimen. There have been infrequent reports of interstitial lung disease-like events, including fatalities in patients receiving Tarceva. Under the agreement, Abbott will develop a test to detect extra copies of the epidermal growth factor receptor gene using its proprietary fluorescence in situ hybridization technology in NSCLC. Presently there are no nucleic acid based tests validated or approved by the FDA that could identify patients who may derive greater treatment benefits from targeted lung cancer therapies. Stafford O'Kelly, vice president, molecular diagnostics, Abbott, pointed out that their goal through this important technology is to improve the practice of medicine by helping to reduce risk, produce targeted cures, and improve the detection and prevention of serious illnesses. Source: Abbott EUSA Pharma to Acquire US Specialty Oncology Company Cytogen EUSA Pharma Inc. entered into a definitive agreement to acquire all the outstanding shares of Cytogen Corporation for $22.6 million. The acquisition of Cytogen brings to the EUSA group a 40-strong specialist oncology sales force and three marketed oncology and pain control products, Caphosol®, ProstaScint® and Quadramet®. Caphosol is a supersaturated calcium phosphate rinse indicated for the treatment of oral mucositis (side-effect of high-dose chemotherapy) ProstaScint is a monoclonal antibody-based agent used to image the extent and spread of prostate cancer. Quadramet is a radiopharmaceutical for the treatment of pain in patients whose cancer has spread to the bones. Bryan Morton, Chief Executive of EUSA Pharma said that the acquisition of Cytogen is of great strategic importance for EUSA as

it completes the building of their transatlantic commercialization infrastructure, via direct sales forces in the US and across Europe, and through distribution partners in a number of territories including Canada, South America and Asia. Source: EUSA Pharma Raven Biotechnologies Advance RAV18 through Agreement with CMC ICOS Biologics Raven Biotechnologies, Inc. and CMC ICOS Biologics, Inc. have entered into an agreement under which CMC ICOS will create a production cell line for Raven's investigational new drug (IND) candidate, RAV18. It is a humanized antibody targeting the ADAM9 protein on cells. ADAM9 is expressed on many solid tumors and is thought to contribute to disease progression and metastasis. Clinical studies have reported overexpression of ADAM9 protein in pancreatic, prostate, gastric, breast and lung cancers. Raven has confirmed that ADAM9 is present on its cancer stem cell lines, and has identified new biology associated with antibodies targeting ADAM9. Raven has also shown that anti-ADAM9 antibodies suppress tumor growth in lung, prostate and skin cancer animal models and suppress metastasis. Raven is targeting 2009 for an IND filing of RAV18. Mads Laustsen, CEO of CMC Biologics said that CMC would be using its proprietary CHEF1™ expression technology for this project. He also said that using this system, the timeline for cell line isolation and production cell line generation would be significantly shorter than conventional technologies. Source: Ravenbio

Business News

Editorial Team: Dr. Chandra Kumar, Ms. Meenu Grover, Dr. Anuradha Dhingra Analysts: Dr. Neetu Singhal, Ms. Sarika Manchanda