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Physicians' Financial News: March 2008

OBTN, March 2008, Volume 2, Issue 3

Physicians' Financial News focuses on news-making and/or notable companies in the oncology biotechnology sector. I

Novartis Leverages Formidable Size and Pipeline to Maintain Strong Oncology Position

Novartis—listed on New York, Swiss, and London stock exchanges—was formed in March 1996 by the combination of Sandoz and Ciba-Geigy, two Swiss-based chemical and life sciences giants. The company, which employs more than 99,000 people in 140 countries around the world, has major production sites in eight countries (Switzerland, Germany, United States, United Kingdom, France, Austria, Turkey, and Ireland) and six major research and development centers spread out over three continents (Switzerland, England and Austria in Europe; Massachusetts, United States in North America; and Japan and China in Asia). The international corporation is composed of a number of business units or divisions. In broad organization terms, Novartis can be broken down into four separate major components: Pharmaceuticals, Vaccines and Diagnostics, Sandoz (which focuses on generic medications), and Consumer Health.

%u25BA Novartis Pharma

Within the pharmaceuticals division of Novartis, the company concentrates on the following seven major therapeutic areas: cardiovascular and metabolism; oncology and hematology; neuroscience; respiratory; infectious diseases, transplantation, and immunology; ophthalmics, dermatology, gastrointestinal, and urinary; and arthritis and bone.

Novartis Pharmaceuticals has received 15 new product approvals in the United States since 2000, which, according to the company, is the most of any pharmaceutical company. The current product portfolio of Novartis Pharmaceuticals includes more than 45 marketed products. Its product development pipeline involves nearly 140 projects—including potential new product candidate compounds as well as potential new indications or formulations for existing products—in various stages of clinical development.

In 2007, Novartis increased its level of research and development investment by 19% (over 2006) to $5.1 billion, 21% of net sales. Last year also marked the creation of the Novartis biologics unit, which the company’s 2007 annual report defines as “a dedicated innovation unit with a strong biotech culture in the areas of discovery and development unique to biologics.” Currently, biologics make up roughly 25% of Novartis’s preclinical research pipeline.

A wealth of strategic alliances and research and development partnerships augment Novartis in-house product development efforts. Currently, Novartis is involved in more than 400 collaborations in 20 countries. About 120 of these partnerships are with biotechnology concerns and more than 280 are with academic centers.

Key Novartis products include Diovan (valsartan) and Lotrel (amlodipine besylate and benazepril HCl), two high-selling hypertension treatments; Gleevec (imatinib mesylate), an oncology product indicated to treat chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST); Lamisil (terbinafine HCI), an antifungal agent; and Zometa (zoledronic acid), an intravenous infusion utilized in the treatment of bone metastasis in a variety of tumor types (including multiple myeloma, breast, lung, and prostate cancers).

%u25BANovartis Oncology

Novartis currently offers seven oncology therapies to American patients. In addition to the aforementioned Gleevec and Zometa, Novartis’ oncology and hematology division has five other products that have attained FDA approval and are currently being marketed in the United States.

The rest of the Novartis cancer care portfolio includes: Newly approved (as of fourth quarter 2007) Tasigna (nilotinib), a Philadelphia chromosome— positive (Ph ) CML treatment indicated for patients who are resistant or intolerant to Gleevec; Femara (letrozole), a breast cancer therapy that a company spokesperson claims is the only aromatase inhibitor approved as adjuvant therapy, extended adjuvant therapy, and advanced (metastatic) breast cancer; Sandostatin (octreotide acetate), indicated for long-term maintenance therapy in patients with acromegaly and in the treatment of symptoms related to carcinoid syndrome and vasoactive intestinal peptide tumors; Exjade (deferasirox), indicated for the treatment of chronic iron overload caused by blood transfusions, particularly in cases of myelodysplastic syndrome and thalassemia; and Proleukin (aldesleukin), an injectable therapy indicated for the treatment of metastatic renal cell carcinoma and metastatic melanoma.

The late 2007 Tasigna approval, which was based on data which demonstrated that Tasigna produced responses in 40% of patients with Ph CML resistant or intolerant to prior treatment, represented one of the watershed events in recent Novartis oncology history. Commenting on the event, David Epstein, President and CEO, Novartis Oncology, stated, “Tasigna represents an important advance for the small number of patients who are resistant or intolerant to prior therapy. This approval means we can offer physicians a comprehensive treatment approach with effective medicines to treat their Ph CML patients.”

The company’s research and development pipeline boasts a number of agents (including new compounds and existing compounds seeking broader indications) in all phases of development (see Figure). Current phase I trials include eight product candidates for hematologic and solid tumors, melanoma, and hereditary hemocromitosis. Eight potential therapies in phase II are being evaluated for the treatment of multiple myeloma, CML, acute myelogenous leukemia (AML), GIST, and solid tumors. Phase III research is focused upon ovarian cancer, Cushing’s disease, carcinoid tumors, glioblastoma multiforme brain cancer (GBM), GIST, and Ph CML.

Novartis’ various oncology research and development initiatives are proceeding forward at a brisk pace. New data from the IRIS study in patients with newly diagnosed Ph CML showed Gleevec halted disease progression to more advanced stages completely in the sixth year of treatment and that 88% of patients in the trial were still alive. In December, the FDA granted Zometa an additional six months of marketing exclusivity until 2013 following the completion of pediatric studies. In 2007, Femara obtained FDA approval for expanded use, gaining an indication for adjuvant (immediately after surgery) use.

Separate phase III studies are underway comparing Tasigna and Gleevec in newly diagnosed CML patients as well as those with suboptimal responses to previous therapy. A Tasigna registration study is also underway in patients with GIST who are resistant or intolerant to prior treatment.

RAD001 (everolimus), a once-daily oral inhibitor of the mTOR pathway that has demonstrated broad clinical activity in multiple tumors, is progressing toward a potential first regulatory submission. Enrollment was recently completed in the registration trial involving metastatic renal cell carcinoma. Registration trials are also underway in chemo-refractory pancreatic islet cell tumors (pICT) in the first-and second-line setting and for chemotherapy refractory carcinoid tumors.

SOM230 (pasireotide) recently completed phase II studies for acromegaly, carcinoid tumors, and Cushing’s disease. A phase III registration study is currently enrolling patients with Cushing’s disease (excessive excretion of the hormone cortisol from a pituitary tumor), a disease for which there is no approved therapy. Additional registration studies will begin for acromegaly and refractory carcinoid tumors in the first half of 2008.

Over the next year, according to the Novartis website, the company will be significantly expanding the scope of its clinical trial investigations. Upcoming trials, currently in the planning or enrollment phases, will examine a variety of existing and investigational compounds in advanced cancer with kidney dysfunction, anemia, bone metastases, breast cancer, carcinoid tumors, chemotherapy-induced diarrhea, colorectal cancer, Cushing's syndrome, fallopian tube cancer, GIST, leukemia, metastatic melanoma, obesity, ovarian cancer, peritoneal cancer, prostate cancer, and iron overload associated with sickle-cell anemia, thalassemia and myelodysplastic syndrome.

Commenting on future prospects, Daniel Vasella, MD, Chairman and CEO, Novartis, stated, “I am pleased that our sustained focus on innovation and drive to address unmet medical needs have enabled us to further strengthen our pipeline. Over the next two years we will launch several innovative medicines and continue to invest aggressively in discovery research and development activities and complement our own skills and technologies through attractive collaborations.”

%u25BANovartis Oncology Pipeline

Drug

Cancer Type

Phase I

LBY135

Solid tumors

HCD122

Hematologic tumors

TKL258

Hematologic and solid tumors

RAF265

Melanoma

BEZ235

Solid tumors

AEE788

Solid tumors

Exjade (deferasirox)

Hereditary hemocromitosis

Phase II

LBH589

Cutaneous T-celllymphoma, chronic myelogenous leukemia, multiple myeloma

Midostaurin

Acute myelogenous leukemia

Gimatecan

Solid tumors

ASA404

Solid tumors

Tasigna (nilotinib)

Gastrointestinal stromal tumors

SOM230 (pasireotide)

Various cancers

RAD001 (everolimus)

Pancreatic islet cell tumors and various solid tumors

Patupilone

Solid tumors

Phase III

Patupilone

Ovarian cancer

SOM230 (pasireotide)

Cushing’s disease

RAD001 (everolimus)

Carcinoid tumors, Renal cell carciinoma

Gleevec (imatinib)

Glioblastoma multiforme brain cancer, adjuvant gastrointestinal stromal tumors

Tasigna (nilotinib)

Philadelphia chromosome—positive chronic myeloid leukemia

Zometa (zoledronic acid)

Aromatose-inhibitor associated with bone loss

Approved

Gleevec (imatinib)

Philadelphia chromosome—posiive chronic myeloid leukemia and gastrointestinal stromal tumors

Zometa (zoledronic acid)

Treatment of bone metastasis in a variety of tumor types (including multiple myeloma, breast, lung, and prostate cancers)

Tasigna (nilotinib)

Philadelphia chromosome—positive chronic myeloid leukemia patients who are resistant or intolerant to Gleevec

Femara (letrozole)

Breast cancer

Sandostatin (octreotide)

Acromegaly, carcinoid syndrome, and Vasoactive intestinal peptide tumors

Exjade (deferasirox)

Chronic iron overload caused by blood transfusions, particularly in cases of myelodysplastic syndrome and thalassemia

Proleukin (aldesleukin)

Metastatic renal cell carcinoma and metastatic melanoma

%u25BA Company Financials

According to recently released 2007 financial results, Novartis group results set a new record as net sales rose 8% to $39.8 billion. Net income was $12 billion (representing a 66% increase over the previous year), increasing per-share earnings to $5.15 (an increase of 68%).

Novartis’s solid 2007 performance was not, however, free of some tarnish. U.S. pharmaceutical net sales fell 8% because of the suspension of Zelnorm and the loss of patent protection for four key products (Lotrel, Lamisil, Trileptal and Famvir). The performance of Novartis’ strong oncology portfolio helped mitigate the setbacks experienced in other therapeutic areas. Novartis’ robust performance in the U.S. oncology sector was spearheaded by a significant increase in the annual sales of Gleevec (up 14% to $3.1 billion) and the ongoing success of recently launched products such as Exjade (a product that saw its 2007 sales increase 141% over 2006 to $357 million) and Tasigna. Other cancer therapies that experienced sharp 2007 increases included Femara (up 25% to $937 million) and Sandostatin (up 7% to over $1 billion). Worldwide, the Novartis pharmaceuticals picture was much brighter. Global sales increased 10%, fueled by double-digit growth in Europe and Latin America.

Looking forward, Novartis expects to continue its record rate of growth. Although it is expected that Novartis Pharmaceuticals will sustain some negative impact the first half of 2008 because of a loss in U.S. net sales (primarily caused by generic competition), this will likely be offset both by the continued strength of other Novartis business units and a strong second half of 2008, fueled by new growth and product approvals.

“Novartis delivered a strong performance in all major regions and in all divisions, with the exception of Pharmaceuticals in the U.S. hit by generic competition and a product withdrawal. The dynamic growth of Sandoz and Vaccines and Diagnostics and the strong contribution of Consumer Health underscore the benefits of our focused diversification strategy in health care businesses to tap new sources of growth and balance risks. The 15 approvals for new prescription medicines obtained in the U.S. and the E.U. lay the foundation for a new growth cycle in Pharmaceuticals, which is expected to emerge in the second half of 2008. I am confident Novartis will deliver record results in 2008 and is well positioned to benefit from current and future trends in health care,” stated Dr. Vasella.

Ventana Medical Systems Taken Over by Roche

Ending a protracted seven-month struggle, a definitive merger agreement has been reached between Roche AG and Ventana Medical Systems after the former company sweetened its initial offer (which was rejected by Ventana last June), agreeing to shell out more money to acquire the latter concern.

Under the terms of the agreement, Roche will amend its existing tender offer to acquire all of the outstanding common shares of Ventana and Ventana’s Board of Directors will recommend that Ventana’s shareholders tender their shares to Roche.

The amended offer will increase the offer price from its original amount of $75 per share to $89.50 per share in cash (or an aggregate of approximately $3.4 billion on a fully diluted basis). This offer represents a premium of 4.9% to Ventana’s closing price on January 18, 2008, a 19.3% premium to Roche’s initial offer in June 2007 (which was extended five times by Roche over the past several months), and a 72.3% premium to Ventana’s closing price in June 2007 (the last trading day prior to the announcement of Roche’s initial offer). Roche is paying about 11.4 times Ventana's estimated 2007 sales.

Roche raised its bid after gaining access in November to confidential information from Ventana, Franz B. Humer, Chairman and CEO, Roche, said in a recent conference call. Ventana had rejected the original offer because the bid didn't take into account new diagnostic tests the U.S. company planned to introduce in 2008.

Christopher Gleeson, Ventana’s President and Chief Executive Officer, will continue as CEO of Ventana’s business following completion of the transaction and become a member of the Roche Diagnostics Executive Committee. Ventana will remain based in Tucson, Arizona and its employees will become part of the combined company.

in-vitro

According to a Roche spokesperson, the acquisition of Ventana, a leader in the fast-growing histopathology (tissue-based diagnostics) segment, will allow Roche to broaden its diagnostic offerings and complement its leadership in both diagnostic systems and oncology therapies. The acquisition will give the Swiss company a test that determines which patients are most likely to benefit from the breast cancer drug Herceptin, Roche's second-biggest seller.

"We are very pleased that we were able to reach an agreement with Ventana. We believe that our offer provides significant value to Ventana's shareholders and that this acquisition ideally complements Roche's strengths. Our combined company will be uniquely positioned to further expand Ventana's business globally and together develop more cost-efficient, differentiated and targeted medicines. We are delighted to welcome the employees and management team of Ventana and look forward to jointly developing novel solutions for our customers," commented Mr. Humer.

The merger agreement has been approved by the boards of Ventana and Roche.

Bloomberg Business News

However, Ventana’s board approved the deal over the objections of Chairman Jack Schuler and Vice Chairman John Patience. Neither have agreed to sell their shares (a combined 12% stake) to Roche. According to , Larry Feinberg, manager of the $1 billion Oracle Partners hedge fund who owns another 8% of Ventana’s stock, may side with Mr. Schuler and Mr. Patience. Since Mr. Feinberg, Mr. Schuler, and Mr. Patience represent one-fifth of the votes, they can potentially disrupt the deal.

According to many industry analysts, the Ventana acquisition, should it go through, can be viewed as a component of a larger strategy that Roche is following in an effort to aggressively invest in and enlarge its presence in the biotechnology field. Recently, for example, Roche announced plans to invest $391 million to expand its research, development and production capabilities in the biotechnology sector. The Ventana acquisition will be Roche's fourth in less than a year.

In March 2007, the Swiss drugmaker agreed to buy Connecticut-based CuraGen Corp.'s 454 Life Sciences for $140 million in cash to gain DNA-mapping technology, which can help identify the genetic cause of a disease or point out ways to treat it. The following month, Roche said it would spend $600 million to acquire BioVeris, and add screening technology that stimulates cells to emit light. In June, the company agreed to buy NimbleGen Systems for $272.5 million to add more genetic tools for drug research. In the months ahead, Roche will continue to look for small- to mid-sized acquisitions, Mr. Humer said.

Indications are that Roche’s biotech push is already beginning to yield significant dividends. Recent returns on Roche’s biotechnology investment have been impressive, particularly in the oncology treatment sector. They include:

The deal is subject to, among other things, the conditions that there are validly tendered and not withdrawn, a number of common shares that, together with the shares owned by Roche and its subsidiaries, represents a majority of the total number of common shares outstanding on a fully-diluted basis.

  • The announcement that MabThera (rituximab) (MabThera is known as Rituxan in the United States, Japan and Canada. Genentech and Biogen Idec comarket MabThera in the United States, and Roche markets MabThera in the rest of the world, except Japan, where MabThera is comarketed by Tokyo-based Chugai and Zenyaku Kogyo Co. Ltd.), according to a German phase III study, can significantly increase the time before patients suffering from chronic lymphocytic leukemia—the most common form of adult leukemia—experience disease progression. The agent is currently indicated to treat non-Hodgkin’s lymphoma.
  • Cancer drug Avastin’s obtainment of approval for wider use in the European Union (In the United States, Avastin is marketed by Genentech, which is majority owned by Roche). Roche said the new broader label will allow Avastin to be used in combination with any chemotherapy, including Roche's oral chemotherapy Xeloda (capecitabine), for first and later treatment lines in patients with metastatic colorectal cancer.

Potential Melanoma Treatment Granted Priority Review

The FDA has accepted the peginterferon alfa-2b supplemental Biologics License Application (sBLA) for review and has granted Priority Review status to the agent. According to the product candidate’s manufacturer, Schering Plough, if peginterferon alfa-2b attains FDA approval, the treatment, indicated for patients with stage III melanoma, would be the first adjuvant therapeutic advance within the melanoma disease state in roughly 10 years.

The Priority Review designation is intended to expedite the review process for therapies that provide a significant improvement in the treatment of serious or life-threatening diseases. Based on this Priority Review status, the FDA reviews the application with the goal of taking action within six months of the sponsor’s submission of the sBLA. The application will be discussed by the FDA Oncology Drugs Advisory Committee on March 12, 2008.

The application, which Schering-Plough originally submitted to the FDA in the Fall of 2007, is based on results from what Schering-Plough claims was the largest adjuvant trial ever conducted in patients exclusively with Stage III melanoma. The study, conducted by the European Organization for the Research and Treatment of Cancer (EORTC), evaluated the tolerability and activity of peginterferon alfa-2b in 1,256 patients with Stage III melanoma at 101 sites across Europe. (The company has also filed a peginterferon alfa-2b application with the European Medicines Evaluation Agency [EMEA].)

P

P

Findings of the EORTC study indicated that median relapse free survival was 34.8 months in the peginterferon alfa-2b arm, versus 25.5 months in the observational arm ( = 0.01). Median distant metastasis-free survival was 45.6 months in subjects receiving peginterferon alfa-2b therapy versus 36.1 months in the observational arm ( = 0.11).

Interferon is a protein produced naturally by white blood cells to help the immune system fight viral infections and certain cancer growths. Interferon alfa-2b has similar actions to natural interferon. Pegylated interferon alfa-2b is a longer-acting form of interferon made by attaching an inert molecule called polyethylene glycol, or PEG, to the alpha interferon molecule. This modification increases the size of the interferon molecule and results in slower elimination from the body, allowing for less frequent dosing than required for standard interferon.

Peginterferon alfa-2b, marketed as Pegintron, is currently indicated for use alone or with ribavirin for the treatment of chronic hepatitis C in patients with compensated liver disease who have not been previously treated with interferon alpha and who are at least 18 years of age.

Approximately 60,000 people worldwide die each year from skin cancer caused in particular by excessive sun exposure according to the World Health Organization. According to the American Cancer Society, there will be almost 108,000 new cases of melanoma in the United States in 2007, and approximately 8,000 people will die from this disease.

Melanoma is the deadliest form of skin cancer and the primary cause of ultraviolet radiation—related disease in the Americas, Europe, Australia, and New Zealand. However, when detected in its earliest stages, melanoma is highly curable.

Studies Suggest Expanded Role for Vectibix in Colorectal Cancer

At the 2008 Gastrointestinal Cancers Symposium in Orlando, Florida, Amgen reported interim pooled, blinded safety data from two phase III trials examining Vectibix (panitumumab) in combination with chemotherapy in first- and second-line metastatic colorectal cancer (mCRC) treatment.

In September 2006, Vectibix was approved in the United States as a monotherapy for the treatment of patients with epidermal growth factor receptor— (EGFr) expressing mCRC after disease progression on or following fluoropyrimidine–, oxaliplatin–, and irinotecan–containing chemotherapy regimens.

The preliminary results, according to Amgen, provide evidence to support the safety of Vectibix in first and second line mCRC treat- ment. Reviews from respective independent data monitoring committees of the combined safety data from both arms of both randomized, multicenter trials endorsed the continuation of these studies per protocol.

The interim analysis of the two studies that were presented at the symposium included the PRIME (Panitumumab Randomized trial In combination with chemotherapy for Metastatic colorectal cancer to determine Efficacy) or “203” trial, a global phase III study investigating Vectibix in combination with FOLFOX (leucovorin, 5-flourouracil, oxaliplatin) chemotherapy as a firstline treatment for patients with mCRC, and the “181” trial, a global phase III study investigating Vectibix in combination with FOLFIRI (irinotecan, 5-fluorouracil and leucovorin) chemotherapy as a second-line treatment for patients with mCRC.

In the PRIME study, patients were randomized to receive either 6.0 mg/kg of Vectibix and FOLFOX once every two weeks or FOLFOX alone once every two weeks. The primary endpoint of the trial is progression-free survival. Other endpoints include overall survival, objective response rate, time to progression, duration of response and safety.

According to the presented interim results, derived from a pooled safety review of 601 patients (302 of whom received Vectibix plus FOLFOX; 299 of whom received FOLFOX only) in which 99% of the subjects received at least one cycle of therapy, the following grade three and four adverse events were observed: neutropenia (25%), diarrhea (10%), fatigue (4%), nausea and pulmonary embolism (3%, respectively), febrile neutropenia, hypomagnesemia, dehydration and deep vein thrombosis (2%, respectively). Fifty-four percent of the pooled patient population had a skin reaction with 11% of patients having a grade three and less than 1% experiencing a grade four. The PRIME study’s target accrual goal of approximately 1,150 patients was reached in January 2008.

In the 181 study, enrolled patients were randomized to receive either 6.0 mg/kg of Vectibix and FOLFIRI once every two weeks or FOLFIRI alone once every two weeks. The co-primary endpoints are progression-free survival and overall survival. Other endpoints of the study include objective response rate, time to progression, duration of response and safety.

The pooled interim safety review of 701 patients (352 of whom received Vectibix plus FOLFIRI; 349 of whom received FOLFIRI only), in which 99% received at least one cycle of therapy, showed the following grade 3 and 4 adverse events: neutropenia (15%), diarrhea (9%), fatigue (4%), febrile neutropenia, nausea, dehydration, pulmonary embolism (2%, respectively), hypomagnesemia and deep vein thrombosis (1%, respectively) and infection (less than 1%). Sixtyone percent of the pooled patient population had a skin reaction with 12% experiencing a grade 3 and less than 1% experiencing a grade 4. Target accrual for this study is approximately 1,100 patients and enrollment is anticipated to be complete by quarter 1 of 2008.

In both arms of both trials, KRAS mutational status in patients’ tumors will be studied as a biomarker for Vectibix activity. Recent data indicate that KRAS gene status may predict efficacy and could potentially serve as a patient selection biomarker for Vectibix monotherapy.

Commenting on the two trials, David Chang, MD, vice president for oncology clinical development, Amgen, stated, “We continue to make progress in elucidating the potential utility of Vectibix in the treatment of colorectal cancer. These phase III studies will provide important information about the efficacy of Vectibix when used in combination with conventional chemotherapy regimens.”

Also presented at ASCO GI were data from “STEPP” (Skin Toxicity Evaluation Protocol with Panitumumab), the first prospective study that examined differences between pre-emptive and reactive skin treatment for skin toxicities. Patients enrolled in the study either received second-line FOLFIRI-based chemotherapy plus 6.0 mg/kg of Vectibix every two weeks (N=32) or irinotecan-based chemotherapy plus 9.0 mg/kg Vectibix (N=26) every three weeks and were randomized to pre-emptive or reactive skin treatment. Pre-emptive skin treatment included the administration of skin moisturizer, sunscreen, topical steroid, and doxycycline.

An interim analysis of 58 patients who completed 14 weeks of Vectibix treatment showed the following adverse events: 72% of patients had a grade three or greater adverse event in the Vectibix plus FOLFIRI arm with the most notable events being neutropenia (19%), diarrhea and dermatitis acneiform (16%) and dehydration (13%). In the Vectibix plus Irinotecan arm, 50% of patients experienced a grade 3 or greater adverse event with hypokalemia (15%) being the most significant.

The interim analysis also assessed best overall response (complete response plus partial response). The best overall response (31%) was demonstrated in the Vectibix plus FOLFIRI arm.

Potential Platinum-Resistant Ovarian Cancer Treatment Hits a Key Phase II Target

According to OxiGene, Zybrestat (combretastatin-A4 phosphate/CA4P), the company’s lead oncology product candidate, has achieved its prespecified primary efficacy endpoint for stage 1 of an ongoing phase II ovarian cancer clinical trial.

The clinical trial utilizes an open-label, Simon two-stage design to evaluate the combination of Zybrestat, carboplatin and paclitaxel in patients with advanced, platinum-resistant ovarian cancer, a refractory form of ovarian cancer for which therapeutic options are currently limited. Having met the stage 1 primary efficacy endpoint, the clinical trial will proceed to its second stage, in which an additional 25 patients will be enrolled.

In the ongoing study, in order to advance to the second stage of the trial, a minimum of three out of the first 18 patients treated with the Zybrestat-chemotherapy combination had to achieve a partial response (PR) or better. Response was determined by the investigators based upon tumor imaging (RECIST) and/or ovarian cancer response biomarker (CA-125) criteria.

In addition to the three patients with confirmed partial responses, preliminary results communicated to OxiGene by principal study investigator Gordon Rustin, MD, Cancer Research UK, indicated that stable disease was observed in seven of the first 11 evaluable subjects in the clinical trial. The combination regimen of Zybrestat, carboplatin and paclitaxel appeared to be well-tolerated, with no observations of colon perforations that had been reported previously with anti-VEGF therapy in this patient population. OxiGene anticipates that updated results from stage 1 of the phase II trial will be reported at an upcoming scientific forum.

“The encouraging initial results with the Zybrestat-chemotherapy combination in this refractory patient population support further testing and development of the drug for ovarian carcinoma and other solid tumors,” commented Dr. Rustin.

“These results add to the growing body of data indicating that Zybrestat has clinical activity against a wide variety of solid tumors, particularly when administered in combination with conventional chemotherapeutic agents,” stated Patricia Walicke, MD, PhD, Chief Medical Officer of OxiGene. “They also corroborate previously-reported phase 1b data in ovarian cancer and provide strong evidence of an efficacy signal in ovarian cancer.”

In November 2005, OxiGene announced results from the phase 1b portion of the clinical trial presented by Dr. Rustin at the AACR/NCI/EORTC International Conference on Molecular Targets and Cancer Therapeutics. Of 15 ovarian cancer patients treated with combinations of Zybrestat and chemotherapy (carboplatin and/or paclitaxel), 10 patients achieved partial responses (per RECIST or CA-125 criteria). Only three of these patients, however, had platinum-resistant disease, which is generally more refractory to all treatments.

Zybrestat is currently being evaluated in an anaplastic thyroid cancer study under a Special Protocol Assessment agreement with the FDA. An OxiGene spokesperson asserted that in a number of recent clinical studies, Zybrestat has demonstrated clinical activity against Anaplastic Thyroid Cancer (ATC), ovarian cancer, and various other solid tumors.

Once Zybrestat obtains FDA approval, added the spokesperson, the agent will likely become the first product in a novel class of small-molecule drug candidates called vascular disrupting agents (VDAs). Through interaction with vascular endothelial cell cytoskeletal proteins, VDA’s selectively target and collapse tumor vasculature, thereby depriving the tumor of oxygen and causing death of tumor cells.