Item 1
. Business
Vion is a development-stage pharmaceutical company committed to extending the lives and improving the quality of life of cancer patients worldwide by developing and commercializing innovative cancer therapeutics. Our Company has been focused over the last three years on executing a clinical development plan for our lead product candidate, Cloretazine
®
(VNP40101M), in acute myelogenous leukemia (AML). Cloretazine
®
(VNP40101M) has received two fast track designations from the U.S. Food and Drug Administration (FDA) for the treatment of: (i) elderly poor-risk AML and (ii) relapsed AML. Cloretazine
®
(VNP40101M) has also received orphan drug designation for the treatment of AML in the United States and the European Union.
In 2008, we plan to file a New Drug Application (NDA) for Cloretazine
®
(VNP40101M) based on our Phase II trial of the drug as a single agent in elderly patients with
de novo
poor-risk AML. In December 2007, we announced preliminary data from this trial at the American Society of Hematology Meeting, reporting an overall response rate of 35% in 80 evaluable patients. Although these preliminary data indicate that we met the criteria for a successful trial based on the primary endpoint, the overall response rate, there can be no assurance that we will be able to file an NDA based on the data from this trial in 2008, or at any time, or that the NDA will be approved on a timely basis by the FDA, if it all.
In January 2008, we announced that the FDA had lifted the clinical hold on our Phase III trial of Cloretazine
®
(VNP40101M) in combination with cytarabine in relapsed AML. The FDA had placed the trial on clinical hold in May 2007 after we suspended enrollment and treatment of patients at the recommendation of the trial’s data safety monitoring board (DSMB). This was based on an interim evaluation by the DSMB that any advantage in the primary endpoint, the overall response rate, was being compromised by the observed mortality on the study. We have reached initial agreement with the FDA on modifications to our original Phase III study protocol resulting in a new Phase III trial. Among other changes, a new trial is likely to include a lowered dose of Cloretazine
®
(VNP40101M) in the experimental arm of the trial, and prophylactic therapy with antibiotics, anti-fungals and growth factors for all patients. Our current plan is to submit a Special Protocol Assessment (SPA) to the FDA in 2008 with these modifications before starting the new trial. There can be no assurance that we will successfully complete an SPA for this trial in 2008, or that we will start the amended trial in 2008 or at any time in the future.
Our efforts and resources are primarily focused on seeking and obtaining regulatory approval of Cloretazine
®
(VNP40101M) for use in the United States for the treatment of AML. We believe that such use of the drug for the treatment of AML presents our best opportunity for an approved product for commercialization. Accordingly, we have limited resources to allocate to additional clinical trials of Cloretazine
®
(VNP40101M) in cancers other than AML. We are evaluating Cloretazine
®
(VNP40101M) in combination with temozolomide in an investigator-sponsored Phase I/II trial in adult brain tumors and in combination with stem cell transplantation in an investigator-sponsored Phase I trial in poor-prognosis hematologic malignancies.
We have limited resources to apply to our second product candidate, Triapine
®
, beyond its evaluation in six clinical trials sponsored by the National Cancer Institute’s (NCI) Cancer Therapy Evaluation Program. We are not at this time allocating any resources to other preclinical product candidates in our portfolio, which include: (a) VNP40541, a cytotoxic (cell-damaging) compound that has been demonstrated in preclinical studies to be highly selective for hypoxic (poorly oxygenated) cells that can be difficult to treat in cancerous tumors, and (b) TAPET
®
, a drug delivery technology for the treatment of cancer. We are looking for partners to provide us with additional resources to develop these product candidates.
‘Preclinical development’ or ‘preclinical studies’ indicate that the product candidates selected for development are being evaluated for potency, specificity, manufacturability and pharmacologic activity
in vitro
, or cell culture, and
in vivo
, or animal models. Clinical evaluation of a product candidate generally involves a three-phase process. In Phase I, clinical trials are conducted with a small number
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of subjects to determine the tolerated drug dose, early safety profile, proper scheduling and the pattern of drug distribution, absorption and metabolism. In Phase II, clinical trials are conducted with groups of patients afflicted with a specific disease in order to determine efficacy, dose-response relationships and expanded evidence of safety. In Phase III, large-scale, multi-center, controlled clinical trials are conducted in order to:
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provide enough data for statistical proof of safety and efficacy;
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compare the experimental therapy to existing therapies;
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uncover unexpected safety problems, such as previously unobserved side-effects; and
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generate product labeling.
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Our product development programs are based primarily on technologies that we license from Yale University (Yale) and other cancer research centers. We have largely engaged in product development with respect to anticancer therapeutics through in-house preclinical and clinical development and through collaboration with academic, research and governmental institutions. As our product candidates advance through trials, depending on financial and pharmaceutical market conditions and the resources required for development, we will determine the best method and/or partnership to develop, and eventually market, our products.
We were incorporated in March 1992 as a Delaware corporation and began operations on May 1, 1994. We have no material source of revenues. We have incurred operating losses since our inception. As of December 31, 2007, we had an accumulated deficit of approximately $209.2 million. We expect to incur substantial operating losses for the next several years due to expenses associated with product development, clinical testing, regulatory activities, manufacturing development, scale-up and commercial-scale manufacturing, pre-commercialization activities, developing a sales and marketing force, and other infrastructure support costs. We may need to obtain additional financing to cover these costs.
For the years ended December 31, 2007, 2006 and 2005, we spent $24.2 million, $21.5 million and $16.6 million, respectively, on company-sponsored research and development activities.
Recent Development
On February 20, 2008, we effected a one-for-ten reverse split of all outstanding shares of our common stock and a corresponding decrease in the number of shares of authorized common stock. As of that date, each ten of our shares were automatically combined, converted and exchanged into one share of our common stock. No fractional shares were issued as a result of the reverse split. Instead, we will pay cash in lieu of fractional shares based on the closing sales price of our common stock on the business day immediately preceding the effective date of the reverse split as reported on the Nasdaq Capital Market
SM
. All share amounts, per share amounts and common stock prices included in this Annual Report on Form 10-K are provided on a post-reverse stock split basis.
Overview of Cancer and Treatment Methods
According to the American Cancer Society (ACS), cancer is the second most common cause of death in the United States, exceeded only by heart disease. The ACS estimates that 1,437,180 new cancer cases are expected to be diagnosed and about 565,650 cancer deaths will occur in the United States in 2008.
Cancer is a heterogeneous group of diseases characterized by uncontrolled cell division and growth resulting in the development of a mass of cells or tumor, as well as the invasion and spreading of these cells to other organs of the body (metastasis). Cancerous tumors can arise in any tissue or organ within the human body and generally cause clinical problems to the patient when the tumor affects the function of that organ or when the tumor spreads to other organs. Cancers which arise in the bone marrow (e.g. acute and chronic leukemias and multiple myeloma) or the lymph nodes (Hodgkin’s disease and lymphomas) spread through the bone marrow and lymphatic systems, affecting
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the growth of normal blood and lymphatic cells. Cancer is believed to occur as a result of a number of factors, such as genetic predisposition, chemical agents, viruses and radiation. These factors result in genetic changes affecting the ability of cells to regulate their growth and differentiation.
The most common methods of treating patients with cancer are surgery, radiation and anticancer drugs (chemotherapy). A cancer patient often receives treatment with a combination of methods. Surgery and radiation therapy are particularly effective in patients where the disease is localized. The most common method of treating patients with cancer that has spread beyond the primary site is to administer systemic chemotherapy. Chemotherapy seeks to damage and kill cancer cells or to interfere with the molecular and cellular processes that control the development, growth and survival of malignant tumor cells. In many cases, chemotherapy consists of the administration of several different drugs in combination. Chemotherapy can cause a number of side effects in patients, including weakness, low blood count, loss of appetite, nausea and vomiting, and damage to various organs that can result in loss of normal body functions.
The effectiveness of current cancer treatments with respect to any particular patient varies greatly, depending upon the cancer diagnosis and the tolerance of the individual patient to treatment. Therefore, a significant need exists for new agents that can be used alone or in combination with existing drugs and treatment approaches and that will result in greater efficacy with less toxicity (or a more favorable benefit to risk profile) than current therapeutic options.
Products for the Treatment of Cancer in Clinical Development
The discussion below sets forth the development status of our product candidates in clinical development (except as otherwise specifically noted below) as of December 31, 2007.
Cloretazine
®
(VNP40101M)
Cloretazine
®
(VNP40101M) is a novel alkylating (DNA-damaging) agent. Alkylating agents directly damage DNA to prevent cancer cells from reproducing, and work in all phases of the cell cycle, affecting both dividing and non-dividing cancer cells. Alkylating agents are among the most widely used class of anticancer drugs, displaying activity across a range of both hematologic and solid tumors, including acute and chronic leukemias, non-Hodgkin’s lymphoma, Hodgkin’s disease, multiple myeloma, and lung, breast, ovarian, brain, and certain other cancers. There are a number of approved alkylating agents used in the treatment of cancer, including busulfan, cisplatin, carboplatin, chlorambucil, cyclophosphamide, ifosfamide, dacarbazine, mechlorethamine, melphalan, and temozolomide.
Preclinical data on Cloretazine
®
(VNP40101M) showed broad anti-tumor activity in
in vivo
models. It was curative in certain preclinical leukemia models, including mice bearing certain derivatives of a leukemia cell line that was resistant to standard alkylating agents. Cloretazine
®
(VNP40101M) was also active against solid tumor models, including lung, colon and brain cancer, and melanoma. Cloretazine
®
(VNP40101M) was also not affected by mechanisms for multiple drug resistance which can limit the effectiveness of treatment. Cloretazine
®
(VNP40101M) has been shown in preclinical studies to be capable of crossing the blood-brain barrier. The blood-brain barrier has been a common obstacle in achieving active concentrations of many anticancer drugs within the brain.
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Below is a table summarizing all Cloretazine
®
(VNP40101M) clinical trials conducted through, or ongoing as of, March 1, 2008:
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Trial
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Indication
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Sponsor
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Commencement
Date
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Status
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Phase III trial in combination with Ara-C
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AML, relapsed
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Vion
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March 2005
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Clinical hold lifted by FDA; New Phase III trial in development
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Phase II single agent trial
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AML, elderly poor-risk
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Vion
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May 2006
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Ongoing
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Phase II single agent trial
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Small cell lung cancer
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Vion
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September 2005
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Closed
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Phase II single agent trial
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Brain tumors, adult
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Investigator
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June 2004
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Completed
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Phase II single agent trial
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AML and high-risk
myelodysplastic syndromes, elderly; AML, relapsed
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Vion
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March 2004
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Completed
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Phase I/II trial in combination with temozolomide
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Brain tumors, adult
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Investigator
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September 2007
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Ongoing
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Phase I/II single agent trial
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Chronic lymphocytic leukemia
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Vion
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July 2005
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Closed
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Phase I trial in combination with stem cell transplantation
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Hematologic Malignancies
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Investigator
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December 2007
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Ongoing
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Phase I trial
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Brain tumors, pediatric
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Investigator
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April 2005
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Completed
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Phase I trial in combination with temozolomide
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Hematologic malignancies
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Vion
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October 2004
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Completed
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Phase I trial in combination with Ara-C
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Hematologic malignancies
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Vion
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July 2003
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Completed
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Phase I single agent trial
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Solid tumors
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Vion
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February 2003
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Completed
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Phase I single agent trial
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Hematologic malignancies
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Vion
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August 2002
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Completed
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Phase I single agent trial
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Solid tumors
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Vion
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June 2001
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Completed
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We would need to reevaluate Cloretazine
®
(VNP40101M) if the data from any of its clinical trials raised issues relative to its safety and efficacy. In such event, we would alter the drug or dose as used in the trial, modify the clinical trial protocol, commence additional trials, or abandon the drug development project. In any such event, our business, operations and prospects would be materially adversely affected, and our ability to apply for or obtain regulatory approval might be delayed, or we might not be able to obtain regulatory approval at all.
In March 2004, we received fast track designation from the FDA for Cloretazine
®
(VNP40101M) in relapsed or refractory AML. In October 2005, we received fast track designation for Cloretazine
®
(VNP40101M) in elderly poor-risk AML. The FDA’s fast track programs are designed to facilitate the development of new drugs that are intended to treat serious or life-threatening conditions and demonstrate the potential to address unmet medical needs.
In October 2004, we received orphan drug designation from the FDA for Cloretazine
®
(VNP40101M) in AML in the United States. Orphan drug designation may be granted to products that treat rare diseases or conditions that affect fewer than 200,000 people in the United States.
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Orphan drug designation does not convey any advantage or shorten the duration of the FDA review and approval process. The designation may provide eligibility for: (i) a seven-year period of market exclusivity for the indication of AML; (ii) potential tax credits for research; (iii) grant funding for research and development; (iv) reduced filing fees for marketing applications; and (v) assistance with the review of clinical trial protocols.
In January 2006, we received orphan drug designation from the European Medicines Agency (EMEA) for Cloretazine
®
(VNP40101M) in AML in the European Union. Orphan drug status is granted by the European Commission to promote development of drugs to treat rare diseases or conditions. Orphan drug designation in Europe does not convey any advantage or shorten the duration of the EMEA review and approval process. Orphan drug designation in Europe may entitle Cloretazine
®
(VNP40101M) to: (i) a ten-year period of market exclusivity for the indication of AML; (ii) protocol assistance from the EMEA to optimize drug development in preparing a dossier that will meet regulatory requirements; (iii) reduced fees associated with applying for market approval; and (iv) access to European Union research funding.
Cloretazine
®
(VNP40101M) in Hematologic Malignancies
In May 2006, we commenced a pivotal Phase II trial of Cloretazine
®
(VNP40101M) in previously untreated elderly patients with
de novo
poor-risk AML. Elderly
de novo
poor-risk AML patients are those elderly patients whose poor-risk AML has not evolved from a prior myelodysplastic syndrome or from prior treatment with chemotherapy. In August 2007, we announced that 85 patients had been enrolled to this trial and that certain sites would continue to accrue patients to conduct an electrocardiograph evaluation (QT/QTc) sub-study. In December 2007, we announced preliminary data from this trial in a poster at the Annual Meeting of the American Society of Hematology reporting an overall response rate of 35% in 80 evaluable patients. In 2008, we plan to file an NDA with the FDA based on this trial. Although the preliminary data from this trial indicate that we met the criteria for a successful trial based on the primary endpoint, the overall response rate, there can be no assurance that we will be able to file an NDA based on the data from this trial in 2008, or at any time, or that the NDA will be approved on a timely basis by the FDA, if it all.
Our Phase III trial of Cloretazine
®
(VNP40101M) in combination with cytarabine in relapsed AML was initiated in March 2005 and has accrued 268 patients. In May 2007, we announced that we would suspend enrollment and patient treatment to this trial pending a detailed review of all of the data from the trial. This decision was based on a planned interim analysis of clinical data from the first 210 treated patients by the trial’s data safety monitoring board (DSMB) that resulted in a recommendation that enrollment and further treatment of patients on study be suspended. The DSMB’s recommendation was based on their evaluation that any advantage in the primary endpoint, the overall response rate, was being compromised by the mortality observed on the study. In May 2007, the FDA placed the trial on clinical hold. We subsequently performed a comprehensive safety and efficacy analysis with our personnel and external and independent medical consultants. In November 2007, we announced that discussions with the DSMB for the trial regarding the findings of the medical and safety review had been completed and the next step of the process was to present the findings and recommendations to the regulatory authorities. In January 2008, we announced that the FDA had lifted the clinical hold on this trial, and that we had reached initial agreement with the FDA on modifications to our original Phase III study protocol resulting in a new Phase III trial. Among other changes, a new trial would likely include a lowered dose of Cloretazine
®
(VNP40101M) in the experimental arm of the trial, and prophylactic therapy with antibiotics, anti-fungals and growth factors for all patients. We now plan to submit a Special Protocol Assessment (SPA) to the FDA in 2008 with these modifications before starting the new trial. There can be no assurance that we will successfully complete an SPA for this trial in 2008, or that we will start the new trial in 2008 or at any time in the future.
A Phase I investigator-sponsored trial in combination with stem cell transplantation for patients with selected poor-prognosis hematologic malignancies was initiated in December 2007.
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Cloretazine
®
(VNP40101M) in Solid Tumors
In January 2008, our Phase II trial of Cloretazine
®
(VNP40101M) as a single agent in small cell lung cancer was closed to patient enrollment due to a reallocation of resources. The trial had accrued 67 out of a planned total of 87 patients. Final data from this trial will be evaluated when available.
A Phase I/II investigator-sponsored trial of Cloretazine
®
(VNP40101M) in combination with temozolomide in adult brain tumors was initiated in September 2007.
Triapine
®
Triapine
®
is a small molecule that in preclinical models inhibits the enzyme ribonucleotide reductase and therefore prevents the replication of tumor cells by blocking a critical step in DNA synthesis. Ribonucleotide reductase inhibition is thought to arrest the growth of, or kill, cancer cell lines, by blocking a critical step in DNA synthesis in cancer cells. Inhibition of this enzyme has also been shown
in vitro
and
in vivo
to enhance the anti-tumor activity of several standard anticancer agents. Accordingly, Triapine
®
has potential to be used as a single agent and in combination with anticancer drugs to prevent damaged anticancer cells from regenerating.
We have evaluated an intravenous formulation of Triapine
®
in five single agent Phase I trials, three single agent Phase II trials, four Phase I combination trials, and two Phase II combination trials. All our other trials of Triapine
®
are closed to accrual or completed.
Clinical trials of Triapine
®
are currently being sponsored by the NCI’s Cancer Therapy Evaluation Program under a long-term clinical trials agreement with the NCI’s Division of Cancer Treatment and Diagnosis for the clinical development of Triapine
®
. We provide the product used in these trials. There are currently five open trials sponsored by the NCI to evaluate an intravenous formulation of Triapine
®
: (i) two trials of Triapine
®
in combination with gemcitabine; (ii) two trials of Triapine
®
in combination with radiation; and (iii) a trial of Triapine
®
in combination with fludarabine. An additional eleven trials are closed to accrual or completed.
Clinical testing of new single agent administration schedules may be possible with the oral form of Triapine
®
, which to date has been studied in a small number of patients to determine its absorption in the bloodstream following a single dose. A Phase I trial sponsored by the NCI of an oral formulation of Triapine
®
is currently ongoing.
In October 2003, we entered into a license with Beijing Pason Pharmaceuticals, Inc. (Pason) whereby we granted Pason the exclusive rights to develop, manufacture and market Triapine
®
in the People’s Republic of China, Taiwan, Hong Kong and Macao. To date, Pason has not conducted clinical trials of Triapine
®
. See ‘‘— License and Research Agreements,’’ below.
Other Products and Product Candidates for Conditions Other than Cancer
MELASYN
®
Melanin is a pigment formed by cells in the skin that gives skin its color and protects it from sun damage by absorbing ultraviolet rays. MELASYN
®
is a patented, water-soluble, synthetic version of melanin, making it a potentially useful ingredient for formulation of skin care products and cosmetics. Our MELASYN
®
patents and technology are licensed from Yale. We have granted non-exclusive sublicenses for MELASYN
®
to Johnson and Johnson Consumer Companies, Inc. and another sublicensee. See ‘‘— License and Research Agreements,’’ below.
Novel Nucleoside Analogs
We have licensed patents and patent applications related to a nucleoside analogue, or synthetic molecule, known as elvucitabine (ß-L-Fd4C) from Yale. In February 2000, we entered into a sublicense agreement for elvucitabine with a sublicensee. Under the terms of the sublicense agreement, the sublicense has funded the development of elvucitabine which is currently in Phase II clinical trials as an antiviral drug for the treatment of human immunodeficiency virus (HIV). See
‘‘— License
and Research Agreements,’’ below.
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License and Research Agreements
Agreements with Yale University
We license various compounds from Yale, including Cloretazine
®
(VNP40101M) and Triapine
®
, which were developed in the laboratory of Dr. Sartorelli, one of our directors, through research funded in part by us. The license agreements with Yale, which are described below, grant us exclusive licenses to make, use, sell and practice the inventions covered by various patents and patent applications relating to our primary product candidates as described below. Yale has retained the right to make, use and practice the inventions for non-commercial purposes. Under the license agreements we are required to exercise due diligence in commercializing the licensed technologies. The licenses may be terminated by Yale in the event that we fail to make a payment when due, we commit a material breach of the license, we become insolvent or file a petition in bankruptcy, or we fail to exercise due diligence in commercializing the licensed products, subject to certain cure periods. In the event that the license agreement dated August 1994, described below, is terminated for breach, all rights under licenses previously granted terminate. Accordingly, a default as to one product could affect our rights in other products. We may terminate the licenses in the event of Yale’s material breach of the licenses if such breach remains uncured for 30 days. Under the license agreements, we are also required to defend and indemnify Yale for any damages arising out of its use or sale of the licensed products by us or our sublicensees.
Subsequent to entering into a license agreement with Yale in August 1994, described below, we have paid approximately $10.8 million to fund research activities at Yale through March 31, 2008. For risks associated with research funding provided to Yale, see ‘‘— If Yale does not conduct research relating to products we would like to pursue, we may never realize any benefits from our funding provided to Yale’’ under ‘‘Risk Factors’’ in Part I, Item 1A of this Annual Report on Form 10-K.
Yale/Vion (formerly MelaRx Pharmaceuticals, Inc.) License Agreement — September 1990
Under this agreement, we have an exclusive license to MELASYN
®
. Under the terms of the license agreement, we pay a license fee to Yale based on a percentage of net sales and sublicensing revenues. The term of the license is dictated by the expiration of patents relating to any invention and, with respect to non-patented inventions or research, 24 years from 1990 (i.e. through 2014).
We have granted non-exclusive sublicenses for MELASYN
®
to Johnson and Johnson Consumer Companies, Inc. and another sublicensee. Under the terms of the sublicense agreements, we receive reimbursement for certain costs and, when and if products including our technology are commercialized, we will receive a royalty based on sales in countries where we have issued patents.
Yale/Vion (formerly OncoRx, Inc.) License Agreement — August 1994
Under this amended agreement, we have a non-transferable worldwide exclusive license to make, have made, use, sell and practice inventions under certain patents and patent applications for therapeutic and diagnostic purpose. The patents and patent applications under this amended license cover Cloretazine
®
(VNP40101M) and other sulfonylhydrazine compounds, Triapine
®
and elvucitabine (ß-L-Fd4C). The term of the license is dictated by the expiration of any patents relating to any inventions or, with respect to non-patented inventions or research, 17 years from 1994 (i.e. through 2011). This amended agreement provides that if Yale, as a result of its own research, identifies potential commercial opportunities for the licensed inventions, we will have the first option to negotiate a commercial license for the commercial opportunities. Yale is entitled to royalties on sales, if any, of resulting products, sublicensing revenues and, with regard to several patents, milestone payments based on the status of clinical trials and/or regulatory approvals.
We have granted a sublicense for elvucitabine (ß-L-Fd4C) to a sublicensee. Under the terms of the sublicense agreement, we received a small equity payment and, when and if a product including our technology is developed and commercialized, we will receive payments based on development milestones and royalties based on product revenue.
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Yale/Vion (formerly OncoRx, Inc.) License Agreements — December 1995
We have an agreement with Yale that provides for a non-transferable worldwide exclusive license, expiring over the lives of the patents, to three inventions relating to gene therapy for melanoma. Technology licensed by us under this agreement relates to TAPET
®
. We have another agreement with Yale pursuant to which we have a non-transferable worldwide exclusive license, expiring over the lives of the patents, to an invention relating to whitening skin. Under these licensing agreements, Yale is entitled to milestone payments based on the status of clinical trials and regulatory approvals. In addition, Yale is entitled to royalties on sales, if any, of resulting products and sublicense revenues.
Other Agreements
License Agreement with Beijing Pason Pharmaceuticals, Inc.
In 2003, we entered into a license with Pason providing them with the exclusive rights to develop, manufacture and market Triapine
®
in the People’s Republic of China, Taiwan, Hong Kong and Macao (the Pason Territory). Under the terms of the agreement, we received an upfront technology license fee and, when and if the product is developed and commercialized by Pason, we will receive milestone payments and royalties based on Triapine
®
revenues in the Pason Territory. Pason is required to fund the preclinical and clinical development necessary for regulatory approval of Triapine
®
in the Pason Territory. To date, Pason has not conducted trials of Triapine
®
.
License Agreement with Austrian Inventors and Austria Wirtschaftsservice Gesellschaft m.b.H.
In 2005, we entered into an exclusive license agreement for certain novel compounds, hydrazones, with a group of inventors from the Institute of Pharmacy and the Institute of Medical Chemistry and Biochemistry at the University of Innsbruck, and Austria Wirtschaftsservice Gesellschaft m.b.H. Under this license agreement, we must make milestone payments based on the progress of product development and pay royalties based on product revenues.
Competition
Competition in the biopharmaceutical industry is intense and based on scientific and technological factors, the availability of patent and other protection for technology and products, the ability to finance and commercialize technological developments, and the ability to obtain governmental approval for testing, manufacturing and marketing drugs. We face competition from pharmaceutical companies and biotechnology companies. Numerous companies have publicly announced their intention to develop anticancer drugs including, in some instances, agents to be used for the treatment of AML or alkylating agents like our compound Cloretazine
®
(VNP40101M), or agents that target ribonucleotide reductase like our compound Triapine
®
. For risks associated with competition, see ‘‘— We face intense competition in the market for anticancer products, and if we are unable to compete successfully, our business will suffer’’ under ‘‘Risk Factors’’ in Part I, Item 1A of this Annual Report on Form 10-K.
Patents, Licenses and Trade Secrets
Our policy is to protect our technology by, among other means, filing patent applications for technology that we consider important to the development of our business. We intend to file additional patent applications, when appropriate, relating to new developments or improvements in our technology and other specific products that we develop. We also rely on trade secrets, know-how and continuing technological innovations, as well as patents we have licensed or may license from other parties to develop and maintain our competitive position.
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In connection with our license agreement with Yale dated August 1994, we are the exclusive licensee, subject to certain rights retained by Yale, of a number of issued patents and pending U.S. and foreign patent applications relating to:
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Cloretazine
®
(VNP40101M), and other compounds in the sulfonylhydrazine class;
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Triapine
®
and other ribonucleotide reductase inhibitors; and
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Elvucitabine (ß-L-Fd4C), its composition and its use for the treatment of HIV and hepatitis B (HBV) infections, and its use in combination with other anti-viral drugs.
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We are also the exclusive licensee from Yale of an issued U.S. patent and several foreign patents on KS119, a hypoxia-selective anticancer agent. Vion has also licensed from Yale one U.S. and several foreign patents relating to synthetic melanin and methods for using synthetic melanin, such as for sunscreen or self-tanning agents, relevant to our MELASYN
®
technology.
Pursuant to our license agreement with Yale dated December 1995, we are the exclusive licensee of a number of issued patents and pending patent applications, U.S. and foreign, relating to our TAPET
®
technology, which include claims for methods of diagnosing and/or treating various solid tumor cancers, including melanoma, lung cancer, breast cancer and colon cancer. We also have rights, either by license and/or by assignment, to issued patents and pending patent applications, U.S. and foreign, relating to our TAPET
®
technology. In addition, we have filed a number of U.S. provisional and non-provisional patent applications, an international patent application and a number of foreign patent applications related to this technology.
We or our licensors are prosecuting the patent applications related to products we license both with the U.S. Patent and Trademark Office (PTO) and various foreign patent agencies, but we do not know whether any of our applications will result in the issuance of any patents or, whether any issued patent will provide significant proprietary protection or will be circumvented or invalidated. During the course of patent prosecution, patent applications are evaluated for, among other things, utility, novelty, non-obviousness, written description and enablement. The PTO may require that the claims of an initially filed patent application be amended if it is determined that the scope of the claims include subject matter that is not useful, novel, non-obvious, described adequately or enabled. Furthermore, in certain instances, the practice of a patentable invention may require a license from the holder of dominant patent rights.
We cannot predict whether our patent applications or our competitors’ patent applications will result in valid patents being issued. An issued patent is entitled to a presumption of validity. The presumption may be challenged in litigation; a court could find any patent of ours or of our competitors invalid and/or unenforceable. Litigation, which could result in substantial cost to us, may also be necessary to enforce our patent and proprietary rights and/or to determine the scope and validity of the proprietary rights of others.
The patent position of biotechnology and pharmaceutical firms generally is highly uncertain and involves complex legal and factual questions. To date, no consistent policy has emerged regarding the breadth of claims allowed in biotechnology and pharmaceutical patents.
Government Regulation
Regulation by governmental authorities in the U.S. and other countries is a significant factor in the development of our products, and will be a significant factor in the manufacture and marketing of these products, if they are successfully developed and approved for sale. All of our products will require regulatory clearances or approvals prior to commercialization. In particular, drugs, biological agents and medical devices are subject to rigorous testing and other approval requirements by the FDA pursuant to the Federal Food, Drug, and Cosmetic Act and the Public Health Service Act and its regulations, as well as by regulatory authorities in other countries. Various statutes and regulations also govern or influence the testing, manufacturing, safety, labeling, packaging, advertising, storage, registration, listing and recordkeeping related to marketing of such products. Regulatory approval is a lengthy process and involves the expenditure of substantial resources. Approval time depends on a
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number of factors, including the severity of the disease in question, the availability of alternative treatments and the risks and benefits demonstrated in clinical trials. We cannot be certain that any required FDA or other regulatory approval will be granted or, if granted, will not be withdrawn.
The development of a therapeutic drug typically first requires preclinical testing. Preclinical development of therapeutic drugs and biological agents is generally conducted in the laboratory to evaluate the safety and the potential efficacy of a compound by relevant
in vitro
and
in vivo
testing. When a product is tested prospectively to determine its safety for purposes of obtaining FDA approvals or clearances, such testing must be performed in accordance with good laboratory practices for non-clinical studies. The results of preclinical testing are submitted to the FDA as part of an Investigational New Drug Application (IND). The IND must become effective, the study must be approved by an institutional review board, and informed consent must be obtained from the clinical subjects, before human clinical trials can begin.
Typically, clinical evaluation involves a three-phase process. In Phase I, clinical trials are conducted with a small number of subjects to determine the tolerated drug dose, early safety profile, proper scheduling and the pattern of drug distribution, absorption and metabolism. In Phase II, clinical trials are conducted with groups of patients afflicted with a specific disease in order to determine efficacy, dose-response relationships and expanded evidence of safety. In Phase III, large-scale, multi-center, controlled clinical trials are conducted in order to:
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provide enough data for statistical proof of safety and efficacy;
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compare the experimental therapy to existing therapies;
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uncover unexpected safety problems, such as previously unobserved side-effects; and
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generate product labeling.
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In the case of drugs for cancer and other life-threatening diseases, the initial human testing is generally conducted in patients rather than in healthy volunteers.
In May 2007, our Phase III trial of Cloretazine
®
(VNP40101M) in combination with cytarabine in relapsed AML was placed on clinical hold by the FDA. The FDA places a trial on clinical hold when the FDA does not believe or cannot confirm that the trial can be conducted without unreasonable risk to patients. We had suspended accrual and treatment of patients on this trial based on an interim evaluation by the DSMB for the trial that any advantage in the trial’s primary endpoint, the overall response rate, was being compromised by the observed mortality rate on the study. We subsequently performed a comprehensive safety and efficacy analysis with our personnel and external and independent medical consultants. In November 2007, we announced that discussions with the DSMB for the trial regarding the findings of the medical and safety review had been completed and the next step of the process was to present the findings and recommendations to the regulatory authorities. In January 2008, we announced that the FDA had lifted the clinical hold on this trial, and that we have reached initial agreement with the FDA on modifications to our original Phase III study protocol resulting in a new Phase III trial. Among other changes, a new trial is likely to include a lowered dose of Cloretazine
®
(VNP40101M) in the experimental arm of the trial, and prophylactic therapy with antibiotics, anti-fungals and growth factors for all patients. We now plan to submit a Special Protocol Assessment (SPA) to the FDA in 2008 with these modifications before starting the new trial. An SPA is a process where the FDA evaluates the adequacy of a clinical trial the results of which are expected to provide evidence of safety and efficacy in an NDA or biologic drug approval. There can be no assurances that we will successfully complete an SPA for this trial in 2008, or that we will start the new trial in 2008 or at any time in the future.
The results of the preclinical and clinical testing are submitted to the FDA either as part of a NDA for drugs, or a biologics license application (BLA) for biologics, for approval to commence commercial distribution. For a biologic drug, the manufacturer generally must also obtain approval of an establishment license application. In responding to an NDA or BLA, the FDA may grant marketing approval, request additional information or deny the application if it determines that the application does not satisfy its regulatory approval criteria. It may take several years to obtain
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approval after submission of an NDA or BLA, although approval is not assured. The FDA also normally conducts a pre-approval inspection and other occasional inspections of an applicant’s facilities to ensure compliance with current good manufacturing practices. Further, stringent FDA regulatory requirements continue after a product is approved for marketing, and changes to products or labeling can require additional approvals. If any of our products is approved for marketing, we will be subject to stringent post-marketing requirements.
We also will be subject to widely varying foreign regulations governing clinical trials and pharmaceutical sales. Whether or not FDA approval has been obtained, approval of a product by the comparable regulatory authorities of other countries must be obtained before marketing the product in those countries. The approval process varies from country to country and the time may be longer or shorter than that required for FDA approval. We intend, to the extent possible, to rely on foreign licensees to obtain regulatory approval to market our products in other countries.
In October 2004, we received orphan drug designation for Cloretazine
®
(VNP40101M) in AML. Under the Orphan Drug Act, a sponsor may obtain designation by the FDA of a drug or biologic as an ‘orphan’ drug for a particular indication. Orphan drug designation is granted to drugs for rare diseases or conditions, including many cancers, with a prevalence of less than 200,000 cases in the United States. The sponsor of a drug that has obtained orphan drug designation and which is the first to obtain approval of a marketing application for such drug is entitled to marketing exclusivity for a period of seven years for the designated indication. This means that no other company can market the same orphan drug for the same indication approved by the FDA for seven years after approval unless such company proves its drug is clinically superior or the approved orphan drug marketer cannot supply demand for the drug. Legislation is periodically considered that could significantly affect the Orphan Drug law. We intend to seek additional orphan drug designations for our products where appropriate.
FDA regulatory procedures established in 1988 are intended to speed further the availability of new drugs intended to treat life-threatening and severely debilitating illnesses. These procedures provide for early and continuous consultation with the FDA regarding preclinical and clinical studies necessary to gain marketing approval. This regulatory framework also provides that if Phase I results demonstrate potential, Phase II clinical trials may be designed that obviate the need for lengthy, expensive Phase III testing. Notwithstanding the foregoing, approval may be denied by the FDA or traditional Phase III studies may be required. The FDA may also seek our agreement to perform post-approval Phase IV studies, which confirm product safety and efficacy.
In January 2006, we received orphan drug designation for Cloretazine
®
(VNP40101M) for the treatment of AML in Europe. Orphan drug status is granted by the European Commission to promote development of drugs to treat rare diseases or conditions. Orphan drug designation does not convey any advantage or shorten the duration of the EMEA review and approval process. Orphan drug designation may entitle Cloretazine
®
(VNP40101M) to: (i) ten years of market exclusivity for the indication of AML; (ii) protocol assistance from the EMEA to optimize drug development in preparing a dossier that will meet regulatory requirements; (iii) reduced fees associated with applying for market approval; and (iv) access to European Union research funding.
In addition to regulations relating to drug development, we are subject to federal, state and local environmental laws and regulations, including those promulgated by the Occupational Safety and Health Administration (OSHA), the Environmental Protection Agency (EPA) and the Nuclear Regulatory Commission (NRC), that govern activities or operations that may have adverse environmental effects, such as discharges to air and water, as well as handling and disposal practices for solid and hazardous wastes. These laws also impose strict liability for the costs of cleaning up, and for damages resulting from, sites of past spills, disposals or other releases of hazardous substances and materials for the investigation and remediation of environmental contamination at properties operated by us and at off-site locations where we have arranged for the disposal of hazardous substances.
We have made, and will continue to make, expenditures for environmental compliance and protection. Expenditures for compliance with environmental laws have not had, and are not expected to have, a material effect on our capital expenditures. For risks associated with environment, see
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‘‘— If environmental laws become stricter in the future, we may face large capital expenditures in order to comply with environmental laws’’ under ‘‘Risk Factors’’ below in Part I, Item 1A of this Annual Report on Form 10-K.
Manufacturing, Distribution and Marketing
We do not have experience in manufacturing any products for commercial use, or in marketing, distributing or selling any products, and have not yet commercially introduced any products. We do not currently have the capability to manufacture or market, distribute or sell on a commercial scale any products that we develop. We have only recently established pre-commercial capabilities in these areas.
We use single source third parties to manufacture limited quantities of our products for use in clinical activities. We manufacture our active pharmaceutical ingredient for Cloretazine
®
(VNP40101M) at SAFC, a member of the Sigma-Aldrich Group, under an amended manufacturing agreement expiring September 2009. Under the terms of a manufacturing agreement expiring in December 2011, Ben Venue Laboratories, a division of Boeringher Ingelheim, is our exclusive manufacturer of Cloretazine
®
(VNP40101M) finished drug product in the United States. We will need to validate our manufacturing process for Cloretazine
®
(VNP40101M) and our other products before we can sell them commercially. We expect to validate the manufacturing process for Cloretazine
®
finished product at Ben Venue Laboratories but will not be able to market any product until we complete the validation as part of the regulatory approval process. For risks associated with manufacturing, see ‘‘— We rely on third-party manufacturers to manufacture our product candidates. If these third-party manufacturers fail to manufacture product candidates of satisfactory quality, in a timely manner, in sufficient quantities or at acceptable costs, development and commercialization of our products could be delayed’’ under ‘‘Risk Factors’’ in Part I, Item 1A of this Annual Report on Form 10-K.
Our pre-commercial marketing efforts for Cloretazine
®
(VNP40101M) in 2007 included attendance at industry conferences, meetings with key opinion leaders, and brand development. If our products are approved for sale by regulatory authorities, we will need to develop our capabilities to market, distribute and sell our products or contract with third parties to do so. In the event we decide to establish a marketing and sales force, we will be required to hire and retain additional personnel. For risks associated with marketing and distribution, see ‘‘— If we are unable to establish sales, marketing and distribution capabilities, or to enter into agreements with third parties to do so, we will be unable to successfully market and sell future drug products’’ under ‘‘Risk Factors’’ in Part I, Item 1A of this Annual Report on Form 10-K.
Employees
As of December 31, 2007, we had 46 employees.
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Executive Officers of the Company
The executive officers of the Company and their respective ages and positions with the Company are as follows:
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Name
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Age
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Position
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Alan Kessman
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61
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Chief Executive Officer and Director
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Howard B. Johnson
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48
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President and Chief Financial Officer
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Ann Lee Cahill
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47
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Vice President, Clinical Development
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Meghan Fitzgerald
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37
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Vice President and Chief Business Officer
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William F. Hahne, M.D.
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54
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Vice President, Medical
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Ivan King, Ph.D.
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52
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Vice President, Research and Development
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Aileen Ryan
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53
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Vice President, Regulatory Affairs
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Karen Schmedlin
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45
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Vice President, Finance, Chief Accounting Officer and Secretary
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James Tanguay, Ph.D.
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46
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Vice President, Chemistry, Manufacturing and Controls
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Business Experience
Alan Kessman
has been our Chief Executive Officer since January 1999 and has served on our Board of Directors since October 1998. Mr. Kessman also served as our President from April 1999 to January 2004. Mr. Kessman is a partner of PS Capital LLC, an international investment and management advisor. From 1983 to 1998, Mr. Kessman was chairman, chief executive officer and president of Executone Information Systems, Inc., a developer and marketer of voice and data communications systems.
Howard B. Johnson
has been our President since January 2004 and our Chief Financial Officer since March 2002. Mr. Johnson was a vice president and a consultant for Nutrition 21, Inc., a nutri-ceutical company, from November 2001 until March 2002. From May 1999 until February 2001, Mr. Johnson was chief financial officer of IBS Interactive, Inc. (now Digital Fusion, Inc.), an information technology services company. Mr. Johnson founded and from 1996 to 1999 was chairman and chief executive officer of MedWorks Corporation, a privately held medical device company. From 1983 to 1993, Mr. Johnson was an investment banker at PaineWebber Group, Inc.
Ann Lee Cahill
has been our Vice President, Clinical Development since October 2004. Ms. Cahill was our Senior Director of Clinical Affairs from October 2003 to October 2004 and Director of Clinical Affairs from January 2002 to October 2003. From 1997 to 2002, Ms. Cahill was a member of the project management group of Schering-Plough Corporation, including leadership roles in clinical affairs for hepatitis and medical oncology. From 1985 to 1997, Ms. Cahill was a physician associate in a medical oncology practice.
Meghan Fitzgerald
has been our Vice President and Chief Business Officer since January 2006. From 2005 to January 2006, Ms. Fitzgerald was Senior Director of Strategic Planning and Business Development and from 2001 to 2005 World Wide Marketing Director of Life Cycle Management for Pfizer Human Health. From 1997 to 2001 Ms. Fitzgerald held marketing positions at Merck, Forest Labs and Sanofi-Synthelabo. Prior to 1997, Ms. Fitzgerald was a registered nurse.
William F. Hahne, M.D.
has been our Vice President, Medical since February 2008. Prior to joining Vion, Dr. Hahne was Vice President, Clinical Development, and then Vice President of Clinical Development and Medical Affairs of Celsion Corporation from January 2006 to December 2007. From 2003 to 2005, Dr Hahne was Vice President of Clinical Development for CuraGen Corporation. From 1986 to 2002, Dr. Hahne worked in various positions in medical affairs for Glaxo Inc., Merrell Dow Research Institute, Marion Merrell Dow, Hoechst Marion Rousel, and Eisai, Inc. Dr. Hahne received his medical degree from Cornell University Medical College and conducted his residency in general surgery at Emory University Affiliated Hospitals in Atlanta, Georgia.
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Ivan King, Ph.D.
has been our Vice President, Research and Development since January 2004. Dr. King was our Vice President of Research from July 1998 to January 2004, Senior Director of Biology from April 1997 to July 1998 and Director of Biology from October 1995 to April 1997. From 1990 to 1995, Dr. King was a section leader in the department of tumor biology at Schering-Plough Research Institute in charge of the cell biology and in vivo biology groups where he was responsible for identifying targets, developing high throughput assays, evaluating in vitro and in vivo activities of drug candidates and recommending candidates for clinical development. Dr. King’s first industrial position was as a senior research scientist at Bristol-Myers Squibb Company.
Aileen Ryan
has been our Vice President, Regulatory Affairs since July 2006. Prior to joining Vion, she was the head of Global Regulatory Strategy, Oncology for Bayer Pharmaceuticals Corporation from January 2004 to July 2006. Prior to joining Bayer, Ms. Ryan was Vice President, Regulatory Affairs for Coley Pharmaceutical Group from 1999 to 2003.
Karen Schmedlin
has been our Vice President, Finance and Chief Accounting Officer since March 2006 and our Secretary since April 2001. Ms. Schmedlin was our Controller from October 2000 to March 2006. From 1990 to 2000, Ms. Schmedlin held various finance and marketing positions at Executone Information Systems, Inc., a developer and marketer of voice and data communications systems, including director of marketing operations, division controller and manager of financial reporting. From 1984 to 1990, Ms. Schmedlin was an auditor with Arthur Andersen & Co.
James Tanguay, Ph.D.
has been our Vice President, Chemistry, Manufacturing and Controls since April 2007. From October 2003 to April 2007, Dr. Tanguay was Vice President, Technical Operations at Kos Pharmaceuticals, acquired by Abbott Laboratories in 2006. In that capacity, he was responsible for strategic planning and administration of all domestic and international commercial manufacturing, testing and distribution. Dr. Tanguay started at Kos Pharmaceuticals in 1996, and held several positions in quality control and analytical sciences while rising to his final position in senior management.
Directors
The directors of the Company and their respective ages are as follows:
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Name
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Age
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Position
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William R. Miller
(1)
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79
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Director
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George Bickerstaff
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52
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Director
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Stephen K. Carter, M.D.
(2)
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70
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Director
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Alan Kessman
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61
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Chief Executive Officer and Director
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Kevin Rakin
(1,3)
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47
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Director
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Alan C. Sartorelli, Ph.D.
(2)
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76
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Director
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Ian Williams, D. Phil.
(2,3)
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53
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Director
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Gary K. Willis
(1,3)
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62
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Director
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(1)
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Member of the Audit Committee of the Board of Directors.
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(2)
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Member of the Nominating and Governance Committee of the Board of Directors.
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(3)
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Member of the Compensation Committee of the Board of Directors.
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Business Experience
William R. Miller
has been Chairman of our Board since April 1995. From February 1995 until April 1995, Mr. Miller was Chairman of the Board of OncoRx, Inc., which merged into the Company (then known as MelaRx, Inc.) in April 1995. Mr. Miller is currently chairman of the board of directors of MedaSorb Technologies Corporation, a medical device company. From 1964 until his retirement in 1991, Mr. Miller was employed by Bristol-Myers Squibb Company in various positions, including vice chairman of the board commencing in 1985.
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George Bickerstaff
has been a director since June 2005. Mr. Bickerstaff has been a managing director of CRT Capital Group LLC, an investment banking company, since June 2005. From October 2000 to May 2004, Mr. Bickerstaff held various positions with Novartis, including chief financial officer of Novartis Pharma AG. From 1998 to September 2000, Mr. Bickerstaff held senior finance and operating roles in venture-funded businesses and, prior to that, held various financial positions with the Dun and Bradstreet Corporation, including Chief Financial Officer of IMS Healthcare.
Stephen K. Carter, M.D.
has been a director since April 2001. Dr. Carter is a director of Alfacell Corp., Callisto Pharmaceuticals, Inc., Cytogen Corp., Emisphere Technologies Inc. and Tapestry Pharmaceuticals, Inc. (each a biotechnology company). From 1998 to 2000, Dr. Carter was senior vice president, clinical and regulatory affairs of SUGEN, Inc. (subsequently acquired by Pharmacia & Upjohn, Inc.). From 1995 to 1996, Dr. Carter was senior vice president, research and development with Boehringer Ingelheim Pharmaceuticals, Inc. and from 1982 to 1995 held various positions with Bristol-Myers Squibb Company, including senior vice president, worldwide clinical research and development.
Kevin Rakin
has been a director since January 2007. He is also a director of Omrix Biopharmaceuticals, Inc. Since February 2007, Mr. Rakin has been chairman and chief executive officer of Advanced BioHealing, Inc. and from January 2006 to February 2007 served as its interim chief executive officer as well as an executive-in-residence at Canaan Partners. From August 2002 to October 2005, he was president and chief executive officer of Genaissance Pharmaceuticals, Inc., a biotechnology company he co-founded. Mr. Rakin also served as a member of the board of directors of Genaissance until it was acquired by Clinical Data, Inc. in October 2005.
Alan C. Sartorelli, Ph.D.
has been a director since 1995. Dr. Sartorelli has been an Alfred Gilman Professor of Pharmacology at Yale University School of Medicine since 1967 and Chairman of our Scientific Advisory Board since April 1995. Dr. Sartorelli was Chairman of the OncoRx, Inc. Scientific Advisory Board from May 1993 to April 1995 and director of Yale Comprehensive Cancer Center from 1984 to 1993.
Ian Williams, D. Phil.
has been a director since June 2006. From 1981 until his retirement in 2004, he was employed at Pfizer, Inc. in various leadership positions in pharmaceutical research and development and strategic planning. He retired as Executive Director of the Strategic Management Group where he was responsible for worldwide strategy for Pfizer Research and Development. Dr. Williams now heads his own consulting company.
Gary K. Willis
has been a director since June 2005. Mr. Willis is a also a director of Rofin-Sinar Technologies and Plug Power Inc. From 1992 to 2000, Mr. Willis was chairman, president and chief executive officer of the Zygo Corporation, a developer and marketer of optical systems and components. From 1984 to 1990, Mr. Willis was chairman, president and chief executive officer of the Foxboro Company, a supplier of instruments, systems, and services for industrial process automation.
Our directors are elected annually to serve until the next annual meeting of stockholders and until their successors shall have been duly elected and shall qualify. Our executive officers are appointed annually by our Board of Directors and serve for such period or until their earlier resignation or removal by the Board.
Available Information
The following information can be found on our website at http://www.vionpharm.com or may be obtained free of charge by contacting our Investor Relations Department at (203) 498-4210 or by sending an email message to info@vionpharm.com:
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our annual report on Form 10-K, quarterly reports on Form 10-Q, current reports on Form 8-K and amendments to those reports, as soon as reasonably practicable after such material is electronically filed with the SEC;
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our policies related to corporate governance, including the charter for the Nominating and Governance Committee of our Board of Directors, Vion’s code of ethics and business conduct applying to our directors, officers and employees, and Vion’s code of ethics applying to our chief executive officer, chief financial officer and senior financial officials; and
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the charters of the Audit Committee and the Compensation Committee of our Board of Directors.
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Table of Contents
Item
1A. Risk Factors
There are many risks and uncertainties that can affect our future business, financial performance or share price. Before you invest in our Company, you should carefully consider the risks described below which could materially affect our business, financial condition or operating results. The risks and uncertainties described below are not the only risks facing our Company. Additional risks and uncertainties not currently known to us or that we currently deem to be immaterial also may materially adversely affect our business, financial condition or operating results. If any of the risks or uncertainties described below or any such additional risks and uncertainties actually occur, our business, results of operations and financial condition could be materially and adversely affected.
We do not have any products approved for sale. Our primary product candidates are in clinical development. If our trials are delayed or achieve unfavorable results, we might not be able to obtain regulatory approval for our products.
Our product candidates are all pharmaceutical products. We must conduct extensive testing of our product candidates, including in human clinical trials, before we can apply for or obtain regulatory approval to sell our products. These tests and trials may not achieve favorable results. We would need to reevaluate any drug that did not test favorably and either alter the drug or dose, modify the trial protocol, commence additional trials, or abandon the drug development project completely. In such circumstances, we would not be able to apply for or obtain regulatory approval for an extended period of time, if ever.
Factors that can cause delay or termination of our clinical trials include:
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slow patient enrollment;
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long treatment time required to demonstrate safety and effectiveness;
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lack of sufficient supplies of the product candidate;
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adverse medical events or side effects in treated patients;
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lack of effectiveness of the product candidate being tested;
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negative or equivocal findings of the DSMB for a trial; and
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lack of sufficient funds.
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If we do not obtain regulatory approval for our product candidates, we will not be able to sell our products and the value of our company and our financial results will be materially adversely affected.
We cannot sell or market our drugs without regulatory approval. If we cannot obtain regulatory approval for our products, the value of our company and our financial results will be materially adversely affected. In the United States, we must obtain approval from the FDA for each drug that we intend to sell.
Accordingly, if and when we complete the several required phases of clinical testing for any drug candidate, we will submit our test results to the FDA. FDA review may generally take up to two years and approval is not assured. Foreign governments also regulate drugs distributed outside the United States. A delay in obtaining regulatory approvals for any of our drug candidates will also have a material adverse effect on our business.
In particular, regulatory approval of Cloretazine
®
(VNP40101M) in combination with cytarabine in relapsed AML has already been delayed and may be further delayed in light of the fact that our Phase III trial of Cloretazine
®
(VNP40101M) in combination with cytarabine in relapsed AML was put on clinical hold by the FDA in May 2007. That trial was commenced in March 2005 and accrued 268 patients. Although in January 2008 the FDA lifted the clinical hold on the trial and we reached initial agreement with the FDA on modifications to the original Phase III study protocol resulting in a new Phase III trial, there can be no assurance that we will start the amended trial in 2008 or at any time in the future, or that any new trial would not in the future be put on regulatory hold or that the new trial will result in regulatory approval of Cloretazine
®
(VNP40101M) in combination with cytarabine in relapsed AML, or what the timing of that approval might be.
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In the near term, we are heavily dependent on the success of our lead product candidate Cloretazine
®
(VNP40101M) which is still under development. If Cloretazine
®
(VNP40101M) is not successful in clinical trials or we do not obtain FDA approval of Cloretazine
®
(VNP40101M), or if FDA delays approval or narrows the indications for which we may market Cloretazine
®
(VNP40101M), our business will be materially adversely affected.
We anticipate that our ability to generate revenues in the foreseeable future will depend on the successful development and commercialization of Cloretazine
®
(VNP40101M) and, in particular and in the nearer term, for the treatment of previously untreated elderly patients with de novo poor-risk AML. We have focused substantially all of our resources on the development of Cloretazine
®
(VNP40101M). The commercial success of Cloretazine
®
(VNP40101M) will depend on several factors, including successful completion of our pivotal Phase II clinical trial for Cloretazine
®
(VNP40101M); filing an NDA based on this trial; receipt of approvals from the FDA and similar foreign regulatory authorities; establishing commercial manufacturing capabilities through third party manufacturers; successfully launching commercial sales and distribution of the products, either ourselves or through third parties; and acceptance of the products in the medical community and by third party payers, none of which can be assured. If the FDA and similar foreign regulatory authorities do grant approval for Cloretazine
®
(VNP40101M), they may narrow the indications for which we are permitted to market it, may impose other restrictions on the use or marketing of the product, or may require us to conduct additional post-marketing trials. A narrowed indication or other restrictions may limit the market potential for Cloretazine
®
(VNP40101M) and any obligation to conduct additional clinical trials would result in increased expenditures and lower revenues. If we are not successful in commercializing our lead product candidate Cloretazine
®
(VNP40101M), or are significantly delayed or limited in doing so, our business will be materially adversely affected and we may need to curtail or cease operations.
In May 2006, we commenced a pivotal Phase II trial of Cloretazine
®
(VNP40101M) in previously untreated elderly patients with
de novo
poor-risk AML. Elderly
de novo
poor-risk AML patients are those elderly patients whose poor-risk AML has not evolved from a prior myelodysplastic syndrome or from prior treatment with chemotherapy. In August 2007, we announced that 85 patients had been enrolled to this trial and that certain sites would remain open and continue to accrue patients to conduct an electrocardiograph evaluation (QT/QTc) sub-study. In December 2007, we announced preliminary data from this trial in a poster at the Annual Meeting of the American Society of Hematology, reporting an overall response rate of 35% in 80 evaluable patients in the trial. Although these preliminary data indicate that we met the criteria for a successful trial based on the primary endpoint, the overall response rate, there can be no assurance that we will be able to file an NDA based on the data from this trial in 2008, or at any time, or that the NDA will be approved on a timely basis by the FDA, if it all.
Our Phase III trial of Cloretazine
®
(VNP40101M) in combination with cytarabine in relapsed AML was initiated in March 2005 and has accrued 268 patients. In May 2007, we announced that we would suspend enrollment and patient treatment pending a detailed review of all of the data from the trial. This decision was based on a planned interim analysis of clinical data from the first 210 treated patients by the trial’s DSMB that resulted in a recommendation that enrollment and further treatment of patients on study be suspended. The DSMB’s recommendation was based on their evaluation that any advantage in the primary end point, the response rate, was being compromised by the mortality observed on the study. In May 2007, the FDA placed the trial on clinical hold. We subsequently performed a comprehensive safety and efficacy analysis with our personnel and external and independent medical consultants. In November 2007, we announced that discussions with the DSMB for the trial regarding the findings of the medical and safety review had been completed and the next step of the process was to present the findings and recommendations to the regulatory authorities. In January 2008, we announced that the FDA had lifted the clinical hold on the trial and that we had reached initial agreement with the FDA on modifications to the original Phase III study protocol resulting in a new Phase III trial. Among other changes, a new trial is likely to include a lowered dose of Cloretazine
®
(VNP40101M) in the experimental arm of the trial, and prophylactic therapy with antibiotics, anti-fungals and growth factors for all patients. We now plan to submit a
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Special Protocol Assessment (SPA) to the FDA in 2008 with these modifications before starting the new trial. There can be no assurance that we will successfully complete an SPA for this trial in 2008, or that we will start the amended trial in 2008 or at any time in the future, or that any such amended trial will result in regulatory approval.
We would need to reevaluate Cloretazine
®
(VNP40101M) if the data from any of its clinical trials raised issues relative to its safety and efficacy. In such event, we would alter the drug or dose as used in the trial, modify the clinical trial protocol, commence additional trials, or abandon the drug development project. In any such event, our business, operations and prospects would be materially adversely affected, and our ability to apply for or obtain regulatory approval might be delayed, or we might not be able to obtain regulatory approval at all.
If we continue to incur operating losses, we may be unable to continue our operations.
We have incurred losses since inception. As of December 31, 2007, we had an accumulated deficit of approximately $209.2 million. If we continue to incur operating losses and fail to become a profitable company, we may be unable to continue our operations. Since we began our business, we have focused on research, development and preclinical and clinical trials of product candidates. We expect to continue to incur losses for at least the next several years as we continue our research and development efforts, continue to conduct drug trials and develop manufacturing, sales, marketing and distribution capabilities. Our future profitability depends on our receiving regulatory approval of our product candidates and our ability to successfully manufacture and market approved drugs. The extent of our future losses and the timing of our profitability are highly uncertain.
If we fail to obtain the capital necessary to fund our operations, we will be unable to continue or complete our product development.
We will need to raise substantial additional capital to fund operations and complete our product development. As of December 31, 2007, we had $61.1 million in cash and cash equivalents to fund our operations and continue our product development. We have determined to focus substantially all of our resources on the development and commercialization of Cloretazine® (VNP40101M). However, we will not have an approved and marketable product for the foreseeable future. Under our current operating plan, if we do not have an approved product for sale which is generating significant revenues, we will need to raise substantial additional capital to have sufficient capital to fund our operations beyond the third quarter of 2009.
We may not get funding when we need it or on favorable terms. If we cannot raise adequate funds to satisfy our capital requirements, we may have to delay, scale-back or eliminate our research and development activities, clinical studies or future operations. We might have to license our technology to others. This could result in sharing revenues which we might otherwise retain for ourselves. Any of these actions may harm our business, financial condition and results of operations.
The amount of capital we may need depends on many factors, including:
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the progress, timing and scope of our product development programs;
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the progress, timing and scope of our clinical trials;
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the time and cost necessary to obtain regulatory approvals;
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the time and cost necessary to further develop manufacturing processes, arrange for contract manufacturing facilities and obtain the necessary regulatory approvals for those facilities;
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the time and cost necessary to develop sales, marketing and distribution capabilities;
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our ability to enter into and maintain collaborative, licensing and other commercial relationships; and
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our partners’ commitment of time and resource to the development of our products.
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We are significantly leveraged.
In February 2007, we issued $60 million principal amount of our convertible senior notes due February 15, 2012. The degree to which we are leveraged could, among other things:
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make it difficult for us to make payments on our notes;
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make it difficult for us to obtain financing for working capital, acquisitions or other purposes on favorable terms, if at all;
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make us more vulnerable to industry downturns and competitive pressures; and
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limit our flexibility in planning for, or reacting to changes in, our business.
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Our ability to meet our debt service obligations on the notes will depend upon our future performance, which will be subject to financial, business and other factors affecting our operations, many of which are beyond our control.
If the testing or use of our product candidates harms people, we could be subject to costly and damaging product liability claims.
Our business exposes us to potential product liability risks that are inherent in the testing, manufacturing and marketing of drug products. These risks are particularly inherent in human trials of our proposed products. Unacceptable side effects may be discovered during preclinical and clinical testing of one or more of our potential products. Side effects and other liability risks could give rise to viable product liability claims against us. While we have obtained insurance coverage for patients enrolled in clinical trials, we may not be able to maintain this insurance on acceptable terms; insurance may not provide adequate coverage against potential liabilities, and we may need additional insurance coverage for expanded clinical trials and commercial activity. As a result, product liability claims, even if successfully defended, could have a material adverse effect on our business, financial condition and results of operations. If the side effects are determined to be unacceptable, we will not be able to commercialize our products.
If we are found to be infringing on patents or trade secrets owned by others, we may be forced to cease or alter our drug development efforts, obtain a license to continue the development or sale of our products, and/or pay damages.
Our manufacturing processes and potential products may conflict with patents that have been or may be granted to competitors, universities or others, or the trade secrets of those persons and entities. As the drug development industry expands and more patents are issued, the risk increases that our processes and potential products may give rise to claims that they infringe the patents or trade secrets of others. These other persons could bring legal actions against us claiming damages and seeking to enjoin clinical testing, manufacturing and marketing of the affected product or process. If any of these actions are successful, in addition to any potential liability for damages, we could be required to obtain a license in order to continue to conduct clinical tests, manufacture or market the affected product or use the affected process. Required licenses may not be available on acceptable terms, if at all, and the results of litigation are uncertain. If we become involved in litigation or other proceedings, it could consume a substantial portion of our financial resources and the efforts of our personnel.
We rely on confidentiality agreements to protect our trade secrets. If these agreements are breached by our employees or other parties, our trade secrets may become known to our competitors.
We rely on trade secrets that we seek to protect through confidentiality agreements with our employees and other parties. If these agreements are breached, our competitors may obtain and use our trade secrets to gain a competitive advantage over us. We may not have any remedies against our competitors and any remedies that may be available to us may not be adequate to protect our business or compensate us for the damaging disclosure. In addition, we may have to expend resources to protect our interests from possible infringement by others.
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A substantial portion of our technology is subject to limited retained rights of our licensors, and we may not be able to prevent the grant of similar rights to third parties.
A substantial portion of our technology is licensed from academic institutions which technology license agreements are subject to the federal Bayh Dole Act, pursuant to which the federal government has certain limited rights to use the technology and to even require us to grant a license to one or more third parties if we are not fully developing the technology.
In certain cases we also have the right to practice improvements on the licensed technology to the extent they are encompassed by the licensed patents and within our field of use. Our licensors may currently own and may in the future obtain additional patents and patent applications that are helpful for the development, manufacture and commercial sale of our anticipated products. We may be unable to agree with one or more academic institutions from which we have obtained licenses that certain intellectual property developed by researchers at these academic institutions is covered by our existing licenses. In the event that the new intellectual property is not covered by our existing licenses, we would be required to negotiate a new license agreement. We may not be able to reach agreement with current or future licensors on commercially reasonable terms, if at all, or the terms may not permit us to sell our products at a profit after payment of royalties, which could harm our business.
Our licenses generally also may be terminated by the licensor if we default in performance of our obligations. If any of our licenses are terminated, we may lose certain rights to manufacture, sell, market and distribute products which would significantly reduce our actual and potential revenues and have a material and negative impact on our operations.
Our proprietary rights may not adequately protect our technologies.
Our commercial success will depend in part on our obtaining and maintaining patent, trade secret, copyright and trademark protection of our technologies in the United States and other jurisdictions as well as successfully enforcing this intellectual property and defending this intellectual property against third-party challenges. We will only be able to protect our technologies from unauthorized use by third parties to the extent that valid and enforceable intellectual property protections, such as patents or trade secrets, cover them. In particular, we place considerable emphasis on obtaining patent and trade secret protection for significant new technologies, products and processes. Furthermore, the degree of future protection of our proprietary rights is uncertain because legal means afford only limited protection and may not adequately protect our rights or permit us to gain or keep our competitive advantage. Moreover, the degree of future protection of our proprietary rights is uncertain for products that are currently in the early stages of development because we cannot predict which of these products will ultimately reach the commercial market or whether the commercial versions of these products will incorporate proprietary technologies.
Our patent position is highly uncertain and involves complex legal and factual questions. Accordingly, we cannot predict the breadth of claims that may be allowed or enforced in our patents or in third-party patents. For example:
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we or our licensors might not have been the first to make the inventions covered by each of our pending patent applications and issued patents;
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we or our licensors might not have been the first to file patent applications for these inventions;
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others may independently develop similar or alternative technologies or duplicate any of our technologies;
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it is possible that none of our pending patent applications or the pending patent applications of our licensors will result in issued patents;
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our issued patents and issued patents of our licensors may not provide a basis for commercially viable technologies, or may not provide us with any competitive advantages, or may be challenged and invalidated by third parties; and
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we may not develop additional proprietary technologies that are patentable.
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As a result, our owned and licensed patents may not be valid and we may not be able to obtain and enforce patents and to maintain trade secret protection for our technology. The extent to which we are unable to do so could materially harm our business.
We or our licensors have applied for and will continue to apply for patents for certain products. Such applications may not result in the issuance of any patents, and any patents now held or that may be issued may not provide us with adequate protection from competition. Furthermore, it is possible that patents issued or licensed to us may be challenged successfully. In that event, if we have a preferred competitive position because of such patents, any preferred position held by us would be lost. If we are unable to secure or to continue to maintain a preferred position, we could become subject to competition from the sale of generic products.
Patents issued or licensed to us may be infringed by the products or processes of others. The cost of enforcing our patent rights against infringers, if such enforcement is required, could be significant, and the time demands could interfere with our normal operations. There has been substantial litigation and other proceedings regarding patent and other intellectual property rights in the pharmaceutical, biotechnology and medical technology industries. We may become a party to patent litigation and other proceedings. The cost to us of any patent litigation, even if resolved in our favor, could be substantial. Some of our competitors may be able to sustain the costs of such litigation more effectively than we can because of their substantially greater financial resources. Litigation may also absorb significant management time.
Unpatented trade secrets, improvements, confidential know-how and continuing technological innovation are important to our scientific and commercial success. Although we attempt to and will continue to attempt to protect our proprietary information through reliance on trade secret laws and the use of confidentiality agreements with our corporate partners, collaborators, employees and consultants and other appropriate means, these measures may not effectively prevent disclosure of our proprietary information, and, in any event, others may develop independently, or obtain access to, the same or similar information.
Certain of our patent rights are licensed to us by third parties. If we fail to comply with the terms of these license agreements, our rights to those patents may be terminated, and we will be unable to conduct our business.
If we fail to recruit and retain key personnel, our research and development programs may be delayed.
We are highly dependent upon the efforts of our senior management and scientific personnel, particularly, Alan Kessman, our chief executive officer and director; Howard B. Johnson, our president and chief financial officer; Ann Lee Cahill, our vice president, clinical development; Meghan Fitzgerald, our vice president and chief business officer; William F. Hahne, M.D., our vice president, medical affairs; Ivan King, Ph.D., our vice president, research and development; Aileen Ryan, our vice president, regulatory affairs and James Tanguay, Ph.D., our vice president, chemistry, manufacturing & control. There is intense competition in the drug development industry for qualified scientific and technical personnel. Since our business is very technical and specialized, we need to continue to attract and retain such people. We may not be able to continue to attract and retain the qualified personnel necessary for developing our business, particularly in light of our need to raise additional financing in order to continue our operations beyond the third quarter of 2009. We have no key man insurance policies on any of the officers listed above and we only have an employment agreement with Mr. Kessman. If we lose the services of our management and scientific personnel or fail to recruit other scientific and technical personnel, our research and product development programs will be significantly and detrimentally affected.
We face intense competition in the market for anticancer products, and if we are unable to compete successfully, our business will suffer.
We face competition from pharmaceutical companies and biotechnology companies. Numerous pharmaceutical and biotechnology companies have publicly announced their intention to develop
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drugs for the treatment of cancer including, in some instances, the development of agents which treat AML and/or are alkylating agents similar to our compound Cloretazine
®
(VNP40101M) and agents which target ribonucleotide reductase similar to our compound Triapine
®
. These companies include, but are not limited to Amgen Inc., AstraZeneca PLC, Genzyme Corporation and its subsidiary, Bioenvision, Inc., Bristol-Myers Squibb Company, Celgene Corporation, Chiron Corporation, Eli Lilly and Co., Cyclacel Pharmaceuticals, Inc., Genentech Inc., ImClone Systems Inc., Johnson & Johnson, Lorus Therapeutics Inc., MGI Pharma, Inc., OSI Pharmaceuticals, Inc., Pfizer Inc., Pharmion Corp., Schering-Plough Corporation, Wyeth, and Xanthus Pharmaceuticals, Inc. These and other large pharmaceutical companies have substantially greater financial and other resources and development capabilities than we do and have substantially greater experience in undertaking preclinical and clinical testing of products, obtaining regulatory approvals, and manufacturing and marketing pharmaceutical products. In addition, our competitors may succeed in obtaining approval for products more rapidly than us and in developing and commercializing products that are safer and more effective than those that we propose to develop. The existence of these products, other products or treatments of which we are not aware or products or treatments that may be developed in the future may adversely affect the marketability of our products by rendering them less competitive or obsolete. In addition to competing with universities and other research institutions in the development of products, technologies and processes, we may compete with other companies in acquiring rights to products or technologies from universities.
If our corporate partners, licensors, licensees, collaborators at research institutions and others do not conduct activities in accordance with our arrangements, our research and development efforts may be delayed.
Our strategy for the research, development and commercialization of our products entails entering into various arrangements with corporate partners, licensors, licensees, collaborators at research institutions and others. We currently depend on the following third parties:
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Healthcare facilities in the United States and other countries to perform human clinical trials of our products;
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Clinical research organizations in the United States and other countries to monitor and collect data related to human clinical trials;
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The NCI to perform human clinical trials of Triapine
®
;
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Contract manufacturers to produce our products for use in clinical and potential commercial activities;
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Consultants to assist with the preparation of our NDA and our commercialization efforts; and
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Yale for research and for technologies that are licensed by them to us.
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If the third parties do not conduct activities in accordance with the arrangements we have with them, or if these arrangements are terminated, our product development efforts may be delayed. We may also rely on other collaborative partners to obtain regulatory approvals and to manufacture and market our products. The amount and timing of resources to be devoted to these activities by these other parties may not be within our control.
If Yale does not conduct research relating to products we would like to pursue, we may never realize any benefits from our funding provided to Yale.
We have paid approximately $10.8 million to fund research at Yale (including research activities of one of our directors, an affiliate of Yale) through March 31, 2008. We may continue to support certain research projects at Yale. We generally do not have the right to control the research that Yale conducts with our funding, and our funds may not be used to conduct research relating to products that we would like to pursue. Additionally, if the research conducted by Yale results in technologies that Yale has not already licensed or agreed to license to us, we may need to negotiate additional license agreements or we may be unable to utilize those technologies.
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If we are unable to establish sales, marketing and distribution capabilities, or to enter into agreements with third parties to do so, we will be unable to successfully market and sell future drug products.
We have no experience with marketing, sales and distribution of drug products and have only recently established pre-commercial capability in those areas. If we are unable to establish capabilities to sell, market and distribute our products, either by developing our own capabilities or entering into agreements with others, we will not be able to successfully sell our future drug products. In that event, we will not be able to generate significant revenues. We cannot guarantee that we will be able to hire the qualified sales and marketing personnel we need. We may not be able to enter into any marketing or distribution agreements with third-party providers on acceptable terms, if at all.
We rely on third-party manufacturers to manufacture our product candidates. If these third-party manufacturers fail to manufacture product candidates of satisfactory quality, in a timely manner, in sufficient quantities or at acceptable costs, development and commercialization of our products could be delayed.
We have no manufacturing facilities, and we have no experience in the commercial manufacturing of drugs or in validating drug manufacturing processes. We have contracted with third-party manufacturers to produce our product candidates for regulatory approvals and clinical trials. We have limited supplies of our product candidates for clinical trials. If our supplies are damaged or destroyed, either during storage or shipping or otherwise, our clinical trials may be delayed, which could have a material adverse effect on our business. We intend to rely on third-party contract manufacturers to manufacture, supply, store and distribute commercial quantities of our product candidates. We will also rely on our third-party manufacturing partners to work with us to complete the Chemistry, Manufacturing and Control, or CMC, section of any nondisclosure agreements or any marketing approval application we may file.
Contract manufacturers are obliged to operate in accordance with government mandated obligations, including FDA-mandated current good manufacturing practices (cGMPs). A failure of any of our contract manufacturers to establish and follow cGMPs or to document their adherence to such practices may lead to significant delays in the availability of material for clinical trials and may delay or prevent filing or approval of marketing applications for our products.
Changing contract manufacturers may be difficult, and the number of potential manufacturers is limited. Changing manufacturers requires validation of the manufacturing processes and procedures in accordance with government mandated obligations, including FDA-mandated cGMPs. Such validation may be costly and time-consuming. It may be difficult or impossible for us to find replacement manufacturers on acceptable terms quickly, if at all. Either of these factors could delay or prevent the completion of our clinical trials, the approval of our product candidates by the FDA or other regulatory agencies, or the commercialization of our products, result in higher costs, or cause a decline in potential product revenues.
Drug manufacturers are subject to on-going, periodic unannounced inspections by the FDA and corresponding state and foreign agencies to ensure strict compliance with cGMPs, other government regulations and corresponding foreign standards. While we are obligated to audit the performance of third-party contractors, we do not have control over our third-party manufacturers’ compliance with these regulations and standards. Failure by our third-party manufacturers or us to comply with applicable regulations could result in sanctions being imposed on us, including fines, injunctions, civil penalties, failure of the government to grant market approval of drugs, delays, suspension of clinical trials, withdrawal of approvals, seizures, detentions or recalls of product, operating restrictions and criminal prosecution.
To date, our product candidates have been manufactured in small quantities by third-party manufacturers for preclinical and clinical trials. We have not validated the manufacturing process for Cloretazine
®
(VNP40101M) to date. In order to obtain marketing approval for any of these product candidates, we will need to enter into and maintain long-term supply agreements with our existing or new third-party manufacturers, such as our agreements with SAFC or Ben Venue Laboratories, and demonstrate that we can manufacture sufficient quantities under a validated manufacturing process for
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commercial sale. Our third-party manufacturers may terminate our agreements, may not be able to successfully increase their manufacturing capacity, validate our manufacturing process, or apply at commercial scale the current manufacturing process for any of our product candidates in a timely or economic manner, or at all. This may require seeking out additional manufacturing partners who may have different equipment requiring additional validation studies, which the relevant government regulator must review and approve. If we are unable to successfully validate or increase the manufacturing capacity for a product candidate, the regulatory approval or commercial launch of that product candidate may be delayed or there may be a shortage in the supply of the product candidate. Our product candidates require precise, high-quality manufacturing. The failure of our third-party manufacturers to achieve and maintain these high manufacturing standards, including the incidence of manufacturing errors, could result in patient injury or death, product recalls or withdrawals, delays or failures in product testing or delivery, cost overruns or other problems that could seriously harm our business.
If environmental laws become stricter in the future, we may face large capital expenditures in order to comply with environmental laws.
We cannot accurately predict the outcome or timing of future expenditures that we may be required to expend to comply with comprehensive federal, state and local environmental laws and regulations. We must comply with environmental laws that govern, among other things, all emissions, waste water discharge and solid and hazardous waste disposal, and the remediation of contamination associated with generation, handling and disposal activities. To date, we have not incurred significant costs and are not aware of any significant liabilities associated with our compliance with federal, state and local laws and regulations. However, environmental laws have changed in recent years and we may become subject to stricter environmental standards in the future and may face large capital expenditures to comply with environmental laws. We have limited capital and are uncertain whether we will be able to pay for significantly large capital expenditures. Also, future developments, administrative actions or liabilities relating to environmental matters may have a material adverse effect on our financial condition or results of operations.
All of our operations are performed under strict environmental and health safety controls consistent with the Occupational Safety and Health Administration, the Environmental Protection Agency and the Nuclear Regulatory Commission regulations. We cannot be certain that we will be able to control all health and safety problems. If we cannot control those problems, we may be held liable and may be required to pay the costs of remediation. These liabilities and costs could be material.
We may expand our business through new acquisitions that could disrupt our business, harm our financial condition and may also dilute current stockholders’ ownership interests in our company.
Our business strategy includes expanding our products and capabilities, and we may seek acquisitions to do so. Acquisitions involve numerous risks, including:
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substantial cash expenditures;
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potentially dilutive issuance of equity securities;
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incurrence of debt and contingent liabilities, some of which may be difficult or impossible to identify at the time of acquisition;
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difficulties in assimilating the operations of the acquired companies;
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diverting our management’s attention away from other business concerns;
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risks of entering markets in which we have limited or no direct experience; and
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the potential loss of our key employees or key employees of the acquired companies.
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We cannot assure you that any acquisition will result in short-term or long-term benefits to us. We may incorrectly judge the value or worth of an acquired company or business. In addition, our future success would depend in part on our ability to manage the rapid growth associated with some of these
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acquisitions. We cannot assure you that we will be able to make the combination of our business with that of acquired businesses or companies work or be successful. Furthermore, the development or expansion of our business or any acquired business or companies may require a substantial capital investment by us. We may not have these necessary funds or they might not be available to us on acceptable terms or at all. We may also seek to raise funds by selling shares of our common stock, which could dilute current stockholder’s ownership interest in our company.
Our common stock could be delisted from the Nasdaq Capital Market
SM
. Among other things, delisting from the Nasdaq Capital Market
SM
would cause us to become ineligible to use Form S-3 for the registration of the resale of our securities held by certain of our security holders.
If the price of our common stock declines below $1.00 per share, we may fail to meet Nasdaq’s maintenance criteria, which may result in the delisting of our common stock from the Nasdaq Capital Market
SM
.
In the event of such delisting, trading, if any, in our common stock may then continue to be conducted in the non-Nasdaq over-the-counter market in what are commonly referred to as the electronic bulletin board and the ‘‘pink sheets.’’ As a result, an investor may find it more difficult to dispose of or obtain accurate quotations as to the market value of our common stock. In addition, we would be subject to a Rule promulgated by the SEC that, if we fail to meet criteria set forth in such Rule, imposes various practice requirements on broker-dealers who sell securities governed by the Rule to persons other than established customers and accredited investors. For these types of transactions, the broker-dealer must make a special suitability determination for the purchaser and have received the purchaser’s written consent to the transactions prior to the sale. Consequently, the Rule may have a materially adverse effect on the ability of broker-dealers to sell our securities, which may materially affect the ability of stockholders to sell our securities in the secondary market.
A delisting from the Nasdaq Capital Market
SM
will also make us ineligible to use Form S-3 to register the sale of shares of our common stock or to register the resale of our securities held by certain of our security holders with the SEC, thereby making it more difficult and expensive for us to register our common stock or other securities and raise additional capital. We are a party to several registration rights agreements, which require us to maintain the effectiveness of registration statements relating to the resale of shares of common stock issuable upon the exercise of outstanding warrants and upon conversion of our outstanding notes by holders of such warrants and notes. If we are ineligible to use Form S-3, we will need to file new registration statements on some other permitted Form and maintenance of the effectiveness of such registration statements will become extremely difficult. Under the applicable registration rights agreements, we could become subject to certain liquidated damages upon and during the continuance of any such failure. We would also incur additional costs under state blue-sky laws to sell equity if we are delisted.
On September 18, 2007, we announced we had received a letter from the Nasdaq Stock Market, Inc. dated September 17, 2007 notifying us that during the preceding 30 consecutive trading days, the bid price of our common stock had closed below the minimum bid price of $1.00 per share as required by the Nasdaq Stock Market under Marketplace Rule 4310(c)(4). The letter stated that, in accordance with Marketplace Rule 4310(c)(8)(D), we had until March 17, 2008 to demonstrate compliance with the Rule (i.e. the bid price of our common stock must close at $1.00 per share or more for a minimum of 10 consecutive trading days, and under certain circumstances, more than 10 trading days). On February 20, 2008, we effected a one-for-ten reverse split of our common stock and, as of March 5, 2008, we regained compliance with the Rule. There can be no assurance that we will be able to maintain compliance with Nasdaq’s listing standards for any length of time.
Our common stock price has been highly volatile, and an investment in our common stock could suffer a decline in value.
The trading price of our common stock has been highly volatile and could continue to be subject to wide fluctuations in price in response to various factors, many of which are beyond our control, including:
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positive or adverse developments with respect to our drug trials;
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actual or anticipated period-to-period fluctuations in financial results;
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litigation or threat of litigation;
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failure to achieve, or changes in, financial estimates by securities analysts;
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announcements of new products or services or technological innovations by us or our competitors;
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comments or opinions by securities analysts or major stockholders;
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conditions or trends in the pharmaceutical, biotechnology and life science industries;
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announcements by us of significant acquisitions, strategic partnerships, joint ventures or capital commitments;
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additions or departures of key personnel;
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sales of our common stock and issuances of common stock to pay interest on our outstanding senior convertible notes;
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economic and other external factors or disasters or crises;
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limited daily trading volume; and
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developments regarding our patents or other intellectual property or that of our competitors.
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In addition, the stock market in general, and the Nasdaq Capital Market
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and the market for biotechnology companies in particular, have experienced significant price and volume fluctuations that have often been unrelated or disproportionate to the operating performance of those companies. Further, there has been significant volatility in the market prices of securities of life science companies. These broad market and industry factors may seriously harm the market price of our common stock, regardless of our operating performance. In the past, following periods of volatility in the market price of a company’s securities, securities class action litigation has often been instituted. A securities class action suit against us could result in substantial costs, potential liabilities and the diversion of management’s attention and resources.
The terms of our outstanding notes and warrants, as well as any additional funding we raise in the future could cause extreme dilution to our stockholders. Further, the large number of our shares that may be held in the market may depress the market price of our stock.
The conversion of some or all of our outstanding notes, our payment of interest or make-whole premiums on the notes under certain circumstances with shares of common stock, and the exercise of the warrants issued in connection with the sale of the notes, will dilute the ownership interests of existing stockholders. Additional shares of common stock will be issued upon the exercise of other outstanding warrants and options, as well as for awards under our 2005 Stock Incentive Plan and purchases under our 2000 Employee Stock Purchase Plan.
Further, to the extent we determine that we need additional financing and we encounter additional opportunities to raise cash, we would likely sell additional equity or debt securities. Depending on our stock price and market conditions at the time of any capital raise, and the amount of capital we need, such debt or equity securities may be sold at relatively low prices, including prices which are below the market price of our common stock, and may have substantial rights to control us. Stockholders would experience extreme dilution as well as subordination of their rights. Other than as set forth in the indenture governing the notes, we do not have any contractual restrictions on our ability to incur debt. Any indebtedness could contain covenants that restrict our operations.
Any sales in the public market of the common stock paid as interest or as a make-whole premium, issuable upon conversion of the notes or exercise of warrants, the exercise of outstanding options or the issuance of equity pursuant to our 2005 Stock Incentive Plan and 2000 Employee Stock Purchase Plan, could adversely affect prevailing market prices of our common stock. Future sales of
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substantial amounts of our common stock in the public market, or the perception that such sales are likely to occur, could also affect prevailing trading prices of our common stock.
The rights that have been and may in the future be granted to our stockholders may allow our Board of Directors and management to deter a potential acquisition in which the Board of Directors and management are to be replaced.
We have in place a stockholder rights plan, or ‘‘poison pill,’’ which enables our Board of Directors to issue rights to purchase common stock when someone acquires 20% or more of the outstanding shares of our common stock. As a result of the plan, anyone wishing to take over the company would most likely be forced to negotiate a transaction with our Board of Directors and management in order not to trigger the pill. The need to negotiate with the Board of Directors or management could frustrate a proposed takeover particularly where the Board of Directors and management wish to remain entrenched. This would prevent our stockholders from participating in a takeover or tender offer, which might be of substantial value to them.
Provisions of our outstanding convertible senior notes could discourage an acquisition of us by a third party.
Certain provisions of our outstanding convertible senior notes could make it more difficult or more expensive for a third party to acquire us, including a provision requiring an acquirer to assume all of our obligations under the notes and the indenture. Upon the occurrence of certain transactions constituting a fundamental change under the indenture relating to the notes, holders of the notes will have the right, at their option, to require us to repurchase all of their notes or any portion of the principal amount of such notes.