Forward Looking Statements
This quarterly report on Form 10-Q contains "forward-looking statements" within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. In particular, statements contained in this Form 10-Q, including but not limited to, statements regarding the costs and timing our clinical trials and of the development and commercialization of our pipeline products and services; the sufficiency of our cash, investments and cash flows from operations and our expected uses of cash; our ability to finance our operations and business initiatives and obtain funding for such activities; our future results of operations and financial position, business strategy and plan prospects, projected revenue or costs and objectives of management for future research, development or operations, are forward-looking statements. These statements relate to our future plans, objectives, expectations and intentions and may be identified by words such as "may," "will," "should," "expects," "plans," "anticipates," "intends," "targets," "projects," "contemplates," "believes," "seeks," "goals," "estimates," "predicts," "potential" and "continue" or similar words. Readers are cautioned that these forward-looking statements are only predictions and are subject to risks, uncertainties, and assumptions that are difficult to predict, including those identified below, under Part II, Item 1A. "Risk Factors" and elsewhere herein. Therefore, actual results may differ materially and adversely from those expressed in any forward-looking statements. We undertake no obligation to revise or update any forward-looking statements for any reason.
ZIOPHARM Oncology, Inc.is a biopharmaceutical company that seeks to acquire, develop and commercialize, on its own or with commercial partners, a diverse portfolio of cancer therapies that can address high unmet medical needs. Pursuant to an exclusive channel agreement with Intrexon Corporation, or Intrexon, we obtained exclusive rights to Intrexon's synthetic biology platform for use in the field of oncology, which included two existing clinical stage product candidates, Ad-RTS-IL-12 + veledimex and DC-RTS-IL-12 + veledimex. The synthetic biology platform employs an inducible gene-delivery system that enables controlled delivery of genes that produce therapeutic proteins to treat cancer. Ad-RTS-IL-12 + veledimex is our lead drug candidate, which uses this gene delivery system to produce Interleukin-12, or IL-12, a potent, naturally occurring anti-cancer protein. We are currently studying Ad-RTS-IL-12 + veledimex in two Phase 2 studies, the first for the treatment of metastatic melanoma, and the second for the treatment of metastatic breast cancer, and expect to announce additional data from these Phase 2 studies in the fourth quarter of 2014. We plan to continue to combine Intrexon's synthetic biology platform with our capabilities to translate science to the patient setting to develop additional products to stimulate key pathways, including those used by the body's immune system to inhibit the growth and metastasis of cancers. We have numerous programs under development and expect to file multiple investigational new drug, or IND, applications through 2015. We also have a portfolio of small molecule drug candidates, which are no longer a strategic focus of our development activities for which we are seeking partners to pursue further development and potential commercialization.
Synthetic biology entails the application of engineering principles to biological systems for the purpose of designing and constructing new biological systems or redesigning/modifying existing biological systems. Biological systems are governed by DNA, which control cellular processes by coding for the production of proteins and other molecules that have a functional purpose and by regulating the activities of these molecules. This regulation occurs via complex biochemical and cellular reactions working through intricate cell signaling pathways, and control over these molecules modifies the output of biological systems. Synthetic biology has been enabled by the application of information technology and advanced statistical analysis, also known as bioinformatics, to genetic engineering, as well as by improvements in DNA synthesis. Synthetic biology aims to engineer gene-based programs or codes to modify cellular function to achieve a desired biological outcome. Its application is intended to allow more precise control of drug concentration and dose, thereby improving the therapeutic index associated with the resulting drug. On
January 6, 2011, we entered into an Exclusive Channel Partner Agreement with Intrexon, which we refer to as the Channel Agreement, to develop and commercialize novel DNA-based therapeutics in the field of cancer treatment by combining Intrexon's synthetic biology platform with our capabilities to translate science to the patient setting. As a result, our DNA synthetic biology platform employs an inducible gene-delivery system that enables controlled delivery of genes that produce therapeutic proteins to treat cancer. The first example of this regulated controlled delivery is achieved by producing IL-12, a potent, naturally occurring anti-cancer protein, under the control of Intrexon's proprietary biological "switch" to turn on/off the therapeutic protein expression at the tumor site. We and Intrexon refer to this "switch" as the RheoSwitch Therapeutic System® or RTS® platform. Our initial drug candidates being developed using the synthetic biology platform are Ad-RTS-IL-12 + veledimex and DC-RTS-IL-12 + veledimex with a current focus on Ad-RTS-IL-12 + veledimex. 23
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We have demonstrated that we are able to simultaneously express multiple effectors under control of the RTS® platform from the same construct. In mice, we have also shown that we are able to express multigenic DNA constructs in an embedded, controlled bioreactor, by injecting into skeletal muscle and measuring the DNA-coded proteins in the blood. Furthermore, we have also demonstrated the ability to express these same three genes under RTS® platform control in mesenchymal stem cells, or MSCs.
More detailed descriptions of Ad-RTS-IL-12 + veledimex, DC-RTS-IL-12 + veledimex, our remaining small molecule programs, and our clinical development and commercialization plans for each are set forth in this report under the caption "Business - Product Candidates."
ZIOPHARM is currently conducting or planning Phase 2 studies of Ad-RTS-IL-12, alone or in combination with existing treatment standards, in melanoma and breast cancer, with plans to initiate a Phase 1 study in high-grade gliomas (brain cancer). The Company also expects to file several investigational new drug (IND) applications for novel, multigenic gene therapies through 2015. We presented at the
American Association for Cancer Research2014 Annual Meeting (AACR 2014) study data from the intratumoral administration of Ad-RTS-mIL-12 in an orthotopic murine glioma model. The data demonstrated that administration of Ad-RTS-mIL-12 + veledimex resulted in dose-related increases in survival of four- to five-fold, without exhibiting an adverse safety profile, when compared to median survival in vehicle control groups that included temozolomide, bevacizumab (Avastin®) and dexamethasone.
The following chart identifies our current synthetic biology product candidates and their stage of development, each of which are described in more detail below.
[[Image Removed: LOGO]] Synthetic Biology Programs: Ad-RTS-IL-12 + veledimex. Ad-RTS-IL-12 + veledimex is currently being tested in two Phase 2 studies, the first for the treatment of metastatic melanoma, and the second for the treatment of unresectable recurrent or metastatic breast cancer. Ad-RTS-IL-12 + veledimex is our lead drug candidate, which uses our gene delivery system to produce Interleukin-12, or IL-12, a potent, naturally occurring anti-cancer protein. 24
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Interleukin-12 (IL-12) is a potent immunostimulatory cytokine which activates and recruits dendritic cells that facilitate the cross-priming of tumor antigen-specific T cells. Intratumoral administration of Ad-RTS-IL-12 + veledimex, which allows for adjustment of IL-12 gene expression upon varying the dose of veledimex, is designed to reduce the toxicity elicited by systemic delivery of IL-12, and increase efficacy through high intratumoral expression. In
March 2013, we announced the initiation of a Phase 2 clinical study of Ad-RTS-IL-12 + veledimex to treat metastatic breast cancer. The two-part, multi-center U.S. study is enrolling patients with unresectable, recurrent or metastatic breast cancer who have visible lesions or lesions accessible by injection. This study was designed to assess the safety and efficacy of the therapeutic effect of Ad-RTS-IL-12 + veledimex in this indication. The primary endpoint of the study is rate of progression-free survival at 16 weeks. Secondary endpoints include objective response rate, duration of response and evaluation of pharmacodynamic tumor markers. In May 2013, we announced promising results from nonclinical and Phase 1 studies in metastatic melanoma using Ad-RTS-IL-12 + veledimex. In these studies, the controlled expression of IL-12, through a regulatable gene therapy strategy, was found to limit systemic toxicity while inducing biological and clinical activity. The findings were presented in an oral session at the 16th Annual Meeting of the American Society of Gene and Cell Therapy(ASGCT). In June, updated results were presented at the 2013 American Society for Clinical Oncology(ASCO). Ad-RTS-IL-12 + veledimex induce production of IL-12 mRNA in the tumor microenvironment (switch on). Upon removal of veledimex, IL-12 mRNA levels return to baseline (switch off). Following treatment with Ad-RTS-IL-12 + veledimex, increases in TILs (CD8+, CD45RO+) were observed in the tumor microenvironment. Clinical activity was observed in injected and non-injected lesions primarily at the higher doses of veledimex. Inflammation, shrinkage, flattening, and depigmentation of lesions correlated with the elevated serum levels of IFN-g. Ad-RTS-IL-12 + veledimex therapy was generally well-tolerated and its safety profile is consistent with other immunotherapies. We reported the controlled local expression of IL-12 as an immunotherapeutic treatment of glioma through the use of the RheoSwitch ® at the October 2013AACR-NCI-EORTC. Veledimex brain penetration was demonstrated in normal mice and monkeys with intact blood brain barriers. Treatment with Ad-RTS-IL-12 + veledimex and DC-RTS-IL-12 + veledimex both demonstrated dose-related increase in survival in the mouse GL-261 glioma model with no adverse clinical signs observed. In December 2013, we announced the unanimous approval of the Recombinant DNA Advisory Committee of the National Institutes of Health(RAC/NIH) for the initiation of a Phase 1 study of Ad-RTS-IL-12 + veledimex, in subjects with recurrent or progressive high grade gliomas (brain cancer). We are currently discussing with the FDAthe nonclinical data in support of the Phase 1 study, and upon agreement, we anticipate initiation mid-year 2014. Glioblastoma is by far the most frequent malignant brain tumor and is associated with a particularly aggressive course and dismal prognosis. The current standard of care is based in surgical resection to the maximum feasible extent, followed by radiotherapy and concomitant adjuvant temozolomide. Such aggressive treatment, however, is associated with only modest improvements in survival resulting in a very high unmet medical need. Newly diagnosed glioblastoma patients have a median overall survival, or OS, of 11-17 months. In December 2013, we presented positive interim results from the ongoing Phase 1/2 study of Ad-RTS-IL-12 + veledimex in patients with advanced melanoma. The results from this multicenter study were presented at Melanoma Bridge2013 Conference at the session "Best Abstracts on News in Immunotherapy", an international conference co-sponsored by Istituto Nazionale Tumori Fondazione, Sidra Medical and Research Center, and the Society for ImmunoTherapy of Cancerwas held in Naples, Italy. In this study, 21 patients with unresectable, recurrent stage III/IV melanoma have been treated with intratumoral injections of Ad-RTS-IL-12 + veledimex and the oral activator veledimex. The purpose of the study is to evaluate the safety and tolerability of the Ad-RTS-IL-12 + veledimex therapy, determine tumor and immune response, and select the optimal dose and schedule of veledimex for future study. To date, expression of IL-12 mRNA in study subjects' tumors was determined to be controlled by veledimex. In addition, upon stopping veledimex dosing, expression of the IL-12 mRNA returned to baseline levels, demonstrating the "on" and "off" control of the RheoSwitch ®. In this dose range, results to date demonstrate that Ad-RTS-IL-12 + veledimex therapy has potent biologic activity, as measured by on-mechanism and on-target toxicity and response in injected and non-injected lesions. Following treatment, 11 of 16 evaluable patients have demonstrated a response of stable disease or better on a per lesion basis. The most common severe adverse events (SAEs) were pyrexia, hypotension, mental status changes, and cytokine release syndrome. Four of seven patients with SAEs had veledimex dosing stopped during cycle one. Three had SAEs during subsequent cycles, and stopped veledimex dosing at that time. Importantly, all SAEs were reversed after veledimex dosing was stopped, demonstrating the "on" and "off" control of veledimex on gene expression. 25
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December 2013, we announced preliminary results from the ongoing Phase 2 clinical study of Ad-RTS-IL-12 + veledimex therapy in patients with unresectable recurrent or metastatic breast cancer. The findings were reported in a poster presentation at the San Antonio Breast Cancer (SABC) Symposium in San Antonio, Texas. This multicenter Phase 2 study is designed to evaluate the safety and efficacy of Ad-RTS-IL-12 + veledimex in subjects with recurrent/metastatic breast cancer with accessible tumor(s). The primary endpoint of the study is rate of progression-free survival at 16 weeks. Secondary objectives include objective response rate, duration of response and evaluation of pharmacodynamic tumor markers. Six patients were evaluable for safety at the time of presentation. The most common severe adverse events (SAEs) were neutropenia, AST elevation and pyrexia. Importantly, in the absence of disease progression, all SAEs were reversed after veledimex dosing was stopped, demonstrating the "on" and "off" control of veledimex on gene expression. Preliminary monotherapy PFS rate was reported for two patients to date, with one subject progressing at 12 weeks and a second at 16 weeks. Recruitment for the Phase 2 clinical trial is ongoing to refine the dose, dosing schedule and optimal combination regimen. With this dosing data, the Company will initiate a Phase 2 clinical trial in combination with standard of care. The Company continues to advance Ad-RTS-IL-12 + veledimex in melanoma, breast cancer and brain cancer. Recently, as the treatment of advanced melanoma has undergone and continues to undergo a rapid evolution with the introduction and approval of highly promising new single and combination agents, the standard of care in this indication has become uncertain, resulting in a much more competitive and commercially unpredictable environment. As a result, the Company has prioritized brain cancer as our highest priority, followed by breast cancer, and then melanoma. DC-RTS-IL-12 + veledimex. We completed enrollment in a Phase 1 dose escalation study of DC-RTS-IL-12 + veledimex in the second quarter of 2012 in the United States. DC-RTS-IL-12 + veledimex employs intratumoral injection of modified dendritic cells from each patient and oral dosing of veledimex to turn on in vivo expression of IL-12. DC-RTS-IL-12 + veledimex , through the RTS® platform, controls the timing and level of transgene expression. The RTS® technology functions as a "gene switch" for the regulated expression of human IL-12 in the patients' dendritic cells which are transduced with a replication incompetent adenoviral vector carrying the IL-12 gene under the control of the RTS® platform. Currently, there are no actively enrolling studies using DC-RTS-IL-12 + veledimex, as we have prioritized our clinical development efforts on Ad-RTS-IL-12 + veledimex. Earlier Stage Programs. At the October 2013AARC-NCI-EORTC we also presented results showing systemic expression of three distinct immune effectors from a single RTS® regulated multigenic construct in mice, in vitro data demonstrating the potential use of MSCs for tumor-targeted delivery of single or multiple RTS® regulated cancer immunotherapies, and data demonstrating functional single chain variable fragment-Fc fusion proteins as an alternate approach to monoclonal antibodies which are more amenable for multi-genic therapies. We are also actively pursuing several other synthetic biology approaches, including gene delivery with human Endometrial Regenerative Cells (ERCs), human MSCs and functional single chain variable fragment-Fc fusion proteins and multigenic approaches in our discovery pipeline to address unmet medical needs in cancer that are expected to result in multiple INDs planned through 2015.
Small Molecule Programs
Palifosfamide, ZIO-201. The small molecule palifosfamide, or isophosphoramide mustard, is a proprietary active metabolite of the pro-drug ifosfamide. Because palifosfamide is the stabilized active metabolite of ifosfamide and a distinct pharmaceutical composition without the acrolein or chloroacetaldehyde metabolites we believe that the administration of palifosfamide may be an effective and well-tolerated agent to treat cancer. In addition to anticipated lower toxicity, palifosfamide may have other advantages over ifosfamide and cyclophosphamide. Palifosfamide cross-links DNA differently than the active metabolite of cyclophosphamide, resulting in a different activity profile. We are seeking transactions with third parties, including the possible out-license of palifosfamide. Soft Tissue Sarcoma. Previously we have studied palifosfamide in combination with doxorubicin in patients with soft tissue sarcoma. In
March 2013, we announced that the pivotal Phase 3 study, PICASSO 3, did not meet its primary endpoint of progression-free survival, and that we would terminate our development program in metastatic soft tissue sarcoma. PICASSO 3 study data was presented in September 2013at the European Cancer Congress. Small-Cell Lung Cancer. Small-Cell Lung Cancer, or SCLC, is almost exclusively associated with smoking. Standard of care for SCLC, which is etoposide and platinum therapy, has changed little in decades. Published studies of ifosfamide in combination with standard of care have evidenced enhanced efficacy but also with enhanced side effects, providing for an unfavorable benefit to risk association. We believe that combining palifosfamide with standard of care could offer a separation of enhanced efficacy from increased toxicity. 26
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Data from a Phase 1 trial of palifosfamide in combination with etoposide and carboplatin informed appropriate dosing for initiating an adaptive Phase 3 trial in first-line, metastatic SCLC. In
June 2012, the Company initiated an international, multi-center, open-label, adaptive, randomized study of palifosfamide in combination with carboplatin and etoposide, or PaCE, chemotherapy versus carboplatin and etoposide, or CE, alone in chemotherapy naÏve patients with metastatic small cell lung cancer, which we refer to as MATISSE. The trial's primary endpoint is overall survival. Based on the outcome of PICASSO 3 in soft tissue sarcoma and the resulting revision in the Company's development plans for palifosfamide, enrollment in this study was suspended with 188 patients enrolled. The interim analysis of overall survival events in MATISSE is forecasted to be reached during the second half of 2014. Darinaparsin, ZIO-101. Darinaparsin is an anti-mitochondrial (organic arsenic) compound (covered by issued patents and pending patent applications in the United Statesand in foreign countries). Phase 1 testing of the intravenous, or IV, form of darinaparsin in solid tumors and hematological cancers was completed. We reported clinical activity and a safety profile from these studies as predicted by preclinical results. We subsequently completed Phase 2 studies in advanced myeloma, primary liver cancer and in certain other hematological cancers. At the May 2009annual meeting of ASCO, we reported favorable results from the IV trial in lymphoma, particularly peripheral T-cell lymphoma, or PTCL. A Phase 1 trial in solid tumors with an oral form of darinaparsin has completed enrollment. We have obtained Orphan Drug Designation for darinaparsin in the United Statesand Europefor the treatment of PTCL and have entered into a licensing agreement with Solasia Pharma K.K., or Solasia, for the Asia/Pacificterritory with a focus on IV-administered darinaparsin in PTCL. Clinical studies are currently ongoing with Solasia. We are seeking transactions with third parties, including the possible out-license of darinaparsin. Indibulin, ZIO-301. Indibulin is a novel, small molecule inhibitor of tubulin polymerization and is potentially safer than other tubulin inhibitors as no neurotoxicity has been observed in preclinical studies or in Phase 1 clinical trials. Indibulin has a different pharmacological profile from other tubulin inhibitors currently on the market as it binds to a unique site on tubulin and is active in multi-drug-resistant (MDR-1, MRP-1) and taxane-resistant tumors. A Phase 1 study was conducted in late stage metastatic breast cancer and was found to be safe and tolerable. We are seeking transactions with third parties, including the possible out-license of indibulin. Our current plans involve using our principal internal financial resources to develop the synthetic biology program, with the intention of ultimately partnering or otherwise raising additional capital to support further development activities for our strategic product candidates. As of March 31, 2014, we had approximately $60.4 millionof cash and cash equivalents. Based upon our current plans, we anticipate that our cash resources will be sufficient to fund our operations into the second quarter of 2015. This forecast of cash resources is forward-looking information that involves risks and uncertainties, and the actual amount of our expenses could vary materially and adversely as a result of a number of factors, including the factors discussed in the "Risk Factors" section of this prospectus supplement and the uncertainties applicable to our forecast for the overall sufficiency of our capital resources. We have based our estimates on assumptions that may prove to be wrong, and our expenses could prove to be significantly higher than we currently anticipate. Furthermore, the successful development of our product candidates is highly uncertain. Product development costs and timelines can vary significantly for each product candidate, are difficult to accurately predict, and will require us to obtain additional funding, either alone or in connection with partnering arrangements. Various statutes and regulations also govern or influence the development, manufacturing, safety, labeling, storage, record keeping and marketing of each product. The lengthy process of seeking approval and the subsequent compliance with applicable statutes and regulations require the expenditure of substantial resources. Any failure by us to obtain, or any delay in obtaining, regulatory approvals could materially, adversely affect our business. To date, we have not received approval for the sale of any product candidates in any market and, therefore, have not generated any revenues from our product candidates. 27
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Overview of Results of Operations
Three months ended
Revenue. Revenue during the three months ended
March 31, 2014and 2013 was as follows: Three months ended March 31, 2014 2013 Change ($ in thousands) Collaboration revenue $ 200 $ 200$ - 0 % Revenue for the three months ended March 31, 2014was the same as the three months ended March 31, 2013. This is due to the continued recognition of income related to our entry into the collaboration agreement with Solasia Pharma K.K. on March 7, 2011. Under this agreement we received $5.0 millionin research and development funding which we are recognizing over the estimated period of performance under the agreement, currently 75 months.
Research and development expenses. Research and development expenses during the three months ended
Three months ended March 31, 2014 2013 Change ($ in thousands) Research and development
$ 6,542 $ 19,112 $ (12,570 )(66 %) Research and development expenses for the three months ended March 31, 2014decreased by $12.6 millionwhen compared to the three months ended March 31, 2013. On March 26, 2013, we announced the decision to immediately terminate development of palifosfamide in first-line metastatic soft tissue sarcoma and during the quarter ended June 30, 2013, completed a workforce reduction plan to reduce costs (see Note 3 in the accompanying unaudited financial statements). This resulted in lower costs of $3.6 millionrelated to the Phase 3 palifosfamide study in SCLC as the decision was made to suspend enrollment pending further data, lower costs related to the Phase 3 palifosfamide study in soft tissue sarcoma ("STS") of $4.5 million, lower other clinical costs of $1.2 million, lower employee-related costs of $1.3 millionand lower manufacturing costs of $3.4 million. The decrease was offset by an increase of $0.4 millionin discovery activities, $0.7 millionin nonclinical activities and $0.3 millionof other costs, all related to our synthetic biology program. 28
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Our research and development expense consists primarily of salaries and related expenses for personnel, costs of contract manufacturing services, costs of facilities and equipment, fees paid to professional service providers in conjunction with our clinical trials, fees paid to research organizations in conjunction with preclinical animal studies, costs of materials used in research and development, consulting, license and milestone payments and sponsored research fees paid to third parties. We have not accumulated and tracked our internal historical research and development costs or our personnel and personnel-related costs on a program-by-program basis. Our employee and infrastructure resources are allocated across several projects, and many of our costs are directed to broadly applicable research endeavors. As a result, we cannot state the costs incurred for each of our oncology programs on a program-by-program basis. Our future research and development expenses in support of our current and future programs will be subject to numerous uncertainties in timing and cost to completion. We test potential products in numerous preclinical studies for safety, toxicology and efficacy. We may conduct multiple clinical trials for each product. As we obtain results from trials, we may elect to discontinue or delay clinical trials for certain products in order to focus our resources on more promising products or indications. Completion of clinical trials may take several years or more, and the length of time generally varies substantially according to the type, complexity, novelty and intended use of a product. It is not unusual for preclinical and clinical development of each of these types of products to require the expenditure of substantial resources.
We estimate that clinical trials of the type generally needed to secure new drug approval are typically completed over the following timelines:
The duration and the cost of clinical trials may vary significantly over the life of a project as a result of differences arising during clinical development, including, among others, the following:
• The number of clinical sites included in the trials; • The length of time required to enroll suitable patents; • The number of patients that ultimately participate in the trials;
• The duration of patient follow-up to ensure the absence of long-term
product-related adverse events; and • The efficacy and safety profile of the product. As a result of the uncertainties discussed above, we are unable to determine the duration and completion costs of our programs or when and to what extent we will receive cash inflows from the commercialization and sale of a product. Our inability to complete our programs in a timely manner or our failure to enter into appropriate collaborative agreements could significantly increase our capital requirements and could adversely impact our liquidity. These uncertainties could force us to seek additional, external sources of financing from time-to-time in order to continue with our product development strategy. Our inability to raise additional capital, or to do so on terms reasonably acceptable to us, would jeopardize the future success of our business. 29
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General and administrative expenses. General and administrative expenses during the three months ended
Three months ended March 31, 2014 2013 Change ($ in thousands) General and administrative
$ 3,442 $ 4,671 $ (1,229 )(26 %) General and administrative expenses for the three months ended March 31, 2014decreased by $1.2 millionwhen compared to the three months ended March 31, 2013. The decrease was primarily due to lower employee-related costs of $0.5 millionas a result of our workforce reduction plan (see Note 3 in the accompanying unaudited financial statements) as well as $0.8 millionin non-employee contracted costs.
Other income (expense). Other income (expense) for three months ended
Three months ended March 30, 2014 2013 Change ($ in thousands) Other income, net
$ (9 ) $ (4 ) $ (5 )125 % Change in fair value of warrants 82 10,788 (10,706 ) (99 %) Total $ 73 $ 10,784 $ (10,711 )The decrease in other income (expense) from the three months ended March 31, 2014compared to the three months ended March 31, 2013was due primarily to the change in the fair value of liability-classified warrants, which yielded a gain of $82 thousandfor the three months ended March 31, 2014as compared to a gain of $10.8 millionfor the three months ended March 31, 2013. The change in liability-classified warrants is primarily attributable to the increase in our stock price, offset by a decrease in the remaining term and a decrease in volatility. 30
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Liquidity and Capital Resources
March 31, 2014, we had approximately $60.4 millionin cash and cash equivalents, compared to $68.2 millionin cash and cash equivalents as of December 31, 2013. We anticipate that our cash resources will be sufficient to fund our operations into the second quarter of 2015. However, changes may occur that would consume our existing capital prior to that time, including the scope and progress of our research and development efforts. Actual costs may ultimately vary from our current expectations, which could materially impact our use of capital and our forecast of the period of time through which our financial resources will be adequate to support our operations. We have estimated the sufficiency of our cash resources based in part on the anticipated advancement of our synthetic biology product candidates in the clinic under our exclusive channel partnership with Intrexon, and we expect that the costs associated with these and additional product candidates will increase the level of our overall research and development expenses significantly going forward. Also included in the estimate are the discontinuation of the PICASSO 3 pivotal trial for first-line metastatic STS and our adaptive Phase 3 trial for first-line SCLC for IV palifosfamide and our current timing expectations for interim overall survival data in the MATISSE trial. Although all human clinical trials are expensive and difficult to design and implement, we believe that due to complexity, costs associated with clinical trials for synthetic biology products are greater than the corresponding costs associated with clinical trials for small molecule candidates. In addition to these factors, our actual cash requirements may vary materially from our current expectations for a number of other factors that may include, but are not limited to, changes in the focus and direction of our development programs, competitive and technical advances, costs associated with the development of our product candidates, our ability to secure partnering arrangements, and costs of filing, prosecuting, defending and enforcing our intellectual property rights. If we exhaust our capital reserves more quickly than anticipated, regardless of the reason, and we are unable to obtain additional financing on terms acceptable to us or at all, we will be unable to proceed with development of some or all of our product candidates on expected timelines and will be forced to prioritize among them. We expect that we will need additional financing to support our long-term plans for clinical trials and new product development. We expect to finance our cash needs through the sale of equity securities, strategic collaborations and/or debt financings, or through other sources that may be dilutive to existing stockholders. There can be no assurance that we will be able to obtain funding from any of these sources or, if obtained, what the terms of such funding(s) may be, or that any amount that we are able to obtain will be adequate to support our working capital requirements until we achieve profitable operations. We have no current committed sources of additional capital. Recently, capital markets have experienced a period of instability that may severely hinder our ability to raise capital within the time periods needed or on terms we consider acceptable, if at all. If we are unable to raise additional funds when needed, we may not be able to continue development and regulatory approval of our products, or we could be required to delay, scale back or eliminate some or all our research and development programs. 31
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The following table summarizes our net increase (decrease) in cash and cash equivalents for the three months ended
Three months ended
March 31, 20142013 ($ in thousands)
Net cash provided by (used in):
$ (8,654 ) $ (18,243 )Investing activities (2 ) (114 ) Financing activities 837 706
Net increase (decrease) in cash and cash equivalents
Net cash used in operating activities was
Net cash used in investing activities was
$2 thousandfor the three months ended March 31, 2014compared to $114 thousandfor the three months ended March 31, 2013. The decrease was due to decreased spending on property, plant, and equipment. Net cash provided by financing activities was $0.8 millionfor the three months ended March 31, 2014compared to $0.7 millionfor the three months ended March 31, 2013. The change is primarily attributable to an increase in stock option activity in the amount of $0.1 million. 32
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Operating capital and capital expenditure requirements
We anticipate that losses will continue for the foreseeable future. At
March 31, 2014, our accumulated deficit was approximately $350.5 million. Our actual cash requirements may vary materially from those planned because of a number of factors including:
• Changes in the focus, direction and pace of our development programs;
• Competitive and technical advances; • Costs associated with the development of our product candidates; • Our ability to secure partnering arrangements;
• Costs of filing, prosecuting, defending and enforcing any patent claims
and any other intellectual property rights, or other developments, and • Other matters identified under Part II - Item 1A. "Risk Factors."
Working capital as of
The following table summarizes our outstanding obligations as of
March 31, 2014and the effect those obligations are expected to have on our liquidity and cash flows in future periods: Less than More than ($ in thousands) Total 1 year 2 - 3 years 4 - 5 years 5 years Operating leases $ 4,060 $ 1,207 $ 2,049$ 804 $ - Royalty and license fees 2,125 1,275 550 300 - Contract milestone payments 362 283 79 - - Total $ 6,547 $ 2,765 $ 2,678 $ 1,104$ - Our commitments for operating leases relate to the lease for our corporate headquarters in Boston, MA, and office space in New York, NY. Our commitments for royalty and license fees relate to our patent agreement with Baxter Healthcare Corporation, our royalty agreements with Southern Research Instituteand Baxter Healthcare Corporationrequiring minimum royalty payments, as well as our license agreement with The University of Texas M. D. Anderson Cancer Center, requiring payment upon the first patient treated in a pivotal trial in darinaparsin, currently being developed under the License and Collaboration Agreement with Solasia. The contract milestone payments relate to our CRO agreements with Novella Clinical, Inc.The timing of the remaining contract milestone payments are dependent upon factors that are beyond our control, including our ability to recruit patients, the outcome of future clinical trials and any requirements imposed on our clinical trials by regulatory agencies. However, for the purpose of the above table, we have assumed that the payment of the milestones will occur within five years of March 31, 2014. On July 16, 2012, we decided to close our Germanton, Marylandoffice. In June 2013, we paid off the remainder of the Germantown, Marylandlease obligation. Included in the above table are obligations for the subleased portion of our Bostonand New Yorkoffices as noted below and in Note 7 to the financial statements. We expect to receive a total of $118 thousandin the next year and $167 thousandin the next 2-3 years from our subtenant in the Bostonoffice. We also expect to receive a total of $334 thousandin the next year, $612 thousandin the next 2-3 years, and $529 thousandin the next 4-5 years from our subtenant in the New Yorkoffice. 33
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Off-balance sheet arrangements
During the three months ended
Critical Accounting Policies and Estimates
In our Annual Report on Form 10-K, as amended, for the fiscal year ended
December 31, 2013, our most critical accounting policies and estimates upon which our financial status depends were identified as those relating to stock-based compensation; net operating losses and tax credit carryforwards; and impairment of long-lived assets. We reviewed our policies and determined that those policies remain our most critical accounting policies for the three months ended March 31, 2014.