The following discussion and analysis of our financial condition and results of operations This discussion contains forward-looking statements that involve risks and uncertainties. Our actual results may differ materially from those discussed in forward-looking statements. Factors that might cause a difference include, but are not limited to, those discussed above under "Cautionary Note Regarding Forward-Looking Statements", and in Item 1A. Risk factors in our Annual Report on Form 10-K for the fiscal year endedDecember 31, 2020 .
Strategic and Clinical Overview
Celsion Corporation ("Celsion" and the "Company") is a fully integrated, clinical stage biotechnology company focused on advancing a portfolio of innovative treatments including DNA-based immunotherapies, next generation vaccines and directed chemotherapies through clinical trials and eventual commercialization. The Company's product pipeline includes GEN-1, a DNA-based immunotherapy for the localized treatment of ovarian cancer and ThermoDox®, a proprietary heat-activated liposomal encapsulation of doxorubicin, currently under investigator-sponsored development for several cancer indications.Celsion has two feasibility stage platform technologies for the development of novel nucleic acid-based immunotherapies and next generation vaccines and other anti-cancer DNA or RNA therapies. Both are novel synthetic, non-viral vectors with demonstrated capability in nucleic acid cellular transfection. IMMUNO-ONCOLOGY Program OnJune 20, 2014 , the Company completed the acquisition of substantially all of the assets ofEGEN , a private company located inHuntsville, Alabama . Pursuant to the Asset Purchase Agreement,CLSN Laboratories acquired all ofEGEN's right, title and interest in substantially all of the assets ofEGEN , including cash and cash equivalents, patents, trademarks and other intellectual property rights, clinical data, certain contracts, licenses and permits, equipment, furniture, office equipment, furnishings, supplies and other tangible personal property. A key asset acquired fromEGEN was the TheraPlas technology platform. The first drug candidate developed from this technology platform is GEN-1.
THERAPLAS Technology Platform TheraPlas is a technology platform for the delivery of DNA and mRNA therapeutics via synthetic non-viral carriers and is capable of providing cell transfection for double-stranded DNA plasmids and large therapeutic RNA segments such as mRNA. There are two components of the TheraPlas system, a plasmid DNA or mRNA payload encoding a therapeutic protein, and a delivery system. The delivery system is designed to protect the DNA/mRNA from degradation and promote trafficking into cells and through intracellular compartments. We designed the delivery system of TheraPlas by chemically modifying the low molecular weight polymer to improve its gene transfer activity without increasing toxicity. We believe that TheraPlas may be a viable alternative to current approaches to gene delivery due to several distinguishing characteristics, including enhanced molecular versatility that allows for complex modifications to potentially improve activity and safety. The design of the TheraPlas delivery system is based on molecular functionalization of polyethyleneimine (PEI), a cationic delivery polymer with a distinct ability to escape from the endosomes due to heavy protonation. The transfection activity and toxicity of PEI is tightly coupled to its molecular weight; therefore, the clinical application of PEI is limited. We have used molecular functionalization strategies to improve the activity of low molecular weight PEIs without augmenting their cytotoxicity. In one instance, chemical conjugation of a low molecular weight branched BPEI1800 with cholesterol and polyethylene glycol (PEG) to form PEG-PEI-Cholesterol (PPC) dramatically improved the transfection activity of BPEI1800 following in vivo delivery. Together, the cholesterol and PEG modifications produced approximately 20-fold enhancement in transfection activity. Biodistribution studies following intraperitoneal or subcutaneous administration of DNA/PPC nanocomplexes showed DNA delivery localized primarily at the injection site with only small amount escaping into the systemic circulation. PPC is the delivery component of our lead TheraPlas product, GEN-1, which is in clinical development for the treatment of ovarian cancer. The PPC manufacturing process has been scaled up from bench scale (1-2 g) to 0.6Kg, and several current Good Manufacturing Practice ("cGMP") lots have been produced with reproducible quality. 26 We believe that TheraPlas has emerged as a viable alternative to current approaches due to several distinguishing characteristics such as strong molecular versatility that may allow for complex modifications to potentially improve activity and safety with little difficulty. The biocompatibility of these polymers reduces the risk of adverse immune response, thus allowing for repeated administration. Compared to naked DNA or cationic lipids, TheraPlas is generally safer, more efficient, and cost effective. We believe that these advantages placeCelsion in a strong position to capitalize on this technology platform.
Ovarian Cancer Overview
Ovarian cancer is the most lethal of gynecological malignancies among women with an overall five-year survival rate of 45%. This poor outcome is due in part to the lack of effective prevention and early detection strategies. There were approximately 22,000 new cases of ovarian cancer in theU.S. in 2014 with an estimated 14,000 deaths. Mortality rates for ovarian cancer declined very little in the last forty years due to the unavailability of detection tests and improved treatments. Most women with ovarian cancer are not diagnosed until Stages III or IV, when the disease has spread outside the pelvis to the abdomen and areas beyond causing swelling and pain, where the five-year survival rates are 25 - 41 percent and 11 percent, respectively. First-line chemotherapy regimens are typically platinum-based combination therapies. Although this first line of treatment has an approximate 80 percent response rate, 55 to 75 percent of women will develop recurrent ovarian cancer within two years and ultimately will not respond to platinum therapy. Patients whose cancer recurs or progresses after initially responding to surgery and first-line chemotherapy have been divided into one of the two groups based on the time from completion of platinum therapy to disease recurrence or progression. This time period is referred to as platinum-free interval. The platinum-sensitive group has a platinum-free interval of longer than six months. This group generally responds to additional treatment with platinum-based therapies. The platinum-resistant group has a platinum-free interval of shorter than six months and is resistant to additional platinum-based treatments. Pegylated liposomal doxorubicin, topotecan, and Avastin are the only approved second-line therapies for platinum-resistant ovarian cancer. The overall response rate for these therapies is 10 to 20 percent with median overall survival ("OS") of eleven to twelve months. Immunotherapy is an attractive novel approach for the treatment of ovarian cancer particularly since ovarian cancers are considered immunogenic tumors. IL-12 is one of the most active cytokines for the induction of potent anti-cancer immunity acting through the induction of T-lymphocyte and natural killer cell proliferation. The precedence for a therapeutic role of IL-12 in ovarian cancer is based on epidemiologic and preclinical data. GEN-1 Immunotherapy
GEN-1 is a DNA-based immunotherapeutic product candidate for the localized treatment of ovarian cancer by intraperitoneally administering an Interleukin-12 ("IL-12") plasmid formulated with our proprietary TheraPlas delivery system. In this DNA-based approach, the immunotherapy is combined with a standard chemotherapy drug, which can potentially achieve better clinical outcomes than with chemotherapy alone. We believe that increases in IL-12 concentrations at tumor sites for several days after a single administration could create a potent immune environment against tumor activity and that a direct killing of the tumor with concomitant use of cytotoxic chemotherapy could result in a more robust and durable antitumor response than chemotherapy alone. We believe the rationale for local therapy with GEN-1 is based on the following:
? Loco-regional production of the potent cytokine IL-12 avoids toxicities and
poor pharmacokinetics associated with systemic delivery of recombinant IL-12;
? Persistent local delivery of IL-12 lasts up to one week and dosing can be
repeated; and ? Local therapy is ideal for long-term maintenance therapy. 27
OVATION I Study. InFebruary 2015 , we announced that theU.S. Food and Drug Administration ("FDA") accepted, without objection, the Phase I dose-escalation clinical trial of GEN-1 in combination with the standard of care in neoadjuvant ovarian cancer (the "OVATION I Study"). OnSeptember 30, 2015 , we announced enrollment of the first patient in the OVATION I Study. The OVATION I Study
was designed to:
(i) identify a safe, tolerable and therapeutically active dose of GEN-1 by
recruiting and maximizing an immune response; (ii) enroll three to six patients per dose level and evaluate safety and efficacy; and (iii) attempt to define an optimal dose for a follow-on Phase I/II study.
In addition, the OVATION I Study established a unique opportunity to assess how cytokine-based compounds such as GEN-1, directly affect ovarian cancer cells and the tumor microenvironment in newly diagnosed ovarian cancer patients. The study was designed to characterize the nature of the immune response triggered by GEN-1 at various levels of the patients' immune system, including:
? Infiltration of cancer fighting T-cell lymphocytes into primary tumor and
tumor microenvironment including peritoneal cavity, which is the primary site
of metastasis of ovarian cancer;
? Changes in local and systemic levels of immuno-stimulatory and
immunosuppressive cytokines associated with tumor suppression and growth,
respectively; and ? Expression profile of a comprehensive panel of immune related genes in pre-treatment and GEN-1-treated tumor tissue. We initiated the OVATION I Study at four clinical sites at theUniversity of Alabama at Birmingham ,Oklahoma University Medical Center ,Washington University in St. Louis , and theMedical College of Wisconsin . During 2016 and 2017, we announced data from the first fourteen patients in the OVATION I Study. OnOctober 3, 2017 , we announced final translational research and clinical data from the OVATION I Study. Key translational research findings from all evaluable patients are consistent with the earlier reports from partial analysis of the data and are summarized below:
? The intraperitoneal treatment of GEN-1 in conjunction with NACT resulted in
dose dependent increases in IL-12 and Interferon-gamma (IFN-?) levels that
were predominantly in the peritoneal fluid compartment with little to no
changes observed in the patients' systemic circulation. These and other
post-treatment changes including decreases in VEGF levels in peritoneal fluid
are consistent with an IL-12 based immune mechanism;
? Consistent with the previous partial reports, the effects observed in the IHC
analysis were pronounced decreases in the density of immunosuppressive T-cell
signals (Foxp3, PD-1, PDL-1, IDO-1) and increases in CD8+ cells in the tumor
microenvironment; ? The ratio of CD8+ cells to immunosuppressive cells was increased in approximately 75% of patients suggesting an overall shift in the tumor
microenvironment from immunosuppressive to pro-immune stimulatory following
treatment with GEN-1. An increase in CD8+ to immunosuppressive T-cell
populations is a leading indicator and believed to be a good predictor of
improved OS; and
? Analysis of peritoneal fluid by cell sorting, not reported before, shows a
treatment-related decrease in the percentage of immunosuppressive T-cell
(Foxp3+), which is consistent with the reduction of Foxp3+ T-cells in the
primary tumor tissue, and a shift in tumor naïve CD8+ cell population to more
efficient tumor killing memory effector CD8+ cells. The Company also reported positive clinical data from the first fourteen patientswho completed treatment in the OVATION I Study. GEN-1 plus standard chemotherapy produced no dose limiting toxicities and positive dose dependent efficacy signals which correlate well with positive surgical outcomes as summarized below:
? Of the fourteen patients treated in the entire study, two patients
demonstrated a complete response, ten patients demonstrated a partial response
and two patients demonstrated stable disease, as measured by RECIST criteria.
This translates to a 100% disease control rate and an 86% objective response
rate ("ORR"). Of the five patients treated in the highest dose cohort, there
was a 100% ORR with one complete response and four partial responses;
28 ? Fourteen patients had successful resections of their tumors, with nine
patients (64%) having a complete tumor resection ("R0"), which indicates a
microscopically margin-negative resection in which no gross or microscopic
tumor remains in the tumor bed. Seven out of eight (88%) patients in the
highest two dose cohorts experienced a R0 surgical resection. All five patients treated at the highest dose cohort experienced a R0 surgical resection; and
? All patients experienced a clinically significant decrease in their CA-125
protein levels as of their most recent study visit. CA-125 is used to monitor
certain cancers during and after treatment. CA-125 is present in greater
concentrations in ovarian cancer cells than in other cells. OnMarch 2, 2019 , the Company announced final progression free survival ("PFS") results from the OVATION I Study. Median PFS in patients treated per protocol (n=14) was 21 months and was 17.1 months for the intent-to-treat ("ITT") population (n=18) for all dose cohorts, including three patientswho dropped out of the study after 13 days or less, and two patientswho did not receive full NAC and GEN-1 cycles. Under the current standard of care, in women with Stage III/IV ovarian cancer undergoing NAC, their disease progresses within about 12 months on average. The results from the OVATION I Study support continued evaluation of GEN-1 based on promising tumor response, as reported in the PFS data, and the ability for surgeons to completely remove visible tumor at interval debulking surgery. GEN-1 was well tolerated, and no dose-limiting toxicities were detected. Intraperitoneal administration of GEN-1 was feasible with broad patient acceptance. OVATION 2 Study. The Company held an Advisory Board Meeting onSeptember 27, 2017 with the clinical investigators and scientific experts including those fromRoswell Park Cancer Institute ,Vanderbilt University Medical School , andM.D. Anderson Cancer Center to review and finalize clinical, translational research and safety data from the OVATION I Study in order to determine the next steps forward for our GEN-1 immunotherapy program. OnNovember 13, 2017 , the Company filed its Phase I/II clinical trial protocol with the FDA for GEN-1 for the localized treatment of ovarian cancer. The protocol is designed with a single dose escalation phase to 100 mg/m² to identify a safe and tolerable dose of GEN-1 while maximizing an immune response. The Phase I portion of the study will be followed by a continuation at the selected dose in approximately 110 patients randomized Phase II study. In the OVATION 2 Study, patients in the GEN-1 treatment arm will receive GEN-1 plus chemotherapy pre- and post-interval debulking surgery ("IDS"). The OVATION 2 Study will include up to 110 patients with Stage III/IV ovarian cancer, with 12 to 15 patients in the Phase I portion and up to 95 patients in Phase II. The study is powered to show a 33% improvement in the primary endpoint, PFS, when comparing GEN-1 with neoadjuvant + adjuvant chemotherapy versus neoadjuvant + adjuvant chemotherapy alone. The PFS primary analysis will be conducted after at least 80 events have been observed or after all patients have been followed for at least 16 months, whichever is later. InMarch 2020 , the Company announced encouraging initial clinical data from the first 15 patients enrolled in the Phase I portion of the OVATION 2 Study for patients newly diagnosed with Stage III and IV ovarian cancer. The OVATION 2 Study combines GEN-1, the Company's IL-12 gene-mediated immunotherapy, with standard-of-care neoadjuvant chemotherapy (NACT). Following NACT, patients undergo interval debulking surgery (IDS), followed by three additional cycles of chemotherapy.
GEN-1 plus standard NACT produced positive dose-dependent efficacy results, with no dose-limiting toxicities, which correlates well with successful surgical outcomes as summarized below:
? Of the 15 patients treated in the Phase I portion of the OVATION 2 Study, nine
patients were treated with GEN-1 at a dose of 100 mg/m² plus NACT and six
patients were treated with NACT only. All 15 patients had successful
resections of their tumors, with eight out of nine patients (88%) in the GEN-1
treatment arm having an R0 resection, which indicates a microscopically
margin-negative complete resection in which no gross or microscopic tumor
remains in the tumor bed. Only three out of six patients (50%) in the NACT
only treatment arm had a R0 resection.
29
? When combining these results with the surgical resection rates observed in the
Company's prior Phase Ib dose-escalation trial (the OVATION 1 Study), a
population of patients with inclusion criteria identical to the OVATION 2
Study, the data reflect the strong dose-dependent efficacy of adding GEN-1 to
the current standard of care NACT:
% of Patients with R0 Resections 0, 36, 47 mg/m² of GEN-1 plus NACT n=12 42 % 61, 79, 100 mg/m² of GEN-1 plus NACT n=17 82 %
? The ORR as measured by Response Evaluation Criteria in Solid Tumors (RECIST)
criteria for the 0, 36, 47 mg/m² dose GEN-1 patients were comparable, as
expected, to the higher (61, 79, 100 mg/m²) dose GEN-1 patients, with both
groups demonstrating an approximate 80% ORR.
OnMarch 23, 2020 , the Company announced that theEuropean Medicines Agency (the "EMA") Committee for Orphan Medicinal Products ("COMP") has recommended that GEN-1 be designated as an orphan medicinal product for the treatment of ovarian cancer. GEN-1 is an IL-12 DNA plasmid vector encased in a non-viral nanoparticle delivery system, which enables cell transfection followed by persistent, local secretion of the IL-12 protein. GEN-1 previously received orphan designation from the FDA. OnMarch 26, 2020 , the Company announced withMedidata , a Dassault Systèmes company, that examining matched patient data provided byMedidata in a synthetic control arm ("SCA") with results from the Company's completed Phase Ib dose-escalating OVATION I Study showed positive results in progression-free survival ("PFS"). The hazard ratio ("HR") was 0.53 in the ITT group, showing strong signals of efficacy.Celsion believes these data may warrant consideration of strategies to accelerate the clinical development program for GEN-1 in newly diagnosed, advanced ovarian cancer patients by the FDA. In itsMarch 2019 discussion withCelsion , the FDA noted that preliminary findings from the Phase Ib OVATION I Study were exciting but lacked a control group to evaluate GEN-1's independent impact on impressive tumor response, surgical results and PFS. The FDA encouraged the Company to continue its GEN-1 development program and consult with FDA with new findings that may have a bearing on designations such as Fast Track and Breakthrough Therapy. SCAs have the potential to revolutionize clinical trials in certain oncology indications and some other diseases where a randomized control is not ethical or practical. SCAs are formed by carefully selecting control patients from historical clinical trials to match the demographic and disease characteristics of the patients treated with the new investigational product. SCAs have been shown to mimic the results of traditional randomized controls so that the treatment effects of an investigational product can be visible by comparison to the SCA. SCAs can help advance the scientific validity of single arm trials, and in certain indications, reduce time and cost, and expose fewer patients to placebos or existing standard-of-care treatments that might not be effective for them.
OnJuly 27, 2020 , the Company announced the randomization of the first two patients in the Phase II portion of the OVATION 2 Study with GEN-1 in advanced ovarian cancer. The Company anticipates completing enrollment of up to 110 patients in the second half of 2021. Because this is an open-label study, the Company intends to provide clinical updates throughout the course of treatment including response rates and surgical resection scores. InFebruary 2021 , the Company announced that it has received Fast Track designation from the FDA for GEN-1, its DNA-mediated IL-12 immunotherapy currently in Phase II development for the treatment of advanced ovarian cancer and also provided an update on the OVATION 2 Study. The Company reported that approximately one-third, or 34 patients, of the anticipated 110 patients had been enrolled into the OVATION 2 Study, of which 20 are in the treatment arm and 14 are in the control. Currently, 27 patients have had their interval debulking surgery with the following results:
? 12 of 15, or 80%, of patients treated with GEN-1 had a R0 resection, which
indicates a microscopically margin-negative complete resection in which no
gross or microscopic tumor remains in the tumor bed.
? 7 of 12 patients, or 58%, of patients in the control arm had an R0 resection.
30
? This interim data represents a 38% improvement in R0 resection rates for GEN-1
patients compared with control arm patients and is consistent with the
reported improvement in resection scores noted in the encouraging Phase I
OVATION I Study, the manuscript of which has been submitted for peer review
publication.
The Company further reported that 22 clinical sites in theU.S. andCanada have been initiated, with three more sites expected to be added by the end of the first quarter. Clinical investigators met in earlyFebruary 2021 in a virtual meeting and expressed excitement about the potential for GEN-1 to treat advanced ovarian cancer and, despite the challenges and earlier delays posed by the COVID-19 pandemic, they remain committed to completing enrollment in the study during the second half of 2021.
PLACCINE DNA VACCINE TECHNOLOGY PLATFORM
InJanuary 2021 , the Company announced the filing of a provisionalU.S. patent application for a novel DNA-based, investigational vaccine for preventing or treating infections from a broad range of infectious agents including the coronavirus disease using its PLACCINE DNA vaccine technology platform ("PLACCINE"). The provisional patent covers a family of novel composition of multi-cistronic vectors and polymeric nanoparticles that comprise the PLACCINE DNA vaccine platform technology for preventing or treating infectious agents that have the potential for global pandemics, including the SARS-CoV-2 virus and its variations, using the Company's platform technology.Celsion's PLACCINE DNA vaccine technology platform is characterized by a single multi-cistronic DNA plasmid vector expressing multiple pathogen antigens along with a potent immune modifier and delivered with a synthetic delivery system. It is easily adaptable to creating vaccines for a multitude of pathogens, including emerging pathogens leading to pandemics as well as infectious diseases that have yet to be effectively addressed with current vaccine technologies. This flexible vaccine platform is well supported by an already established supply chain to produce any plasmid vector and its assembly into a respective vaccine formulation. PLACCINE is an extension of the Company's synthetic, non-viral TheraPlas delivery technology currently in a Phase II trial for the treatment of late-stage ovarian cancer with GEN-1.Celsion's proprietary multifunctional DNA vaccine technology concept is built on the flexible PLACCINE technology platform that is amenable to rapidly responding to the SARS-CoV-2 virus, as well as possible future mutations of SARS-CoV-2, other future pandemics, emerging bioterrorism threats, and novel infectious diseases.Celsion's extensive experience with TheraPlas suggests that the PLACCINE-based nanoparticles are stable at storage temperatures of 4oC to 25oC, making vaccines developed on this platform easily suitable for broad world-wide distribution.Celsion's vaccine approach is designed to optimize the quality of the immune response dictating the efficiency of pathogen clearance and patient recovery.Celsion has taken a multivalent approach in an effort to generate an even more robust immune response that not only results in a strong neutralizing antibody response, but also a more robust and durable T-cell response. Delivered withCelsion's synthetic polymeric system, the proprietary DNA plasmid is protected from degradation and its cellular uptake is facilitated. COVID-19 Vaccine Overview
Emerging data from the recent literature indicates that the quality of the immune response as opposed to its absolute magnitude is what dictates SARS-CoV-2 viral clearance and recovery and that an ineffective or non-neutralizing enhanced antibody response might actually exacerbate disease. The first-generation COVID-19 vaccines were developed for rapid production and deployment and were not optimized for generating cellular responses that result in effective viral clearance. Though early data has indicated some of these vaccines to be over 95% effective, these first-generation vaccines were primarily designed to generate a strong antibody response and, while they have been shown to provide prophylactic protection against disease, the durability of this protection is currently unclear. The vast majority of these vaccines have been specifically developed to target the SARS-CoV-2 Spike (S) protein (antigen), though it is known that restricting a vaccine to a sole viral antigen creates selection pressure that can serve to facilitate the emergence of viral resistance. Indeed, even prior to full vaccine rollout, it has been observed that the S protein is a locus for rapid evolutionary and functional change as evidenced by the D614G, Y453F, 501Y.V2, and VUI-202012/01 mutations/deletions. This propensity for mutation of the S protein leads to future risk of efficacy reduction over time as these mutations accumulate. 31
Our Next Generation Vaccine Initiative
Celsion's next generation vaccine initiative stands at the confluence of immunotherapy and immunogenicity and envisions delivery, on a single plasmid, multiple SARS-CoV-2 antigens in conjunction with a potent immune modifier, interleukin-12 (IL-12), which directs a TH-1 immune response, stimulates T-cell immunity, and also promises the promotion of humoral immunity (antibody response). While most COVID-19 vaccines in late-stage clinical development are monovalent (S protein antigen only),Celsion has taken this multivalent approach in an effort to generate an even more robust immune response that not only results in a strong neutralizing antibody response, but also a more robust
and durable T-cell response.Celsion's vaccine candidate approach comprises a single plasmid vector containing the DNA sequence encoding the cytokine IL-12 and multiple SARS-CoV-2 antigens, including S antigen in combination with the membrane (M) or nucleocapsid (N) antigen. Delivery will be evaluated intramuscularly, intradermally, or subcutaneously with a non-viral synthetic DNA delivery carrier that facilitates vector delivery into the cells of the injected tissue and has potential immune adjuvant properties. Unique designs and formulations ofCelsion vaccine candidates may offer several potential key advantages.
? While the antibodies against S antigen would prevent virus entry into cells,
the M and N antibodies could help virus clearance through antibody-mediated
opsonization and phagocytosis. The presentation of multiple antigens on the
cell surface of vaccine-injected tissue produces a broad variety of killer
T-cells which could potentially produce more efficient viral clearance than a
single antigen vaccine.
? Since IL-12 is an essential regulator of the differentiation, proliferation,
and maintenance of T helper 1 (TH-1) cells that generate killer T-cells and
memory T-cells against virally infected cells, its simultaneous expression
could boost the viral clearance by the vaccine and improve the immune system's
memory against any future exposure of the same virus.
? Finally, the synthetic polymeric DNA carrier is an important component of the
vaccine composition as it has the potential to facilitate the vaccine
immunogenicity by improving vector delivery and, due to potential adjuvant
properties, attract professional immune cells to the site of vaccine delivery.
Future vaccine technology will need to address viral mutations and the challenges of efficient manufacturing, distribution, and storage. We believe an adaptation of our TheraPlas technology, PLACCINE, has the potential to meet these challenges. Our approach is described in our provisional patent filing and is summarized as a DNA vaccine technology platform characterized by a single plasmid DNA with multiple coding regions. The plasmid vector is designed to express multiple pathogen antigens along with a potent immune modifier. It is delivered via a synthetic delivery system and has the potential to be easily modified to create vaccines against a multitude of infectious diseases, addressing:
? Viral Mutations: PLACCINE may offer broad-spectrum and mutational resistance
(variants) by targeting multiple antigens on a single plasmid vector.
? Enhanced Efficacy: The potent immune modifier IL-12 may improve humoral and
cellular responses to viral antigens and can be incorporated in the plasmid.
? Durable Efficacy: PLACCINE delivers a DNA plasmid-based antigen that can
result in durable antigen exposure and a robust vaccine response to viral
antigens.
? Storage & Distribution: PLACCINE allows for stability that is compatible with
manageable vaccine storage and distribution.
? Simple Dosing & Administration: PLACCINE is a synthetic delivery system that
should require a simple injection that does not require viruses or special
equipment to deliver its payload. 32
We are conducting preliminary research associated with our recently announced proprietary DNA vaccine platform provisional patent filing. At the same time, we are redoubling our efforts and R&D resources in our immuno-oncology and next generation vaccine program.
THERMODOX® - DIRECTED CHEMOTHERAPY
Liposomes are manufactured submicroscopic vesicles consisting of a discrete aqueous central compartment surrounded by a membrane bilayer composed of naturally occurring lipids. Conventional liposomes have been designed and manufactured to carry drugs and increase residence time, thus allowing the drugs to remain in the bloodstream for extended periods of time before they are removed from the body. However, the current existing liposomal formulations of cancer drugs and liposomal cancer drugs under development do not provide for the immediate release of the drug and the direct targeting of organ specific tumors, two important characteristics that are required for improving the efficacy of cancer drugs such as doxorubicin. A team of research scientists atDuke University developed a heat-sensitive liposome that rapidly changes its structure when heated to a threshold minimum temperature of 39.5º to 42º Celsius. Heating creates channels in the liposome bilayer that allow an encapsulated drug to rapidly disperse into the surrounding tissue. This novel, heat-activated liposomal technology is differentiated from other liposomes through its unique low heat-activated release of encapsulated chemotherapeutic agents. We are able to use several available focused-heat technologies, such as radiofrequency ablation ("RFA"), microwave energy and high intensity focused ultrasound ("HIFU"), to activate the release of drugs from our novel heat sensitive liposomes.
THERMODOX® for the Treatment of Primary Liver Cancer
Primary Liver Cancer Overview
Hepatocellular carcinoma ("HCC") is one of the most common and deadliest forms of cancer worldwide. It ranks as the third most common solid tumor cancer. It is estimated that up to 90% of liver cancer patients will die within five years of diagnosis. The incidence of primary liver cancer is approximately 35,000 cases per year in theU.S. , approximately 65,000 cases per year inEurope and is increasing at approximately 2-3% per year worldwide. Global incidence (per 2017 GLOBALCAN statistics) is reported at 755,000 cases. TheWorld Health Organization (the "WHO") has projected that HCC will be the most prevalent form of cancer by 2030. HCC is commonly diagnosed in patients with longstanding hepatic disease and cirrhosis (primarily due to hepatitis C in theU.S. ,Japan andEurope and hepatitis B inAsia ). At an early stage, the standard first line treatment for liver cancer is surgical resection of the tumor. Up to 80% of patients are ineligible for surgery or transplantation at time of diagnosis because early-stage liver cancer generally has few symptoms and when finally detected the tumor frequently is too large for surgical resection. There are few alternative treatments since radiation therapy and chemotherapy are largely ineffective in treating liver cancer. For tumors generally up to 5 centimeters in diameter, RFA has emerged as the standard of care treatment which directly destroys the tumor tissue through the application of high temperatures administered by a probe inserted into the core of the tumor. Local recurrence rates after RFA directly correlate to the size of the tumor. For tumors 3 cm or smaller in diameter the recurrence rate has been reported to be 10 - 20%; however, for tumors greater than 3 cm, local recurrence rates of 40% or higher have been observed.Celsion's Approach While RFA uses extremely high temperatures (greater than 90° Celsius) to ablate the tumor, it may fail to treat micro-metastases in the outer margins of the ablation zone because temperatures in the periphery may not be high enough to destroy cancer cells. Our ThermoDox® treatment approach is designed to utilize the ability of RFA devices to ablate the center of the tumor while simultaneously thermally activating our ThermoDox® liposome to release its encapsulated doxorubicin to kill any remaining viable cancer cells throughout the heated region, including the ablation margins. This novel treatment approach is intended to deliver the drug directly to those cancer cells that survive RFA. This approach is designed to increase the delivery of the doxorubicin at the desired tumor site while potentially reducing drug exposure distant to the
tumor site. 33 OPTIMA Study The OPTIMA Study represents an evaluation of ThermoDox® in combination with a first line therapy, RFA, for newly diagnosed, intermediate stage HCC patients. The OPTIMA Study was designed to enroll up to 550 patients globally at approximately 65 clinical sites in theU.S. ,Canada ,European Union (EU),China and other countries in theAsia-Pacific region and will evaluate ThermoDox® in combination with standardized RFA, which will require a minimum of 45 minutes across all investigators and clinical sites for treating lesions three to seven centimeters, versus standardized RFA alone. The primary endpoint for the OPTIMA Study is OS, and the secondary endpoints are progression free survival and safety. The statistical plan calls for two interim efficacy analyses by an independent Data Monitoring Committee ("DMC"). OnFebruary 24, 2014 , we announced that the FDA provided clearance for the OPTIMA Study, which is a pivotal, double-blind, placebo-controlled Phase III trial of ThermoDox®, in combination with standardized RFA, for the treatment of primary liver cancer. The trial design of the OPTIMA Study is based on the comprehensive analysis of data from an earlier Phase III clinical trial called the HEAT Study (the "HEAT Study"). The OPTIMA Study is supported by a hypothesis developed from an OS analysis of a large subgroup of patients from the HEAT Study. Post-hoc data analysis from our earlier Phase III HEAT Study suggests that ThermoDox® may substantially improve OS, when compared to the control group, in patients if their lesions undergo a 45-minute RFA procedure standardized for a lesion greater than 3 cm in diameter. Data from nine OS sweeps have been conducted since the top line progression free survival PFS data from the HEAT Study were announced inJanuary 2013 , with each data set demonstrating substantial improvement in clinical benefit over the control group with statistical significance. OnAugust 15, 2016 , we announced updated results from its final retrospective OS analysis of the data from the HEAT Study. These results demonstrated that in a large, well bounded, subgroup of patients with a single lesion (n=285, 41% of the HEAT Study patients), treatment with a combination of ThermoDox® and optimized RFA provided an average 54% risk improvement in OS compared to optimized RFA alone. The HR at this analysis is 0.65 (95% CI 0.45 - 0.94) with a p-value of 0.02. Median OS for the ThermoDox® group has been reached which translates into a two-year survival benefit over the optimized RFA group (projected to be greater than 80 months for the ThermoDox® plus optimized RFA group compared to less than 60 months projection for the optimized RFA only group). This information should be viewed with caution since it is based on a retrospective analysis of a subgroup.
We also conducted additional analyses that further strengthen the evidence for the HEAT Study subgroup.
? We commissioned an independent computational model at the University of
South Carolina Medical School . The results unequivocally indicate that longer RFA heating times correlate with significant increases in doxorubicin concentration around the RFA treated tissue.
? In addition, we conducted a prospective preclinical study in 22 pigs using
two different manufacturers of RFA and human equivalent doses of
ThermoDox® that clearly support the relationship between increased heating
duration and doxorubicin concentrations.
OnAugust 13, 2019 , the Company announced that results from an independent analysis of the Company's ThermoDox® HEAT Study conducted by theNational Institutes of Health (NIH) were published in the peer-reviewed publication,Journal of Vascular and Interventional Radiology . The analysis was conducted by the intramural research program of theNIH and theNIH Center for Interventional Oncology , with the full data set from the Company's HEAT Study. The analysis evaluated the full data set to determine if there was a correlation between baseline tumor volume and RFA heating time (minutes/tumor volume in milliliters), with or without ThermoDox® treatment, for patients with HCC. TheNIH analysis was conducted under the direction of Dr.Bradford Wood , MD, Director,NIH Center for Interventional Oncology and Chief , NIH Clinical Center Interventional Radiology. The article titled, "RFA Duration Per Tumor Volume May Correlate with Overall Survival in Solitary Hepatocellular Carcinoma Patients Treated with RFA Plus Lyso-thermosensitive Liposomal Doxorubicin," discussed theNIH analysis of results from 437 patients in the HEAT Study (all patients with a single lesion representing 62.4% of the study population). The key finding was that increased RFA heating time per tumor volume significantly improved OS in patients with single-lesion HCCwho were treated with RFA plus ThermoDox®, compared to patients treated with RFA alone. A one-unit increase in RFA duration per tumor volume was shown to result in about a 20% improvement in OS for patients administered ThermoDox®, compared to RFA alone. The authors conclude that increasing RFA heating time in combination with ThermoDox® significantly improves OS and establishes an improvement of over two years versus the control arm when the heating time per milliliter of tumor is greater than 2.5 minutes. This finding was consistent with the Company's own results, which defined the optimized RFA procedure as a 45-minute treatment for tumors with a diameter of 3 centimeters. Thus, theNIH analysis lent support to the hypothesis underpinning the OPTIMA Study. 34 InAugust 2018 , the Company announced that the OPTIMA Study was fully enrolled. OnAugust 5, 2019 , the Company announced that the prescribed number of OS events had been reached for the first prespecified interim analysis of the OPTIMA Phase III Study. Following preparation of the data, the first interim analysis was conducted by the DMC. The DMC's pre-planned interim efficacy review followed 128 patient events, or deaths, which occurred inAugust 2019 . OnNovember 4, 2019 , the Company announced that the DMC unanimously recommended the OPTIMA Study continue according to protocol. The recommendation was based on a review of blinded safety and data integrity from 556 patients enrolled in the OPTIMA Study. Data presented demonstrated that PFS and OS data appeared to be tracking with patient data observed at a similar point in the Company's subgroup of patients followed prospectively in the earlier Phase III HEAT Study, upon which the OPTIMA Study was based.
OnApril 15, 2020 , the Company announced that the prescribed minimum number of events of 158 patient deaths had been reached for the second pre-specified interim analysis of the OPTIMA Phase III Study. The hazard ratio for success at 158 deaths is 0.70, which represents a 30% reduction in the risk of death compared with RFA alone. OnJuly 13, 2020 , the Company announced that it has received a recommendation from the DMC to consider stopping the global OPTIMA Study. The recommendation was made following the second pre-planned interim safety and efficacy analysis by the DMC onJuly 9, 2020 . The DMC analysis found that the pre-specified boundary for stopping the trial for futility of 0.900 was crossed with an actual value of 0.903. However, the 2-sided p-value of 0.524 for this analysis provides uncertainty, subsequently, the DMC left the final decision of whether or not to stop the OPTIMA Study toCelsion . There were no safety concerns noted during the interim analysis. The Company followed the advice of the DMC considered its options either to stop the study or continue to follow patients after a thorough review of the data, and an evaluation of our probability of success. OnAugust 4, 2020 , the Company issued a press release announcing it would continue following patients for OS, noting that the unexpected and marginally crossed futility boundary, suggested by the Kaplan-Meier analysis at the second interim analysis onJuly 9, 2020 , may be associated with a data maturity issue. OnOctober 12, 2020 , the Company provided an update on the ongoing data analysis from its Phase III OPTIMA Study with ThermoDox® as well as growing interest among clinical investigators in conducting studies with ThermoDox® as a monotherapy or in combination with other therapies.
?
forensic statistical analysis capability that specializes in data management,
statistical consulting, statistical analysis and data sciences, with particular
expertise in evaluating unusual data from clinical trials and experience with
associated regulatory issues. The primary objective of the CRO's work was to
determine the basis and reasoning behind continuing to follow patients for
survival, and if there were outside influences that may have impacted the
forecast of futility.
? In parallel, the Company submitted all OPTIMA Study clinical trial data to the
report on the following:
? A Cox Regression Analysis for single solitary lesions including minimum
burn time per tumor volume, evaluating similarities to the hypothesis
generated from the
Interventional Radiology, in which the key finding was that increased RFA
heating time per tumor volume significantly improved OS in patients with
single lesion HCC
patients treated with RFA alone.
? A site-by-site evaluation for RFA heating time-based anomalies that may
have contributed to the treatment arm performance.
? An image-based evaluation comparing results from the OPTIMA Study to the
data from the HEAT Study that led to the RFA heating time hypothesis.
35
OnFebruary 11, 2021 , the Company provided a final update on the Phase III OPTIMA Study and the decision to stop following patients in the Study. Independent analyses conducted by a global biometrics contract research organization and theNIH , did not find any evidence of significance or factors that would justify continuing to follow patients for OS. Therefore, the Company notified all clinical sites to discontinue following patients. The OPTIMA Study database of 556 patients will now be frozen at 185 patient deaths. While the analyses did identify certain patient subgroups that appear to have had a clinical benefit, the Company concluded that it would not be in its best interest to pursue these retrospective findings as the regulatory hurdles supporting further discussion will be significant.
Investigator-Sponsored Studies with ThermoDox®
Celsion continues working closely and supporting investigations by others throughout the world in breast cancer, pancreatic cancer and in solid tumors in children. Following inquiries from theNIH , we intend to renew ourCooperative Research and Development Agreement (CRADA) with the Institute at a nominal cost, one goal of which is to pursue their interest in a study of ThermoDox® to treat patients with bladder cancer. Importantly,Celsion is developing a business model to support these investigator-sponsored studies in a manner that will not interfere with the Company's focus on our GEN-1 program and vaccine development initiative.
Below are summaries of several investigator-sponsored studies using ThermoDox®:
?
cancer study with ThermoDox® in combination with High Intensity Focused
Ultrasound (HIFU) in the first half of 2021. The primary objective of this
trial, the PanDox Study: Targeted Doxorubicin in Pancreatic Tumors, is to
quantify the enhancement in intratumoral doxorubicin concentration when
delivered with ThermoDox® and HIFU, versus doxorubicin monotherapy. This study
is being undertaken pursuant to promising data in a mouse model of pancreatic
cancer, which was published in the
2018. That preclinical study showed a 23x increase in intratumoral doxorubicin
concentration with ThermoDox® + HIFU, compared with a 2x increase in
intratumoral doxorubicin concentration with free doxorubicin plus HIFU.
?
I breast cancer study to determine the safety, tolerability and feasibility of
ThermoDox® in combination with Magnetic Resonance Guided High Intensity
local treatment of the primary tumor in metastatic breast cancer (mBC). This
investigator-sponsored study, which is being funded by the Dutch Cancer
Society, the
partnership in
Center Utrecht and will enroll up to 12 newly diagnosed mBC patients.
will supply Thermodox® clinical product for the trial.
? As evidence of the ongoing support
organized a clinical project to evaluate ThermoDox® plus the chemotherapy drug
mitomycin in bladder cancer. Depending on the
commence as early as 2021. Business Plan Since inception, the Company has incurred substantial operating losses, principally from expenses associated with the Company's research and development programs, clinical trials conducted in connection with the Company's product candidates, and applications and submissions to theU.S. Food and Drug Administration . The Company has not generated significant revenue and has incurred significant net losses in each year since our inception. As ofMarch 31, 2021 , the Company has incurred approximately$318 million of cumulative net losses and we had approximately$54.6 million in cash and cash equivalents, short-term investments, and receivable on sale of net operating losses. We have substantial future capital requirements to continue our research and development activities and advance our product candidates through various development stages. The Company believes these expenditures are essential for the commercialization of its technologies. 36 The Company expects its operating losses to continue for the foreseeable future as it continues its product development efforts, and when it undertakes marketing and sales activities. The Company's ability to achieve profitability is dependent upon its ability to obtain governmental approvals, manufacture, and market and sell its product candidates. There can be no assurance that the Company will be able to commercialize its technology successfully or that profitability will ever be achieved. The operating results of the Company have fluctuated significantly in the past. InJanuary 2020 , theWHO declared an outbreak of coronavirus, COVID-19, to be a "Public Health Emergency of International Concern," and theU.S. Department of Health and Human Services declared a public health emergency to aid theU.S. healthcare community in responding to COVID-19. This virus has spread to over 100 countries, including theU.S. Governments and businesses around the world have taken unprecedented actions to mitigate the spread of COVID-19, including, but not limited to, shelter-in-place orders, quarantines, significant restrictions on travel, as well as restrictions that prohibit many employees from going to work. Uncertainty with respect to the economic impacts of the pandemic has introduced significant volatility in the financial markets. The Company did not observe significant impacts on its business or results of operations during 2020 and into 2021 due to COVID-19. While the extent to which COVID-19 impacts the Company's future results will depend on future developments, the pandemic and associated economic impacts could result in a material impact to the Company's future financial condition, results of operations and cash flows. The Company's ability to raise additional capital may be adversely impacted by potential worsening global economic conditions and the recent disruptions to, and volatility in, financial markets in theU.S. and worldwide resulting from the ongoing COVID-19 pandemic. The disruptions caused by COVID-19 may also disrupt the clinical trials process and enrolment of patients. This may delay commercialization efforts. The Company continues to monitor its operating activities in light of these events. The specific impact, if any, is not readily determinable as of the date of these financial statements. The actual amount of funds the Company will need to operate is subject to many factors, some of which are beyond the Company's control. These factors include the following:
? the progress of research activities;
? the number and scope of research programs;
? the progress of preclinical and clinical development activities;
? the progress of the development efforts of parties with whom the Company has
entered into research and development agreements;
? the costs associated with additional clinical trials of product candidates;
? the ability to maintain current research and development licensing arrangements
and to establish new research and development and licensing arrangements;
? the ability to achieve milestones under licensing arrangements;
? the costs involved in prosecuting and enforcing patent claims and other
intellectual property rights; and
? the costs and timing of regulatory approvals.
OnJuly 13, 2020 , the Company announced that it has received a recommendation from the independent DMC to consider stopping the global Phase III OPTIMA Study of ThermoDox® in combination with RFA for the treatment of HCC, or primary liver cancer. The recommendation was made following the second pre-planned interim safety and efficacy analysis by the DMC onJuly 9, 2020 . The DMC's analysis found that the pre-specified boundary for stopping the trial for futility of 0.900 was crossed with an actual value of 0.903. The Company followed the advice of the DMC and considered its options to either stop the study or continue to follow patients after a thorough review of the data, and an evaluation of the probability of success. OnFebruary 11, 2021 , the Company issued a letter to shareholders stating that the Company was notifying all clinical sites to discontinue following patients in the OPTIMA Study. 37 During 2020, 2019 and 2018, the Company submitted applications to sell a portion of the Company'sState of New Jersey net operating losses as part of the Technology Business Tax Certificate Program sponsored byThe New Jersey Economic Development Authority . Under the program, emerging biotechnology companies with unused NOLs and unused research and development credits are allowed to sell these benefits to otherNew Jersey -based companies. In 2018 and 2019, the Company sold NOLs totaling$13 million receiving net proceeds of$12.2 million . InJune 2020 and as updated inSeptember 2020 , the Company filed an application with theNew Jersey Economic Development Authority to sell substantially all of its remainingState of New Jersey net operating losses totaling$2.0 million available under the program. OnFebruary 12, 2021 , theNew Jersey Economic Development Authority approved the full amount of the Company's application. In February of 2021, the Company entered into an agreement to sell the net operating losses from the 2020 application and the Company received net proceeds of approximately$1.85 million onMay 10, 2021 . During 2021, theNew Jersey State Legislature increased the maximum lifetime benefit per company from$15 million to$20 million , which will allow the Company to participate in this innovative funding program in future years. InJune 2018 , the Company entered into a Credit Agreement with Horizon Technology Finance Corporation ("Horizon") that provided$10 million in capital (the "Horizon Credit Agreement"). The obligations under the Horizon Credit Agreement are secured by a first-priority security interest in substantially all assets ofCelsion other than intellectual property assets. Payments under the loan agreement are interest only (calculated based on one-month LIBOR plus 7.625%) for the first twenty-four (24) months throughJuly 2020 , followed by a 21-month amortization period of principal and interest starting onAugust 1, 2020 and ending through the scheduled maturity date onApril 1, 2023 . OnAugust 28, 2020 , in connection with an Amendment to the Horizon Credit Agreement,Celsion repaid$5 million of the$10 million loan and$0.2 million in related end of term charges, and the remaining$5 million in obligations were restructured as more fully discussed in Note 8 to these financial statements. As more fully discussed in Note 10, during 2021 through the date of the filing of this Quarterly Report on Form 10-Q, the Company has raised approximately$6.9 million in gross proceeds from the use of itsJonesTrading Capital on DemandTM financing facility,$35 million from a registered direct financing completed inJanuary 2021 ,$15 million from a registered direct financing completed onApril 5, 2021 , and$1.5 million from warrant exercises. With$54.6 million in cash and cash equivalents, short-term investments and income tax receivable from the sale of itsNew Jersey net operating loss atMarch 31, 2021 , coupled with$15 million of gross proceeds received from the sale of equity from a registered direct offering it completed onApril 5, 2021 , the Company believes it has sufficient capital resources to fund its operations through the end of 2024. The Company has based its estimates on assumptions that may prove to be wrong. The Company may need to obtain additional funds sooner or in greater amounts than it currently anticipates. Potential sources of financing include strategic relationships, public or private sales of the Company's shares or debt, the sale of the Company'sState of New Jersey net operating losses and other sources. If the Company raises funds by selling additional shares of common stock or other securities convertible into common stock, the ownership interest of existing stockholders may be diluted. Financing Overview
Equity, Debt and Other Forms of Financing
During 2020, 2019 and 2018, the Company submitted applications to sell a portion of the Company'sState of New Jersey net operating losses as part of the Technology Business Tax Certificate Program sponsored byThe New Jersey Economic Development Authority . Under the program, emerging biotechnology companies with unused NOLs and unused research and development credits are allowed to sell these benefits to otherNew Jersey -based companies. In 2018 and 2019, the Company sold NOLs totaling$13 million receiving net proceeds of$12.2 million . InJune 2020 and as updated inSeptember 2020 , the Company filed an application with theNew Jersey Economic Development Authority to sell substantially all of its remainingState of New Jersey net operating losses totaling$2.0 million available under the program. OnFebruary 12, 2021 , theNew Jersey Economic Development Authority approved the full amount of the Company's application. In February of 2021, the Company entered into an agreement to sell the net operating losses from the 2020 application and the Company received net proceeds of approximately$1.85 million onMay 10, 2021 . Beginning in 2021, theNew Jersey State Legislature increased the maximum lifetime benefit per company from$15 million to$20 million , which will allow the Company to participate in this innovative funding program in future years. 38 InJune 2018 , the Company entered into a Credit Agreement with Horizon Technology Finance Corporation ("Horizon") that provided$10 million in capital (the "Horizon Credit Agreement"). The obligations under the Horizon Credit Agreement are secured by a first-priority security interest in substantially all assets ofCelsion other than intellectual property assets. Payments under the loan agreement are interest only (calculated based on one-month LIBOR plus 7.625%) for the first 24 months throughJuly 2020 , followed by a 21-month amortization period of principal and interest starting onAugust 1, 2020 and ending through the scheduled maturity date onApril 1, 2023 . OnAugust 28, 2020 , in connection with an Amendment to the Horizon Credit Agreement,Celsion repaid$5 million of the$10 million loan and$0.2 million in related end of term charges, and the remaining$5 million in obligations were restructured as more fully discussed in Note 8 to our Consolidated Financial Statements contained in this Form 10-K. InSeptember 2018 , the Company filed with theSEC a$75 million shelf registration statement on Form S-3 (the 2018 Shelf Registration Statement) that allows the Company to issue any combination of common stock, preferred stock or warrants to purchase common stock or preferred stock. This shelf registration was declared effective onOctober 12, 2018 and duringJanuary 2021 , had been fully utilized by the end ofJanuary 2021 . OnMarch 19, 2021 , the Company filed with theSEC a$100 million shelf registration statement on Form S- (File No. 333-254515) (the "2021 Registration Statement") that allows the Company to issue any combination of common stock, preferred stock or warrants to purchase common stock or preferred stock. This shelf registration was declared effective onMarch 30, 2021 .
During 2020 and 2021 through the date of this Quarterly Report filed on Form
10-Q, we issued a total of 62.5 million shares of common stock as discussed
below for an aggregate
? On
with JonesTrading, pursuant to which the Company may offer and sell, from time
to time, through JonesTrading shares of Common Stock having an aggregate
offering price of up to
issued an aggregate of 0.5 million shares under the Capital on Demand
Agreement, receiving approximately
2020, the Company sold and issued an aggregate of 5.2 million shares under the
Capital on Demand Agreement, receiving approximately
proceeds. During 2021 through the date of this Quarterly Report on Form 10-Q,
the Company sold 7.2 million shares under the Capital on Demand Agreement,
receiving approximately
Demand Agreement.
? On
"
pursuant to which we agreed to issue and sell, in a registered direct offering
(the "
stock at an offering price of
approximately
and offering expenses. In a concurrent private placement (the "Private
Placement"), the Company issued to the investors that participated in the
up to 2,971,428 shares of common stock (the "Original Warrants"). The Original
Warrants were initially exercisable six months following their date of issue
and were set to expire on the five-year anniversary of such initial exercise
date. The Original Warrants had an exercise price of
to adjustment as provided therein. On
private exchange agreements (the "Exchange Agreements") with holders of the
Original Warrants. Pursuant to the Exchange Agreements, in return for a higher
exercise price of
warrants to the Investors to purchase up to 3,200,000 shares of common stock
(the "Exchange Warrants") in exchange for the Original Warrants. The Exchange
Warrants, like the Original Warrants, are initially exercisable six months
following their issuance (the "Initial Exercise Date") and expire on the
five-year anniversary of their Initial Exercise Date. Other than having a
higher exercise price, different issue date, Initial Exercise Date and
expiration date, the terms of the Exchange Warrants are identical to those of
the Original Warrants. On
Registration Statement to register the shares of common stock issuable under
the Exchange Warrants; the Registration Statement was declared effective by
the
During 2021 through the date of this Quarterly Report on Form 10-Q, the
Company issued 1.2 million shares pursuant to investors exercising Exchange
Warrants, receiving approximately$1.5 million . 39
? On
"Underwriting Agreement") with
relating to the issuance and sale (the "Underwritten Offering") of 2,666,667
shares of the Company's common stock. Pursuant to the terms of the
Underwriting Agreement, the Underwriter agreed to purchase the shares at a
price of
offering price of
to
Company from the Underwritten Offering, after deducting the underwriting
discount and estimated offering expenses payable by the Company, were
approximately
? On
Purchase Agreement") and a Registration Rights Agreement (the "Registration
Rights Agreement") with
pursuant to which, upon the terms and subject to the conditions and
limitations set forth therein, the Company has the right to sell to Lincoln
Park up to
Company's discretion as described below (the "LPC Offering"). During 2020, the
Company sold and issued an aggregate of 3.3 million shares, including the LPC
Commitment Shares, under the LPC Purchase Agreement, receiving approximately
terminating the LPC Offering effective
sell any shares under the LPC Purchase Agreement in 2021.
? On
(the "
pursuant to which the Company agreed to issue and sell, in a registered direct
offering (the "
the Company's common stock at an offering price of
proceeds of approximately
Placement Agents (as defined below) fee and offering expenses. The closing of
the
(the "
Partners (together with
Agents") pursuant to which the Company agreed to pay the
Placement Agents a cash fee equal to 7% of the aggregate gross proceeds raised
from the sale of the securities sold in the
reimburse the
an amount not to exceed
? On
(the "
pursuant to which the Company agreed to issue and sell, in a registered direct
offering (the "
Company's common stock, at an offering price of
proceeds of approximately
agents fee and offering expenses. The shares were offered by the Company
pursuant to the 2021 Registration Statement. The
contains customary representations, warranties and agreements by the Company
and customary conditions to closing. The closing of the Offering occurred on
second quarter of 2021. In connection with the
Company entered into a placement agent agreement (the "
Agent Agreement") with A.G.P./
agent ("AGP," and together with
co-placement agents, the "
Company agreed to pay the
equal to 7% of the aggregate gross proceeds raised from the sale of the
securities sold in the Offering and reimburse the Placement Agents for certain
of their expenses in an amount not to exceed
Purchase Agreement and
its subsidiaries are prohibited, for a period of 90 days after the closing
from issuing, entering into any agreement to issue or announcing any issuance
or proposed issuance of common stock or any other securities that are at any
time convertible into, or exercisable or exchangeable for, or otherwise
entitle the holder thereof to receive common stock without the prior written
consent of AGP or the investors participating in the offering. For purposes of
the
Offering waived a similar 90-day restriction in the placement agent agreement
and purchase agreement for that transaction. 40
Significant Accounting Policies
Our significant accounting policies are more fully described in Note 1 to our consolidated financial statements included in our 2020 Annual Report on Form 10-K for the year endedDecember 31, 2020 filed with theSEC onMarch 19, 2021 . See Note 4 to the Condensed Consolidated Financial Statements contained in this Quarterly Report on Form 10-Q. As a clinical stage biopharmaceutical company, our business and our ability to execute our strategy to achieve our corporate goals are subject to numerous risks and uncertainties. Material risks and uncertainties relating to our business and our industry are described in "Item 1A. Risk Factors" under "Part II: Other Information" included herein.
FINANCIAL REVIEW FOR THE THREE MONTHS ENDED
Results of Operations
For the three months ended
With$54.6 million in cash and cash equivalents, short-term investments, and receivable on sale of net operating losses atMarch 31, 2021 , coupled with approximately$15 million of gross proceeds received from the sale of equity in theMarch 2021 Offering closed onApril 5, 2021 and with future sales of the Company'sState of New Jersey net operating losses, the Company believes it has sufficient capital resources to fund its operations through 2024. Three Months EndedMarch 31 , (In thousands)
Change Increase (Decrease)
2021 2020 % Licensing Revenue:$ 125 $ 125 $ - - % Operating Expenses: Clinical Research 1,154 1,819 (665 ) (36.6 )% Chemistry, Manufacturing and Controls 1,418 1,233 185 15.0 % Research and development expenses 2,572 3,052 (480 ) (15.7 )% General and administrative expenses 2,936 1,839 1,097 59.7 % Total operating expenses 5,508 4,891
617 12.6 % Loss from operations$ (5,383 ) $ (4,766 ) $ (617 ) (12.9 )%
Comparison of the Three Months Ended
Licensing Revenue InJanuary 2013 , we entered into a technology development contract with Hisun, pursuant to which Hisun paid us a non-refundable technology transfer fee of$5.0 million to support our development of ThermoDox® in theChina territory. The$5.0 million received as a non-refundable payment from Hisun in the first quarter 2013 has been recorded to deferred revenue and will be amortized over the ten-year term of the agreement; therefore, we recorded deferred revenue of$125,000 in each of the first quarters of 2021 and 2020.
Research and Development Expenses
Research and development ("R&D") expenses decreased by$0.5 million to$2.6 million in the first quarter of 2021 from$3.1 million in the same period of 2020. Costs associated with the OPTIMA Study decreased to$0.1 million in the first quarter of 2021 compared to$0.7 million in the same period of 2020. InJuly 2020 , the Company unblinded the OPTIMA Study at the recommendation of the DMC to halt the study due to futility. Costs associated the OVATION 2 Study increased to$0.4 million in the first quarter of 2021 compared to$0.3 million in the same period of 2020. The Company initiated enrollment in the Phase 2 portion of the study during the third quarter of 2020. Regulatory costs were$0.1 million in the first quarter of 2021 compared to$0.2 million in the same period of 2020. Other clinical costs were$0.5 million the first quarter of 2021 compared to$0.6 million in the same period of 2020. R&D costs associated with the development of GEN-1 to support the OVATION 2 Study as well as development of the PLACCINE DNA vaccine technology platform increased to$1.0 million in the first quarter of 2021 compared to$0.9 million in the same period of 2020.
41
General and Administrative Expenses
General and administrative expenses increased to$2.9 million in the first quarter of 2021 compared to$1.8 million in the same period of 2020. This increase is primarily attributable to higher non-cash stock compensation expense of approximately$0.8 million , an increase in professional fees of$0.2 million and an increase in premiums for directors' and officers' insurance in the first quarter of 2021 when compared to the same period of 2020.
Change in Earn-out Milestone Liability and Warrant Expense
OnMarch 28, 2019 , the Company andEGWU, Inc , entered into an amendment to its purchase agreement ("Amended Asset Purchase Agreement"), whereby payment of the earnout milestone liability related to the Ovarian Cancer Indication of$12.4 million had been modified. The Company has the option to make the payment as follows:
a)
either, within one year of achieving the milestone. As ofMarch 31, 2021 , andDecember 31, 2020 , the Company fair valued the earn-out milestone liability at$7.2 million and$7.0 million , respectively, and recognized a non-cash charge of$0.2 million for the three-months endedMarch 31, 2021 . In assessing the earnout milestone liability atMarch 31, 2021 , the Company fair valued each of the two payment options per the Amended Asset Purchase Agreement and weighted them at 50% and 50% probability for the$7.0 million and the$12.4 million payments, respectively. As ofMarch 31, 2020 , andDecember 31, 2019 , the Company fair valued the earn-out milestone liability at$5.8 million and$5.7 million , respectively, and recognized a non-cash charge of$0.1 million for the three-months endedMarch 31, 2020 . In assessing the earnout milestone liability atMarch 31, 2020 , the Company fair valued each of the two payment options per the Amended Asset Purchase Agreement and weighted them at 80% and 20% probability for the$7.0 million and the$12.4 million payments, respectively.
Investment income and interest expense
The Company realized
The Company entered into a new loan facility with Horizon Technology Finance Corporation onJune 27, 2018 . In connection with this debt facility the Company incurred$0.2 million in interest expense in the first quarter of 2021 compared to$0.3 million during the same period of 2020.
Financial Condition, Liquidity and Capital Resources
Since inception we have incurred significant losses and negative cash flows from operations. We have financed our operations primarily through the net proceeds from the sales of equity, credit facilities and amounts received under our product licensing agreement withYakult and our technology development agreement with Hisun. The process of developing and commercializing ThermoDox®, GEN-1 and other product candidates and technologies requires significant research and development work and clinical trial studies, as well as significant manufacturing and process development efforts. We expect these activities, together with our general and administrative expenses, to result in significant operating losses for the foreseeable future. Our expenses have significantly and regularly exceeded our revenue, and we had an accumulated deficit of$318 million atMarch 31, 2021 . AtMarch 31, 2021 , we had total current assets of$56.2 million (including cash and cash equivalents, short-term investments, and receivable from sale of itsNew Jersey net operating losses of$54.6 million ) and current liabilities of$6.7 million , resulting in net working capital of$49.5 million . AtDecember 31, 2020 , we had total current assets of$18.8 million (including cash and cash equivalents of$17.2 million ) and current liabilities of$6.8 million , resulting in net working capital of$12.0 million . We have substantial future capital requirements to continue our research and development activities and advance our product candidates through various development stages. The Company believes these expenditures are essential for the commercialization of its technologies. 42 Net cash used in operating activities for the first three months of 2021 was$4.7 million . Net cash used in investing activities was$15.1 million during the first three months of 2021. Net cash provided by financing activities was$40.5 million during the first three months of 2021 from net proceeds received through the sale of our common stock. With$54.6 million in cash, investments and income tax receivable atMarch 31, 2021 , coupled with approximately$15 million of gross proceeds received from the sale of equity in theMarch 2021 Offering closed onApril 5, 2021 and with future sales of the Company'sState of New Jersey net operating losses, the Company believes it has sufficient capital resources to fund its operations through 2024. We expect to seek additional capital through further public or private equity offerings, debt financing, additional strategic alliance and licensing arrangements, collaborative arrangements, potential sales of our net operating losses, or some combination of these financing alternatives. If we raise additional funds through the issuance of equity securities, the percentage ownership of our stockholders could be significantly diluted, and the newly issued equity securities may have rights, preferences, or privileges senior to those of the holders of our common stock. If we raise funds through the issuance of debt securities, those securities may have rights, preferences, and privileges senior to those of our common stock. If we seek strategic alliances, licenses, or other alternative arrangements, such as arrangements with collaborative partners or others, we may need to relinquish rights to certain of our existing or future technologies, product candidates, or products we would otherwise seek to develop or commercialize on our own, or to license the rights to our technologies, product candidates, or products on terms that are not favorable to us. The overall status of the economic climate could also result in the terms of any equity offering, debt financing, or alliance, license, or other arrangement being even less favorable to us and our stockholders than if the overall economic climate were stronger. We also will continue to look for government sponsored research collaborations and grants to help offset future anticipated losses from operations and, to a lesser extent, interest income. If adequate funds are not available through either the capital markets, strategic alliances, collaborators, or sales of our net operating losses, we may be required to delay or, reduce the scope of, or terminate our research, development, clinical programs, manufacturing, or commercialization efforts, or effect additional changes to our facilities or personnel, or obtain funds through other arrangements that may require us to relinquish some of our assets or rights to certain of our existing or future technologies, product candidates, or products on terms not favorable to us.
Off-Balance Sheet Arrangements and Contractual Obligations
None.
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