10-K
1
form10-k.htm
UNITED
STATES
SECURITIES
AND EXCHANGE COMMISSION
Washington,
D.C. 20549
FORM
10-K
(Mark
One)
For
the fiscal year ended December 31, 2020.
or
For
the transition period from _______ to _______
Commission
file number: 001-15911
CELSION
CORPORATION
(Exact
Name of Registrant as Specified in Its Charter)
(Address of Principal Executive Offices) (Zip Code)
Registrant’s
telephone number, including area code: (609) 896-9100
Securities
registered pursuant to Section 12(b) of the Act:
Title of each class Trading Symbol(s) Name of each exchange on which registered
Common Stock, Par Value $0.01 Per Share CLSN NASDAQ CAPITAL MARKET
Securities
registered pursuant to section 12(g) of the Act:
None
Indicate
by check mark if the Registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act.
Yes
[ ] No [X]
Indicate
by check mark if the Registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act.
Yes
[ ] No [X]
Indicate
by check mark whether the Registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange
Act of 1934 during the preceding 12 months (or for such shorter period that the Registrant was required to file such reports)
and (2) has been subject to such filing requirements for the past 90 days. Yes [X] No [ ]
Indicate
by check mark whether the Registrant has submitted electronically every Interactive Data File required to be submitted pursuant
to Rule 405 of Regulation S-T (§232.405 of this chapter) during the preceding 12 months (or for such shorter period that
the Registrant was required to submit such files). Yes [X] No [ ]
Indicate
by check mark whether the Registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting
company or an emerging growth company. See the definitions of “large accelerated filer”, “accelerated filer”,
“smaller reporting company” and “emerging growth company” in Rule 12b-2 of the Exchange Act.
Large Accelerated Filer [ ] Accelerated Filer [ ]
Non-accelerated Filer [ ] Smaller Reporting Company [X]
Emerging Growth Company [ ]
If
an emerging growth company, indicate by check mark if the Registrant has elected not to use the extended transition period for
complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. [ ]
Indicate
by check mark whether the Registrant has filed a report on and attestation to its management’s assessment of the effectiveness
of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered
public accounting firm that prepared or issued its audit report. [ ]
Indicate
by check mark whether the Registrant is a shell company (as defined in Rule 12b-2 of the Securities Exchange Act of 1934).
Yes
[ ] No [X]
The
aggregate market value of the common stock held by non-affiliates of the Registrant was approximately $121.8 million as of June
30, 2020 (the last business day of the Registrant’s most recently completed second fiscal quarter) based on the closing
sale price of $3.72 for the Registrant’s common stock on that date as reported by The Nasdaq Capital Market (“NASDAQ”).
For purposes of this calculation, shares of common stock held by directors, officers and stockholders who own greater than 10%
of the Registrant’s outstanding stock at June 30, 2020 were excluded. This determination of executive officers and directors
as affiliates is not necessarily a conclusive determination for any other purpose.
As
of March 18, 2021, 75,011,774 shares of the Registrant’s common stock were issued and outstanding.
DOCUMENTS
INCORPORATED BY REFERENCE
None
CELSION
CORPORATION
FORM
10-K
TABLE
OF CONTENTS
PART I
ITEM 1. BUSINESS 1
FORWARD-LOOKING STATEMENTS 1
OVERVIEW 2
IMMUNO-ONCOLOGY PROGRAM 2
THERAPLAS Technology Platform 2
Ovarian Cancer Overview 3
GEN-1 Immunotherapy 3
OVATION I Study 3
OVATION 2 Study 5
PLACCINE DNA VACCINE TECHNOLOGY PLATFORM 7
COVID-19 Vaccine Overview 7
Our Next Generation Vaccine Initiative 8
THERMODOX® DIRECTED CHEMOTHERAPY 9
THERMODOX® for the Treatment of Primary Liver Cancer 9
Primary Liver Cancer Overview 9
Celsion’s Approach 9
OPTIMA Study 10
Investigator-Sponsored Studies with ThermoDox® 12
BUSINESS STRATEGY AND DEVELOPMENT PLAN 13
RESEARCH AND DEVELOPMENT EXPENDITURES 13
GOVERNMENT REGULATION 14
MANUFACTURING AND SUPPLY 26
SALES AND MARKETING 26
PRODUCT LIABILITY AND INSURANCE 26
COMPETITION 27
ThermoDox ® 27
INTELLECTUAL PROPERTY 27
Patents and Proprietary Rights 27
EMPLOYEES 28
COMPANY INFORMATION 28
AVAILABLE INFORMATION 29
RECENT EVENTS 29
ITEM 1A. RISK FACTORS 29
ITEM 1B. UNRESOLVED STAFF COMMENTS 54
ITEM 2. PROPERTIES 54
ITEM 3. LEGAL PROCEEDINGS 55
ITEM 4. MINE SAFETY DISCLOSURES 55
i
CELSION
CORPORATION
FORM
10-K
TABLE
OF CONTENTS (continued)
PART II
Market for Our Common Stock 56
Record Holders 56
Dividend Policy 56
Securities Authorized for Issuance Under Equity Compensation Plans 56
Unregistered Shares of Equity Securities 56
Issuer Purchases of Equity Securities 56
ITEM 6. SELECTED FINANCIAL DATA 56
Overview 57
Business Plan 68
Financing Overview 70
Critical Accounting Policies and Estimates 73
Results of Operations 74
Financial Condition, Liquidity and Capital Resources 76
Off-Balance Sheet Arrangements 77
ITEM 7A. QUANTITATIVE AND QUALITATIVE DISCLOSURES ABOUT MARKET RISK 77
ITEM 8. FINANCIAL STATEMENTS AND SUPPLEMENTARY DATA 78
ITEM 9A. CONTROLS AND PROCEDURES 78
ITEM 9B. OTHER INFORMATION 78
PART III
ITEM 10. DIRECTORS, EXECUTIVE OFFICERS AND CORPORATE GOVERNANCE 79
ITEM 11. EXECUTIVE COMPENSATION 85
ITEM 14. PRINCIPAL ACCOUNTANT FEES AND SERVICES 105
PART IV
ITEM 15. EXHIBITS AND FINANCIAL STATEMENT SCHEDULES 107
1. FINANCIAL STATEMENTS 107
2. FINANCIAL STATEMENT SCHEDULES 107
ii
PART
I
ITEM 1. BUSINESS
FORWARD-LOOKING
STATEMENTS
Certain
of the statements contained in this Annual Report on Form 10-K (this “Annual Report”) are forward-looking and constitute
forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended (the “Securities
Act”) and Section 21E of the Securities Exchange Act of 1934, as amended (the “Exchange Act”). In addition,
from time to time we may publish forward-looking statements relating to such matters as anticipated financial performance, business
prospects, technological developments, product pipelines, clinical trials and research and development activities, the adequacy
of capital reserves and anticipated operating results and cash expenditures, current and potential collaborations, strategic alternatives
and other aspects of our present and future business operations and similar matters that also constitute such forward-looking
statements. These statements involve known and unknown risks, uncertainties, and other factors that may cause our or our industry’s
actual results, levels of activity, performance, or achievements to be materially different from any future results, levels of
activity, performance, or achievements expressed or implied by such forward-looking statements. Such factors include, among other
things, unforeseen changes in the course of research and development activities and in clinical trials; possible changes in cost,
timing and progress of development, preclinical studies, clinical trials and regulatory submissions; our collaborators’
ability to obtain and maintain regulatory approval of any of our product candidates; possible changes in capital structure, financial
condition, future working capital needs and other financial items; changes in approaches to medical treatment; introduction of
new products by others; success or failure of our current or future collaboration arrangements, risks and uncertainties associated
with possible acquisitions of other technologies, assets or businesses; our ability to obtain additional funds for our operations;
our ability to obtain and maintain intellectual property protection for our technologies and product candidates and our ability
to operate our business without infringing the intellectual property rights of others; our reliance on third parties to conduct
preclinical studies or clinical trials; the rate and degree of market acceptance of any approved product candidates; possible
actions by customers, suppliers, strategic partners, potential strategic partners, competitors and regulatory authorities; compliance
with listing standards of The Nasdaq Capital Market; and those listed under “Risk Factors” below and elsewhere in
this Annual Report.
In
some cases, you can identify forward-looking statements by terminology such as “expect,” “anticipate,”
“estimate,” “plan,” “believe, “could,” “intend,” “predict”,
“may,” “should,” “will,” “would” and words of similar import regarding the Company’s
expectations. Forward-looking statements are only predictions. Actual events or results may differ materially. Although we believe
that our expectations are based on reasonable assumptions within the bounds of our knowledge of our industry, business and operations,
we cannot guarantee that actual results will not differ materially from our expectations. In evaluating such forward-looking statements,
you should specifically consider various factors, including the risks outlined under “Risk Factors.” The discussion
of risks and uncertainties set forth in this Annual Report is not necessarily a complete or exhaustive list of all risks facing
the Company at any particular point in time. We operate in a highly competitive, highly regulated and rapidly changing environment
and our business is in a state of evolution. Therefore, it is likely that new risks will emerge, and that the nature and elements
of existing risks will change, over time. It is not possible for management to predict all such risk factors or changes therein,
or to assess either the impact of all such risk factors on our business or the extent to which any individual risk factor, combination
of factors, or new or altered factors, may cause results to differ materially from those contained in any forward-looking statement.
Except as required by law, we assume no obligation to revise or update any forward-looking statement that may be made from time
to time by us or on our behalf for any reason, even if new information becomes available in the future. Unless the context requires
otherwise or unless otherwise noted, all references in this Annual Report to “Celsion”, “the Company”,
“we”, “us”, or “our” are to Celsion Corporation, a Delaware corporation and its wholly owned
subsidiary, CLSN Laboratories, Inc., also a Delaware Corporation.
Trademarks
The
Celsion brand and product names, including but not limited to Celsion® and ThermoDox®, contained
in this document are trademarks, registered trademarks or service marks of Celsion Corporation or its subsidiary in the United
States (the “U.S.”) and certain other countries. This document also contains references to trademarks and service
marks of other companies that are the property of their respective owners.
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
On
June 20, 2014, the Company completed the acquisition of substantially all of the assets of EGEN, a private company located in
Huntsville, Alabama. Pursuant to the Asset Purchase Agreement, CLSN Laboratories acquired all of EGEN’s right, title and
interest in substantially all of the assets of EGEN, 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 from EGEN 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.
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 place Celsion 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 the U.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:
● Local therapy is ideal for long-term maintenance therapy.
OVATION
I Study. In February 2015, we announced that the U.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”). On September 30, 2015, we announced enrollment of the first patient in the OVATION
I Study. The OVATION I Study was designed to:
(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:
We
initiated the OVATION I Study at four clinical sites at the University of Alabama at Birmingham, Oklahoma University Medical Center,
Washington University in St. Louis, and the Medical College of Wisconsin. During 2016 and 2017, we announced data from the first
fourteen patients in the OVATION I Study. On October 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
Company also reported positive clinical data from the first fourteen patients who 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:
On
March 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 patients who dropped out of the study after 13 days or less, and two patients who
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 on September 27, 2017 with the clinical investigators and scientific
experts including those from Roswell Park Cancer Institute, Vanderbilt University Medical School, and M.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.
On
November 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.
In
March 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 Patients with R0 Resections
On
March 23, 2020, the Company announced that the European 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.
On
March 26, 2020, the Company announced with Medidata, a Dassault Systèmes company, that examining matched patient data provided
by Medidata 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 its
March 2019 discussion with Celsion, 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.
On
July 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.
On
February 22, 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.
On
February 25, 2021, the Company 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:
● 7 of 12 patients, or 58%, of patients in the control arm had an R0 resection.
The
Company further reported that 22 clinical sites in the U.S. and Canada have been initiated, with three more sites expected to
be added by the end of the first quarter. Clinical investigators met in early February 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
In
January 2021, the Company announced the filing of a provisional U.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 with Celsion’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.
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 of Celsion
vaccine candidates may offer several potential key advantages.
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:
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 at Duke 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 the U.S., approximately 65,000 cases per year in Europe and
is increasing at approximately 2-3% per year worldwide. Global incidence (per 2017 GLOBALCAN statistics) is reported at 755,000
cases. The World 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
the U.S., Japan and Europe and hepatitis B in Asia).
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.
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 the U.S., Canada, European Union (EU), China and other countries in the Asia-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”).
On
February 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 in January 2013, with each data set demonstrating substantial improvement in clinical benefit over
the control group with statistical significance. On August 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.
On
August 13, 2019, the Company announced that results from an independent analysis of the Company’s ThermoDox®
HEAT Study conducted by the National 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 the NIH and the
NIH 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. The NIH 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 the NIH 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 HCC who 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, the NIH analysis lent support
to the hypothesis underpinning the OPTIMA Study.
In
August 2018, the Company announced that the OPTIMA Study was fully enrolled. On August 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 in August 2019. On November 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.
On April 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. On July 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 on July 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 to Celsion. 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.
On
August 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
on July 9, 2020, may be associated with a data maturity issue. On October 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.
On
February 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 the NIH, 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 the NIH, we intend to renew our Cooperative 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®: