Company Advances ThermoDox® for Treatment of
Primary Liver Cancer Following Independent Data Monitoring
Committee’s Unanimous Recommendation to Continue Phase III OPTIMA
Study
Celsion Corporation (NASDAQ:CLSN), an oncology drug
development company, today provided a year-end 2017 corporate
review and announced clinical progress for two of its development
programs: ThermoDox®, a proprietary, heat-activated liposomal
encapsulation of doxorubicin, which is in Phase III development for
treatment of primary liver cancer; and GEN-1, an IL-12 DNA plasmid
vector encased in a nanoparticle delivery system, which enables
cell transfection followed by persistent, local secretion of the
IL-12 protein, and which is in Phase I development for the
localized treatment of ovarian cancer.
“In 2017, Celsion achieved our key development
goals for our two lead programs, ThermoDox® and GEN-1. We expect to
build upon this success in 2018 as we work toward advancing our
pipeline of clinical and preclinical development programs, which
hold the potential to enhance the power of proven chemotherapy and
immunotherapy platforms,” stated Michael H. Tardugno, Celsion's
chairman, president and chief executive officer. “After
successful and highly efficient financings in the second half of
2017, we have capital sufficient to complete enrollment of our
Phase III OPTIMA Study and advance development through the first
pre-planned efficacy analysis, which is expected in the first
quarter of 2019. We further expect that our current cash position
will allow us to make meaningful progress in our open-label,
randomized, 86-patient Phase I/II study of GEN-1 in newly diagnosed
patients with stage III and IV ovarian cancer. We are well
positioned to execute on our clinical development plans to achieve
meaningful milestones in the next year, and I look forward to
sharing our progress.”
Clinical Developments
ThermoDox®
OPTIMA Study Update. The
Company announced that, as of year-end 2017, enrollment in the
OPTIMA Study reached 74% of the 550 patients necessary to ensure
that its primary endpoint, overall survival, can be evaluated with
statistical significance. The OPTIMA Study is currently enrolling
at 69 sites in North America, Europe, China and the Asia-Pacific
region. The statistical plan for the OPTIMA Study calls for two
interim efficacy analyses by the independent Data Monitoring
Committee (DMC).
On August 7, 2017, the Company announced that
the DMC completed a planned interim analysis of the first 50% of
patients randomized in the trial. The DMC unanimously recommended
that the OPTIMA Study continue according to protocol to its final
data readout, based on the risk-to-benefit analysis conducted by
the Committee. The DMC’s role is to review study data at regular
intervals, with the primary responsibilities of ensuring the safety
of all patients enrolled in the study and monitoring the quality
and overall conduct of the trial, including each site's compliance
with the minimum radiofrequency ablation (RFA) heating time of 45
minutes specified in the study protocol.
Published HEAT Study Data Support the
Phase III OPTIMA Study. A manuscript titled "Phase III
HEAT Study Adding Lyso-Thermosensitive Liposomal Doxorubicin to
Radiofrequency Ablation in Patients with Unresectable
Hepatocellular Carcinoma Lesions," was published in the high
impact, peer-reviewed medical journal, Clinical Cancer Research, in
November 2017. The article detailed learnings from the Company's
701 patient HEAT Study of ThermoDox® in the treatment of primary
liver cancer, including overall survival data from a well-balanced
subgroup of 285 patients supporting the OPTIMA Study.
- The final overall survival (OS) analysis from the HEAT study
demonstrated that in a large, well-bounded subgroup of patients
(n=285 patients, 41% of the previous 701 patient HEAT Study),
treatment with a combination of ThermoDox® and standardized RFA
provided an average 58% improvement in OS compared to standardized
RFA alone. The Hazard Ratio (HR) was 0.63 (95% CI 0.43 -
0.93) with a p-value of 0.0198. In this large subgroup, median OS
for the ThermoDox® plus standardized RFA group translated into a
25.4-month (more than 2.1 years) survival benefit over the
standardized RFA-only group, totaling approximately 80 months
(6-1/2 years, which is considered a curative treatment for HCC) for
the ThermoDox® plus standardized RFA group, versus 53 months for
the standardized RFA-only group.
Conclusions from the publication were further
supported by results from a 2016 independent retrospective analysis
of the HEAT Study conducted by the National Institutes of Health.
The NIH findings are consistent with Celsion's own analysis of the
HEAT Study data, which demonstrated that over a 3.5-year period,
there was a statistically significant survival benefit in patients
treated with ThermoDox® plus optimized RFA over the optimized RFA
only group.
R&D Day. Lead investigators
(Asia-Pacific and Europe) from the OPTIMA study, representing
multiple medical disciplines (hepatology, interventional radiology
and surgery), presented their past and current clinical experiences
with ThermoDox® as a potential treatment for HCC at a
Company-hosted R&D Day event in October 2017.
GEN-1 Immunotherapy
OVATION Study Update. In
October 2017, the Company announced completion of enrollment and
final clinical and translational research data from its OVATION
Study, a Phase Ib dose-escalating clinical trial combining GEN-1,
the Company's DNA-based immunotherapy, with the standard of care
for the treatment of newly diagnosed patients with advanced Stage
III/IV ovarian cancer who will undergo neoadjuvant chemotherapy
followed by interval debulking surgery. GEN-1 is an IL-12 DNA
plasmid vector formulated as a nanoparticle in a non-viral delivery
system to cause the sustained local production and secretion of the
Interleukin-12 (IL-12) protein loco-regionally to the tumor
site.
The Company further reported encouraging
clinical data from the first fourteen patients who completed
treatment in the OVATION Study. GEN-1 plus standard chemotherapy
produced positive clinical results, with no dose-limiting
toxicities and promising dose-dependent efficacy signals, which
correlate well with successful surgical outcomes as summarized
below:
- Of the fourteen patients treated in the entire study, two (2)
patients demonstrated a complete response, ten (10) patients
demonstrated a partial response and two (2) patients demonstrated
stable disease, as measured by RECIST criteria. This translates to
a 100% disease control rate ("DCR") and an 86% objective response
rate ("ORR"). Of the five patients treated in the highest
dose cohort, there was a 100% objective response rate with one (1)
complete response and four (4) partial responses.
- Fourteen patients had successful resections of their tumors,
with nine (9) patients (64%) having an R0 resection, which
indicates a microscopically margin-negative resection in which no
gross or microscopic tumor remains in the tumor bed. Seven out
of eight (87%) 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.
- 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.
Key translational research findings from all
evaluable patients in the study were consistent with the earlier
reports from partial analysis of the data and are summarized
below:
- The intraperitoneal treatment of GEN-1 in conjunction with
neoadjuvant chemotherapy resulted in dose-dependent increases in
IL-12 and Interferon-gamma (IFN-g) 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 overall
survival.
- These translational research findings demonstrate that GEN-1 in
ovarian cancer patients is biologically active and creates a shift
in the primary tumor and in the surrounding tumor environment in
the peritoneal cavity that promotes a pro-immune T-cell population
dynamic and conversion of tumor naïve T-cell into cytotoxic
effector T-cells in the tumor microenvironment.
Progression-Free Survival for Patients
Treated per Protocol in the Phase IB OVATION Study Continues to be
Followed. Of the thirteen patients who received
GEN-1 treatment in all four dose-escalating cohorts, only four
patients' cancer have progressed as of January 15, 2018. This
compares favorably to the historical median progression-free
survival of 12 months for newly diagnosed patients with Stage III
and IV ovarian cancer that undergo neoadjuvant chemotherapy
followed by interval debulking surgery. Summarized below are the
latest PFS results for all patients treated per protocol in the
Phase IB OVATION Study:
- Cohort 1 (36 mg/m²) - All patients have progressed; Average PFS
was 19.25 months; Longest progression-free patient in 1st cohort
was 24.8 months.
- Cohort 2 (47 mg/m²) - No patients have progressed after 21
months.
- Cohort 3 (61 mg/m²) - One patient has progressed after 14
months; Two other patients in 3rd cohort are progression free over
18 months
- Cohort 4 (79 mg/m²) - No patients have progressed; Average PFS
for these five patients in 4th cohort is 15 months.
Advisory Board Recommendation and FDA
Submission Enable OVATION II Study Enrollment Initiation, Expected
in First Half of 2018. 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 Study in order to
determine the next steps forward for GEN-1. With the endorsement
and recommendations from the Advisory Board, the Company filed a
next phase protocol with U.S. Food and Drug Administration (FDA) in
November 2017.
In January 2018, the Company announced that
after a two-month review period, the FDA accepted the Company’s
submission without comment, providing clearance for the OVATION II
Study, the Company's planned Phase I/II clinical trial of GEN-1,
its DNA-based immunotherapy for the localized treatment of ovarian
cancer. Since then, the Company did receive minor comments from the
FDA focusing primarily on the role of the Data Safety Monitoring
Board and the need for a 3 + 3 evaluation of the single phase I
cohort and full evaluation of the maintenance treatment at the
highest dose prior to initiation of the Phase II portion of the
trial. The Company agrees with FDA’s comments and is modifying the
protocol accordingly. The Company continues to expect to
initiate enrollment in the study in the first half of 2018.
The Phase I/II trial was developed with
extensive input from the Company's Medical Advisory Board. The
OVATION II Study builds on the highly promising clinical and
translational research data from the Phase IB dose-escalating
OVATION Study where enrolled patients received escalating weekly
doses of GEN-1, from levels beginning at 36mg/m², to 47mg/m²,
61mg/m² and 79mg/m² weekly for 8 treatments in total, in
combination with neoadjuvant chemotherapy, followed by interval
debulking surgery.
The OVATION II Study is designed with a single
dose escalation phase to 100 mg/m², followed by a continuation at
the selected dose in Phase II in an open label, 1:1 randomized
design up to 90 patients with Stage III/IV ovarian cancer at up to
fifteen U.S. centers. The study is powered to show a 33%
improvement in the primary endpoint, progression-free survival
(PFS), when comparing GEN-1 with neoadjuvant chemotherapy versus
neoadjuvant chemotherapy alone.
Corporate Development
Raised Approximately $28.6 Million in
Gross Proceeds in the Second Half of 2017. Equity
offerings totaling approximately $28.6 million in gross proceeds
strengthened the Company's balance sheet, providing additional
capital to advance its ThermoDox® and GEN-1 clinical programs
through the second quarter of 2019.
In October 2017, the Company raised $17.0
million in gross proceeds through the exercise of outstanding
common stock warrants. In addition, the Company completed an
underwritten equity offering of shares of common stock and warrants
to purchase common stock with Oppenheimer & Co. The gross
proceeds of the offering were approximately $6.6 million.
Financial Guidance/Unaudited Cash and
Investments
Celsion had approximately $25.5 million in cash
and investments at the beginning of 2018, which the Company expects
will be sufficient to complete the following anticipated
milestones:
ThermoDox®
- Complete enrollment of Phase III pivotal OPTIMA Study for
primary liver cancer
- First pre-planned efficacy analysis in first half of 2019
- Second pre-planned efficacy analysis expected in the second
half of 2019
GEN-1 Immunotherapy
- Initiate Phase I portion of OVATION II Study in the first half
of 2018
- Data from Phase I portion of trial in second half of
2018
- Initiate Phase II randomized portion of OVATION II Study in
second half of 2018
- Data from Phase II randomized portion of OVATION II Study to be
reported throughout 2019 (Open Label Design)
About the OPTIMA Study
The Phase III OPTIMA Study is expected to enroll
up to 550 patients in up to 75 clinical sites in the United States,
Europe, China and the Asia-Pacific region, and will evaluate
ThermoDox® in combination with optimized radiofrequency ablation
(RFA), which will be standardized to 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 trial is Overall Survival, which is supported by
post-hoc analysis of data from the Company's 701 patient HEAT
Study, where optimized RFA has demonstrated the potential to
significantly improve survival when combined with ThermoDox®. The
statistical plan calls for two interim efficacy analyses by an
independent Data Monitoring Committee (iDMC).
About GEN-1 Immunotherapy
GEN-1, designed using Celsion's proprietary
TheraPlas platform technology, is an IL-12 DNA plasmid vector
encased in a nanoparticle delivery system, which enables cell
transfection followed by persistent, local secretion of the IL-12
protein. 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 (NK) cell
proliferation. The Company has previously reported positive safety
and encouraging Phase I results with GEN-1 given as monotherapy in
patients with peritoneally metastasized ovarian cancer, and a Phase
Ib trial of GEN-1 in combination with PEGylated doxorubicin in
patients with platinum-resistant ovarian cancer.
About Celsion
Corporation
Celsion is a fully-integrated oncology company
focused on developing a portfolio of innovative cancer treatments,
including directed chemotherapies, immunotherapies and RNA- or
DNA-based therapies. The Company's lead program is ThermoDox®, a
proprietary heat-activated liposomal encapsulation of doxorubicin,
currently in Phase III development for the treatment of primary
liver cancer. The pipeline also includes GEN-1, a DNA-based
immunotherapy for the localized treatment of ovarian and brain
cancers. Celsion has two platform technologies for the development
of novel nucleic acid-based immunotherapies and other anti-cancer
DNA or RNA therapies.
For more information on Celsion, visit our
website: http://www.celsion.com.
Celsion wishes to inform readers that
forward-looking statements in this release are made pursuant to the
"safe harbor" provisions of the Private Securities Litigation
Reform Act of 1995. Readers are cautioned that such forward-looking
statements involve risks and uncertainties including, without
limitation, unforeseen changes in the course of research and
development activities and in clinical trials; the uncertainties of
and difficulties in analyzing interim clinical data, particularly
in small subgroups that are not statistically significant; FDA and
regulatory uncertainties and risks; the significant expense, time,
and risk of failure of conducting clinical trials; the need for
Celsion to evaluate its future development plans; possible
acquisitions or licenses of other technologies, assets or
businesses; possible actions by customers, suppliers, competitors,
regulatory authorities; and other risks detailed from time to time
in Celsion's periodic reports and prospectuses filed with the
Securities and Exchange Commission. Celsion assumes no obligation
to update or supplement forward-looking statements that become
untrue because of subsequent events, new information or
otherwise.
ThermoDox is a registered trademark of Celsion
Corporation.
Celsion Investor Contact
Jeffrey W. Church
Sr. Vice President and CFO
609-482-2455
jchurch@celsion.com
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