Celsion Corporation (NASDAQ: CLSN), an oncology drug development
company, today announced that Michael H. Tardugno, the company’s
chairman, president and chief executive officer, issued the
following letter to stockholders providing an update on the ongoing
data analysis from its Phase III OPTIMA Study with ThermoDox® plus
radiofrequency ablation (RFA) in patients newly diagnosed with
primary liver cancer, or hepatocellular carcinoma (HCC), as well as
growing interest among clinical investigators in conducting studies
with ThermoDox® as a monotherapy or in combination with other
therapies.
To My Fellow Stockholders:
In response to the recent inquiries that we are
receiving, I’d like to provide you with the following update
regarding the OPTIMA Study’s ongoing analysis of probable futility
findings, and ThermoDox®, generally.
As I have indicated in earlier press
announcements and conference calls, since the unblinding of the
OPTIMA Study at the second preplanned interim data analysis on July
9, 2020, which was conducted after reaching the prescribed 158
patient deaths in late April 2020, Celsion continues to follow
patients for overall survival. Since April 27, 2020, a total of 14
new deaths have been reported, five of which occurred since July.
These deaths are reasonably in line with deaths of 3.0 per month,
or 0.7 per week, that had been forecasted by our consulting
statistician. We now have a total of 174 deaths in the Study from a
total patient enrollment of 556. The Study’s statistical plan
specifies a minimum of 197 deaths for the final data analysis.
At the second interim analysis by the
independent Data Monitoring Committee (DMC), which covered 80% of
the deaths needed for the final analysis, indicated that the OPTIMA
Study had narrowly crossed the futility boundary of Hazard Ratio
(HR)=0.90 with substantial uncertainty. The reported HR suggested
by the Kaplan-Meier analysis was 0.903 with a p-value of 0.524. The
DMC advised Celsion of its findings, leaving the decision to stop
the study up to the Company.
In our preliminary evaluation of the topline
data, Celsion determined that we should continue to follow patients
until such time as futility is either confirmed or dispelled. We
based this decision on enrollment trends at study sites in China
and Vietnam, among other observations, suggesting that data
maturity may be at issue. Additionally, despite the Study’s first
interim analysis appearing to be on track for a successful outcome,
we noted a timed-based change in deaths in the ThermoDox® treatment
arm suggested a proportionality issue that required further
evaluation. Specifically, 16 deaths occurred in five different
Asia-Pacific countries between the first and second interim
analyses, and 15 of these deaths were in the ThermoDox® treatment
arm.
What steps are we taking?
As promised, Celsion has engaged a global
biometrics contract research organization, with 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 is 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.
Also as promised, and in parallel, the Company
has submitted all OPTIMA Study clinical trial data to the National
Institutes of Health (NIH) and expects to receive a 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 NIH paper published in the Journal of Vascular and
Interventional Radiology, available here, in which the key finding
was that increased RFA heating time per tumor volume significantly
improved overall survival in patients with single lesion HCC who
were treated with RFA plus ThermoDox®, compared with patients
treated with RFA alone. The completed HEAT Study subgroup finding
upon which the OPTIMA Study design is based 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.
- 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.
We expect to report findings from these
independent statistical analyses before the end of the year, either
or both of which will guide our decision to continue to follow
patients to the final analysis at 197 or more deaths, a milestone
that should be reached sometime in mid-2021.
The DMC’s recommendation on July 9, 2020 to
consider discontinuation of the OPTIMA Study was beyond
disappointing. It was never anticipated, nor was it supported by
the science, independent clinical evaluation of the HEAT Study
subgroup or prospective preclinical research conducted by Celsion
and our consultants to support the OPTIMA Study. We firmly believe,
therefore, that Celsion is obligated to undertake this rigorous
evaluation of the data while we continue to follow patients.
Investigator-Sponsored Studies with
ThermoDox®
I also would like to update you on the multiple
requests we are receiving from investigators to include ThermoDox®
in their own studies involving several clinical indications. Below
are summaries of several investigator-sponsored studies:
- Oxford University plans to begin
enrolling patients in a Phase I pancreatic cancer study with
ThermoDox® in combination with High Intensity Focused Ultrasound
(HIFU) in early 2021. The primary objective of this trial, known as
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 International Journal of Hyperthermia in 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.
- Utrecht University in the
Netherlands continues to enroll patients in a Phase I breast cancer
study to determine the safety, tolerability and feasibility of
ThermoDox® in combination with Magnetic Resonance Guided High
Intensity Focused Ultrasound (MR-HIFU) hyperthermia and
cyclophosphamide therapy for the 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 Center for Translational Molecular Medicine (a
multi-million dollar public-private partnership in the
Netherlands), will be conducted at University Medical Center
Utrecht and will enroll up to 12 newly diagnosed mBC patients.
Celsion will supply Thermodox® clinical product for the
trial.
- As evidence of the ongoing support
Celsion enjoys from the NIH, they have organized a clinical project
to evaluate ThermoDox® plus the chemotherapy drug mitomycin in
bladder cancer. Depending on the NIH timelines, this study may
commence as early as 2021.
A Final Comment
Celsion feels strongly that we owe it to
patients, physicians and our investors to continue examining the
data from the OPTIMA Study, particularly given how surprising the
recommendation was from the DMC. While the trial outcome as
predicted by the second interim analysis may not change, and as
unlikely as it may be, in the event we see substantial clinical
benefit from the CRO and NIH analyses, we will carefully review our
options with the 14 regulatory agencies under which the OPTIMA
Study is being conducted.
In the meantime, we are heartened by multiple
requests from investigators to include ThermoDox® in their own
studies involving a number of clinical indications. We believe this
interest in investigator-sponsored trials reflects support for the
potential of ThermoDox® despite the confounding findings from the
OPTIMA Study second preplanned interim analysis.
While we await the outcome of additional data
analyses from the OPTIMA Study, we continue to enroll patients in
the Phase II portion of the OVATION 2 study evaluating GEN-1 for
the treatment of advanced ovarian cancer. We expect patient
enrollment in this clinical trial to be completed by the end of the
second quarter of 2021.
Thank you for your continued interest in
Celsion.
Sincerely,
Michael H. TardugnoChairman, President and
CEO
About ThermoDox®
Celsion’s most advanced program is based on a
drug delivery technology that employs a novel heat-sensitive
liposome engineered to address a range of difficult-to-treat
cancers. The first application of this platform is ThermoDox®, a
lyso-thermosensitive liposomal doxorubicin (LTLD) whose novel
mechanism of action delivers high concentrations of doxorubicin to
a region targeted with the application of localized heat at 40°C,
just above body temperature. ThermoDox® is positioned for use with
multiple heating technologies and has the potential to treat of a
broad range of cancers including metastatic liver, recurrent chest
wall breast cancer and non-muscle invading bladder cancers.
Celsion’s LTLD technology leverages two
mechanisms of tumor biology to deliver higher concentrations of
drug directly to the tumor site. In the first mechanism, rapidly
growing tumors have leaky vasculature, which is permeable to
liposomes and enables their accumulation within tumors. Leaky
vasculature influences a number of factors within the tumor,
including the access of therapeutic agents to tumor cells.
Administered intravenously, ThermoDox® is engineered with a
half-life to allow significant accumulation of liposomes at the
tumor site as these liposomes recirculate in the blood stream. In
the second mechanism, when an external heating device heats tumor
tissue to a temperature of 40°C or greater, the heat-sensitive
liposome rapidly changes structure and the liposomal membrane
selectively dissolves, creating openings that can release a
chemotherapeutic agent directly into the tumor and the surrounding
vasculature. Drug concentration increases as a function of the
accumulation of liposomes at the tumor site, but only where the
heat is present. This method damages only the tumor and the area
subject to tumor invasion, supporting more precise drug
targeting.
About Celsion
Corporation
Celsion is a fully integrated oncology company
focused on developing a portfolio of innovative cancer treatments,
including immunotherapies, DNA-based therapies and directed
chemotherapies. 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 in Phase III development
for the treatment of primary liver cancer and in development for
other cancer indications. Celsion has two feasibility stage
platform technologies for the development of novel nucleic
acid-based immunotherapies and other anti-cancer DNA or RNA
therapies. Both are novel synthetic, non-viral vectors with
demonstrated capability in nucleic acid cellular transfection. For
more information on Celsion, visit: http://www.celsion.com.
(CLSN-FIN).
Forward-looking Statements
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, Celsion's intended use of proceeds, the amount and
prices of any such sales under the agreement, unforeseen changes in
the course of research and development activities and in clinical
trials; the uncertainties of and difficulties in analyzing interim
clinical data; 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.
Celsion Investor Contact
Jeffrey W. ChurchExecutive Vice President and
CFO609-482-2455jchurch@celsion.com
Or
LHA Investor RelationsKim Sutton
Golodetz212-838-3777kgolodetz@lhai.com
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