Excellarate Offers Potential for Simpler and Enhanced Treatment
Opportunities within the Spectrum of Advanced Wound Care Biologics,
Bio-Engineered Dermal Substitutes and Medical Devices SAN DIEGO,
Oct. 14 /PRNewswire-FirstCall/ -- Cardium Therapeutics (NYSE Amex:
CXM) today reported positive data from its Matrix Phase 2b clinical
trial of Excellarate(TM) for the potential treatment of patients
with chronic non-healing diabetic foot ulcers based on the
Company's Gene Activated Matrix (GAM) technology platform. The
study evaluated patients treated with the Excellarate product
candidate (GAM501, which is a combination of Ad5PDGF-B and 2.6%
collagen) or 2.6% collagen alone (matrix), compared to patients who
received only the protocol-specified standard of care without any
applied Ad5PDGF-B or collagen matrix. The Company will hold a
webcast and conference call to discuss the clinical results of the
Excellarate Matrix Phase 2b clinical study today, October 14, 2009,
at 5:00 p.m. ET (access information is provided below). (Logo:
http://www.newscom.com/cgi-bin/prnh/20051018/CARDIUMLOGO) The
Excellarate product candidate and its components Ad5PDGF-B and
collagen matrix appear to be both safe and well tolerated by
patients. The Phase 2b study was abbreviated and enrollment ended
early after key efficacy measures among blinded groups were
observed at rates substantially higher than those expected for
patients receiving only standard of care. Consistent with those
observations, the unblinded data set showed a substantial (55%)
relative improvement in achieving complete wound closure by 12
weeks (the key efficacy measure for a Phase 3 product registration
program) among patients treated with a single dose of Excellarate
as compared to patients receiving standard of care. Nearly half of
patients (48%) receiving a one-time Excellarate treatment had
complete wound closure by 12 weeks, compared to a 31% wound closure
rate for standard of care. Among combined one and two dose groups
of Excellarate approximately 41% of patients achieved complete
closure by 12 weeks. However, since re-dosing was based on group
randomization rather than apparent need, a majority of patients
randomized to receive a second dose of Excellarate at 4 weeks
following initial product administration either did not receive one
because their wounds were closed by that point, or they received
only a very small second dose (less than 100 microliters) because
their wounds were extremely small. In addition to overall wound
closures by 12 weeks, the Phase 2b study also evaluated wound
closure rates and trajectories following product administration in
order to assess the timing and extent of bioactivity. The unblinded
data revealed that patients receiving Excellarate exhibited early
and rapid wound healing responses as evidenced by very substantial
reductions in wound radius over the first several weeks following
product administration, which responses were both greater and
faster than those observed among patients that had received
standard of care. For example, a 108% relative improvement
(decrease in ulcer radius) compared to standard of care was
observed over the first week following administration of
Excellarate, and a 50% relative improvement was observed as an
average over the first four weeks. The collagen matrix, which forms
an integral component of Excellarate (by promoting Ad5PDGF-B
binding and PDGF-B protein retention within the wound site), had
not been associated with substantial wound healing responses in
preclinical animal models used for design of the clinical studies.
In human diabetic patients, however, the collagen matrix appeared
to contribute substantially to wound healing responses. As a
result, the collagen arm was not a negative control as expected
based on preclinical studies. While the clinical study was not
powered to nor did it differentiate between the relative
contributions of the individual Ad5PDGF-B and collagen components
that make up Excellarate -- both the Excellarate and the collagen
matrix study arms showed substantial improvements in achieving
wound closure as compared to standard of care. The standard of care
(SOC) arm is the accepted control based on FDA guidance for wound
healing products, and is expected to be used as the control arm in
a planned Phase 3 program for product registration. The Company's
customized collagen matrix is a modified form of collagen that
includes certain structural stabilizers and hydrolytic enzyme
inhibitors. Based on observations from the Phase 2b clinical study,
it appears that this collagen formulation which is referred to as
Excellagen(TM), may play an active role in promoting wound healing,
particularly when used in combination with standard of care
(including surgical debridement). It is believed that the collagen
matrix supports the body's inherent processes of wound repair by
providing a molecular scaffolding within the wound bed to promote
the infiltration and proliferation of cells associated with tissue
repair such as monocytes, fibroblasts and endothelial cells.
Surgical debridement, a process of removing dead or damaged tissue
in and around the wound site, forms a key part of standard of care
and is known to promote wound healing. Regular debridement was
practiced in all patients in the Phase 2b clinical study and is
believed to account for a substantial portion of the wound healing
response observed in the SOC group. The data from this Phase 2b and
prior studies suggest that collagen may further support the wound
healing process in humans and that PDGF-B, which is a growth factor
known to stimulate a variety of wound repair cells, may provide an
additional biologic stimulus. Based on these data, the Company
believes that its collagen matrix may prove to be very beneficial
as an adjunct to existing wound care therapies, such as
debridement. Since collagen has been approved by the FDA as a
medical device, Cardium intends to a develop a registration pathway
for its collagen to be used in conjunction with debridement, which
is typically applied as standard of care for all diabetic foot
ulcers and many other types of soft tissue wounds. As announced
today, the Company plans to advance this collagen-based product
termed Excellagen(TM) along an abbreviated 510(k) registration
process in consultation with the FDA. Following completion of
safety and preliminary efficacy data, the Company also plans to
schedule a meeting with the FDA to review the complete integrated
data set and outline plans for a Phase 3 clinical study program
designed to confirm the safety and effectiveness of Excellarate as
compared to standard of care, since PDGF-B is known to contribute
to the biologic process of wound healing and is itself an approved
protein product for use in advanced wound care. The Company
believes that the combination of collagen and PDGF-B as provided by
the Excellarate product candidate holds the potential to further
promote wound healing in non-healing diabetic foot ulcers and other
difficult-to-treat wounds. Based on feedback from study
investigators, and with the additional positive safety data from
the Phase 2b study, the Phase 3 program is also expected to allow
for one or two follow-up doses in patients that exhibit a slower
healing rate or who have not yet achieved substantial closure
following the initial administration of product. Regranex®
(becaplermin, 0.01%) is a PDGF-B protein therapy that is currently
the only FDA-approved advanced care biologic for the treatment of
patients with lower extremity neuropathic diabetic foot ulcers.
PDGF-B protein-based therapy is a daily use prescription medication
for treatment for up to 20 weeks, which would require up to 140
daily administrations of product and an additional 140 daily wound
cleansings by patients. Based on published studies reflected in the
prescribing information sheet for becaplermin, daily application of
product combined with daily wound cleansings resulted in a 35%
relative improvement in wound closures at 20 weeks (i.e. a 50%
wound closure rate for becaplermin-treated patients compared to a
37% wound closure rate for control patients). Based on additional
published data from these studies, by 12 weeks (as in the shorter
Excellarate study period), the wound closure rate was about 34% for
becaplermin-treated patients as compared to a 25% complete closure
rate for control patients, representing a 36% relative improvement
in wound closure. In contrast to becaplermin, the Excellarate
product candidate is designed to stimulate a physiologic level of
sustained and locally-confined PDGF-B protein by cells at the wound
site. It is estimated from preclinical analyses that following a
single Excellarate administration the localized cellular expression
of PDGF-B would be about 55 nanograms, which is on the order of
60,000-fold lower than the approximately 3.0 million nanograms of
PDGF-B protein that would be topically applied by patients over a
20-week treatment course with becaplermin. Also, unlike
becaplermin, the PDGF-B protein encoded by Excellarate is a
naturally-occurring version of the protein that retains its native
extracellular matrix-binding domain, which further promotes
retention of the growth factor within the wound site. "The
completion of the Matrix Phase 2b clinical study represents a major
advance in our plans to establish an important new therapeutic
class of biologics for the potential treatment of diabetic foot
ulcers and other wounds. Despite years of research and effort,
diabetic wounds remain a serious unmet clinical need. Lower limb
amputations occur up to 30 times more often in diabetic patients,
and the resulting mortality rates for these patients can be similar
to or worse than many forms of cancer. We believe that, because of
the complex nature of lower extremity diabetic ulcers, patients
will benefit from the availability of multiple wound healing agents
and therapies that can be tailored to appropriately address their
specific medical conditions, and our Excellarate and Excellagen
development efforts seek to expand treatment options for patients
requiring advanced wound care therapy," stated Christopher J.
Reinhard, Chairman and Chief Executive Officer of Cardium. Webcast
and Conference Call The Company will hold a webcast and conference
call to discuss the clinical results of the Excellarate Matrix
Phase 2b clinical study today, October 14, 2009, at 5:00 p.m. ET.
Participants can access the live conference call by dialing
800-259-0251 (U.S.) or 617-614-3671 (International) using the
conference passcode 98344451. The call and accompanying slides can
also be accessed via the webcast through the Company's website at
http://phx.corporate-ir.net/phoenix.zhtml?c=77949&p=irol-calendar.
If you are unable to attend the webcast, a replay of the conference
call will be available approximately two hours after the conclusion
of the call by dialing 888-286-8010 (U.S.) or 617-801-6888
(International) using passcode 68300091. The webcast will be
archived for 90 days. Excellarate Product Candidate Observations
Two patients in the Matrix clinical trial were featured in local
television news programs because of the rapid healing of previously
non-healing wounds observed by their physicians. Data unblinding
revealed that both patients had received the Excellarate product
candidate. To learn more about the clinical experiences of these
patients, click here to view a television segment featuring an
investigator in the study, Dr. Peter A. Blume of the Yale
University School of Medicine, and click here to view a segment
featuring Dr. Barbara Aung of the Aung Foothealth Clinics, and
their patients enrolled in the Matrix clinical study. The Matrix
study media segments can also be accessed at
http://www.cardiumthx.com/. Matrix Phase 2b Clinical Study The
Matrix Phase 2b clinical study was a multi-center U.S.-based study
designed to evaluate Excellarate for the potential treatment of
non-healing diabetic foot ulcers. Enrollment in the study was ended
early after key efficacy measures among blinded groups were
observed at rates substantially higher than those expected for
patients receiving only standard of care. The study, which was
conducted at 20 medical centers, evaluated patients that were
treated with the gene-activated Excellarate product candidate
(Ad5PDGF-B / 2.6% collagen) or the collagen matrix component of
Excellarate, compared to patients who received only standard of
care treatment without any applied Ad5PDGF-B or collagen. A per
protocol data analysis included 113 patients with lower extremity
neuropathic ulcers that were chronically non-healing despite
receiving standard of care. Eleven additional patients who were
initially recruited into the trial were excluded (7 patients were
lost to evaluation or had a disqualifying surgical procedure and 4
were determined to have been mis-enrolled based on prespecified
enrollment criteria, which led to exclusions before study
completion and unblinding). The Matrix study evaluated safety as
assessed by adverse events, clinical laboratory measurements, vital
signs, concomitant medications, physical exam findings and serum
antibody concentrations to collagen and adenovector. Preliminary
measures of efficacy included the incidence of complete wound
closure by 12 weeks and the effect of Excellarate on healing rates
as measured by the change of the ulcer radius during the 4-week
period following Excellarate treatment. In addition, patients whose
wounds were successfully closed are being followed for up to three
additional months to further evaluate wound healing durability.
Durability results will be reported at a later date. Excellarate
appeared to be both safe and well tolerated in human patients with
diabetic neuropathy. There were no substantial differences observed
with respect to adverse events, clinical laboratory results,
physical exam findings or immunological antibody responses to
collagen or the adenovector in patients receiving either one or two
doses of Excellarate or collagen matrix, as compared to each other
or to standard of care. Collagen, an FDA approved medical device,
is an important and required element of the Company's Gene
Activated Matrix technology and was also included as a key
comparator group in the Phase 2b study, as an independent
collagen-only treatment arm. Based on preclinical animal data
suggesting that collagen would not contribute substantially to
wound healing, the study was expected to demonstrate that collagen
administration would be equivalent to standard of care, and that
these groups would collectively form a control group. However,
based on a preliminary review of the top line data, collagen
appears to contribute to the healing response in human diabetic
patients. While the standard of care (SOC) control group in the
Phase 2b study was too small to support statistical differentiation
of the groups, the 31% wound closure rate observed in the SOC group
was similar to that observed in prior published studies and
substantially lower than that observed for patients receiving
Excellarate or collagen alone. Among patients receiving a single
dose of Excellarate, there was a 55% relative improvement in
complete wound closure by 12 weeks as compared to the SOC group,
which is considered to be a key efficacy criterion for a Phase 3
product registration program. During the course of the Phase 2b
Matrix study, some investigators expressed an interest in having
the flexibility to re-dose patients (to allow for a second or third
treatment during the 12-week study period) in response to observed
healing slowdowns or plateaus following an initially rapid healing
response among some patients. In addition, while early rapid
healing following product administration was not a prespecified
efficacy measure, the unblinded Phase 2b data revealed that
patients receiving Excellarate exhibited a 108% relative
improvement (decrease in ulcer radius) as compared to SOC over the
first week following a one-time administration of product, and a
50% relative improvement was observed as an average over the first
four weeks. The Phase 2b clinical study included a second dose
treatment cohort, but the observed healing slowdowns or plateaus
did not necessarily coincide with the protocol's established second
dosing at week 4 following initial dosing, and a number of patients
prespecified by randomization to receive a second dose either did
not require it (because their wounds had already closed) or
received only an extremely small second dose (because their wounds
were almost closed). Based on continuing safety data from the
Matrix Phase 2b study, as well as the open label Phase 1/2 clinical
study and preclinical research, all of which included some
re-dosing, the Excellarate product candidate appears to be both
safe and well tolerated, with no significant differences observed
in immunological antibody responses to either collagen or to the
adenovector in patients receiving Excellarate as compared to those
receiving only standard of care. These findings together with the
initial healing rate change over time observed in the Phase 2b
study support allowing investigators in future studies to re-dose a
subset of patients who have not yet achieved a prespecified rate or
extent of wound closure. As a result, subject to review with the
FDA, we would consider the inclusion of a re-dosing protocol into
the planned Phase 3 clinical study program. Cardium believes that
this added feature may offer the potential to further enhance
efficacy in practical real world clinical settings by optimizing
the interaction between Ad5PDGF-B production, which is believed to
occur predominantly over the first few weeks following
administration, with the individual patient's underlying physiology
within the wound site. Planned Phase 3 Clinical Program Following
completion of the Phase 2b study's durability phase and a complete
statistical data analysis, Cardium plans to meet with the FDA to
review the complete clinical trial results and to review the
Company's proposed Phase 3 clinical study program. The Company will
seek to establish a clinical development plan, which could include
a special protocol agreement, to define the size and scope of the
proposed program which will be based on the important information
acquired from the Phase 1/2 and Phase 2b clinical studies. Based on
FDA guidance documents and other clinical studies that have
supported other product registrations, the Phase 3 program will
include a prospective, randomized, double-blind, controlled
multi-center study that will evaluate continued safety and
definitive efficacy. Cardium is also planning that this study
program will utilize a single primary efficacy endpoint, percent of
complete wound closure at 12 weeks or earlier, as compared to
standard of care. Excellarate Product Candidate The Excellarate
product candidate is initially being developed to facilitate wound
closure in non-healing diabetic foot ulcers. Excellarate is a
collagen-based topical gel employing Cardium's Gene Activated
Matrix(TM) technology to locally stimulate the release of
platelet-derived growth factor-B protein (PDGF-B) and provide a
matrix for cell migration, which are believed to be important keys
in the human body's wound healing process. The sustained localized
release and retention of PDGF-B by a patient's own cells directly
at the wound site is believed to stimulate angiogenesis and
granulation tissue formation through the recruitment and
proliferation of cells such as monocytes, fibroblasts and
endothelial cells. These cell types are considered critical for the
effective stimulation of a variety of wound healing processes. The
Excellarate product candidate is being designed to provide
physicians and patients with a potentially simpler, easy-to-use
treatment regimen compared to most diabetic wound healing agents or
devices in use that require repeated administrations over a long
term (weeks to months). Based on recently announced advancements,
Excellarate is also expected be re-formulated as an easy-to-use
single syringe that would be pre-mixed and ready to be applied to
patients' wounds. The reformulation will allow Excellarate to be
maintained in a physician's office using a standard refrigerator
(at a temperature of about 4 degrees C) and is expected to have a
shelf life of at least 15-18 months. Gene Activated Matrix
Technology Platform Cardium's proprietary Gene Activated Matrix(TM)
technology platform is designed to provide a therapeutic level of
protein synthesis at a specific site in the body and can be used in
soft tissue such as skin, ligament, tendons and cartilage, as well
as in hard tissue such as bone. The technology is distinctive in
that it is immobilized gene delivery that allows for gene uptake
restricted to the application site. The Gene Activated Matrix
comprises any biocompatible matrix containing a gene or DNA vector
encoding for a growth factor or any therapeutic protein. The
technology allows for a broad spectrum of formulations and the use
of any biocompatible matrix, natural or synthetic, which would
include, but not be limited to, collagen, de-mineralized bone,
allograft and other synthetic graft materials. The Company's
studies have shown that proliferative cells migrate into the Gene
Activated Matrix and then take up the immobilized gene resulting in
localized and sustained production of small but physiologically
active quantities of growth factor proteins or other therapeutic
proteins based on the protein-producing DNA of choice. Compared
with current protein therapy, which may be limited due to the
inherently short half-life of proteins, the Company believes that
the localized and sustained production of therapeutically
significant concentrations of DNA-driven proteins at the delivery
site can significantly enhance the stimulation of localized
therapeutic processes such as tissue repair. About Cardium Cardium
is focused on the acquisition and strategic development of new and
innovative bio-medical product opportunities and businesses that
have the potential to address significant unmet medical needs and
definable pathways to commercialization, partnering and other
economic monetizations. Cardium's investment portfolio includes the
Tissue Repair Company and Cardium Biologics, medical technology
companies primarily focused on the development of innovative
therapeutic products for wound healing, bone repair, and
cardiovascular indications. In July 2009, Cardium completed the
sale of its InnerCool Therapies medical device business to Royal
Philips Electronics, the first asset monetization from the
Company's biomedical investment portfolio. News from Cardium is
located at http://www.cardiumthx.com/. Forward-Looking Statements
Except for statements of historical fact, the matters discussed in
this press release are forward looking and reflect numerous
assumptions and involve a variety of risks and uncertainties, many
of which are beyond our control and may cause actual results to
differ materially from stated expectations. For example, there can
be no assurance that Excellarate or our other candidates will prove
to be sufficiently safe and effective, or that results or trends
observed in one clinical study or procedure will be reproduced in
subsequent studies or procedures, or that clinical studies even if
successful will lead to product advancement or partnering; that the
Excellarate product candidate offers the potential for simpler or
more cost-effective treatment for physicians and patients than
other FDA-approved products that currently are or will be on the
market; that the Matrix clinical study program or other human
clinical trials can be conducted and completed in an efficient and
successful manner; that we can develop a DNA-based orthobiologics
product portfolio; that our products or product candidates will not
be unfavorably compared to competitive products that may be
regarded as safer, more effective, easier to use or less expensive;
that FDA or other regulatory clearances or other certifications, or
other commercialization efforts will be successful or will
effectively enhance our businesses or their market value; that our
products or product candidates will prove to be sufficiently safe
and effective after introduction into a broader patient population;
or that third parties on whom we depend will perform as
anticipated. Actual results may also differ substantially from
those described in or contemplated by this press release due to
risks and uncertainties that exist in our operations and business
environment, including, without limitation, risks and uncertainties
that are inherent in the development of complex biologics and in
the conduct of human clinical trials, including the timing, costs
and outcomes of such trials, our ability to obtain necessary
funding, regulatory approvals and expected qualifications, our
dependence upon proprietary technology, our history of operating
losses and accumulated deficits, our reliance on collaborative
relationships and critical personnel, and current and future
competition, as well as other risks described from time to time in
filings we make with the Securities and Exchange Commission. We
undertake no obligation to release publicly the results of any
revisions to these forward-looking statements to reflect events or
circumstances arising after the date hereof. Copyright 2009 Cardium
Therapeutics, Inc. All rights reserved. For Terms of Use Privacy
Policy, please visit http://www.cardiumthx.com/. Cardium
Therapeutics(TM) and Generx® are trademarks of Cardium
Therapeutics, Inc. Tissue Repair(TM), Gene Activated Matrix(TM),
GAM(TM), Excellagen(TM), Excellarate(TM) and Osteorate(TM) are
trademarks of Tissue Repair Company. Regranex® and other trademarks
are the property of their respective owners.
http://www.newscom.com/cgi-bin/prnh/20051018/CARDIUMLOGO
http://photoarchive.ap.org/ DATASOURCE: Cardium Therapeutics
CONTACT: Bonnie Ortega, Director, Investor/Public Relations of
Cardium Therapeutics, Inc., +1-858-436-1018, Web Site:
http://www.cardiumthx.com/
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