Schon ein Monat her, dass der Artikel von C.R.Jackson erschienen
ist. Ist aber eine gute Übersicht, über die Projekte die bei CLDX
There Is A Lot To Like About Celldex Therapeutics
For some time, rindopepimut was the major reason why many have
invested in Celldex Therapeutics (CLDX). However, late last year,
Celldex generated a great deal of excitement after the final
results from the company's Phase 2b metastatic breast cancer study
of CDX-011 were released. The results were so good that the company
plans to initiate a randomized trial suitable for accelerated
approval in patients with triple negative breast cancer in the
second half of 2013.
In addition to the CDX-011 accelerated approval study, Celldex
plans to initiate new clinical studies and expansion studies for
four other Celldex programs this year.
Celldex's primary focus is in oncology. There are four programs
currently in clinical development for treatment of several cancers,
and additional oncology programs are progressing toward clinical
development. Celldex also expects data from three clinical studies
by year end, including results from its Phase 2 study of
rindopepimut with Avastin (bevacizumab) in refractory glioblastoma.
The company also hopes to complete enrollment in the Phase 3
rindopepimut ACT IV registration trial in frontline
Celldex's expertise is the design of new therapeutics and treatment
regimens that maximize the beneficial aspects of the immune system,
and counter its negative elements that are exploited by cancers and
pathogens. These innovative programs include:
APC Targeting Technology, a new class of vaccines based on
Celldex's proprietary antibody-targeted vaccine technology that is
used to generate an immune response against cancer and other
Therapeutic Antibody Programs, a well validated approach to using
antibodies that target cancer and other diseases directly or by
interfering with the disease; and
Immune System Modulators, drugs that activate or suppress specific
parts of the immune system, including such molecules as Toll-like
receptor (TLR) agonists that can activate patients' innate and
In June 2010, Celldex stock crashed after Pfizer (PFE) decided to
end its collaboration with Celldex for CDX-110. Celldex vowed to
continue research and development of rindopepimut, also known as
CDX-110. CDX-110 is a immunotherapeutic that targets the
tumor-specific molecule, epidermal growth factor receptor variant
III, or EGFRvIII.
EGFRvIII is a mutated form of the epidermal growth factor receptor,
or EGFR, that is only expressed in cancer cells and not in normal
tissue, and can directly contribute to cancer cell growth. EGFRvIII
is expressed in approximately 30% of glioblastoma tumors, also
referred to as glioblastoma multiforme, the most common and
aggressive form of brain cancer.
Glioblastoma multiforme tumor cells show a high resistance to
radiation and chemotherapy. These tumors spread and infiltrate
tissue so quickly that eradicative surgery is often impossible with
recurrence occurring within months of the initial treatment.
According to the US National Cancer Registry, approximately 28,000
new cases of malignant gliomas are diagnosed in the United States
and the European Union each year. The current standard of care
involves surgery, followed by radiotherapy and chemotherapy. The
relative survival rate for adults diagnosed with glioblastoma is
less than 30% within one year of diagnosis. According to the
Central Brain Tumor Registry of the United States, only 3% of
patients live longer than five years after primary diagnosis. The
median overall survival does not exceed 15 months despite surgical
resection, radiotherapy, and chemotherapy even in selected clinical
The research firm, GlobalData, estimated that the global
glioblastoma multiforme therapeutics market was valued at $370
million in 2010. GlobalData forecasted that the market will grow at
a compound annual growth rate of 2.4% to reach $449 million by
2018. This low growth rate is primarily attributed to the patent
expiry of Merck & Co.'s (MRK) Temodal/Temodar (temozolomide) in
Europe in 2009, and in the United States in 2014. GlobalData
research found that the entry of low cost generics in Europe in
2010 led to a decrease in the market valuation.
According to the pharmaceutical industry research firm, Decision
Resources, there is a significant opportunity for investigational
glioblastoma drugs. Despite advances in treatment such as adjuvant
radiotherapy in combination with Temodar/Temodal, prognosis remains
poor as the majority of glioblastoma patients experience disease
Both the US Food and Drug Administration (FDA) and the European
Medicines Agency (EMA), have granted orphan drug designation to
rindopepimut for the treatment of EGFRvIII expressing GB. The FDA
has also granted a Fast Track designation to the investigational
On November 15, 2012, Celldex announced the presentation of
three-year survival data from the Phase 2 rindopepimut clinical
program in EGFRvIII-positive glioblastoma, a more aggressive form
of glioblastoma typically associated with reduced long-term
survival in comparison to the glioblastoma population as a whole.
Across three Phase 2 studies of rindopepimut, survival data has
remained consistent, suggesting that a substantial and continuing
survival benefit exists in comparison to independent control
datasets at the median and at three years.
In the multi-center Phase 2 ACT III study, the median overall
survival was 24.6 months from diagnosis (21.8 months from study
entry) and overall survival is 26% at three years. In the Phase 2
ACT II study, the median overall survival was 24.4 months from
diagnosis (20.5 months from study entry) and overall survival is
23% at three years.
The long-term survival data across all three rindopepimut Phase 2
clinical trials was consistent and suggested that rindopepimut
provided long-term survival beyond what is historically seen in
this subset of EGFRvIII-expressing glioblastoma patients, a group
that typically has more aggressive disease associated with a worse
prognosis than the general glioblastoma patient population.
In addition to the presentation of updated survival data, Celldex
also announced the presentation of data from a retrospective
analysis of EGFRvIII expression status and associated clinical
outcome in the Phase 3 Radiation Therapy Oncology Group's (RTOG)
0525 study. This analysis was conducted by the University of Texas
MD Anderson Cancer Center in cooperation with RTOG to provide an
assessment of the prognosis for patients with EGFRvIII-positive
disease contemporary with the ACT III data.
"The results presented at SNO provide further validation for the
rindopepimut clinical program," said Anthony Marucci, President and
CEO of Celldex Therapeutics. "The median and long-term survival
rates are impressive in comparison to both the MD Anderson and RTOG
historical control datasets, with 23% to 33% of patients on
rindopepimut surviving to the three-year mark versus 6% to 18% of
patients in the historical control datasets. In addition, while the
ACT II and ACT III data continue to mature, across all three Phase
2 rindopepimut studies, approximately 15% of patients are alive at
five years compared to an expectation of 0%. These results support
our belief that rindopepimut has the potential to dramatically
alter the prognosis for patients with EGFRvIII-positive
glioblastoma. To that end, we continue to actively enroll patients
in the pivotal ACT IV study with more than 150 clinical sites
around the world selected to participate and, to date, 118 of these
sites actively screening patients."
In December 2011, Celldex initiated ACT IV, a pivotal, randomized,
double-blind, controlled Phase 3 study of rindopepimut in patients
with surgically resected, EGFRvIII-positive GB. The primary
objective of the study is to determine whether rindopepimut plus
adjuvant GM-CSF improves the overall survival of patients with
newly diagnosed EGFRvIII-positive GB after Gross Total Resection,
or GTR, when compared to treatment with TMZ and a control injection
of KLH. KLH is a component of rindopepimut and was selected due to
its ability to generate a similar injection site reaction to that
observed with rindopepimut.
The ACT IV trial will enroll up to 440 patients at over 150 centers
worldwide to recruit approximately 374 patients with GTR to be
included in the primary analysis. Celldex expects to complete
patient accrual by the end of 2013 and anticipate receiving data 18
to 24 months after completing accrual. The company anticipates ACT
IV to cost over $60 million during its duration.
In December 2011, Celldex also initiated ReACT, a Phase 2 study of
rindopepimut in combination with Avastin in patients with recurrent
EGFRvIII-positive GB. ReACT will enroll approximately 95 patients
in a first or second relapse of GB following standard therapy. The
study will be conducted at approximately 20 sites across the United
States. Approximately 70 patients who have yet to receive Avastin
will be randomized to receive either rindopepimut and Avastin or a
control injection of KLH and Avastin in a blinded fashion. Another
25 patients who are refractory to Avastin having received Avastin
in either the frontline or recurrent setting with subsequent
progression will receive rindopepimut plus Avastin in a single
treatment arm. We expect data from this study to be available in
the second half of 2013.
In addition, researchers at Stanford University are conducting an
investigator sponsored, pilot trial of rindopepimut in pediatric
patients with pontine glioma. Patient enrollment is ongoing for
In June 2012, a survey of US oncologists surveyed conducted by the
research and advisory firm, Decision Resources, found that they
would prescribe CDX-110 to 36% of their newly diagnosed
glioblastoma multiforme patients if the drug is approved.
Decision Resources predicted that CDX-110 would earn an 18% patient
share in the US newly diagnosed glioblastoma multiforme market by
2020 because only about one-third of glioblastoma multiforme
patients harbor the EGFRVIII variant targeted by the drug. The firm
concluded that this limitation, combined with increased competition
in the glioblastoma multiforme drug market, will limit the patient
population eligible for the therapy.
CDX-011, also known as glembatumumab vedotin, is a fully-human
monoclonal antibody-drug conjugate (ADC) that targets glycoprotein
NMB (GPNMB). GPNMB is a protein overexpressed by multiple tumor
types, including melanoma, breast cancer and glioma. The FDA has
granted Fast Track designation to CDX-011 for the treatment of
advanced, refractory/resistant GPNMB-expressing breast cancer.
GPNMB has been shown to be associated with the ability of the
cancer cell to invade and metastasize, and to correlate with
reduced time to progression and survival in breast cancer. The
GPNMB-targeting antibody, CR011, is linked to a potent cytotoxic,
monomethyl auristatin E (MMAE), using Seattle Genetics' (SGEN)
In June 2008, Celldex initiated a Phase 1/2 study of CDX-011
administered intravenously once every three weeks to patients with
locally advanced or metastatic breast cancer who had received prior
therapy. For all patients treated at the maximum dose level, tumor
shrinkage was seen in 62% (16 of 26 patients) and median
progression free survival (PFS) was 9.1 weeks. A subset of 10
patients had "triple negative disease," a more aggressive breast
cancer subtype that carries a high risk of relapse and reduced
survival as well as limited therapeutic options due to lack of
over-expression of HER2/neu, estrogen and progesterone receptors.
In these patients, 78% (7 of 9 patients) had some tumor shrinkage,
12-week PFS rate was 70% (7 of 10 patients), and median PFS was
In December 2012, Celldex presented positive final results from the
Phase 2b EMERGE clinical trial of CDX-011 in patients with both
triple negative breast cancer and high GPNMB expression. In
December 2012, Celldex announced final results from the EMERGE
study which suggested that CDX-011 induced significant response
rates compared to currently available therapies in patient subsets
with advanced, refractory breast cancers with GPNMB over-expression
(expression in greater than 25% of tumor cells) and in patients
with triple negative breast cancer. The overall survival, or OS,
and progression free survival, or PFS, of patients treated with
CDX-011 was also observed to be greatest in patients with triple
negative breast cancer who also over-express GPNMB and all patients
with GPNMB over-expression.
In December 2012, Celldex had its end of Phase 2b meeting with the
FDA for the CDX-011 program. Based on this meeting, Celldex intends
to initiate a randomized study of CDX-011 for accelerated approval
in patients with triple negative breast cancer that also
over-express GPNMB in the second half of 2013.
Since triple negative breast cancers do not express estrogen,
progesterone, and HER2 receptors, these cancers are resistant to
conventional targeted treatments, including hormonal and
HER2-targeted therapies. According to the National Breast Cancer
Foundation, triple negative breast cancer occurs in about 10% to
20% of diagnosed breast cancers.
Celldex plans to initiate a pivotal, randomized, accelerated
approval study of CDX-011 in patients with triple negative breast
cancers that over-express GPNMB in the second half of 2013. Last
year, the FDA drafted new guidelines for clinical trials
researching early stage triple negative breast cancer in an effort
to expedite the development of drugs to treat these cancers.
CDX-1401, developed from Celldex's APC Targeting Technology, is a
fusion protein consisting of a fully human monoclonal antibody with
specificity for the dendritic cell receptor, DEC-205, linked to the
NY-ESO-1 tumor antigen.
Researchers have detected NY-ESO-1 in 20% to 30% of all melanoma,
lung, esophageal, liver, gastric, prostate, ovarian and bladder
cancers. CDX-1401 is intended to selectively deliver the NY-ESO-1
antigen to dendritic cells to generate strong immune responses
against cancer cells expressing NY-ESO-1.
Celldex is developing CDX-1401 for the treatment of malignant
melanoma and a variety of solid tumors which express the
proprietary cancer antigen NY-ESO-1, which the company licensed
from the Ludwig Institute for Cancer Research in 2006. Preclinical
studies have shown that CDX-1401 is effective for activation of
human T cell responses against NY-ESO-1.
On October 29, 2012, Celldex announced that The Phase 1 study of
CDX-1401 was the first clinical study to demonstrate that an
off-the-shelf vaccine targeting dendritic cells in vivo through
DEC-205 could safely lead to robust immunity when combined with TLR
agonists in cancer patients. Significant anti-NY-ESO-1 titers
occurred in 79% of evaluable patients.
In 2013, Celldex plans to initiate a Phase 2 study of CDX-1401 in
combination with CDX-301 sponsored by the Cancer Immunotherapy
Trials Network of the National Cancer Institute.
CDX-1127 is a human monoclonal antibody that targets CD27, a
potentially important target for immunotherapy of various cancers.
Celldex entered into license agreements with the University of
Southampton in the United Kingdom for intellectual property related
to uses of anti-CD27 antibodies and with Medarex, a Bristol-Myers
Squibb (BMY) subsidiary, for access to the UltiMab technology to
develop and commercialize human antibodies to CD27.
CDX-1127 has been shown to activate immune cells that can target
and eliminate cancerous cells in tumor-bearing mice and to directly
kill or inhibit the growth of CD27 expressing lymphomas and
leukemias. Both mechanisms have been seen even at low doses in
appropriate preclinical models.
In November 2011, Celldex initiated an open label, dose-escalating
Phase 1 study of CDX-1127 in patients with selected malignant solid
tumors or hematologic cancers at multiple clinical sites in the
United States. The Phase 1 study is designed to test five
escalating doses of CDX-1127 to determine a Phase 2 dose for
further development based on safety, tolerability, potential
activity and immunogenicity.
On April 8, 2013, Celldex reported the results of an in vitro study
analyzing the activation of human T cells with CDX-1127 at the
American Association of Cancer Research (AACR) annual meeting.
"The results of this study confirm that CDX-1127 elicits potent
activation of T cells by inducing their proliferation and release
of important immune modulating cytokines," Tibor Keler, PhD,
Celldex's Senior Vice President and Chief Scientific Officer
stated. "Most importantly, we have shown that the activation is
highly regulated, which limits any safety concerns related to
non-specific stimulation of the immune system that similar
candidates in this class have faced. This finding is supported by
the good safety profile seen to date in our ongoing multi-dose
Phase 1 human clinical trial. We believe CDX-1127 is an exciting
entrant to the field of immunotherapy and look forward to
presenting clinical data from planned solid tumor and hematologic
expansion cohorts from our Phase 1 study by year-end."
The company anticipates reporting data from the CDX-1127 program in
the second half of 2013.
CDX-301 is a FMS-like tyrosine kinase 3 ligand, or Flt3L, stem cell
mobilizer and dendritic cell growth factor. CDX-301 has
demonstrated a unique capacity to increase the number of
circulating dendritic cells in both laboratory and clinical
studies. In addition, CDX-301 has shown impressive results in
models of cancer, infectious diseases and inflammatory/autoimmune
Celldex licensed CDX-301 from Amgen Inc. (AMGN) in March 2009.
In February 2013, Celldex presented final results from a Phase 1
multi-dose study of CDX-301 in 30 healthy subjects. The Phase 1
study evaluated seven different dosing regimens of CDX-301 to
determine the appropriate dose for further development based on
safety, tolerability, and biological activity. The data from the
study were consistent with previous clinical experience and
demonstrated that CDX-301 was well-tolerated and could effectively
mobilize hematopoietic stem cell populations in healthy volunteers.
Based on the safety profile and the increases observed for CD34+
stem cells and dendritic cells, Celldex plans to initiate a pilot
study in hematopoietic stem cell transplant by the end of 2013.
CDX-1307 utilizes monoclonal antibodies to deliver vaccine directly
to the patient's immune system and focuses the immune system
against hCG beta (hCG-β), a cancer-associated target believed to
play a role in more aggressive forms of the disease. hCG-β is an
established tumor-associated antigen that is over-expressed in a
variety of common cancers including those of the colon, lung,
pancreas, esophagus, breast, bladder, cervix, stomach, and
prostate, but not expressed in most normal tissues.
CDX-1307 has been evaluated for the treatment of advanced
colorectal, pancreatic, bladder, ovarian and breast cancers in two
Phase 1 trials.
In October 2009, Celldex announced positive results from Phase 1
studies of CDX-1307 in patients with advanced epithelial cancers,
including breast, colon, bladder and pancreatic cancer.
The studies enrolled more than 80 patients with heavily pretreated,
advanced-stage breast, colon, bladder and pancreatic cancer, with
an average of 4.6 prior therapies across the treatment population.
All patient cohorts demonstrated a favorable safety profile with no
dose limiting toxicity to date.
Researchers found that the combination of CDX-1307 with TLR
agonists significantly enhanced immune responses against hCG-β,
providing strong humoral responses in 88% of patients and cellular
immune responses in 57% of patients analyzed to date. Immune
responses occurred even in the presence of high circulating levels
of hCG-β, suggesting that the CDX-1307 can overcome antigen
tolerance in advanced and heavily pretreated cancers. Nine patients
in the studies experienced disease stabilization from 2.3 months to
11.4 months following the initiation of CDX-1307 vaccination. Two
of these patients have received multiple courses of CDX-1307 and
continue treatment with stable disease at 6.4 and 11.4 months.
Celldex believe these data provide the basis for advancing CDX-1307
into a front-line patient population selected for hCG-β expressing
CDX-1135 is a molecule that inhibits a part of the human immune
system called the complement system. The complement system is
comprised of proteins that are initiators of the body's
inflammatory response against disease, infection and injury.
Excessive complement activation also plays a role in some
persistent inflammatory conditions.
CDX-1135 is being assessed for certain rare renal diseases
involving dysregulated complement and therapeutic intervention in
Antibody-Mediated Rejection (AMR) and other inflammatory conditions
where the complement system is thought to have a critical role in
the disease pathogenesis.
Celldex is conducting a Phase 1 study of CDX-1135 as a therapy for
dense deposit disease (DDD), a rare genetic condition affecting 2
to 3 people per million worldwide. DDD is a devastating disease
that is caused by uncontrolled activation of the alternative
pathway of complement and leads to progressive kidney damage in
children. There is currently no treatment for patients with DDD and
about one-half of those with DDD progress to end-stage renal
disease within 10 years. Because DDD recurs in virtually all
patients who receive a kidney transplant, transplantation is not a
viable option for these patients. In animal models of DDD, CDX-1135
treatment showed evidence of reversal of kidney damage.
Celldex is planning to initiate a pilot study of CDX-1135 in a
small number of DDD patients to determine the appropriate dose and
regimen for further clinical development based on safety,
tolerability and biological activity with data expected by the end
Celldex is developing therapeutic human antibodies to a signaling
molecule known as CD89 or Fcα receptor type I (FcαRI). CD89 is
expressed by some white blood cells and leukemic cell lines, and
has been shown to be important in controlling inflammation and
tumor growth in animal models.
Celldex has proprietary, fully human antibodies to CD89 in
preclinical development. Depending upon the specific antibody used,
anti-CD89 antibodies can either be activating and thus stimulate
immune responses, or down-regulating and anti-inflammatory.
Celldex also has a preclinical program, CDX-014, a fully-human
monoclonal antibody-drug conjugate that targets TIM-1, a molecule
that is highly expressed on renal and ovarian cancers with minimal
expression in normal tissues. CDX-014 has shown potent activity in
preclinical models of ovarian and renal cancer.
Celldex and Rockefeller University investigators are collaborating
on an effort to develop a vaccine against the human
immunodeficiency virus (HIV), the virus known to cause Acquired
Immune Deficiency Syndrome (AIDS). The vaccine, called DCVax-001,
is an APC-targeted vaccine consisting of a fusion protein of a
human monoclonal antibody with specificity for the dendritic cell
receptor, DEC-205 linked to an HIV antigen. This program has been
funded through a grant from the Bill & Melinda Gates
Foundation. The vaccine is currently being tested in a Phase 1
trial in healthy volunteers at Rockefeller University.