FDA Accepts New Drug Application Filing for
Ridaforolimus, Investigational mTOR Inhibitor
WHITEHOUSE STATION, N.J. & CAMBRIDGE, Mass., Oct. 5, 2011 -- Merck (NYSE:MRK),
known outside the United States and Canada as MSD, and ARIAD Pharmaceuticals,
Inc., (NASDAQ:ARIA), today announced that the U.S. Food and Drug Administration
(FDA) has accepted for filing and review the New Drug Application (NDA) for
ridaforolimus, an investigational oral mTOR inhibitor under development for the
treatment of metastatic soft-tissue or bone sarcomas in patients who had a
favorable response to chemotherapy. The FDA assigned a Standard review
classification to this application.
Merck and ARIAD previously announced that the European Medicines Agency had
accepted the marketing authorization application for ridaforolimus. As part of
an exclusive license agreement with ARIAD, Merck is responsible for the
development and worldwide commercialization of ridaforolimus in oncology. ARIAD
intends to co-promote ridaforolimus in the United States.
About Sarcoma
Sarcomas are a group of cancers of connective tissue of the body for which there
are currently limited treatment options. Sarcomas can arise anywhere in the body
and are divided into two main groups – bone tumors and soft-tissue sarcomas.
About Ridaforolimus
Ridaforolimus is an investigational targeted and potent small-molecule inhibitor
of the protein mTOR, a protein that acts as a central regulator of protein
synthesis, cell proliferation, cell cycle progression and cell survival,
integrating signals from proteins, such as PI3K, AKT and PTEN, known to be
important to malignancy.
Merck's Commitment to Oncology
Merck is committed to advancing all aspects of cancer care – prevention,
treatment and supportive care. Through strong internal research capabilities,
selective alliances and acquisitions, and enabling technologies, Merck is
looking to lead in the discovery, development and delivery of anticancer
therapies.
About Merck
Today's Merck is a global healthcare leader working to help the world be well.
Merck is known as MSD outside the United States and Canada. Through our
prescription medicines, vaccines, biologic therapies, and consumer care and
animal health products, we work with customers and operate in more than 140
countries to deliver innovative health solutions. We also demonstrate our
commitment to increasing access to healthcare through far-reaching policies,
programs and partnerships. For more information, visit
www.merck.com and connect
with us on Twitter, Facebook and YouTube.
About ARIAD
ARIAD Pharmaceuticals, Inc. is an emerging global oncology company focused on
the discovery, development and commercialization of medicines to transform the
lives of cancer patients. ARIAD's approach to structure-based drug design has
led to three internally discovered, molecularly targeted product candidates for
drug-resistant and difficult-to-treat cancers, including certain forms of
chronic myeloid leukemia, soft tissue and bone sarcomas and non-small cell lung
cancer. For additional information, visit
http://www.ariad.com.
Merck Forward-Looking Statement
This news release includes "forward-looking statements" within the meaning of
the safe harbor provisions of the United States Private Securities Litigation
Reform Act of 1995. Such statements may include, but are not limited to,
statements about the benefits of the merger between Merck and Schering-Plough,
including future financial and operating results, the combined company's plans,
objectives, expectations and intentions and other statements that are not
historical facts. Such statements are based upon the current beliefs and
expectations of Merck's management and are subject to significant risks and
uncertainties. Actual results may differ from those set forth in the
forward-looking statements.
The following factors, among others, could cause actual results to differ
from those set forth in the forward-looking statements: the possibility that the
expected synergies from the merger of Merck and Schering-Plough will not be
realized, or will not be realized within the expected time period; the impact of
pharmaceutical industry regulation and health care legislation; the risk that
the businesses will not be integrated successfully; disruption from the merger
making it more difficult to maintain business and operational relationships;
Merck's ability to accurately predict future market conditions; dependence on
the effectiveness of Merck's patents and other protections for innovative
products; the risk of new and changing regulation and health policies in the
United States and internationally and the exposure to litigation and/or
regulatory actions.
Merck undertakes no obligation to publicly update any forward-looking
statement, whether as a result of new information, future events or otherwise.
Additional factors that could cause results to differ materially from those
described in the forward-looking statements can be found in Merck's 2010 Annual
Report on Form 10-K and the company's other filings with the Securities and
Exchange Commission (SEC) available at the SEC's Internet site (www.sec.gov).
ARIAD Forward-Looking Statement
This press release contains "forward-looking statements" including, but not
limited to, statements relating to clinical data for ridaforolimus in the
treatment of metastatic soft-tissue and bone sarcomas. Forward-looking
statements are based on management's expectations and are subject to certain
factors, risks and uncertainties that may cause actual results, outcome of
events, timing and performance to differ materially from those expressed or
implied by such statements. These risks and uncertainties include, but are not
limited to, results of clinical studies of the Company's product candidates,
timing and acceptance of regulatory filings for drug approval, and other factors
detailed in the Company's public filings with the U.S. Securities and Exchange
Commission. The information contained in this press release is believed to be
current as of the date of original issue. The Company does not intend to update
any of the forward-looking statements after the date of this document to conform
these statements to actual results or to changes in the Company's expectations,
except as required by law.
Elspeth M.
Beauchamp1,
Lymor Ringer1,
Gülay Bulut1,
Kamal P. Sajwan1,
Michael D. Hall1,
Yi-Chien Lee1,
Daniel Peaceman1,
Metin Özdemirli1,
Olga Rodriguez1,
Tobey J. Macdonald2,
Chris Albanese1,
Jeffrey A. Toretsky1
and Aykut Üren1
1Lombardi
Comprehensive Cancer Center, Georgetown University Medical Center, Washington,
DC, USA. 2Department
of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.
Address correspondence to: Aykut Üren, 3970
Reservoir Rd. NW, NRB, Room E312, Washington, DC 20057, USA. Phone:
202.687.9504; Fax: 202.687.1434; E-mail: au26@georgetown.edu.
First published December 22, 2010
Received for publication March 4, 2010, and accepted in revised form October 13,
2010.
The Hedgehog (Hh) pathway is
activated in some human cancers, including medulloblastoma. The glioma-associated
oncogene homolog (GLI) transcription factors are critical mediators of the
activated Hh pathway, and their expression may be elevated in some tumors
independent of upstream Hh signaling. Thus, therapies targeting GLI
transcription factors may benefit a wide spectrum of patients with mutations
at different nodal points of the Hh pathway. In this study, we present
evidence that arsenic trioxide (ATO)
suppresses human cancer cell growth and tumor development in mice by
inhibiting GLI1. Mechanistically, ATO directly bound to GLI1 protein,
inhibited its transcriptional activity, and decreased expression of
endogenous GLI target genes. Consistent with this, ATO inhibited the growth
of human cancer cell lines that depended on upregulated GLI expression in
vitro and in vivo in a xenograft model of Ewing sarcoma. Furthermore, ATO
improved survival of a clinically relevant spontaneous mouse model of
medulloblastoma with activated Hh pathway signaling. Our results establish
ATO as a Hh pathway inhibitor acting at the level of GLI1 both in vitro and
in vivo. These results warrant the clinical investigation of ATO for tumors
with activated Hh/GLI signaling, in particular patients who develop
resistance to current therapies targeting the Hh pathway upstream of GLI.
Yondelis(R) Receives Five New Approvals Outside the European
Economic Area
Yondelis(R) has been approved for soft
tissue sarcoma (STS) in Israel, Panama and Ukraine. Additionally, the
authorities in Paraguay and Azerbaijan have approved the drug for
platinum-sensitive recurrent ovarian cancer (ROC).
Yondelis(R) is
currently approved in 56 countries.
MADRID, March 15
/PRNewswire/ -- Centocor Ortho Biotech Products has informed PharmaMar
SA (Grupo Zeltia, ZEL.MC) that the regulatory authorities in Israel, Panama
and Ukraine have approved Yondelis(R)
for advanced soft tissue sarcoma (STS) in adults. Furthermore, the
authorities in Paraguay and Azerbaijan have approved the drug for
platinum-sensitive recurrent ovarian cancer (ROC). Yondelis is already
approved for STS in Paraguay and Azerbaijan.
The
European Commission approved Yondelis(R) for platinum-sensitive ROC in September 2009. Outside the European Economic
Area (EEA), Yondelis(R) has now been approved for platinum-sensitive ROC
in Azerbaijan and Paraguay; it had already been approved in Kazakhstan and the
Philippines.
In view of
the three new approvals for STS, Yondelis(R) now has authorization for
this indication in 25 countries outside the EEA: Argentina, Azerbaijan,
Bolivia, Chile,
Colombia, Curacao,
Hong Kong, India,
Israel, Kazakhstan,
Macao, Malaysia,
Mexico, Panama,
Paraguay, The
Philippines, Russia, Singapore, South
Korea, Switzerland, Thailand, Ukraine,
Uruguay, Venezuela
and Vietnam. PharmaMar has already
begun collecting royalties from sales in the aforementioned countries.
Clinical
trials are under way to expand the use of Yondelis(R) in sarcoma,
including a trial as first-line treatment in patients with
translocation-associated tumors, in children with Ewing sarcoma,
rhabdomyosarcoma and other forms of STS. Yondelis(R) is also undergoing
trials in solid tumors, such as prostate, breast and lung cancer.
Yondelis(R)
has orphan drug status for soft tissue sarcoma and ovarian cancer in
the European Union, the United States, Switzerland, and for soft tissue sarcoma in South Korea.
According
to the licensing agreement between PharmaMar (Zeltia, S.A. subsidiary)
and Centocor Ortho Biotech Products, L.P., PharmaMar has the rights to
sell Yondelis(R) in Europe (including Eastern Europe), while Centocor Ortho
Biotech Products, L.P. has the rights to sell the drug everywhere else,
except in Japan, where Taiho
Pharmaceutical Co., Ltd. has a licensing agreement for the development
and sale of Yondelis(R).
About
PharmaMar
PharmaMar
is Zeltia Group's biotechnology subsidiary; it is a world leader in
discovering, developing and selling marine-based drugs to treat cancer.
Yondelis(R) is Spain's first
anti-cancer drug. It is currently approved for STS in 25 countries
outside the EEA, and in five of those countries for platinum-sensitive
ROC as well. Yondelis(R) is approved for STS and platinum-sensitive ROC
in all 30 countries of the EEA; in Switzerland
it is approved for STS. Phase II clinical trials with Yondelis(R) are
also under way on prostate, breast, lung and pediatric cancers.
PharmaMar has four other compounds in clinical development: Aplidin(R),
Irvalec(R), Zalypsis(R) and PM01183. PharmaMar also has a rich pipeline
of pre-clinical candidates and a major R&D programs.
Important
note
PharmaMar,
which is headquartered in Madrid (Spain), is a subsidiary of the Zeltia Group
(Spanish stock exchange: ZEL), which has been listed on the Spanish
Stock Exchange since 1963 and on Spain's
Electronic Market since 1998. This document is a press release, not a
prospectus. This document does not constitute or form part of an
offering or invitation to sell or a solicitation to purchase, offer or
subscribe shares of the company. Moreover, no reliance should be placed
upon this document for any investment decision or contract and it does
not constitute a recommendation of any type with regard to the shares of
the company.
A novel class of cancer therapies called live biologics is offering new
hope for patients affected by hard-to-treat cancers, according to two
different studies testing the therapies in patients with sarcomas and
head and neck cancers.
Traditional cancer treatments such as chemotherapy and radiotherapy come
with a serious disadvantage: they cannot distinguish cancer cells from
normal cells. Since normal cells can be stunted by chemotherapy and
destroyed by radiation along with abnormal cells, patients may
experience serious health issues during a course of extended treatment.
Calgary-based Oncolytics Biotech Inc. has developed an innovative
approach to cancer therapy that might help patients avoid such serious
side effects. Their strategy relies on one of the human body’s
traditional foes: viruses. Specifically, Oncolytics is testing a live
cancer biologic called REOLYSIN®, which is derived from the human
reovirus.
“One of the distinguishing characteristics of the reovirus is its
tendency to replicate within certain cancer cells, namely, those that
possess a feature known as an activated Ras pathway,” said Brad
Thompson, Chairman, President and Chief Executive Officer of Oncolytics
Biotech. “Approximately two-thirds of all cancers involve cells that are
Ras-activated. REOLYSIN® appears to kill off these cancer cells by
rupturing their walls, creating a chain reaction of ‘explosions’ that
rip through tumors.”
A team lead by Dr. Monica Mita at the Institute of Drug Development (IDD),
the Cancer Therapy and Research Center at the University of Texas Health
Science Center (UTHSC) in San Antonio, Texas, recently provided updated
results from a Phase II study using REOLYSIN® in patients with sarcomas
metastatic to the lung.
The investigators reported that the treatment has been well-tolerated to
date, and that 19 of 44 patients experienced stable disease ranging from
2 to 20 months, resulting in a total clinical benefit rate (complete
response + partial response + stable disease) of 43%. The response
objective for the study was three or more patients having prolonged
stabilization of disease (>6 months) or better, for the agent to be
considered. The trial exceeded its established objective with six
patients experiencing stable disease for more than six months. Two
patients have experienced stable disease for more than 19 months. One of
these patients has synovial cell sarcoma that relapsed following
surgery, while the other has Ewing’s Sarcoma and had previously
progressed following multiple treatments.
“We were very happy to participate in the study,” said Dr. Mita.
“REOLYSIN® is a promising option for patients with sarcoma, as shown by
the results of this study. As a single agent, the virus had a clinical
benefit rate of 43% and it was very well-tolerated. We are contemplating
further studies combining REOLYSIN® with chemotherapy in order to
integrate the virus in the panoply of agents used for sarcoma
treatment.”
New Progress on Head and Neck Cancer
While the new viral treatment will not completely dispose of the need
for chemotherapy, its ability to weaken and shrink tumors might restrict
the amount of chemo that is required or help agents such as paclitaxel
and carboplatin do their jobs.
The company recently provided updated results from a Phase I/II UK trial
(REO 011) of REOLYSIN® combined with paclitaxel/carboplatin for patients
with advanced cancers in a poster presentation at the 2009
AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics conference in
Boston. The investigators reported that REOLYSIN® was well-tolerated
when administered intravenously in combination with paclitaxel and
carboplatin. Of 19 evaluable patients with head and neck cancer, mostly
SCCHN refractory to prior platinum-based chemotherapy for
recurrent/metastatic disease, eight experienced partial responses and
six had stable disease. The total clinical benefit rate (complete
response + partial response + stable disease) observed in head and neck
cancer patients in the trial was 74%. Of four patients with malignant
melanoma on the trial, one experienced a partial response and one had
stable disease.
“A 42% response rate and a 74% clinical benefit rate in a platinum
refractory patient population that typically has a poor prognosis and
limited therapeutic options is very encouraging,” said Dr. Thompson.
“These results further validate our decision to advance REOLYSIN® in
combination with paclitaxel and carboplatin into a Phase III trial in
this patient population.”
Figitumumab has anti-tumor activity in Ewing's sarcoma, a cancer which
affects mainly teenage boys
A preliminary study of the anticancer drug figitumumab has found that it has
antitumour activity in Ewing's sarcoma—a cancer which affects mainly teenage
boys. The results have led to the drug's progression to a Phase 2 trial in
patients with Ewing's sarcoma, which has recently finished recruiting. These are
the conclusions of an Article published Online First in the Lancet Oncology.
The study is by Dr Johann S de Bono, The Institute for Cancer Research (ICR),
Sutton, UK, and The Royal Marsden NHS Foundation Trust, Sutton, UK, and
colleagues.
Ewing's sarcoma is a rare disease in which cancer cells are found in the bone
or soft tissue, most commonly the pelvis, femur, humerus, and ribs. It occurs
most commonly it male teenagers with a male to female ratio of 1.6 to 1.
Data from preclinical studies have suggested that Ewing's sarcoma, and some
other sarcoma subtypes, are dependent on the insulin-like growth factor
signalling pathway. Figitumumab is a drug which targets the insulin-like
growth-factor-1 receptor (IGF-1R). This phase I study was carried out to assess
the effects of figitumumab in these sarcoma subtypes.
Between January, 2006, and August, 2008, patients with refractory, advanced
sarcomas received figitumumab (20 mg/kg) in two groups within a phase 1 trial.
The first cohort (15 patients) included patients with multiple sarcoma subtypes,
age 18 years or older, and the second cohort (14 patients) consisted of patients
with refractory Ewing's sarcoma, age nine years or older. The primary endpoint
was to assess the safety and tolerability of figitumumab.
Of the 29 patients that were enrolled, 16 had Ewing's sarcoma, and the 29
received a total of 177 cycles of treatment (median 2, mean 6, range 1). In
terms of adverse events, grade 3 deep venous thrombosis, grade 3 back pain, and
grade 3 vomiting were each noted once in individual patients; one patient had
grade 3 or 4 raised liver enzymes. The only other grade 4 adverse event was
raised concentrations of uric acid, noted in one patient. A total of 28 patients
were assessed for response; two patients, both with Ewing's sarcoma, had
objective responses (one complete response and one partial response) and eight
patients had disease stabilisation (six with Ewing's sarcoma, one with synovial
sarcoma, and one with fibrosarcoma) lasting four months or longer.
The authors say: "Figitumumab is well tolerated and has antitumour activity
in Ewing's sarcoma, warranting further investigation in this disease."
They conclude: "Our results show that figitumumab can be safe for both adult
and paediatric sarcoma patients, and has single-agent antitumour activity in
different sarcoma subtypes, including Ewing's sarcoma. Phase 2 studies of
figitumumab and other anti-IGF-R agents in Ewing's sarcoma and other sarcoma
subtypes are now completing accrual and rational combinations with other
treatments are also being pursued."
In an accompanying Reflection and Reaction comment, Dr Jeffrey A Toretsky,
Georgetown University, Washington DC, USA, and Dr Richard Gorlick, The Albert
Einstein College of Medicine of Yeshiva University, The Children's Hospital at
Montefiore, Bronx, NY, USA, say: "With several different companies developing
IGF-1R inhibitors, there could be ample opportunity to optimise clinical benefit
from IGF-1R blockade, although the development of these antibodies may be
complicated. Five-drug chemotherapy is routine in the treatment of Ewing's
sarcoma, therefore improvement in outcome for these patients will likely require
demonstration of the feasibility of combining the antibody with standard
chemotherapy. Ultimately, a phase 3 randomised study investigating the benefit
of this combination might provide the proof of activity that will achieve the
IGF-1R-pathway promise."
###
For Dr Johann S de Bono, The Institute for Cancer Research, The Royal Marsden
NHS Foundation Trust, Sutton, UK, and other authors, please contact ICR Science
Press Officer Jane Bunce T) +442071535106 E)
jane.bunce@icr.ac.uk
Dr Richard Gorlick, The Albert Einstein College of Medicine of Yeshiva
University, The Children's Hospital at Montefiore, Bronx, NY, USA. T) +1 718 741
2342 E) rgorlick@montefiore.org
Safety, pharmacokinetics, and preliminary activity of the anti-IGF-1R antibody figitumumab (CP-751,871) in patients with sarcoma and Ewing's sarcoma: a phase 1 expansion cohort study
The Lancet Oncology, Volume 11, Issue 2, Pages 129 -
135, February 2010
doi:10.1016/S1470-2045(09)70354-7
Published Online: 24 December 2009
Safety, pharmacokinetics, and
preliminary activity of the anti-IGF-1R
antibody figitumumab
(CP-751,871) in
patients with sarcoma and Ewing's
sarcoma: a
phase 1 expansion cohort
study
David Olmos MD a, Sophie
Postel-Vinay MD a, L Rhoda Molife MD a, Scott H Okuno MD
b, Scott M Schuetze MD c, M Luisa Paccagnella PhD d,
Gretchen N Batzel MD b, Donghua Yin PhD d, Prof Kathryn
Pritchard-Jones MD a, Prof Ian Judson MD a, Francis P
Worden MD c, Antonio Gualberto MD d, Michelle Scurr MD
a, Dr Johann S
de Bono MD a , Paul Haluska MD b
Summary
Background
Figitumumab is a fully human IgG2 monoclonal
antibody targeting the insulin-like
growth-factor-1 receptor (IGF-1R). Preclinical
data suggest a dependence on insulin-like
growth-factor signalling for sarcoma subtypes,
including Ewing's sarcoma, and early reports
show antitumour activity of IGF-1R-targeting
drugs in these diseases.
Methods
Between January, 2006, and August, 2008,
patients with refractory, advanced sarcomas
received figitumumab (20 mg/kg) in two
single-stage expansion cohorts within a solid-tumour
phase 1 trial. The first cohort (n=15) included
patients with multiple sarcoma subtypes, age 18
years or older, and the second cohort (n=14)
consisted of patients with refractory Ewing's
sarcoma, age 9 years or older. The primary
endpoint was to assess the safety and
tolerability of figitumumab. Secondary endpoints
included pharmacokinetic profiling and
preliminary antitumour activity (best response
by Response Evaluation Criteria in Solid Tumours
[RECIST]) in evaluable patients who received at
least one dose of medication. This study is
registered with
ClinicalTrials.gov, number
NCT00474760.
Findings
29 patients, 16 of whom had Ewing's sarcoma,
were enrolled and received a total of 177 cycles
of treatment (median 2, mean 6·1, range 1—24).
Grade 3 deep venous thrombosis, grade 3 back
pain, and grade 3 vomiting were each noted once
in individual patients; one patient had grade 3
increases in aspartate aminotransferase and
gammaglutamyltransferase concentrations. This
patient also had grade 4 increases in alanine
aminotransferase concentrations. The only other
grade 4 adverse event was raised concentrations
of uric acid, noted in one patient.
Pharmacokinetics were comparable between
patients with sarcoma and those with other solid
tumours. 28 patients were assessed for response;
two patients, both with Ewing's sarcoma, had
objective responses (one complete response and
one partial response) and eight patients had
disease stabilisation (six with Ewing's sarcoma,
one with synovial sarcoma, and one with
fibrosarcoma) lasting 4 months or longer.
Interpretation
Figitumumab is well tolerated and has antitumour
activity in Ewing's sarcoma, warranting further
investigation in this disease.
GUMC Discovery Highlights New Direction For Drug Discovery
Researchers
did what others thought was not possible by finding a small molecule to
stop “slippery” protein from binding to another, causing Ewing’s Sarcoma
Washington, DC – In a discovery that rebuffs conventional scientific thinking, researchers at the Lombardi Comprehensive Cancer Center at Georgetown University Medical Center (GUMC)
have discovered a novel way to block the activity of the fusion protein
responsible for Ewing’s sarcoma, a rare cancer found in children and
young adults.
In the paper published online July 5 in Nature
Medicine, they report discovering and successfully testing a small
molecule that keeps the fusion protein from sticking to another protein
that is critical for tumor formation. The researchers say this
interaction is unique – and is especially surprising since the Ewing’s
sarcoma fusion protein is extremely flexible, which allows it to change
shape constantly.
“Most targeted small molecule cancer drugs
inhibit the intrinsic activity of a single protein, but our agent stops
two proteins from interacting. This has never been shown before with a
cancer-causing fusion protein and represents a potentially novel
medical therapy in the future,” says the study’s lead investigator, Jeffrey Toretsky, MD, a pediatric oncology physician and researcher at GUMC’s Lombardi Comprehensive Cancer Center.
The
study could provide a model upon which to design treatment for other
disorders caused by the interaction between two proteins, and may be
especially useful in cancers caused by translocations of genes, such as
sarcomas and leukemias, the researchers say. Agents in use now that
work against fusion proteins inhibit a single protein to stop intrinsic
enzymatic activity; one example is Gleevec, used for chronic
myelogenous leukemia (CML). The Ewing’s sarcoma fusion protein, known
as EWS-FLI1, lacks enzymatic activity, “and this difference is why our
work is significant,” Toretsky says.
In the United States,
about 500 patients annually are diagnosed with the cancer, and they are
treated with a combination of five different chemotherapy drugs.
Between 60-70 percent of patients survive over time, but with side
effects from the treatment. Few additional treatment options are
available for patients whose cancer progresses, Toretsky says.
Ewing’s
sarcoma is caused by the exchange of DNA between two chromosomes, a
process known as a translocation. The new EWS-FLI1 gene is created when
the EWS gene on chromosome 22 fuses to the FLI1 gene on chromosome 11,
and its product is the fusion protein responsible for cancer formation.
It is a so-called disordered protein, which means it does not have a
rigid structure. A number of cancer-causing proteins are disordered.
In
their 15-year search for a new treatment for Ewing’s sarcoma, Toretsky
and his colleagues were the first to make a recombinant EWS-FLI1 fusion
protein. They used it to discover that the fusion protein stuck to
another protein, RNA helicase A (RHA), a molecule that forms protein
complexes in order to control gene transcription. “We believe that when
RHA binds to EWS-FLI1, the combination becomes more powerful at turning
genes on and off,” says the study’s first author, Hayriye Verda
Erkizan, PhD, a postdoctoral researcher in Toretsky’s lab.
Then,
from a library of 3,000 small molecules loaned to Georgetown from the
National Cancer Institute, the researchers searched for a small
molecule that would bind on to EWS-FLI1. They found one, and further
discovered the same molecule, NSC635437, could stop EWS-FLI1’s fusion
protein from sticking to RHA.
This was a wonderful discovery,
Erkizan says, because the notion long accepted among scientists is that
it is not possible to block protein-protein interactions given that the
surface of many of these proteins are slippery - much too flexible for
a drug to bind to. They tested the agent in laboratory cell
culture, and with the help of GUMC’s Drug Discovery Program, the
researchers designed a stronger derivative compound they called
YK-4-279. In this study, they tested YK-4-279 in two different animal
models of Ewing’s sarcoma and found that the agent significantly
inhibited the growth of tumors. There was an 80% reduction in the
growth of treated tumors compared to untreated tumors.
Toretsky
says that while the agent needs to be “optimized,” these results serve
as a proof of principle that inhibiting protein-protein interaction can
work as a novel therapeutic that will target only cancer cells.
“We may be able to use this strategy to attack proteins we thought to be impervious to manipulation,” he says.
The
study was funded by grants from the National Institutes of Health,
Children’s Cancer Foundation of Baltimore, MD, Go4theGoal Foundation,
Dani’s Foundation of Denver, the Liddy Shriver Sarcoma Initiative, the
Amschwand Sarcoma Cancer Foundation, the Burroughs-Wellcome Clinical
Scientist Award in Translational Research, and the GUMC Drug Discovery
Program.
Toretsky and co-authors Milton L. Brown, Aykut Üren
and Yali Kong are inventors on a patent application that has been filed
by Georgetown University related to the technology described in this
paper. The other authors report no related financial interests.
About Georgetown University Medical Center Georgetown
University Medical Center is an internationally recognized academic
medical center with a three-part mission of research, teaching and
patient care (through Georgetown’s affiliation with MedStar Health).
GUMC’s mission is carried out with a strong emphasis on public service
and a dedication to the Catholic, Jesuit principle of cura personalis
-- or "care of the whole person." The Medical Center includes the
School of Medicine and the School of Nursing and Health Studies, both
nationally ranked, the world-renowned Lombardi Comprehensive Cancer
Center and the Biomedical Graduate Research Organization (BGRO), home
to 60 percent of the university’s sponsored research funding.
PharmaMar announced Yondelis® has gained approval for price and reimbursement in Italy
Madrid, 26th January 2009:
PharmaMar announced today that Yondelis® has gained approval for price
and reimbursement in Italy. With this approval, PharmaMar has
successfully finalised negotiations for the price and reimbursement of
Yondelis® with the Italian authorities. Yondelis® will have same price
it has in the rest of European countries.
Once
price and reimbursement approval for Yondelis® has been gained, the
next steps towards the commercialization of the drug in Italy will be
taken soon. This means Yondelis ® may be commercially available to
patients in Italy in the nest weeks.
YONDELIS®
is currently being marketed in the European Union for the treatment of
Soft tissue Sarcoma in adults after the failure of standard therapy.
PharmaMar has started a phase III multicenter study of Yondelis® as
first-line therapy in patients with tumor traslocation, Ewing's
sarcoma, or not rhabdomyosarcomatose soft tissue sarcomas and other
types of STS. Yondelis® is being studied in solid tumors with high
incidence and prevalence in the population, such as prostate, breast
and lung cancer.
Yondelis® has been designated
orphan drug for the treatment of soft tissue sarcomas and ovarian
cancer in the European Union, United States and Switzerland, and for
soft tissue sarcomas in Korea.
According to the
agreement between PharmaMar a subsidiary of Zeltia, S.A- and Ortho
Biotech Products, L.P. a subsidiary of Johnson & Johnson- , under
which Yondelis® is developed, PharmaMar will market Yondelis® in Europe
(including Eastern Europe) and Japan, and Ortho Biotech Products, L.P.
will market Yondelis® in the rest of the world. Both companies filed a
registration dossier to the EMEA and the FDA for Yondelis for the
treatment of refractory ovarian cancer at the end of 2008. At the end
of 2008 both companies submitted a Registration Dossier of Yondelis® in
relapsed ovarian cancer (ROC) to the EMEA and the FDA. A decision on
the approval for this indication is expected to take place during 2009.
Soft tissue sarcomas STS
are a diverse group of more than 50 types of tumours that appear in
fatty tissue, muscle, nerve tissue, tendons and blood and lymph
vessels. Nearly half of them affect the extremities. According to
data from GEIS (Spanish research group in sarcomas) soft tissue
sarcomas (STS) have an incidence of around 3/100,000 new cases per
year, which represents 2% of the overall mortality from cancer. The
highest incidence is situated in patients around 50 years of age. The
five-year survival rate of patients with STS is around 90% when
detected early (stage I), that is, when the tumour is small and with no
metastasis. However, the five-year survival rate in patients with
metastatic disease is 10-20% . The estimated life expectancy in
metastatic patients is 8-12 months after receiving the first line of
cytotoxic therapy.
PharmaMar PharmaMar
is the world-leading biopharmaceutical company of the Zeltia Group,
committed to advancing the treatment of cancer through the discovery
and development of new marine-derived medicines. Yondelis® is the first
Spanish antitumoral compound, currently marketed in the European Union
for the treatment of soft tissue sarcomas in adults after the failure
of standard therapy. Last December 4th, 2008 PharmaMar submitted a
Registration Dossier of Yondelis® in relapsed ovarian cancer (ROC) to
the EMEA. A decision on the approval for this indication is expected to
take place by mid-2009. PharmaMar has four novel compounds in
clinical development: Yondelis® is also in Phase II studies in
prostate, breast and pediatric cancers. Aplidin ®, Zalypsis ®, and
Irvalec ® are new marine-derived agents in clinical development.
PharmaMar also has an extensive portfolio of products in preclinical
research and a sound R&D program.
Important note PharmaMar,
based in Madrid, Spain, is a company of the Zeltia Group (Spanish Stock
Exchange, ZEL) that has been listed on the Spanish Stock Exchange since
1963. This document is a press release, not a brochure. This document
does not constitute nor is it part of any offer or invitation to sell
or issue any application of purchase, offer, or shares subscription of
the Group. Likewise, this document nor its distribution is part or
can be of base for any contract or investment decision and does not
constitute any kind of recommendation in relation with the shares of
the Company.
For further information:
Media Relations (Ph: +34 91 846 60 00) Fernando Mugarza Carlos Martínez de la Serna Carolina Lanzas Otazu
Capital Markets ( Ph: +34 91 444 45 00) Alfonso Hurtado de Mendoza Florencia Radizza
This press release is also available in the News Area of www.pharmamar.com
PharmaMar presents new data of Zalypsis® and Irvalec® in pediatric,
solid tumours and lymphoma at the 20th AACR-NCI-EORTC Symposium
23 October 2008
- Irvalec® and Zalypsis® are two compounds of marine origin, with a novel
mechanism of action, in phase I clinical development for the treatment of
various tumors
- A clinical study of 37 patients with solid tumors or lymphoma shows
Zalypsis has a good safety profile and is highly active. These findings
enable the continuation of Zalypsis clinical development
- Irvalec® shows significant antiproliferative activity in trials against
different tumor cell lines, at doses equivalent to the clinical
administration and higher to those obtained with five other antitumoral
compounds of ErbB pathway
- Two new preclinical studies made in collaboration with the European
Consortium for Innovative Therapies for Children with Cancer (ITCC) show
significant activity of the two compounds in pediatric tumors
- PharmaMar, a company of the Zeltia Group, is presenting data on four
trials during the 20th EORTC-NCI-AACR symposium, held in Geneva from 21- 24
October
Geneva, 23 October, 2008: PharmaMar, a biotechnology company of Zeltia
Group, has presented new data on two antitumoral compounds of marine origin,
Zalypsis® and Irvalec®, in Phase I trials in clinical development and in
vitro studies and with animal models.
Zalypsis® is a novel chemical entity related to the marine natural compounds
Jorumycin and the family of Renieramycins, obtained from molluscs and
sponges, respectively. Irvalec®, a new synthetic depsipeptide derived from
PharmaMar Development Program of marine origin compounds, is a new drug with
antiproliferative activity against a wide range of tumors, including breast,
colon, pancreas, lung and prostate.
PharmaMar has presented the results of 4 studies at the 20th annual
symposium of the European Organization for Research and Treatment of Cancer
(EORTC), the U.S. National Cancer Institute (NCI) and the American
Association for Cancer Research (AACR), taking place in Geneva (Switzerland)
from 21 to October 24.
In the first study, the safety of Zalypsis ® in 37 patients with solid
tumors or lymphoma was evaluated. The trial shows a good safety profile of
the drug, which enables the
continuation of its clinical development. The study was made in
collaboration with the Institut Gustave Roussy (Villejuif, France) and the
Northern Centre for Cancer Treatment (Newcastle, United Kingdom).
The second study presented at the Geneva meeting evaluated the activity of
Irvalec® in of colon cancer, breast, ovarian, lung, prostate, head and neck
and pancreas cell lines. Cytotoxicity data obtained with Irvalec® were
compared with five other compounds that inhibit the Erb-B/HER Pathway.
According to the results, Irvalec® shows a significant antiproliferative
activity at doses that may be achieved in the clinic, being a more potent
inhibitor of cell proliferation than other ErB inhibitors used in the
trials, and showing a differential activity profile. The study was made in
collaboration with the Beaujon University Hospital (Clichy, France).
In two other new studies presented at the meeting in Geneva, PharmaMar
evaluated the therapeutic potential of Irvalec® and Zalypsis® in pediatric
tumors.
The preclinical evaluation of the first compound for the treatment of
pediatric cancer was made against six types of pediatric tumors cell lines
that represent 50% of treatment failures in this population: neuroblastoma,
Ewing's sarcoma, rhabdomyosarcoma, acute lymphoblastic leukemia,
medulloblastoma and osteosarcoma. Osteosarcoma and rhabdomyosarcoma cell
lines were the most sensitive to the drug.
The same methodology was followed for the evaluation of Zalypsis®. The most
significant results in in vitro tests were obtained in neuroblastoma and
rhabdomyosarcoma cell lines. The evaluation of the compound in animal models
also showed significant results, especially in the activity in
rhabdomyosarcoma.
The trials were conducted by the R&D Department of PharmaMar in partnership
with the Emma Children's Hospital (Amsterdam, Netherlands), the University
Children's Hospital (Munster, Germany) and the Institut Gustave Roussy
(Villejuif, France), and members of the Innovative Therapies for Children
with Cancer (ITCC) which brings together 35 centres specializing in
pediatric oncology of six European countries.
The aim of the studies carried out in collaboration with ITCC is to
facilitate the identification of new compounds with significant potential in
the treatment of pediatric tumors.
Within PharmaMar Cancer Research Program and as part of the companys
commitment with cancer patients, this biotech company of the Zeltia Group is
also evaluating the therapeutic potential of its marine origin compounds in
pediatric tumors.
About Zalypsis® (PM00104) Zalypsis® (PM00104/50) is a new marine derived compound in Phase II
clinical trials for the treatment of solid tumours. Zalypsis® is a novel
chemical entity related to the marine natural compounds Jorumycin and the
family of Renieramycins, obtained from molluscs and sponges, respectively.
Zalypsis binds to DNA and is cytotoxic; however, it does not activate the
DNA damage checkpoint response. Thus, Zalypsis has cytotoxic effects
dependent on DNA binding that are not associated with DNA damage. In
pre-clinical trials, Zalypsis demonstrated strong in vitro and in vivo
antitumoural activity in a wide variety of solid and haematological tumour
cell lines and human transplantable breast, gastric, prostate and renal
xenografted tumours. Zalypsis also demonstrated a manageable and reversible
preclinical toxicology profile.
About Irvalec® (PM02734) Irvalec® is a new depsipeptide from PharmaMars internal research
program for derivatives of the marine natural compounds. PM02734 is
manufactured synthetically by PharmaMar. Preliminary in vitro in-house
studies identified PM02734 as a new antiproliferative drug demonstrating
activity against a broad spectrum of tumor types: breast, colon, pancreas,
lung and prostate, among others. PM02734 has been selected for clinical
development based on its in vivo activity in xenografted human tumors, as
well as an acceptable non-clinical toxicology profile. PM02734 is in Phase I
clinical trials in patients with advanced malignant solid tumors.
PharmaMar PharmaMar is the world-leading biopharmaceutical company of the Zeltia
Group, and is committed to advancing the treatment of cancer through the
discovery and development of new marine-derived medicines. PharmaMar has
four novel compounds in clinical development. Yondelis® has received
Authorization for Commercialization from the European Commission for
treating advanced soft tissue sarcoma. Yondelis® is currently being marketed
in the European Union for the treatment of soft tissue sarcomas in adults
after failure of standard therapy. Aplidin®, Zalypsis®, and Irvalec® are
other marine-derived new agents in clinical development by PharmaMar, which
also has a rich pipeline of preclinical candidates, and a strong R&D
program.
For further information:
Media Relations (Ph: +34 91 846 60 00)
Fernando Mugarza
Carlos Martínez de la Serna
Carolina Lanzas Otazu
Capital Markets (Ph: +34 91 444 45 00)
Alfonso Hurtado de Mendoza
Florencia Radizza
This press release is also available in the News area at www.pharmamar.com
Neotropix® Announces
Presentation of Relevant Preclinical Results of NTX-010 in Pediatric Oncology
Models
Malvern, PA, October 22, 2008 Neotropix®,
Inc., a clinical-stage development company focused on neuroendocrine cancer
treatments, announced today exciting data from an extensive pediatric
preclinical study performed by the National Cancer Institute (NCI) funded
Pediatric Preclinical Testing Program on the use of NTX-010 (Seneca Valley
Virus-001), a tumor-selective naturally-occurring oncolytic virus. The results
support the initiation of clinical development of Neotropixs lead candidate,
NTX-010 for the treatment of pediatric cancers. NTX-010 has been developed as a
cancer therapeutic to treat some of the most aggressive cancers known which
occur in adults including small cell lung cancer, large cell non-small cell lung
cancer, as well as other adult cancers such as carcinoid and various
neuroendocrine cancers.
The detailed study results are being presented at the 20th
AnnualMolecular Targets and Cancer Therapeutics International Meeting
in Geneva, Switzerland from October 21-24, 2008. The meeting is hosted jointly
by the European Organization for Research and Treatment of Cancer (EORTC), the
National Cancer Institute (NCI), and the American Association for Cancer
Research (AACR).
The Pediatric Preclinical Testing Program (PPTP) presentation
described encouraging results from an extensive evaluation of NTX-010 in over 30
different tumor models representing the most common types of childhood solid
tumors. Extensive analysis has previously determined that these carefully
selected models, many derived directly from patients tumors, are predictive of
clinical activity and an important tool for screening promising new drug
candidates for their relevance for specific childhood cancers. The PPTP results
indicated that NTX-010 was active against a wide range of pediatric solid
cancers, including neuroblastoma, rhabdomyosarcoma, Wilms tumors, rhabdoid,
Ewing sarcoma and glioblastoma. Complete responses were observed following a
single intravenous treatment in the majority of neuroblastoma models and in all
alveolar rhabdomyosarcoma tumor models, demonstrating both activity and potency.
Paul Hallenbeck, Ph.D., President and Chief Scientific Officer
of Neotropix®, Inc., commented, "We are very encouraged by the results of this
extensive analysis of NTX-010 in pediatric oncology models, particularly because
these in vivo cancer models that the NCI has developed can
prospectively identify novel agents subsequently shown to have clinical activity
against specific cancers of children and adolescents.
Dr. Hallenbeck continued, We are excited that the
NCI-supported Childrens Oncology Group Phase I Consortium has expressed the
interest to lead an effort to test NTX-010 in pediatric patients with cancer in
the near future.
Neotropix® has been working closely with many collaborators around the world,
including the NCI to create a treatment paradigm shift for hard to treat
cancers. The Company has developed an innovative approach to harness the power
of natural products screening using viruses to kill or slow down the spread of
cancer. The result has been that many viruses have been identified that may
provide simple, safe and effective ways to treat patients who would otherwise
fail conventional treatments using traditional small molecule and antibody
approaches.
About NTX-010 and the Current Clinical Trial
NTX-010 is a natural occurring oncolytic virus, which is highly selective for
certain tumor cell types expressing a biomarker that indicates the cancer has
neuroendocrine properties such as synaptophysin, chromogranin A, or CD56. At
least one of them is required to be positive before treatment. Unlike many
previous oncolytic virus product candidates developed by others, NTX-010 is a
stable, naturally occurring virus, is systemically deliverable, and has not been
observed to be pathogenic to humans, and therefore, has not had to be
genetically modified.
NTX-010 is systemically delivered in a single one-hour
infusion on an outpatient basis at each of the treatment centers, which
simplifies the treatment process for patients. The product is anticipated to
have enhanced efficacy and less toxicity than currently approved therapies for
permissive cancers.
The clinical trial is being conducted at multiple institutions
around the country, including John Hopkins (MD), Mary Crowley (TX), Lahey Clinic
(MA) and many U.S. Oncology Cooperative Group treatment sites (FL, IN, NY, OH,
SC, TX, VA, and WA). In addition, other treatment centers are joining the trial
in the New England area of the U.S.
The current Phase I / II clinical trial is enrolling adults
(18 and over) that meet the criteria for the following cancers: carcinoid
cancers (all types), large cell lung cancer-neuroendocrine, alveolar rhabdomyosarcoma,
neuroblastoma, glioblastoma, Ewings family of tumors, Wilms tumors,
retinoblastoma, rhabdoid, and medulloblastoma. For more about the clinical
trials:
www.clinicialtrials.gov
Also of note, CEO Peter Lanciano of Neotropix®
will be available for one-on-one meetings with potential investors at
the 7th Annual BIO Investor Forum that is taking place from October 29-31, 2008,
in San Francisco, CA. At the conference, Mr. Lanciano will present a corporate
overview on the Company. For more information, please visit:
www.investorforum.bio.org
About Neotropix®
Neotropix® Inc., is focused on the development of anti-cancer
products that have a high degree of selectivity for cancer cells resulting in an
excellent safety and therapeutic efficacy profile. Neotropix® develops and
commercializes systemically deliverable oncolytic viruses for the treatment of
solid tumors. Capitalizing on its unique sources of naturally occurring viruses
that selectively target tumors discovered using the companys proprietary
technology platform Viruscreen, the Company has the knowledge and skills to
translate these discoveries into commercial products. Neotropix® is committed
to making a difference in the lives of cancer patients.
Neotropix® commenced operations in 2005 in Malvern,
Pennsylvania. Neotropix ® is funded by venture-capital investors including
Aurora Funds, Quaker BioVentures and VIMAC Ventures. For more information,
please visit
http://www.neotropix.com
About the Pediatric Preclinical Testing Program
The NCI-supported Pediatric Preclinical Testing Program (PPTP) is a
comprehensive program to systematically evaluate new agents against childhood
solid tumor and leukemia preclinical models. The PPTP is supported through an
NCI research contract to St. Jude Childrens Research Hospital (SJCRH) with Dr.
Peter Houghton as the Principal Investigator. Testing occurs both at SJCRH and
also at subcontract sites that have expertise in specific childhood cancers,
including: Childrens Hospital of Philadelphia (John Maris), Albert Einstein
Medical Center (E. Anders Kolb & Richard Gorlick), Duke University (Stephen Keir),
Texas Tech University Health Sciences Center (Patrick Reynolds), and Childrens
Cancer Institute Australia (Richard Lock). Detailed information about the PPTP
and its testing procedures is available at
http://www.pptp.stjude.org.
FDA Approves Orphan Drug Status for Revolutionary
Cancer Drug for Children
LOS ANGELES, Calif.
– October 20, 2008 – The Cure Our
Children Foundation, a nonprofit charitable foundation dedicated to children,
announced today that the U.S. Food and Drug Administration (FDA) has approved
the Orphan Drug Designation of the foundation’s unique drug product for children
with Ewing’s Sarcoma cancer.The efforts
to develop this drug were made possible by the generous volunteers and researchers
in private industry and at two universities.
Orphan Drug status allows for
recognition of the potential viability of a drug therapy while providing a
variety of benefits during the drug approval process.These benefits include waivers of certain FDA
fees, the availability of government grants, and FDA attention and assistance
during the review process.
This ground-breaking new drug
combines two modern technologies: biotechnology and nanotechnology.This incredible technology is analogous to
the concept of a Trojan Horse, and is expected to have very far reaching
implications for other cancer treatments.The product consists of cell matter that is modified to have the same
genetic code as the cancer cells, but that matter is not viable food for the tumor
cells.The cell matter is then placed in
a nanotechnology formulation which allows the matter to migrate through the
body’s own vessels directly to the tumor cells.When the tumor cells uptake the matter, they cannot reproduce, and they
die.Key elements of this drug technology are:
·Fewer side effects may be possible
·The drug is directed only at the tumor cell and not at healthy cells
·The product is so small that it migrates right through blood vessels
and cell walls
·This technology may be applied to other diseases in the future that
have a genetic component
The
President of the foundation, Barry Sugarman, a 30-year veteran executive and
consultant in the pharmaceutical industry, and father of a son who has survived
Ewing’s Sarcoma, will continue the development
of the drug product by raising money from individuals and foundations.
The
Cure Our Children Foundation identifies important under-researched children's
issues and devotes extensive resources to educate and guide parents,
professionals, government and the public.The foundation website at www.cureourchildren.org
receives thousands of website visits every month.The results of the research are provided as a
public service, and are supported by donations to the foundation.The foundation has a number of other research
projects underway that will continue to benefit children and families.
Contact:Barry Sugarman, B.S.ENGR., President, The
Cure Our Children Foundation, mailto:barry@cureourchildren.org ,Phone: 310-355-6046, Fax: 310-454-9592,
http://www.cureourchildren.org
Requests for reprints: Crystal L. Mackall,
Pediatric Oncology Branch, Center for Cancer Research, National Cancer
Institute, NIH, 10-CRC/1W-3940, 10 Center Drive, MSC 1104, Bethesda, MD
20892-1104. Phone: 301-402-5940; Fax: 301-451-7052; E-mail Crystal L. Mackall: cm35c@nih.gov
Immunotherapy in High-Risk Pediatric Sarcomas including
Ewing's Sarcoma Shows Promising Response
August 1, 2008
PHILADELPHIA - Based on a pilot study in children with sarcoma,
researchers at the National Institutes of Health (NIH) believe that
immunotherapy could prove beneficial in treating high-risk forms of
this cancer.
The researchers tested a novel dendritic vaccine as well as a
standard flu vaccine to potentially strengthen the immune system post
chemotherapy. Their findings, published in the August 1 issue of Clinical Cancer Research,
a journal of the American Association for Cancer Research, show that
although the dendritic vaccine they tested did not perform as well as
hoped, children participating in the study responded well to the
standard flu vaccine- suggesting that a strategy to bolster immune
function in these patients holds promise for fighting their cancer.
Researchers also found that survival in these patients was at the
higher end of what is generally seen with recurrent and/or metastatic
Ewing's sarcoma (ESFT) or alveolar rhabdomyosarcoma (AR) - the two
sarcomas tested in this single arm study. The 22 enrolled patients who
did not receive immunotherapy had a 31 percent five-year overall
survival, compared to 43 percent five-year survival in 30 patients who
ultimately received the novel immunotherapy.
Although the study is small, these early findings are promising,
says the study's senior investigator, Crystal Mackall, M.D., of the
National Cancer Institute's (NCI) Pediatric Oncology Branch. "We need
new therapies. While outcomes overall for these tumors have improved
during the past 40 years, there has not been substantial improvement
for patients with metastatic or recurrent disease. This study shows
that immunotherapy is safe and well tolerated, and could ultimately be
beneficial for this high risk population. Mackall calls the study a
rational approach to improving treatment of ESFT and AR. "We now know
that the immune system of patients recovering from chemotherapy is
malleable, so we just need to find the best immunologic approach to
exploit this window of opportunity," she said.
Both ESFT and AR develop due to chromosomal translocations, which
fuse a gene from one chromosome to a different chromosome. The
dendritic vaccine included peptides derived from each patient's
individual cancer in a way that was designed to alert a patient's
immune system to the unique genetic alteration on the cancer cells.
In this clinical trial of 52 patients, researchers attempted to use
immunotherapy as "consolidation" therapy - that is, after standard
therapy provided a remission. Patients underwent aphaeresis to harvest
blood lymphocytes that were then frozen. From this, dendritic cells
were later extracted. These are cells that present an antigen to T
cells and other immune system fighters in order to elicit a response.
All patients then had chemotherapy, radiation or surgery, as
appropriate, and in some cases a stem cell transplant to induce
remission. The 30 patients who initiated immunotherapy received a
common flu vaccine, as well as their own lymphocytes and their own
dendritic cells, which had been infused with tumor antigens. Some of
these patients also received interleukin-2, which stimulates activity
of T cell lymphocytes.
"The good news was the surprisingly nice T cell response patients
had to the flu vaccination, even relatively soon after completing
chemotherapy," Mackall said. "That shows that the general idea of using
immunotherapy following chemotherapy to prevent recurrence is not a
flawed one. Chemotherapy depleted the immune system, but we could
restore it."
The bad news, she added, is that the dendritic vaccine "was not very
immunogenic. We have a long way to go to optimizing this vaccine."
Current studies are underway to test a new version of the vaccine,
which utilizes more mature dendritic cells and tumor lysate in lieu of
the translocation peptides. Ultimately, effective immunotherapy
requires that one is capable of reproducing a strong and sustained
immune response to tumor antigens," she said.
Mackall also notes that the vaccine in this trial was tested in
patients whose cancer had recurred or metastasized. If the favorable
safety profile continues and the efficacy of the vaccine is improved
with the subsequent versions, one could ultimately consider the use of
immunotherapy to consolidate remission in lower risk populations.
# # #
The mission of the American Association for Cancer Research is to
prevent and cure cancer. Founded in 1907, AACR is the world's oldest
and largest professional organization dedicated to advancing cancer
research. The membership includes more than 28,000 basic, translational
and clinical researchers; health care professionals; and cancer
survivors and advocates in the United States and 80 other countries.
AACR marshals the full spectrum of expertise from the cancer community
to accelerate progress in the prevention, diagnosis and treatment of
cancer through high-quality scientific and educational programs. It
funds innovative, meritorious research grants. The AACR Annual Meeting
attracts more than 17,000 participants who share the latest discoveries
and developments in the field. Special conferences throughout the year
present novel data across a wide variety of topics in cancer research,
treatment and patient care. AACR publishes five major peer-reviewed
journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention. Its most recent publication and its sixth major journal, Cancer Prevention Research, is dedicated exclusively to cancer prevention, from preclinical research to clinical trials. The AACR also publishes CR, a magazine for cancer survivors and their families, patient advocates, physicians and scientists. CR
provides a forum for sharing essential, evidence-based information and
perspectives on progress in cancer research, survivorship and advocacy.
Phase I/II Study of Targeted Gene Delivery In Vivo - Intravenous Infusions of REXIN-G - Demonstrates Dose-Dependent Anti-Tumor Activity Without Toxicity in Patients With Progressive Chemo-Resistant Bone and Soft Tissue Sarcoma (ASCO 2008)
Phase I/II Study of Targeted Gene Delivery In
Vivo - Intravenous Infusions of REXIN-G - Demonstrates Dose-Dependent
Anti-Tumor Activity Without Toxicity in Patients With Progressive
Chemo-Resistant Bone and Soft Tissue Sarcoma (ASCO 2008)
SAN MARINO, Calif., May 29, 2008 -- Epeius Biotechnologies
(http://www.epeiusbiotech.com)
announced today the results of an on-going Phase I/II study of Rexin-G
for metastatic bone and soft tissue sarcoma (J Clin Oncol 26: 14509,
2008). Rexin-G is the first and so far only targeted gene therapy
vector that has been tested in the clinic (Nature Reviews/Genetics
2007). In this open label study, cohorts of 6 to 7 patients with all
types of sarcoma, including osteosarcoma, Ewing's sarcoma,
leiomyosarcoma, malignant fibrous histiocytoma, chondrosarcoma,
fibrosarcoma, liposarcoma, angiosarcoma, spindle cell sarcoma, and
malignant mixed Mullerian tumor of ovary, were treated with 1 x 10e11
cfu Rexin-G, administered i.v. over 5 minutes, 2 times a week for 4
weeks (Cumulative Dose = 8 x 10e11 cfu) followed by a 2-week rest
period. Patients with Grade 1 or less toxicity were given progressive
intra-patient dose-escalations consisting of additional treatment
cycles of 1 to 2 x 10e11 cfu three times a week for 4 weeks (Cumulative
Dose per cycle: 1.2-2.4 x 10e12 cfu).
These higher dosing regimens were associated with prolonged disease
stabilization and a median overall survival of greater than 6 months,
which was three times longer than that observed in the low-dose group.
Further, histologic examination of resected tumors showed 50-90%
necrosis. No dose-limiting toxicity was observed, even at the higher
doses of Rexin-G, thus confirming that repeated infusions of Rexin-G
are safe and well-tolerated. Taken together with previous clinical
studies conducted in the Philippines and Japan, these studies confirm
the exemplary safety and dose-dependent efficacy of Rexin-G in a broad
spectrum of chemotherapy-resistant cancers.
For more information about Rexin-G, on-going clinical trials in
the USA and abroad, and/or Epeius pathotropic (disease-seeking) gene
delivery systems, please contact Dr. Erlinda M. Gordon at . egordon@epeiusbiotech.com
CONTACT: Erlinda M. Gordon, M.D., of Epeius Biotechnologies Corporation,+1-626-441-6695, egordon@epeiusbiotech.com
ADVIGO CP-751,871 Global Phase III Clinical Trial Program
Initiated (ADVancing IGF-1R in Oncology)
2008 ASCO Annual Meeting
CHICAGO--Pfizer announced today results from several clinical trials further
describing the activity of its investigational compound CP-751,871 in
non-small cell lung cancer (NSCLC) and Ewing’s
Sarcoma, both diseases with high unmet medical need. The three oral
presentations and one poster discussion underscore that the insulin-like
growth factor receptor (IGF-1R) is increasingly recognized by the
medical community as a relevant target for investigation in cancer
research. The results were presented at the 44th
Annual Meeting of the American Society of Clinical Oncology (ASCO) in
Chicago, IL.
Updated Response Data from the 1002 NSCLC Trial
Updated study results from a Phase II, randomized, non-comparative study
showed 54 percent of patients with Stage III/IV treatment-naïve
NSCLC receiving the combination CP-751,871 plus carboplatin and
paclitaxel (n=97) experienced objective responses. The response rate
observed for patients treated with carboplatin and paclitaxel alone was
41 percent.
Of note, 78 percent of a subset of patients with squamous cell carcinoma
(n=23) and 57 percent of a subset of patients with adenocarcinoma (n=28)
receiving 20 mg/kg of CP-751,871 plus carboplatin and paclitaxel
experienced objective responses. Response rates were 46 percent and 25
percent, respectively, for squamous cell (n=13) and adenocarcinoma
patients (n=20) receiving carboplatin and paclitaxel alone. No response
advantage with CP-751,871 was seen in a subset of patients with
undifferentiated tumors (Not otherwise specified, NOS).
“Patients with advanced NSCLC typically face a
poor prognosis and we need to develop new strategies and new treatment
combinations to improve their survival,” said
lead investigator Daniel Karp, M.D., director of the M.D. Anderson
Cancer Center Clinical and Translational Research Center (CTRC). “The
updated study results add to our growing understanding of the potential
safety and efficacy of CP-751,871. In this trial, increasing the dose to
20 mg/kg in Stage 2 of the trial resulted in an increased overall
response rate in all differentiated histologies, including
adenocarcinoma, non-adenocarcinoma, and particularly in squamous
histologies, which we consider to be of interest for future study.”
Dr. Karp also presented progression-free survival (PFS) results from the
study. At the dose level of 20 mg/kg, the observed progression-free
survival was 5 months in the CP-751,871 plus carboplatin/paclitaxel arm
and 4 months in the carboplatin/paclitaxel only arm. The highest
observed PFS was in the group of patients with squamous histologies (5.6
months in the CP-751,871 plus carboplatin/paclitaxel arm and 4.3 months
in the carboplatin/paclitaxel only arm) corresponding to the patients
that demonstrated the highest response rates. PFS was defined as either
the length of time before the cancer progressed or death.
In this study, CP-751,871 was generally well tolerated. The most common
Grade 3 or 4 side effects reported were hyperglycemia (increased blood
sugar) (20 percent) and neutropenia (30 percent).
Correlative Science Study Results Support Karp Data
This abstract summarized ancillary studies conducted to investigate the
molecular make up of lung tumors and its relevance to anti-IGF-IR
therapy. Members of the IGF-IR pathway appear to be expressed
differentially across lung tumor histologies which may help to explain
the differential activity of CP-751,871 across these histologies. Tumor
differentiation also appears to play a role. Data were also presented
demonstrating that EGFR inhibition sensitizes tumors to CP-751,871
treatment.
“These results help us to understand better
how CP-751,871 works, provide support for our phase III trial strategy
and underscore Pfizer’s commitment to bring
science and innovation to the forefront of drug development,”
said Antonio Gualberto, M.D., Ph.D., Global Clinical Lead for the
CP-751,871 program, Pfizer Global Research and Development.
ADVIGO Phase III Registration
Program (ADVancing IGF-IR in Oncology)
Based on these data, Pfizer has initiated a large global Phase III
clinical trial program for CP-751,871 in NSCLC, including some studies
with patients with non-adenocarcinoma (ADVIGO 1016, ADVIGO 1018). The
program includes trials for patients who are newly diagnosed and for
those who have already been treated with other therapies.
Pfizer has made a major commitment to CP-751,871 and has invested
significant resources in the Phase III program, which will include more
than 2,000 patients around the world.
Preliminary Data Presented on CP-751,871 in Sarcoma
Phase I data presented at ASCO showed single agent CP-751,871 was
generally well-tolerated in patients with relapsed or refractory sarcoma
(n=22), including Ewing’s sarcoma (n=9). A
response of stable disease or better was seen in 12 out of 20 evaluable
patients, including one confirmed partial response in a 12-year-old
patient with Ewing’s sarcoma, the second most
common malignant bone tumor in young patients and the most deadly bone
tumor.
CP-751,871 was generally well tolerated in patients with relapsed or
refractory sarcoma. Grade 3 or 4 treatment-related side effects reported
included Grade 4 uric acid increase (n=1) and Grade 3 bilateral
deep-vein thrombosis (n=1).
About CP-751,871
CP-751,871, a fully human IgG2 monoclonal antibody, is a highly specific
inhibitor of the IGF-1R pathway. It is believed that through this
inhibition, CP-751,871 blocks one of the key signaling pathways in
cancer cells that lead to uncontrolled growth and survival of tumor
cells.
Pfizer recently initiated a global Phase III clinical trial registration
program for CP-751,871 in non-adenocarcinoma NSCLC. In addition, Pfizer
is studying CP-751,871 in clinical trials for the treatment of many
other cancers, including prostate, breast and colon cancers and Ewing’s
sarcoma. To date, more than 500 patients have participated in CP-751,871
clinical trials in multiple tumor types.
About Pfizer Oncology
Pfizer Oncology is committed to the discovery, investigation and
development of treatments and currently has 22 innovative compounds in
clinical development across four platforms. By leveraging the strength
of our resources and scientific talent, Pfizer Oncology strives to
discover and develop novel treatment options to improve the outlook for
oncology patients. Pfizer currently devotes more than 22 percent of its
total R&D budget to the field of oncology, investing annually in
worldwide research initiatives. We also partner with healthcare
providers, governments and local communities around the world to provide
better quality healthcare and health system support.
DISCLOSURE NOTICE: The information contained in this release is as of
June 2, 2008. Pfizer assumes no obligation to update any forward-looking
statements contained in this release as the result of new information or
future events or developments.
This release contains forward-looking information about a product
candidate, CP-751,871, including its potential benefits, that involves
substantial risks and uncertainties. Such risks and uncertainties
include, among other things, the uncertainties inherent in research and
development; decisions by regulatory authorities regarding whether and
when to approve any drug applications that may be filed for such product
candidate as well as their decisions regarding labeling and other
matters that could affect its availability or commercial potential; and
competitive developments.
A further description of risks and uncertainties can be found in
Pfizer’s Annual Report on Form 10-K for the
fiscal year ended December 31, 2007 and in its reports on Form 10-Q and
Form 8-K.
Contacts
Pfizer Inc Media: Vanessa Aristide, 917-697-0481 or
212-733-3784 or Investors: Jennifer Davis, 212-733-0717
More Frequent Chemotherapy Improves Outcome for Ewing’s Sarcoma Patients Results of Children's Oncology Group Study Protocol No. AEWS0031
ORAL PRESENTATION Lead Author: Richard B. Womer, MD
American Society for Clinical Oncology Annual Meeting http://www.asco.org
SATURDAY, MAY 31, 3:00 PM (CDT) Children’s Hospital of Philadelphia
W375b Philadelphia, PA
Investigators from the Children’s Oncology Group (COG) have found for the first time that giving combination chemotherapy every two weeks is more effective than the same therapy given every three weeks in patients with Ewing’s sarcoma, without increasing side effects.
“These findings are convincing enough to change the standard of care for patients with localized Ewing’s sarcoma,” said lead author Richard B. Womer, MD, senior oncologist and professor of pediatrics at the Children’s Hospital of Philadelphia and the University of Pennsylvania School of Medicine. “This study shows that progress against Ewing’s sarcoma can be made by giving commonly used anti-cancer drugs in new ways.”
Ewing’s sarcoma is a cancer that most often develops in the bones but can also form in soft tissue. It is generally diagnosed in children. Until this study, the standard treatment for this cancer included chemotherapy with the drugs vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide given every three weeks, as well as surgery and/or radiation therapy. With the development of better ways to bolster the immune and blood-forming systems of the body—enabling patients to tolerate more frequent chemotherapy—researchers seeking to improve treatments for several types of cancer have hypothesized that giving chemotherapy more frequently might be more effective than conventional approaches, without causing undue side effects.
In this study, researchers at 160 COG institutions sought to determine if giving the same five drugs every two weeks was more effective than giving them every three weeks in patients with Ewing’s sarcoma who were younger than 50 and had not yet had chemotherapy or radiation therapy. Primary treatment (surgery, radiation therapy, or both) began 13 weeks after chemotherapy was initiated. Event-free survival (the percentage of patients who did not die or experience a relapse or second cancer) was compared between 284 patients who received chemotherapy every two weeks and 284 who received the same regimen every three weeks. Patients in both groups received a total of 14 cycles of chemotherapy.
After a median follow-up of three years, event-free survival was 76 percent among the patients who received chemotherapy every other week, compared with 65 percent among those who received chemotherapy every three weeks. The incidence and severity of side effects remained similar between the two groups. Fever with low white blood cell count occurred in 7 percent
of those in the two-week arm and 6 percent of those in the three-week
arm; the incidence of infection was 4.8 percent and 4.6 percent,
respectively.
Abstract #10504
Randomized comparison of every-two-week v. every-three-week
chemotherapy in Ewing sarcoma family tumors (ESFT). R. B. Womer, D. C.
West, M. D. Krailo, P. S. Dickman, B. Pawel, E. for the Children's
Oncology Group AEWS0031 Committee
Background: Chemotherapy with
alternating cycles of vincristine-doxorubicin-cyclophosphamide and
ifosfamide-etoposide, and primary tumor treatment with surgery and/or
radiation therapy, is the usual approach to localized ESFT in North
America. We conducted a trial asking whether chemotherapy
intensification through interval compression could improve outcome.
Methods: This was a prospective
randomized-controlled trial for patients less than 50 y old with
extra-dural ESFT, without distant metastases or prior chemotherapy or
radiation therapy; and with adequate renal, cardiac, and hepatic
function. Patients were treated with vincristine (2 mg/sq.m, max. 2
mg), doxorubicin (75 mg/sq.m) and cyclophosphamide (1.2 g/sq.m)
alternating with ifosfamide (9 g/sq.m) and etoposide (100 mg/sq.m/),
for 14 cycles, with filgrastim (5 mg/kg/day, maximum 300 mg) between
cycles. Patients assigned to Regimen A were scheduled to begin
chemotherapy cycles every 21 days, and patients assigned to Regimen B
were scheduled to begin cycles every 14 days, or when ANC > 750 and
platelets > 75. Primary tumor treatment (surgery, radiation, or
both) was scheduled to begin week 13 (after 4 cycles in Regimen A and 6
cycles in Regimen B). The primary endpoint was event-free survival
using a two-sided log-rank test with size 0.05 and power 0.8 to detect
a 13% Embargoed Until May 15, 2008 at 9:00pm (EDT) 12 change in EFS
from 60%, with 264 patients in each arm.
Results: 587 patients were
enrolled and randomized, and 568 were eligible, 284 in each regimen.
For all courses, the median cycle interval for Regimen A was 21 days,
mean 23.3 days; in Regimen B, the median interval was 15 days, mean
18.5 days. Event-free survival at a median of 3 years was 65% in
Regimen A and 76% in Regimen B, p=0.028. The occurrence of specific
toxicities and the number of hospital days were similar for the two
regimens.
Conclusions: Every-2-week chemotherapy is more effective than every-three-week chemotherapy for localized ESFT, with no increase in toxicity.
Disclosures for Research Team: Nothing to disclose.
BETHESDA,
Md., Mar 20, 2008 (BUSINESS WIRE) -- ZIOPHARM Oncology, Inc.
(NASDAQ:ZIOP) announced today that it presented promising early data
from a Phase Ib study of indibulin, the Company's novel, orally
administered, synthetic tubulin targeted agent, at the 6th
International Symposium on Targeted Anticancer Therapies held in
Bethesda, Maryland, March 20 to 22.
A
total of 14 patients with a variety of cancers, including sarcomas and
carcinomas, have been treated to date in the study. Following a total
of 30 cycles of treatment, indibulin has been shown to be very well
tolerated, with no drug-related Grade 2 or higher toxicities reported.
Of note, no neurotoxicities, a common and serious side effect typically
associated with microtubule targeting agents, have been observed.
In
addition to confirming indibulin's safety profile, this study evaluates
early treatment responses by PET scans. Among 8 evaluable patients,
these PET scans demonstrated a substantial anti-tumor effect by
indibulin. Week 7 PET scans identified 1 complete reduction in uptake,
4 with partial reduction in uptake, and 3 with increased uptake. Tumor
responses measured by PET scan are generally referred to as metabolic
responses, and usually correlate with treatment responses in cancer.
"Safely
and effectively targeting microtubules in cancer cells has long been a
goal of researchers as it leads to a variety of anti-cancer activity,
including antiangiogenesis and antimetastasis," commented Sant P.
Chawla, MD, Director, Sarcoma Oncology Center and a lead investigator
of the study. "Yet to date, these agents have all demonstrated serious
side effects. Oral indibulin, by contrast, has been very well
tolerated, with none of the neurotoxicity or bone marrow suppression
seen with taxanes and vinca alkaloids. Indibulin has also demonstrated
promising early activity by PET scan, including a complete response in
Ewing's Sarcoma and a partial response in a neuroendocrine cancer.
Taken together, these results are highly compelling, making ongoing
study a priority."
Indibulin
is a novel synthetic anti-mitotic agent that binds to tubulin,
destabilizes microtubule polymerization, arrests tumor cell growth at
the G2/M phase and inhibits cell mobility and metastasis. Microtubules
are well-established targets for anti-cancer drug development and
tubulin-binding drugs such as taxanes and vinca alkaloids are currently
widely used to treat cancer. Indibulin is orally available, lacks
neurotoxicity and has efficacy in taxane refractory preclinical models.
About ZIOPHARM Oncology, Inc.
ZIOPHARM Oncology, Inc. is a
biopharmaceutical company engaged in the development and
commercialization of a diverse, risk-sensitive portfolio of in-licensed
cancer drugs to address unmet medical needs. The Company applies new
insights from molecular and cancer biology to understand the efficacy
and safety limitations of approved and developmental cancer therapies
and identifies proprietary and related molecules for better patient
treatment. For more information, visit www.ziopharm.com.
Forward-Looking Safe Harbor Statement:
This
press release contains forward-looking statements for ZIOPHARM
Oncology, Inc. that involve risks and uncertainties that could cause
the Company's actual results to differ materially from the anticipated
results and expectations expressed in these forward-looking statements.
These statements are based on current expectations, forecasts and
assumptions that are subject to risks and uncertainties, which could
cause actual outcomes and results to differ materially from these
statements. Among other things, there can be no assurance that any of
the Company's development efforts relating to its product candidates
will be successful, or such product candidates will be successfully
commercialized. Other risks that affect forward-looking information
contained in this press release include the possibility of being unable
to obtain regulatory approval of the Company's product candidates, the
risk that the results of clinical trials may not support the Company's
claims, and risks related to the Company's ability to protect its
intellectual property and its reliance on third parties to develop its
product candidates. The Company assumes no obligation to update these
forward-looking statements, except as required by law.
Amgen Presents Preclinical and Clinical Data from Oncology Programs Early Data Presented from Investigational Molecules that Target Apoptosis and Growth Regulation Pathways
SAN DIEGO--(BUSINESS WIRE)--April 15, 2008--Amgen (NASDAQ:AMGN)
today announced data generated by the company's robust oncology
research and development programs in the areas of apoptosis
(programmed cell death) and cell growth regulation. The data,
presented at the American Association for Cancer Research (AACR)
Annual Meeting in San Diego were from five preclinical studies
evaluating anti-tumor activity, pharmacodynamics, and potential
pre-clinical and clinical biomarkers for investigational molecules AMG
655, AMG 479 and AMG 102.
"We are excited to be pushing the boundaries of knowledge around
known oncology pathways such as apoptosis and growth regulation by
exploring new and innovative approaches to attack tumor cells," said
David Chang, M.D., vice president, Global Oncology Development at
Amgen. "While still early, we are pleased to be presenting a broad
spectrum of data at this meeting reinforcing the biologic plausibility
of targeting newly-discovered approaches to attack cancer via these
pathways."
Targeting Apoptosis via Death Receptors
AMG 655 is an investigational fully human monoclonal antibody
(mAb) agonist directed against death receptor 5 (DR5). AMG 655 is
designed to activate caspases and induce apoptosis in sensitive tumor
cells.
Apoptosis is a form of cell suicide in which a controlled sequence
of biochemical events leads to cell death. In cancer, the
dysregulation of apoptosis is critical in the development and survival
of tumors. Apoptosis can be triggered by cell stress and DNA damage,
but it also occurs normally during development of the body.
Data presented at AACR showed that, when combined with the
chemotherapeutic agent gemcitabine, AMG 655 enhanced apoptosis in both
in vitro, and in vivo, pancreatic cancer models. The combination of
AMG 655 and gemcitabine was more effective in these models than either
agent alone.
In another study, AMG 655 was combined with a chemotherapeutic
agent (irinotecan or 5-fluorouracil (5-FU)) enhanced apoptosis
relative to either agent alone in both in vitro and in vivo colon
cancer cell models. AMG 655 is currently being tested against
colorectal cancer in a Phase 1b/2 clinical trial.
In a third study, positron emission tomography (PET) was evaluated
for its potential as a non-invasive method to measure receptor
occupancy of DR5, the target of AMG 655. The preclinical results
support the potential of using PET for imaging DR5 positive tumors and
measuring receptor occupancy in patients. This imaging technology also
is being applied to the study of other antibodies in the Amgen
pipeline.
Targeting Growth Regulation in Cancer
AMG 479 is an investigational fully human monoclonal antibody that
binds to insulin-like growth factor-1 receptor (IGF-1R) without
cross-reacting with the closely related insulin receptor.
IGF-1 and IGF-2 activate the IGF-1R receptor, which is expressed
in many human cancers. The expression of IGF-1 mediates tumor
proliferation and reduces apoptosis and is associated with higher
incidences and more aggressive progression of many common cancers.
Activation of these growth and survival pathways may allow tumor
cells to resist the apoptosis-inducing activity of chemotherapy,
radiation, and hormonal therapy and can increase cellular
proliferation.
The preclinical data presented showed that AMG 479 inhibited more
than 80 percent of IGF-1 induced growth activation in certain sarcoma
cell line. Treatment of these cell lines with a combination of AMG 479
and cyclophosphamide resulted in significant (p=0.0020 vs. AMG 479,
p=0.0002 vs. cyclophosphamide) tumor growth inhibition compared to
either treatment alone. AMG 479 is currently in phase 2 Ewing's
sarcoma trial.
AMG 102
AMG 102 is an investigational fully human monoclonal antibody that
targets the action of anti-hepatocyte growth factor (HGF)/scatter
factor (SF). HGF signaling through its receptor c-Met appears to play
an important role in many types of human cancers.
The HGF/SF:c-Met pathway mediates a large number of normal
activities in cells of epithelial origin - including proliferation,
survival, migration, and invasion. The dysregulation of the
HGF/SF:c-Met pathway appears to play an important role in many types
of cancers, often leading to tumorigenesis and metastasis.
The data presented at AACR examined exploratory biomarkers that
might be useful pharmacodynamic or patient enrichment markers for
HGF/SF:c-Met therapies like AMG 102. Preclinical glioblastoma tumor
xenograft models were treated with a single dose of AMG 102 ranging
from 3- 300 ug IP. On days 3 and 7 after treatment initiation, plasma
was harvested and levels of tumor-derived total human HGF, soluble
human c-Met and CD44v6 (a c-Met associated protein) were quantified.
Plasma samples from patients enrolled in the AMG 102 first-in-human
trial were also examined. Total HGF and soluble c-Met levels were
determined in plasma from patients in sequential dose cohorts (4-6
pts/cohort) that had been treated with AMG 102 at 0.5, 1, 3, 5, 10, or
20 mg/kg.
The study found that the treatment of tumor bearing preclinical
models or cancer patients with AMG 102 gave rise to a dose-dependent
increase in circulating HGF levels which suggests that monitoring HGF
levels during treatment may serve as a biomarker for inhibition of the
HGF/SF:c-Met pathway
.
About Amgen
Amgen discovers, develops, manufactures and delivers innovative
human therapeutics. A biotechnology pioneer since 1980, Amgen was one
of the first companies to realize the new science's promise by
bringing safe and effective medicines from lab, to manufacturing
plant, to patient. Amgen therapeutics have changed the practice of
medicine, helping millions of people around the world in the fight
against cancer, kidney disease, rheumatoid arthritis and other serious
illnesses. With a deep and broad pipeline of potential new medicines,
Amgen remains committed to advancing science to dramatically improve
people's lives. To learn more about our pioneering science and our
vital medicines, visit www.amgen.com.
Forward-Looking Statements
This news release contains forward-looking statements that are
based on management's current expectations and beliefs and are subject
to a number of risks, uncertainties and assumptions that could cause
actual results to differ materially from those described. All
statements, other than statements of historical fact, are statements
that could be deemed forward-looking statements, including estimates
of revenues, operating margins, capital expenditures, cash, other
financial metrics, expected legal, arbitration, political, regulatory
or clinical results or practices, customer and prescriber patterns or
practices, reimbursement activities and outcomes and other such
estimates and results. Forward-looking statements involve significant
risks and uncertainties, including those discussed below and more
fully described in the Securities and Exchange Commission (SEC)
reports filed by Amgen, including Amgen's most recent annual report on
Form 10-K and most recent periodic reports on Form 10-Q and Form 8-K.
Please refer to Amgen's most recent Forms 10-K, 10-Q and 8-K for
additional information on the uncertainties and risk factors related
to our business. Unless otherwise noted, Amgen is providing this
information as of April 14, 2008 and expressly disclaims any duty to
update information contained in this news release.
No forward-looking statement can be guaranteed and actual results
may differ materially from those we project. Discovery or
identification of new product candidates or development of new
indications for existing products cannot be guaranteed and movement
from concept to product is uncertain; consequently, there can be no
guarantee that any particular product candidate or development of a
new indication for an existing product will be successful and become a
commercial product. Further, preclinical results do not guarantee safe
and effective performance of product candidates in humans. The
complexity of the human body cannot be perfectly, or sometimes, even
adequately modeled by computer or cell culture systems or animal
models. The length of time that it takes for us to complete clinical
trials and obtain regulatory approval for product marketing has in the
past varied and we expect similar variability in the future. We
develop product candidates internally and through licensing
collaborations, partnerships and joint ventures. Product candidates
that are derived from relationships may be subject to disputes between
the parties or may prove to be not as effective or as safe as we may
have believed at the time of entering into such relationship. Also, we
or others could identify safety, side effects or manufacturing
problems with our products after they are on the market. Our business
may be impacted by government investigations, litigation and products
liability claims. We depend on third parties for a significant portion
of our manufacturing capacity for the supply of certain of our current
and future products and limits on supply may constrain sales of
certain of our current products and product candidate development.
In addition, sales of our products are affected by the
reimbursement policies imposed by third-party payors, including
governments, private insurance plans and managed care providers and
may be affected by regulatory, clinical and guideline developments
domestic and international trends toward managed care and health care
cost containment as well as U.S. legislation affecting pharmaceutical
pricing and reimbursement. Government and others' regulations and
reimbursement policies may affect the development, usage and pricing
of our products. In addition, we compete with other companies with
respect to some of our marketed products as well as for the discovery
and development of new products. We believe that some of our newer
products, product candidates or new indications for existing products,
may face competition when and as they are approved and marketed. Our
products may compete against products that have lower prices,
established reimbursement, superior performance, are easier to
administer, or that are otherwise competitive with our products. In
addition, while we routinely obtain patents for our products and
technology, the protection offered by our patents and patent
applications may be challenged, invalidated or circumvented by our
competitors and there can be no guarantee of our ability to obtain or
maintain patent protection for our products or product candidates. We
cannot guarantee that we will be able to produce commercially
successful products or maintain the commercial success of our existing
products. Our stock price may be affected by actual or perceived
market opportunity, competitive position, and success or failure of
our products or product candidates. Further, the discovery of
significant problems with a product similar to one of our products
that implicate an entire class of products could have a material
adverse effect on sales of the affected products and on our business
and results of operations.
The scientific information discussed in this news release related
to our product candidates is preliminary and investigative. Such
product candidates are not approved by the U.S. Food and Drug
Administration (FDA), and no conclusions can or should be drawn
regarding the safety or effectiveness of the product candidates. Only
the FDA can determine whether the product candidates are safe and
effective for the use(s) being investigated. Further, the scientific
information discussed in this news release relating to new indications
for our products is preliminary and investigative and is not part of
the labeling approved by the FDA for the products. The products are
not approved for the investigational use(s) discussed in this news
release, and no conclusions can or should be drawn regarding the
safety or effectiveness of the products for these uses. Only the FDA
can determine whether the products are safe and effective for these
uses. Healthcare professionals should refer to and rely upon the
FDA-approved labeling for the products, and not the information
discussed in this news release.
In Lab Study,
Researchers Find Molecule That Disrupts
Ewing’s Sarcoma Oncogene
SAN DIEGO – Researchers at
Georgetown
University Medical Center have found a small molecule they say can
block the action of the oncogene that causes Ewing’s sarcoma, a rare
cancer found in children and young adults. If further studies continue
to prove beneficial, they say the novel agent could be the first
targeted therapy to treat the disease, which can produce tumors anywhere
in the body.
The findings, presented today at the annual meeting of the
American Association for
Cancer Research (AACR) in San Diego, suggest that the unique way in
which this molecule works – through a so-called protein-protein
interaction – could provide a model upon which to design other
therapies, says the study’s lead investigator,
Jeffrey Toretsky, M.D., a pediatric oncology physician and
researcher at Georgetown University’s
Lombardi
Comprehensive Cancer Center.
“I think this holds really wonderful promise as a unique way of
targeting fusion proteins,” he says. “People thought it wasn’t possible
to have a small molecule that can bind between flexible proteins, but we
have shown that it can be done.”
This study was conducted in laboratory cells, so additional research is
necessary before the novel agent can be tested in patients, Toretsky
says. In vivo studies are now underway, he says.
Ewing’s sarcoma is caused by the exchange of DNA between two
chromosomes, a process known as a translocation. The new gene, known as
EWS-FLI1, is created when the EWS gene on chromosome 22 fuses to the
FLI1 gene on chromosome 11, and its product is the fusion protein
responsible for cancer formation.
In the United States, about 500 patients annually are diagnosed with the
cancer, and they are treated with a combination of five different
chemotherapy drugs. Between 60-70 percent of patients survive over time,
but many have effects that linger from the therapy.
Toretsky has long led research into the causes of, and treatments for,
Ewing’s sarcoma. He and his laboratory colleagues were the first to make
a recombinant EWS-FLI1 fusion protein. “We did this in order to find out
if EWS-FLI1 might be binding with other cellular proteins,” he says.
They found that, indeed, the fusion protein stuck to another protein,
RNA helicase A (RHA), a molecule that forms protein complexes in order
to control gene transcription. “We believe that when RHA binds to
EWS-FLI1, the combination becomes more powerful at turning genes on and
off,” says the study’s first author, Hayriye Verda Erkizan, Ph.D., a
postdoctoral researcher in Toretsky’s lab who is presenting the study
results at AACR.
The researchers used a laboratory technique to keep RHA apart from the
fusion protein, and found that both were important to cancer formation.
Knowing that, they worked to identify the specific region on RHA that
stuck to EWS-FLI1, and then collaborated with investigators in
Georgetown’s Drug Discovery Program to find a molecule that would keep
the two proteins separated. In other words, such an agent would stick to
EWS-FLI1 in the very place that RHA bound to the fusion molecule.
Using a library of small molecules loaned to Georgetown from the
National Cancer Institute, the team of investigators tested 3,000
compounds to see if any would bind to immobilized EWS-FLI1 proteins.
They found one that did, and very tightly.
This was a wonderful discovery, Erkizan says, because the notion long
accepted among scientists is that it is not possible to block
protein-protein interactions given that the surface of these proteins
are slippery, and much too flexible for a drug to bind to.
“These are wiggly proteins yet this study shows that inhibition of
protein-protein interactions with a small molecule is possible,”
Toretsky says. This possibility means that fusion proteins, such as
those produced in other sarcomas as well as diverse disorders, might be
inhibited, he says. This is a different process than other drugs that
have been shown to work against fusion proteins, such as Gleevec, which
blocks the enzyme produced by the chromosomal translocation responsible
for chronic myelogenous leukemia (CML). “Gleevec inhibits a single
protein, while we are trying to block the binding of two proteins, and
we are very enthusiastic about the results so far,” Toretsky says.
About Lombardi Comprehensive Cancer Center
The Lombardi Comprehensive Cancer Center, part of Georgetown University
Medical Center and Georgetown University Hospital, seeks to improve the
diagnosis, treatment, and prevention of cancer through innovative basic
and clinical research, patient care, community education and outreach,
and the training of cancer specialists of the future. Lombardi is one of
only 39 comprehensive cancer centers in the nation, as designated by the
National Cancer Institute, and the only one in the Washington, DC, area.
For more information, go to http://lombardi.georgetown.edu.
About Georgetown University Medical Center
Georgetown University Medical Center is an internationally recognized
academic medical center with a three-part mission of research, teaching
and patient care (through our partnership with MedStar Health). Our
mission is carried out with a strong emphasis on public service and a
dedication to the Catholic, Jesuit principle of cura personalis -- or
"care of the whole person." The Medical Center includes the School of
Medicine and the School of Nursing and Health Studies, both nationally
ranked, the world-renowned Lombardi Comprehensive Cancer Center and the
Biomedical Graduate Research Organization (BGRO), home to 60 percent of
the university’s sponsored research funding.
A
novel class of cancer therapies called live biologics is offering new hope
for patients affected by hard-to-treat cancers.
