Another company, Celldex
Therapeutics, is also launching its own anti-HCG candidate, CDX-1307.
Like CG201, Celldexs' vaccine is a fusion formula, but it doesn't consist
of a toxin. Instead, HCG materials are combined with immune system
proteins designed to provoke highly potent T-cell responses
against HCG.
In an already completed Phase I trial (used to
determine appropriate vaccine dosages and toxicity levels prerequisite
to later trials which will assess tumor response), Celldex
researchers found early evidence of disease stabilization, limited side-effects,
and further evidence that HCG levels are present in "higher than expected
frequency" among patients with pancreatic, breast and colorectal cancers."
(See here
for the Celldex trial abstract).
In reiterating the
fundamental concept of anti-HCG therapy, Celldex recognizes HCG
as "an established tumor-associated antigen that is over-expressed in a
variety of common cancers including those of the colon, lung, pancreas,
esophagus, breast, bladder, cervix, stomach, and prostate." They explain
that HCG "may function at several different levels to facilitate cancer
progression: as a transforming growth factor, an immunosuppressive agent, an
inducer of metastasis, and/or as an angiogenic factor."
Department of Immunology and Molecular Pathology, Division of Infection and Immunity, University College London, 46 Cleveland Street, London W1T 4JF, United Kingdom. p.delves@ucl.ac.uk
The heterodimeric 'pregnancy-specific' hormone human chorionic gonadotropin (hCG) has been used as the basis for a contraceptive vaccine. More recently, the observation that hCG, particularly in the form of the beta-chain expressed in the absence of alpha-chain, is aberrantly expressed in a number of different tumors has opened up a second potential application for such vaccines. Drawbacks of the currently available vaccines are that they are either relatively weakly immunogenic or that they induce antibodies that cross-react with human leuteinizing hormone (hLH). We have explored the possibility of creating mutated versions of the hCG beta-chain with improved immunologic properties.
PMID: 17049720 [PubMed - indexed for MEDLINE]
Monoclonal antibodies to two epitopes of beta-human chorionic gonadotropin
for the treatment of cancer.
Curr Opin Mol Ther. 2003
Apr;5(2):156-60.
Iversen PL, Mourich DV, Moulton HM.
Source: AVI
BioPharma Inc., 4575 SW Research Way, Corvallis, OR 97333, USA.
piversen@avibio.com
. Vaccination of patients with the
therapeutic peptide Avicine (CTP37; AVI BioPharma Inc/SuperGen Inc), that
contains 37 amino acids from the carboxyl terminus (CTP37; AVI BioPharma
Inc/SuperGen Inc) of hCG, can result in two distinct antibody responses to
separate epitopes within the peptide. . These observations provide a compelling rationale for the
development of two human monoclonal antibodies (mAbs), one for each of the
epitopes within the 37 amino acid peptide region of hCG. Two such human mAbs,
both exhibiting a high degree of specificity and affinity have been prepared
using XenoMouse technology. These mAbs may prove useful in multiple clinical
settings for the treatment of various cancers. Treatment options may include
passive immunotherapy with both mAbs, mixed passive supplement to active
specific immunotherapy with Avicine and conjugation of the mAbs with
radioisotopes or cytotoxic drugs. The requirement for dual mAb therapy is
consistent with current trends in the development of complex, non-toxic
therapies for cancer.
December 7, 2001 -AVI BioPharma, Inc. announced today that its therapeutic
cancer vaccine, AVICINE, provided a substantial survival benefit in patients
with pancreatic cancer.
In a 55-patient Phase II study, patients were
treated with AVICINE alone or in combination with gemcitabine (Gemzar®, Eli
Lilly & Co.). The randomized trial was designed to evaluate the safety and
effectiveness of these treatments, and was conducted at seven centers across the
United States.
One-year survival data for the AVICINE alone group is
similar to that reported for Gemzar. However, patients had no significant
vaccine-related side effects, in contrast to the often severe side effects
associated with Gemzar. Importantly, one-year survival of 30% for the patient
group treated with AVICINE plus Gemzar was significantly better than either
treatment alone. Patients continue to be treated and followed, with 22 months
the longest patient survival to date. These results provide support for previous
observations that AVICINE is an effective cancer-fighting
agent.
Principal Investigator John Marshall, M.D. of Lombardi Cancer
Center, Georgetown University, Washington, DC, commented, "These results compare
very favorably to the best published results of chemotherapy alone in this
condition. The results in the combination group are the best I've observed with
this difficult cancer. The findings provide ample support for AVI's ongoing
AVICINE cancer vaccine program."
In addition to survival, study endpoints
included specific antibody responses to the vaccine and the influence of
chemotherapy on antibody response. Patients treated with chemotherapy and
vaccine together had nearly equivalent antibody responses to vaccination,
indicating that gemcitabine had little or no impact on pancreatic cancer
patients' ability to respond to a new immune challenge.
"We are very
encouraged by the results of this study. Our preliminary data, presented at the
annual meeting of the American Society of Oncology (ASCO) in May, 2001,
suggested that AVICINE is as effective as traditional chemotherapy, but without
the devastating side effects associated with that treatment," said.
David
H. Mason, Jr., M.D., AVI's Senior Vice President of Clinical Development and
Regulatory Affairs. "We are particularly pleased at this time to report that
one-year survival data suggest an advantage to the addition of AVICINE to
traditional chemotherapy. That patients continue in the study, some beyond 18-20
months, bodes well for potential long term benefits to patients from treatment
with our immunotherapeutic agent."
Dr. Mason added, "Having reviewed the
complete data from the study, we are encouraged that Gemzar did not seem to have
a negative influence on patients' immune response to cancer vaccine treatment.
Patients can undergo combination treatment without concern that this
chemotherapy will reduce vaccine effectiveness."
AVICINE is a therapeutic
cancer vaccine that elicits a highly specific immune response to human chorionic
gonadoptropin (hCG), a cancer-associated oncofetal protein. The vaccine blocks
hCG's function, which is to facilitate tumor growth, angiogenesis, invasion and
immunosuppression. The most common side effects of AVICINE are mild reactions at
the site of injection. Six completed clinical trials have shown that it is
considerably less toxic than traditional
chemotherapy.
....AVICINE™.....has completed a Phase II trial in
pancreatic cancer and is in a Phase III pivotal trial in colorectal cancer. More
information about AVI is available on the Company's website at
http://www.avibio.com.
AVI BioPharma Initiates Multicenter Phase II Clinical Trial of AVICINE in
Pancreatic Cancer-PORTLAND, Oregon--(BW HealthWire)--June 2,
1999
John Marshall, M.D. of Georgetown University To Serve As Lead
Principal Investigator
AVI BIOPHARMA INC. today announced that it will
initiate a multicenter Phase II clinical trial of the company's therapeutic
cancer vaccine, AVICINE(TM), in pancreatic cancer patients on June 15, 1999. The
randomized trial, involving at least 50 patients, is being conducted at seven
centers nationwide and is designed to evaluate the safety and efficacy of
AVICINE alone and the potential synergistic effects of AVICINE in combination
with Eli Lilly & Co.'s gemcitabine chemotherapy (Gemzar(TM)). This protocol
was filed with the FDA on April 23, 1999 and marks two advances in AVI's AVICINE
development strategy. The study will include the new AVICINE formulation
containing an additional peptide domain, which the company believes will enhance
the effectiveness of the vaccine. Moreover, this study marks the first trial in
which the vaccine will be administered with a chemotherapeutic agent. John
Marshall, M.D. of Georgetown University will serve as lead principal
investigator for the study, which will be managed by Premier Research Worldwide,
a clinical research organization located in Philadelphia, PA.
This trial
follows Phase Ib/II clinical trials of AVICINE, which were designed to evaluate
safety and efficacy in pancreatic cancer patients. The evidence from these
studies suggested that AVICINE is a well-tolerated vaccine without systemic
toxicity. The median survival in the ten pancreatic cancer patients treated with
AVICINE was 33 weeks without drug-related toxic side effects, compared to the 23
week median historical survival for this disease for patients treated with
chemotherapy.
Denis Burger, Ph.D., President and CEO of AVI BioPharma,
stated, "The initiation of Phase II trials of AVICINE in pancreatic cancer
represents a significant milestone for the company, and is the result of
extensive clinical efforts to demonstrate the applicability of our unique
technology to a broad range of cancers. As such, we have made great strides in
our development activities to support our premise that the peptides of the hCG
hormone are the key components in a cancer vaccine, which may result in survival
benefits even in the most aggressive tumors. Extensive analysis of our clinical
data from 77 patients with advanced colorectal cancer showed that a dual
antibody response to hCG peptides correlated with nearly a doubling of survival
benefits compared to chemotherapy. By including a second hCG peptide in AVICINE
in this protocol, we believe that most patients will produce the advantageous
dual antibody response. Because pancreatic cancer is so aggressive, the
combination of AVICINE and gemcitabine may provide additional benefits beyond
either therapy alone."
Dr. Marshall stated, "We have been impressed with
the AVICINE data from AVI's Phase II study in colorectal cancer where
statistically significant survival benefits correlated with a dual antibody
response. As a result, we are very pleased to be involved in this study,
especially since AVICINE appears to work through a unique mechanism, distinctly
different from gemcitabine chemotherapy. Given the vaccine's excellent safety
profile and lack of systemic toxicity, we are encouraged that AVICINE alone may
provide survival benefits over chemotherapy. Moreover, the evaluation of AVICINE
plus gemcitabine may also provide evidence for the inclusion of the vaccine in
combination therapy."
Cancer of the pancreas is the fifth leading cause
of cancer death in the United States. This year an estimated 28,000 people in
the U.S. will die from this disease. Currently, fewer than 10% of patients live
more than 1 year after diagnosis and fewer than 50% will survive 6
months.
AVICINE, a therapeutic cancer vaccine, is AVI BioPharma's lead
product candidate. AVICINE elicits a highly specific immune response to the
human hormone and growth factor hCG, a cancer-associated oncofetal protein.
AVICINE is essentially a non-toxic immunotherapy and has been evaluated in five
clinical trials. To date, 174 patients have been treated. Early studies have
provided evidence of objective tumor responses and apparent survival benefits in
patients who have failed conventional therapy.
AVI BioPharma Inc. Announces Additional Data From Multi-Center Phase II
Study of AVICINE in Advanced Colorectal Cancer. PORTLAND, Ore.--(BW
HealthWire)--May 26, 1999.
New Data Suggests Increased Survival Linked
To Dual Antibody Response -
AVI BIOPHARMA INC.....today announced
analysis of additional clinical data from its multi-center Phase II clinical
trial of AVICINE(TM), a therapeutic cancer vaccine, in advanced colorectal
cancer. This data builds upon previously announced results gathered from a
two-year clinical trial of AVICINE in 77 patients with metastatic colorectal
cancer. Overall, 51 of the 77 patients demonstrated an immune response to human
chorionic gonadotropin (hCG), with a median survival of 42 weeks. The additional
data suggests that patients who responded to both targets (epitopes) of the hCG
peptide (CTP-37) experienced a median survival of approximately 65 weeks,
compared to a median survival rate of 39 weeks for Pharmacia-Upjohn's FDA
approved drug, Camptosar(R).
Intensive investigation over the past six
months found that the vaccine peptide is composed of two epitopes, one of which
is dominant. The dominant epitope orchestrates a single antibody response in
approximately half of the patients. The balance of the patients responded to
both epitopes (dual response). This dual response correlated with a
statistically significant survival benefit (65 weeks) compared to a single
antibody response (35 weeks), or standard chemotherapy with Camptosar. The new
data support the addition of a second hCG peptide to the vaccine formulation in
order to modulate immunological dominance. Overall, these data suggest that
patient survival is linked to hCG antibody response, with dual responses
providing a significantly more favorable outcome than responses to a single
epitope. The inclusion of a second hCG peptide in the Company's AVICINE
formulation is expected to increase immunological response to multiple epitopes
resulting in improved patient survival.
Denis R. Burger, Ph.D. AVI's
President and CEO, stated, "Based upon the new data, we are encouraged to go one
step further in our development efforts in order to make AVICINE a more potent
vaccine. Specifically, we have formulated a new vaccine that contains an
additional hCG peptide domain, referred to as the loop peptide. The addition of
the loop peptide modulates the dominance of the past formulation, resulting in a
strong, balanced antibody response. Simply by adding an additional peptide we
are able to force the immune system into responding to multiple epitopes, which
leads to improved survival. The FDA has reviewed the new AVICINE formulation and
AVI plans to use the new formulation in our upcoming clinical
trials."
AVICINE, a therapeutic cancer vaccine, is AVI BioPharma's lead
product candidate. AVICINE elicits a highly specific immune response to the
human hormone and growth factor hCG, a cancer-associated oncofetal protein.
AVICINE is essentially a non-toxic immunotherapy and has been evaluated in five
clinical trials. To date, 174 patients have been treated. Early studies have
provided evidence of objective tumor responses and apparent survival benefits in
patients who have failed conventional therapy.
Avicine Data Published in Oncology Reports
PORTLAND, Ore.--(BW
HealthWire)--Jan. 26, 1999--AVI BIOPHARMA INC. today announced the publication
of a review article, "Human chorionic gonadotropin as a target for cancer
vaccines," in Oncology Reports (5: 7-17, 1999) by Pierre L. Triozzi, M.D.
and Vernon C. Stevens, Ph.D. of The Ohio State University Comprehensive Cancer
Center, Columbus Ohio.
In summary, Drs. Triozzi and Stevens, who have
been examining the application of AVI's therapeutic vaccine Avicine(tm) in
cancer, conclude that "hCG is expressed by a variety of very common cancers, and
that several lines of evidence suggest that it may be an appropriate target for
cancer vaccines." The authors report that "synthetic peptide vaccines offer a
safe, stable, and cost-effective alternative to many preparations currently
being evaluated." They further report that hCG "may play a role in cell
transformation as well as angiogenic, metastatic, and immune escape phenomena
that are central to cancer progression." With respect to Avicine's ability to
neutralize hCG biological activity, Drs. Triozzi and Stevens note that
"tolerance to this oncofetal antigen can be broken and that both humoral and
cellular responses have been generated in clinical trials conducted to
date."
Furthermore, Drs. Triozzi and Stevens report that the
transcription of hCG genes appears to be a common feature of malignant cells.
They also observed that the production of hCG may also play a role in cancer
progression by modifying tumor angiogenesis and metastasis and may provide
tumors with a mechanism by which they can evade immune effectors. Additionally,
the anti-hCG antibody induced with Avicine can "potentially mediate tumor
elimination by modulating the cellular biology mediated by hCG."
Denis R.
Burger, Ph.D., President and Chief Executive Officer of AVI BioPharma,
commented, "The extensive data presented by Drs. Triozzi and Stevens validate
our belief that hCG is an excellent cancer vaccine target. We are confident that
our lead anti-hCG vaccine agent, Avicine, can generate highly specific hCG
antibody responses with essentially no toxicity to patients. As a result, we
look forward to continuing down our clinical trial path for Avicine in
colorectal, pancreatic and prostate cancer over the next six months. These
studies in advanced cancer patients are expected to provide further evidence of
Avicine's ability to effect patient outcome by neutralizing the negative
biological activity of tumor-associated hCG."
Avicine is AVI BioPharma's
lead product candidate. As previously reported, Avicine elicits a highly
specific immune response to human chorionic gonadotropin (hCG), a hormonal
cancer-associated oncofetal growth factor. Detailed analysis of the Company's
recently completed Avicine Phase II clinical study in 77 patients with
metastatic colorectal cancer provided evidence of survival benefits comparable
to Camptosar(R) (Lilly) chemotherapy and 5 Fluorouracil (5-FU). Among all
patients responding to Avicine immunotherapy, median survival was 42 weeks
compared to only 17 weeks in patients that did not respond immunologically. This
compares favorably to median survival of similar patients treated with Camptosar
and 5-FU (39 and 28 weeks respectively). When responding patients were evaluated
further, median survival increased to 46 weeks in patients randomized to the
Avicine low dose treatment arm.
"AVI BIOPHARMA INC. Reports Encouraging Clinical Data From Multi-Center
Phase II Study of Avicine in Advanced Colorectal Cancer" PORTLAND, Ore.--(BW
HealthWire)--Dec. 10, 1998
Patients Responding to Avicine Demonstrate
Increased Survival
AVI BIOPHARMA INC. today released clinical data from a
multi-center Phase II clinical trial of Avicine(tm), a therapeutic cancer
vaccine, in advanced colorectal cancer. The data reflects a two-year clinical
trial at 11 cancer centers throughout the United States in which two doses of
Avicine were compared in 77 patients with measurable metastatic colorectal
cancer. The patients were randomized to two treatment arms and evaluated to
assess immunogenicity, safety and efficacy of the vaccine. Overall, patient data
demonstrates a measurable immune response to human chorionic gonadotropin (hCG),
increased survival in immune responders, and from a safety standpoint,
essentially no toxicity.
Colorectal cancer is the third most frequent
cancer type in the U.S. with approximately 131,000 diagnoses and 55,000 deaths
in 1997. Approximately one in 17 Americans will develop colorectal cancer in
their lifetime. Patients with advanced disease and 5-fluorouracil (5-FU)
treatment failures are currently treated with Camptosar(R) (Pharmacia &
Upjohn, Inc. (NYSE: PNU)) or an additional regimen of 5-FU. In this clinical
setting, supporting therapy results in a median survival of approximately 28
weeks, 5-FU results in a median survival of approximately 37 weeks and Camptosar
approximately 39 weeks.
Detailed analysis of the clinical data revealed
that approximately two-thirds of the patients responded to the vaccine by
producing antibodies to hCG, while the remaining one-third were too ill or
otherwise unable to mount an immune response. Importantly, overall median
survival in the group of patients responding to the vaccination was 42 weeks,
compared with a median survival of 17 weeks in patients that did not produce
specific antibodies. When the responding patients were evaluated further, and
data segmented into high- and low-dose treatment arms, low-dose immunotherapy
resulted in a median survival of 46 weeks, while the high-dose treatment group
demonstrated a 39 week median survival.
Patrick L. Iversen, Ph.D., AVI's
Vice President of Research and Development, commented, "It is important to note
that in order to have effective vaccine therapy, patients must be able to
respond immunologically over 4-8 weeks, the period it takes to mount an immune
response. Patients unable to sustain an immune response cannot hope to benefit
from any cancer vaccine therapy. In this regard, patients who received all doses
of the vaccine over a 16-week evaluation period demonstrated median survival of
58 weeks with low-dose immunotherapy and 44 weeks with the high-dose regimen.
Considering the advanced stage of cancer in these study patients, these are
truly remarkable and noteworthy results."
Denis R. Burger, Ph.D.,
President and CEO of AVI BioPharma, stated, "Based on the data collected to date
in both colorectal and pancreatic cancer, we are encouraged that Avicine has
demonstrated efficacy and safety, and may provide patients with an essentially
non-toxic therapy. The extensive Phase II data in advanced colorectal cancer
validate our belief that hCG is an excellent cancer vaccine target. As a result,
we look forward to initiating a multi-center Phase III licensing trial in 300
patients, which is expected to provide further evidence of Avicine's ability to
effect patient outcome by both anti-tumor effector mechanisms and neutralizing
the biological activity of tumor-associated hCG."
AVI is also planning a
Phase II study comparing patients with pancreatic cancer treated with Avicine to
patients treated with the combination of Avicine plus gemcitabine (Gemzar(R))
produced by Eli Lilly & Co.; and a Phase II study treating pancreatic cancer
patients with Avicine in combination with a drug in Phase III clinical trials
developed by SuperGen, Inc. (Nasdaq NM: SUPG) called RFS-2000, an improved
topoisomerase-I inhibitor.
Avicine, a therapeutic cancer vaccine, is AVI
BioPharma's lead product candidate. Avicine elicits a highly specific immune
response to the human hormone and growth factor hCG, a cancer-associated
oncofetal protein. Avicine is essentially a non-toxic immunotherapy and has been
evaluated in five clinical trials. To date, more than 125 cancer patients have
been treated. Early studies have provided evidence of objective tumor responses
and apparent survival benefits in patients who have failed conventional therapy.
"Abgenix and AVI BioPharma Sign License Agreementto Develop Human Antibody
to Treat Cancer"
FREMONT, Calif. and PORTLAND, Ore., Jan. 7
/PRNewswire/ -- Abgenix, Inc. and AVI BioPharma, Inc. today announced that they
have signed a research license and option agreement to develop fully human
antibodies to human chorionic gonadotropin (hCG). Under the terms of the
agreement, AVI will utilize the Abgenix XenoMouse(TM) technology to generate
product candidates for the treatment of cancer. AVI will be responsible for
product development, manufacturing and commercialization of any products
developed through the use of this technology. As part of the agreement, Abgenix
has received certain payments and could receive milestone payments based on
product development progress plus royalties on future product sales.
"We
are very pleased to be working with AVI BioPharma, our eighth corporate
collaborator involving XenoMouse(TM) technology, " stated R. Scott Greer,
president and chief executive officer of Abgenix. "AVI's clinical evaluation of
hCG indicates that it may be a target with significant potential as a cancer
treatment."
Denis R. Burger, Ph.D., president and chief executive officer
of AVI BioPharma, stated, "We look forward to applying Abgenix's human antibody
technology to our hCG development program. To date, we are very encouraged by
the results generated from our Phase II clinical trials of Avicine(TM), our
therapeutic cancer vaccine, in colorectal and pancreatic cancer. These studies
indicated that hCG may be an excellent cancer target, evidenced by increased
survival in immune responders. Although Avicine was highly effective in two
thirds of our colorectal patient study, patients unable to generate an immune
response did not benefit from this essentially non-toxic therapy. Using the
Abgenix XenoMouse(TM) technology, we plan to generate fully human antibodies to
hCG for potential use with the patient population that could not previously
respond to any form of immunotherapy. AVI's goal will be to use our hCG
technology to treat all cancer patients, including those with weakened immune
systems."
Avicine is AVI BioPharma's lead product candidate. As
previously reported, Avicine elicits a highly specific immune response to the
human hormone and growth factor hCG, a cancer-associated oncofetal protein.
Avicine is essentially non-toxic immunotherapy, which has been evaluated in five
clinical trials. To date, more than 125 cancer patients have been treated.
Detailed analysis of the clinical data gathered from Phase II colorectal studies
revealed that approximately two-thirds of the patients responded to the vaccine
by producing antibodies to hCG, while the remaining one-third were too ill or
otherwise unable to mount an immune response. Importantly, overall median
survival in the group of patients responding to the vaccination was 42 weeks,
compared with a median survival of 17 weeks in patients that did not produce
specific antibodies. When the responding patients were evaluated further,
low-dose Avicine treatment resulted in a median survival of 46
weeks.