ANTI-HCG TRIALS

CURRENT TRIALS UPDATE
PRE-2002 TRIALS


NOTE: The following abstracts and news wires regarding anti-HCG vaccines are, we believe, crucial as they relate to the issue of cancer bacteria. As discussed throughout this website, an association has been shown between the growth hormone of pregnancy HCG, and cancer. Further, there is also a compelling association between cancer associated bacteria and HCG. We therefore believe that all three components of this cancer trinity are interrelated and warrant careful scrutiny by the medical and scientific communities. 

CURRENT TRIALS UPDATE

Phase II trials involving a combination of the anti-HCG vaccine Avicine (AVI Biopharma), and the newer generation chemotherapy drug, Gemzar (Lilly), were showing statistically significant responses involving the most difficult-to-treat cancer (pancreatic) than from either treatment alone. But plans to extend the Avicine trials to Phase III in 2003 never got off the ground. Meanwhile, Lilly continues to market and produce Gemzar as a "first line" therapy for pancreatic, colon, and other later stage, poor-prognosis cancers. This, in spite of Avicine significantly improving overall response rates and with far less toxic side-effects than Gemzar. Were economic factors a role in AVI's decision to scrap its Avicine project?

A recent article in the Xconomy Seattle sheds some light on the difficulties in bringing to market an anti-HCG vaccine. The Seattle bio-tech company CG Therapeutics, for example, is now actively engaged in launching its own HCG trial of a vaccine they call CG201, but the company is struggling to raise the millions in capital to do so. Without the financial resources of a drug giant like Eli Lilly (and given a degree of stigma that has been attached to vaccine immunotherapies for cancer), CG admits that they have an uphill battle. Still, Tom Hopp, leader of the company's scientific team and a veteran scientist formerly associated with biopharma giant Immunex, makes the bold assertion that CG's new vaccine, "will be the biggest cancer target of all time". He adds that "(w)e think we will have the first successful cancer vaccine. It's too good to quit on".

Hopps' claims are, frankly, stunning, but considering Avicine's earlier successes, and given the striking role of HCG as a universal cancer marker, his statement may, in theory, have merit.  Of course, only human testing will bear him out, but it is worth noting that CG201 is a second generation formulation considered "ten times" more potent than Avicine. For example, while Avicine was made from several subunits of the HCG molecule, CG201 combines HCG materials with highly stimulatory diptheria toxoids. According to CG, this newer fusion induces a double antibody response in the body. Then, the newly formed antibodies bind with HCG molecules on the cancer cell, rendering them ineffective.

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."


PRE-2002 TRIALS 

Designing a new generation of anti-hCG vaccines for cancer therapy.
Mol Cell Endocrinol. 2007 Jan 2;260-262:276-81. Epub 2006 Oct 17


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

Human chorionic gonadotropin (hCG) is expressed by many histological types of cancer and may play an important role in tumor maintenance and progression. 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. Colorectal cancer patients who develop both anti-hCG responses show a significant improvement in median survival time. 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. 


TOP